March 2014

THE AMERICAN JOURNAL OF

PSYCHIATRY
Vol. 171, No. 3:249–380

Emotion Dysregulation in
Attention Deficit Hyperactivity
Disorder
Philip Shaw, M.B.B.Ch., Ph.D., et al. 276

Fluoxetine Administered to
Juvenile Monkeys: Effects on
the Serotonin Transporter and
Behavior
Stal Saurav Shrestha, B.A., et al. 323

Association of Violence With

Emergence of Persecutory
Delusions in Untreated
Schizophrenia
Robert Keers, Ph.D., et al. 332

Randomized Trial of an Electronic

Personal Health Record for
Patients With Serious Mental
THE AMERICAN JOURNAL OF PSYCHIATRY

Illnesses
Benjamin G. Druss, M.D., M.P.H., et al. 360

March 2014
Volume 171 • Number 3

Official Journal of the

AMERICAN PSYCHIATRIC ASSOCIATION
See the naughty restless child ajp.psychiatryonline.org
Growing still more rude and wild.
Till his chair falls over quite.
Philip screams with all his might.
 AMERICAN PSYCHIATRIC ASSOCIATION

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For your patients
struggling with
bipolar depression
 Offer your patients with
bipolar depression proven
antidepressant efficacy

Discover more at LATUDAhcp.com/info

LATUDA HELPS PATIENTS STRUGGLING WITH BIPOLAR DEPRESSION

• Efficacy established in both a monotherapy study and an adjunctive therapy study
with lithium or valproate1
–In these studies LATUDA was superior to placebo in reduction of Montgomery-Åsberg
Depression Rating Scale (MADRS) scores at Week 61
• Safety and tolerability evaluated in multiple bipolar depression studies for 6 weeks
and 24 weeks1
• Once-daily dosing, taken with food (at least 350 calories)1

INDICATIONS AND USAGE

LATUDA is indicated for treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy
and as adjunctive therapy with lithium or valproate. The efficacy of LATUDA was established in a 6-week monotherapy study and a
6-week adjunctive therapy study with lithium or valproate in adult patients with bipolar depression. The effectiveness of LATUDA for
longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to
use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. The
efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established.

IMPORTANT SAFETY INFORMATION FOR LATUDA WARNINGS AND PRECAUTIONS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-
term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant
use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In
patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of
suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication
with the prescriber. LATUDA is not approved for use in patients under the age of 18 years.
CONTRAINDICATIONS
LATUDA is contraindicated in the following:
• Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone.
• Strong CYP3A4 inhibitors (e.g., ketoconazole)
• Strong CYP3A4 inducers (e.g., rifampin)
Cerebrovascular Adverse Reactions, Including Stroke: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine
in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and
transient ischemic attacks) including fatalities compared to placebo-treated subjects. LATUDA is not approved for the treatment of
patients with dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of
antipsychotic drugs, including LATUDA. NMS can cause hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated
creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
Management should include immediate discontinuation of antipsychotic drugs and
other drugs not essential to concurrent therapy, intensive symptomatic treatment and
medical monitoring, and treatment of any concomitant serious medical problems.
Please see additional Important Safety Information for LATUDA,
including Boxed Warning, and Brief Summary of Prescribing
Information on adjacent pages.
IMPORTANT SAFETY INFORMATION FOR
Latuda® (lurasidone HCI) (Continued)
Tardive Dyskinesia (TD): TD is a syndrome consisting of
potentially irreversible, involuntary, dyskinetic movements that can
develop in patients with antipsychotic drugs. There is no known
For your patients
treatment for established cases of TD, although the syndrome
may remit, partially or completely, if antipsychotic treatment is
struggling with
withdrawn. The risk of developing TD and the likelihood that it
will become irreversible are believed to increase as the duration
of treatment and the total cumulative dose of antipsychotic drugs
bipolar depression
administered to the patient increase. However, the syndrome
can develop, although much less commonly, after relatively brief
treatment periods at low doses. Given these considerations,
LATUDA should be prescribed in a manner that is most likely
to minimize the occurrence of TD. If signs and symptoms appear
in a patient on LATUDA, drug discontinuation should be considered.
Metabolic Changes
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some
cases extreme and associated with ketoacidosis or hyperosmolar
coma or death, has been reported in patients treated with
atypical antipsychotics. Patients with risk factors for diabetes
mellitus (e.g., obesity, family history of diabetes) who are starting
treatment with atypical antipsychotics should undergo fasting
blood glucose testing at the beginning of and periodically during
treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including
polydipsia, polyuria, polyphagia, and weakness. Patients who
develop symptoms of hyperglycemia during treatment with
atypical antipsychotics should undergo fasting blood glucose
testing. In some cases, hyperglycemia has resolved when the
atypical antipsychotic was discontinued; however, some patients
required continuation of anti-diabetic treatment despite
discontinuation of the suspect drug.
Dyslipidemia: Undesirable alterations in lipids have been
observed in patients treated with atypical antipsychotics.
Weight Gain: Weight gain has been observed with atypical
antipsychotic use. Clinical monitoring of weight is recommended.
Hyperprolactinemia: As with other drugs that antagonize
dopamine D2 receptors, LATUDA elevates prolactin levels.
Galactorrhea, amenorrhea, gynecomastia, and impotence have
been reported in patients receiving prolactin-elevating compounds.
In the short-term, placebo-controlled monotherapy study, the
median change from baseline to endpoint in prolactin levels for
LATUDA-treated females was 3.1 ng/mL and was 1.5 ng/mL for
males. The proportion of female patients with prolactin elevations
≥5x ULN was 0.6% for LATUDA-treated patients versus 0% for
placebo-treated female patients. The proportion of male patients
with prolactin elevations ≥5x ULN was 0% for LATUDA-treated
patients versus 0% for placebo-treated male patients.
In the short-term, placebo-controlled adjunctive therapy with
lithium or valproate study, the median change from baseline to
endpoint in prolactin levels for LATUDA-treated females was
3.2 ng/mL and was 2.4 ng/mL for males. The proportion of female
patients with prolactin elevations ≥5x ULN was 0% for LATUDA-
treated patients versus 0% for placebo-treated female patients.
The proportion of male patients with prolactin elevations ≥5x ULN
was 0% for LATUDA-treated patients versus 0% for placebo-
treated male patients.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/
neutropenia has been reported during treatment with antipsychotic
agents. Agranulocytosis (including fatal cases) has been reported
with other agents in the class. Patients with a preexisting low
white blood cell count (WBC) or a history of drug-induced
leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy,
and LATUDA should be discontinued at the first sign of a decline
in WBC in the absence of other causative factors.
Orthostatic Hypotension and Syncope: LATUDA may cause
orthostatic hypotension. Orthostatic vital signs should be monitored
in patients who are vulnerable to hypotension, in patients with
known cardiovascular disease or history of cerebrovascular disease
and in patients who are antipsychotic-naïve.
Seizures: LATUDA should be used cautiously in patients with a
history of seizures or with conditions that lower seizure threshold
(e.g., Alzheimer’s dementia).
Potential for Cognitive and Motor Impairment: Patients should
be cautioned about operating hazardous machinery, including motor
vehicles, until they are reasonably certain that therapy with
LATUDA does not affect them adversely.
Body Temperature Regulation: Disruption of the body’s
ability to reduce core body temperature has been attributed to
antipsychotic agents. Appropriate care is advised when prescribing
LATUDA for patients who will be experiencing conditions that
may contribute to an elevation in core body temperature, e.g.,
exercising strenuously, exposure to extreme heat, receiving
concomitant medication with anticholinergic activity, or being
subject to dehydration.
Suicide: The possibility of suicide attempt is inherent in
psychotic illness and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for LATUDA should be
written for the smallest quantity of tablets consistent with good
patient management in order to reduce the risk of overdose.
Dysphagia: Esophageal dysmotility and aspiration have been
associated with antipsychotic drug use. Aspiration pneumonia is
a common cause of morbidity and mortality in elderly patients, in
particular those with advanced Alzheimer’s dementia. LATUDA and
other antipsychotic drugs should be used cautiously in patients at
risk for aspiration pneumonia.
ADVERSE REACTIONS
Commonly observed adverse reactions (≥5% incidence and at least
twice the rate of placebo) for LATUDA were akathisia, extrapyramidal
symptoms, and somnolence.
INDICATIONS
LATUDA is indicated for the treatment of major depressive
episodes associated with bipolar I disorder (bipolar depression)
as monotherapy and as adjunctive therapy with lithium or valproate
in adults.
Please see Brief Summary of Prescribing Information, including
Boxed Warning, on adjacent pages.
Reference: 1. LATUDA prescribing information. Sunovion Pharmaceuticals Inc. July 2013.
LATUDA and are registered trademarks of Dainippon Sumitomo Pharma Co., Ltd.
Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Dainippon Sumitomo Pharma Co., Ltd.
©2013 Sunovion Pharmaceuticals Inc. All rights reserved. 11/13 LAT903-13
BRIEF SUMMARY OF LATUDA FULL PRESCRIBING INFORMATION
WARNINGS:
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS;
AND SUICIDAL THOUGHTS AND BEHAVIORS
• Elderly patients with dementia-related psychosis treated with antipsychotic drugs
are at an increased risk of death [see Warnings and Precautions (5.1)].
For your patients
• LATUDA is not approved for use in patients with dementia-related psychosis [see
Warnings and Precautions (5.1)].
• Antidepressants increased the risk of suicidal thoughts and behavior in children,
struggling with
adolescents, and young adults in short-term studies. These studies did not show
an increase in the risk of suicidal thoughts and behavior with antidepressant use in
patients over age 24; there was a reduction in risk with antidepressant use in patients
bipolar depression
aged 65 and older [see Warnings and Precautions (5.2)].
• In patients of all ages who are started on antidepressant therapy, monitor closely for
worsening, and for emergence of suicidal thoughts and behaviors. Advise families
and caregivers of the need for close observation and communication with the
prescriber [see Warnings and Precautions (5.2)].
1 INDICATIONS AND USAGE
1.1 Schizophrenia
LATUDA is indicated for the treatment of patients with schizophrenia.
The efficacy of LATUDA in schizophrenia was established in five 6-week controlled studies of
adult patients with schizophrenia [see Clinical Studies (14.1)].
The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been
established in controlled studies. Therefore, the physician who elects to use LATUDA for extended
periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient [see Dosage and Administration (2)].
1.2 Depressive Episodes Associated with Bipolar I Disorder
Monotherapy: LATUDA is indicated as monotherapy for the treatment of patients with major
depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA
was established in a 6-week monotherapy study in adult patients with bipolar depression [see
Clinical Studies (14.2)].
Adjunctive Therapy with Lithium or Valproate: LATUDA is indicated as adjunctive therapy
with either lithium or valproate for the treatment of patients with major depressive episodes
associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA as adjunctive therapy
was established in a 6-week study in adult patients with bipolar depression who were treated with
lithium or valproate [see Clinical Studies (14.2)].
The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been
established in controlled studies. Therefore, the physician who elects to use LATUDA for extended
periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient [see Dosage and Administration (2.2)].
The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been
established.
4 CONTRAINDICATIONS
• Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has
been observed with lurasidone [see Adverse Reactions (6.1)].
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil,
etc.) [see Drug Interactions (7.1)].
• Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine,
etc.) [see Drug Interactions (7.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely
in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of
between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical
10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to
a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the
deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g.,
pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs,
treatment with conventional antipsychotic drugs may increase mortality. The extent to which the
findings of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. LATUDA is not approved for the
treatment of patients with dementia-related psychosis [see Boxed Warning].
5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening
of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has
been a long-standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and
others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9
antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults
with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of
2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation
in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for
almost all drugs studied. There were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk of differences (drug vs. placebo), however,
were relatively stable within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
<18
18-24
Increases Compared to Placebo
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥65 6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania,
have been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although
a causal link between the emergence of such symptoms and either the worsening of depression
and/or the emergence of suicidal impulses has not been established, there is concern that such
symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should
be alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidal thoughts and behaviors, and to report such symptoms immediately
to health care providers. Such monitoring should include daily observation by families and
caregivers. Prescriptions for LATUDA should be written for the smallest quantity of capsules
consistent with good patient management, in order to reduce the risk of overdose.
5.3 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with
Dementia-Related Psychosis
In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with
dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular
accidents and transient ischemic attacks), including fatalities, compared to placebo-treated
subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis
[see also Boxed Warning and Warnings and Precautions (5.1)].
5.4 Neuroleptic Malignant Syndrome
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA.
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and
cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria
(rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. It is important to
exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia,
systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms
(EPS). Other important considerations in the differential diagnosis include central anticholinergic
toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic
drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment
and medical monitoring; and 3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be
carefully monitored, since recurrences of NMS have been reported.
5.5 Tardive Dyskinesia
Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic
movements that can develop in patients treated with antipsychotic drugs. Although the prevalence
of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible
to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which
patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their Adjunctive Therapy with Lithium or Valproate
potential to cause tardive dyskinesia is unknown. Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are studies are presented in Table 4.
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic Table 4: Change in Fasting Glucose in the Adjunctive Therapy Bipolar Depression Studies
drugs administered to the patient increase. However, the syndrome can develop, although much
LATUDA
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome Placebo 20 to 120 mg/day

For your patients

may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment,
itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and
thereby may possibly mask the underlying process. The effect that symptomatic suppression has Serum Glucose
Mean Change from Baseline (mg/dL)
n=302
-0.9
n=319
+1.2

struggling with
upon the long-term course of the syndrome is unknown.
Given these considerations, LATUDA should be prescribed in a manner that is most likely to
minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be
Serum Glucose
(≥ 126 mg/dL)
Proportion of Patients with Shifts to ≥ 126 mg/dL
1.0%
(3/290)
1.3%
(4/316)

bipolar depression
reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic
drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are
not available or appropriate. In patients who do require chronic treatment, the smallest dose and
Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium
or valproate.
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received
the shortest duration of treatment producing a satisfactory clinical response should be sought. The
LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued
need for continued treatment should be reassessed periodically.
in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).
If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation
should be considered. However, some patients may require treatment with LATUDA despite the Dyslipidemia
presence of the syndrome. Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
5.6 Metabolic Changes Schizophrenia
Atypical antipsychotic drugs have been associated with metabolic changes that may increase Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 5.
cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, Table 5: Change in Fasting Lipids in Schizophrenia Studies
dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce LATUDA
some metabolic changes, each drug has its own specific risk profile. Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
Hyperglycemia and Diabetes Mellitus Mean Change from Baseline (mg/dL)
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma
or death, has been reported in patients treated with atypical antipsychotics. Assessment of the n=660 n=71 n=466 n=499 n=268 n=115
relationship between atypical antipsychotic use and glucose abnormalities is complicated by the Total Cholesterol -5.8 -12.3 -5.7 -6.2 -3.8 -6.9
possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and Triglycerides -13.4 -29.1 -5.1 -13.0 -3.1 -10.6
the increasing incidence of diabetes mellitus in the general population. Given these confounders, the Proportion of Patients with Shifts
relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not
completely understood. However, epidemiological studies suggest an increased risk of treatment- Total Cholesterol 5.3% 13.8% 6.2% 5.3% 3.8% 4.0%
(≥ 240 mg/dL) (30/571) (8/58) (25/402) (23/434) (9/238) (4/101)
emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.
Because LATUDA was not marketed at the time these studies were performed, it is not known if Triglycerides 10.1% 14.3% 10.8% 6.3% 10.5% 7.0%
(≥ 200 mg/dL) (53/526) (7/49) (41/379) (25/400) (22/209) (7/100)
LATUDA is associated with this increased risk.
Patients with an established diagnosis of diabetes mellitus who are started on atypical In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies),
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356)
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively.
treatment and periodically during treatment. Any patient treated with atypical antipsychotics Bipolar Depression
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, Monotherapy
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical Data from the short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has study are presented in Table 6.
resolved when the atypical antipsychotic was discontinued; however, some patients required Table 6: Change in Fasting Lipids in the Monotherapy Bipolar Depression Study
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
LATUDA
Schizophrenia
Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 2. Placebo 20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mg/dL)
Table 2: Change in Fasting Glucose in Schizophrenia Studies
n=147 n=140 n=144
LATUDA Total cholesterol -3.2 +1.2 -4.6
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day Triglycerides +6.0 +5.6 +0.4
Mean Change from Baseline (mg/dL) Proportion of Patients with Shifts
n=680 n=71 n=478 n=508 n=283 n=113 Total cholesterol 4.2% 4.4% 4.4%
Serum Glucose -0.0 -0.6 +2.6 -0.4 +2.5 +2.5 (≥ 240 mg/dL) (5/118) (5/113) (5/114)
Proportion of Patients with Shifts to ≥ 126 mg/dL Triglycerides 4.8% 10.1% 9.8%
Serum Glucose 8.3% 11.7% 12.7% 6.8% 10.0% 5.6% (≥ 200 mg/dL) (6/126) (12/119) (12/122)
(≥ 126 mg/dL) (52/628) (7/60) (57/449) (32/472) (26/260) (6/108) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo
In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA
LATUDA was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), as monotherapy in the short-term and continued in the longer-term study had a mean change in
+0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307). total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively.
Bipolar Depression Adjunctive Therapy with Lithium or Valproate
Monotherapy Data from the short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression
Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study studies are presented in Table 7.
are presented in Table 3. Table 7: Change in Fasting Lipids in the Adjunctive Therapy Bipolar Depression Studies
Table 3: Change in Fasting Glucose in the Monotherapy Bipolar Depression Study
LATUDA
LATUDA Placebo 20 to 120 mg/day
Placebo 20 to 60 mg/day 80 to 120 mg/day Mean Change from Baseline (mg/dL)
n=148 n=140 n=143 n=303 n=321
Mean Change from Baseline (mg/dL) Total cholesterol -2.9 -3.1
Serum Glucose +1.8 -0.8 +1.8 Triglycerides -4.6 +4.6
Proportion of Patients with Shifts to ≥ 126 mg/dL Proportion of Patients with Shifts
Serum Glucose 4.3% 2.2% 6.4% Total cholesterol 5.7% 5.4%
(≥ 126 mg/dL) (6/141) (3/138) (9/141) (≥ 240 mg/dL) (15/263) (15/276)
Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo Triglycerides 8.6% 10.8%
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received (≥ 200 mg/dL) (21/243) (28/260)
LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium
mean change in glucose of +1.2 mg/dL at week 24 (n=129). or valproate.
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Table 11: Median Change in Prolactin (ng/mL) from Baseline in Schizophrenia Studies
LATUDA, as adjunctive therapy with either lithium or valproate in the short-term study and continued LATUDA
in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
5.3 (n=88) mg/dL at week 24, respectively.
-1.9 -1.1 -1.4 -0.2 +3.3 +3.3
Weight Gain All Patients
(n=672) (n=70) (n=476) (n=495) (n=284) (n=115)
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is -5.1 -0.7 -4.0 -0.2 +6.7 +7.1
recommended. Females
Schizophrenia For your patients
Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 8. The Males
(n=200)
-1.3
(n=472)
(n=19)
-1.2
(n=51)
(n=149)
-0.7
(n=327)
(n=150)
-0.2
(n=345)
(n=70)
+3.1
(n=214)
(n=36)
+2.4
(n=79)

struggling with
mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebo- The proportion of patients with prolactin elevations ≥ 5× upper limit of normal (ULN) was 2.8%
treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female
extended-release was +2.09 kg in Studies 3 and 5 [see Clinical Studies (14.1)], respectively. The patients with prolactin elevations ≥ 5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for
proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for LATUDA-
bipolar depression
treated patients versus 3.3% for placebo-treated patients.
Table 8: Mean Change in Weight (kg) from Baseline in Schizophrenia Studies
placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN
was 1.6% versus 0.6% for placebo-treated male patients.
In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies),
LATUDA LATUDA was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357),
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).
(n=696) (n=71) (n=484) (n=526) (n=291) (n=114) Bipolar Depression
All Patients -0.02 -0.15 +0.22 +0.54 +0.68 +0.60 Monotherapy
In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed,
LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with
at week 36 (n=443) and -0.73 kg at week 52 (n=377). LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with
Bipolar Depression placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and
for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 12.
Monotherapy
Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression Table 12: Median Change in Prolactin (ng/mL) from Baseline in the Monotherapy Bipolar
study are presented in Table 9. The mean weight gain was +0.29 kg for LATUDA-treated patients Depression Study
compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase LATUDA
in body weight (at Endpoint) was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated Placebo 20 to 60 mg/day 80 to 120 mg/day
patients. All Patients +0.3 +1.7 +3.5
Table 9: Mean Change in Weight (kg) from Baseline in the Monotherapy Bipolar Depression (n=147) (n=140) (n=144)
Study Females 0.0 +1.8 +5.3
(n=82) (n=78) (n=88)
LATUDA
Males +0.4 +1.2 +1.9
Placebo 20 to 60 mg/day 80 to 120 mg/day (n=65) (n=62) (n=56)
(n=151) (n=143) (n=147)
All Patients -0.04 +0.56 +0.02 Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo
Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.4%
for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female
In the uncontrolled, open-label, longer-term bipolar depression study, patients who received patients with prolactin elevations ≥ 5x ULN was 0.6% for LATUDA-treated patients versus 0% for
LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN
change in weight of -0.02 kg at week 24 (n=130). was 0% versus 0% for placebo-treated male patients.
Adjunctive Therapy with Lithium or Valproate In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated
Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a
studies are presented in Table 10. The mean weight gain was +0.11 kg for LATUDA-treated patients median change in prolactin of -1.15 ng/mL at week 24 (n=130).
compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase Adjunctive Therapy with Lithium or Valproate
in body weight (at Endpoint) was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed,
patients. placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA
Table 10: Mean Change in Weight (kg) from Baseline in the Adjunctive Therapy Bipolar 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from
Depression Studies baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes
LATUDA for prolactin across the dose range are shown in Table 13.
Placebo 20 to 120 mg/day Table 13: Median Change in Prolactin (ng/mL) from Baseline in the Adjunctive Therapy
(n=307) (n=327) Bipolar Depression Studies
All Patients +0.16 +0.11
LATUDA
Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium
Placebo 20 to 120 mg/day
or valproate.
All Patients 0.0 +2.8
In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated (n=301) (n=321)
with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued Females +0.4 +3.2
in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86). (n=156) (n=162)
5.7 Hyperprolactinemia Males -0.1 +2.4
As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels. (n=145) (n=159)
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium
gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal or valproate.
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0%
and impotence have been reported with prolactin-elevating compounds. Long-standing for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female
hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in patients with prolactin elevations ≥ 5x ULN was 0% for LATUDA-treated patients versus 0% for
both female and male patients [see Adverse Reactions (6)]. placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN
Tissue culture experiments indicate that approximately one-third of human breast cancers are was 0% versus 0% for placebo-treated male patients.
prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated
considered in a patient with previously detected breast cancer. As is common with compounds with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued
which increase prolactin release, an increase in mammary gland neoplasia was observed in a in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).
LATUDA carcinogenicity study conducted in rats and mice [see Nonclinical Toxicology (13)]. Neither
clinical studies nor epidemiologic studies conducted to date have shown an association between 5.8 Leukopenia, Neutropenia and Agranulocytosis
chronic administration of this class of drugs and tumorigenesis in humans, but the available Leukopenia/neutropenia has been reported during treatment with antipsychotic agents.
evidence is too limited to be conclusive. Agranulocytosis (including fatal cases) has been reported with other agents in the class.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
Schizophrenia (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC
In short-term, placebo-controlled schizophrenia studies, the median change from baseline to or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC)
endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the monitored frequently during the first few months of therapy and LATUDA should be discontinued at
placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and the first sign of decline in WBC, in the absence of other causative factors.
for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 11.
 Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of
infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia
(absolute neutrophil count < 1000/mm3) should discontinue LATUDA and have their WBC followed
until recovery.
5.9 Orthostatic Hypotension and Syncope
LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic
receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness,
For your patients
tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and
during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of
developing complications from hypotension include those with dehydration, hypovolemia, treatment
struggling with
with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial
infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as
patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and
bipolar depression
slower titration, and monitor orthostatic vital signs.
Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following
vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥ 10 bpm increase in pulse
from sitting to standing or supine to standing position.
Schizophrenia
The incidence of orthostatic hypotension and syncope reported as adverse events from short-term,
placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic
hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)].
In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs,
occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with
LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo.
Bipolar Depression
Monotherapy
In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there
were no reported adverse events of orthostatic hypotension and syncope.
Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with
LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo.
Adjunctive Therapy with Lithium or Valproate
In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy
studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic
hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to
120 mg compared to 0.9% with placebo.
5.10 Seizures
As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of
seizures or with conditions that lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions
that lower the seizure threshold may be more prevalent in patients 65 years or older.
Schizophrenia
In short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1%
(2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients.
Bipolar Depression
Monotherapy
In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, no
patient experienced seizures/convulsions.
Adjunctive Therapy with Lithium or Valproate
In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies,
no patient experienced seizures/convulsions.
5.11 Potential for Cognitive and Motor Impairment
LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills.
Caution patients about operating hazardous machinery, including motor vehicles, until they are
reasonably certain that therapy with LATUDA does not affect them adversely.
In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence,
sedation and somnolence.
Schizophrenia
In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0%
(256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg,
15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to
7.1% (50/708) of placebo patients.
Bipolar Depression
Monotherapy
In the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study,
somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and
80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.
Adjunctive Therapy with Lithium or Valproate
In the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies,
somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared
to 5.1% (17/334) of placebo patients.
5.12 Body Temperature Dysregulation
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic
agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing
conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously,
exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being
subject to dehydration [see Patient Counseling Information (17.9)].
5.13 Suicide
The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-
risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the
smallest quantity of tablets consistent with good patient management in order to reduce the risk
of overdose.
Schizophrenia
In short-term, placebo-controlled schizophrenia studies, the incidence of treatment-emergent
suicidal ideation was 0.4% (6/1508) for LATUDA-treated patients compared to 0.8% (6/708) on
placebo. No suicide attempts or completed suicides were reported in these studies.
Bipolar Depression
Monotherapy
In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the
incidence of treatment-emergent suicidal ideation was 0.0% (0/331) with LATUDA-treated patients
compared to 0.0% (0/168) with placebo-treated patients. No suicide attempts or completed
suicides were reported in this study.
Adjunctive Therapy with Lithium or Valproate
In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies,
the incidence of treatment-emergent suicidal ideation was 1.1% (4/360) for LATUDA-treated
patients compared to 0.3% (1/334) on placebo. No suicide attempts or completed suicides were
reported in these studies.
5.14 Activation of Mania/Hypomania
Antidepressant treatment can increase the risk of developing a manic or hypomanic episode,
particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.
In the bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies,
less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes.
5.15 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration
pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with
advanced Alzheimer’s dementia. LATUDA and other antipsychotic drugs should be used cautiously
in patients at risk for aspiration pneumonia.
5.16 Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia
with Lewy Bodies
Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased
sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling:
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and
Warnings and Precautions (5.1)]
• Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions (5.2)]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related
Psychosis [see Warnings and Precautions (5.23)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4)]
• Tardive Dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see
Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11)]
• Body Temperature Dysregulation [see Warnings and Precautions (5.12)]
• Suicide [see Warnings and Precautions (5.13)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.14)]
• Dysphagia [see Warnings and Precautions (5.15)]
• Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy
Bodies [see Warnings and Precautions (5.16)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in clinical practice.
The information below is derived from an integrated clinical study database for LATUDA
consisting of 3799 patients exposed to one or more doses of LATUDA for the treatment of
schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds
with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least
24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure.
Adverse events during exposure to study treatment were obtained by general inquiry and
voluntarily reported adverse experiences, as well as results from physical examinations, vital
signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical
investigators using their own terminology. In order to provide a meaningful estimate of the proportion
of individuals experiencing adverse events, events were grouped in standardized categories using
MedDRA terminology.
Schizophrenia
The following findings are based on the short-term, placebo-controlled premarketing studies
for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg
(n=1508).
Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and
at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia,
extrapyramidal symptoms, and nausea.
Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508)
LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to
adverse reactions. There were no adverse reactions associated with discontinuation in subjects Percentage of Patients Reporting Reaction
treated with LATUDA that were at least 2% and at least twice the placebo rate. LATUDA LATUDA All
Placebo
Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse Body System or Organ Class
(N=168)
20-60 mg/day 80-120 mg/day LATUDA
reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest Dictionary-derived Term (N=164) (N=167) (N=331)
(%)
percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to (%) (%) (%)
6 weeks in patients with schizophrenia) are shown in Table 14. Infections and Infestations

Studies
For your patients
Table 14: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred
at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia
Nasopharyngitis
Influenza
Urinary Tract Infection
1
1
<1
4
<1
2
4
2
1
4
2
2

struggling with 20
Percentage of Patients Reporting Reaction

40 80
LATUDA
120 160 All
Musculoskeletal and Connective Tissue Disorders
Back Pain <1 3 <1 2
Placebo
Body System or
Organ Class bipolar depression
(N=708)
(%)
mg/day
(N=71)
(%)
mg/day

(%)
mg/day

(%)
mg/day
(N=487) (N=538) (N=291) (N=121)
(%)
mg/day

(%)
LATUDA
(N=1508)
(%)
Nervous System Disorders
Extrapyramidal Symptoms* 2 5 9 7
Akathisia 2 8 11 9
Gastrointestinal Disorders
Somnolence** 7 7 14 11
Nausea 5 11 10 9 13 7 10
Psychiatric Disorders
Vomiting 6 7 6 9 9 7 8
Dyspepsia 5 11 6 5 8 6 6 Anxiety 1 4 5 4
Salivary Note: Figures rounded to the nearest integer
<1 1 1 2 4 2 2 *Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia,
Hypersecretion
extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular
Musculoskeletal and Connective Tissue Disorders dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus
Back Pain 2 0 4 3 4 0 3 **Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

Nervous System Disorders Dose-Related Adverse Reactions in the Monotherapy Study:

In the short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) [see
Somnolence* 7 15 16 15 26 8 17
Clinical Studies (14.2)] the adverse reactions that occurred with a greater than 5% incidence in
Akathisia 3 6 11 12 22 7 13 the patients treated with LATUDA in any dose group and greater than placebo in both groups were
Extrapyramidal nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal
6 6 11 12 22 13 14
Disorder** symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively.
Dizziness 2 6 4 4 5 6 4
Bipolar Depression
Psychiatric Disorders Adjunctive Therapy with Lithium or Valproate
Insomnia 8 8 10 11 9 7 10 The following findings are based on two short-term, placebo-controlled premarketing studies for
Agitation 4 10 7 3 6 5 5 bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg as
Anxiety 4 3 6 4 7 3 5 adjunctive therapy with lithium or valproate (n=360).
Restlessness 1 1 3 1 3 2 2 Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and
Note: Figures rounded to the nearest integer at least twice the rate of placebo) in subjects treated with LATUDA were akathisia and somnolence.
*Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) LATUDA-
**Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse
extrapyramidal disorder, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, reactions. There were no adverse reactions associated with discontinuation in subjects treated with
psychomotor retardation, tongue spasm, torticollis, tremor, and trismus LATUDA that were at least 2% and at least twice the placebo rate.
Dose-Related Adverse Reactions in the Schizophrenia Studies Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse
Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest
with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to
LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients 6 weeks in patients with bipolar depression) are shown in Table 16.
receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of Table 16: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred
extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% at Greater Incidence than in the Placebo-Treated Patients in the Short-term Adjunctive
for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Therapy Bipolar Depression Studies
Bipolar Depression (Monotherapy) Percentage of Patients Reporting Reaction
The following findings are based on the short-term, placebo-controlled premarketing study for LATUDA
bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg Placebo
Body System or Organ Class 20 to 120 mg/day
(n=331). (N=334)
Dictionary-derived Term (N=360)
(%)
Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5%, (%)
in either dose group, and at least twice the rate of placebo) in patients treated with LATUDA were Gastrointestinal Disorders
akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.
Nausea 10 14
Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) LATUDA-
Vomiting 1 4
treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse
reactions. There were no adverse reactions associated with discontinuation in subjects treated with General Disorders
LATUDA that were at least 2% and at least twice the placebo rate. Fatigue 1 3
Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse Infections and Infestations
reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest Nasopharyngitis 2 4
percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to Investigations
6 weeks in patients with bipolar depression) are shown in Table 15. Weight Increased <1 3
Table 15: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred Metabolism and Nutrition Disorders
at Greater Incidence than in the Placebo-Treated Patients in a Short-term Monotherapy Increased Appetite 1 3
Bipolar Depression Study
Nervous System Disorders
Percentage of Patients Reporting Reaction
LATUDA LATUDA All Extrapyramidal Symptoms* 9 14
Placebo Somnolence** 5 11
Body System or Organ Class 20-60 mg/day 80-120 mg/day LATUDA
(N=168)
Dictionary-derived Term (N=164) (N=167) (N=331) Akathisia 5 11
(%)
(%) (%) (%)
Psychiatric Disorders
Gastrointestinal Disorders
Restlessness <1 4
Nausea 8 10 17 14 Note: Figures rounded to the nearest integer
Dry Mouth 4 6 4 5 *Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia,
Vomiting 2 2 6 4 extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular
Diarrhea 2 5 3 4 dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus
**Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence
Extrapyramidal Symptoms Schizophrenia
Schizophrenia The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was
In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global
incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal
restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 14.4%; placebo,
LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS 7.1%), the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%).
by dose is provided in Table 17. Bipolar Depression
For your patients
Table 17: Incidence of EPS Compared to Placebo in Schizophrenia Studies
LATUDA
Monotherapy
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was
comparable to placebo-treated patients. The percentage of patients who shifted from normal
struggling with
Adverse Event Term
Placebo
(N=708)
(%)
20 mg/day
(N=71)
(%)
40 mg/day
(N=487)
(%)
80 mg/day 120 mg/day 160 mg/day
(N=538)
(%)
(N=291)
(%)
(N=121)
(%)
to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA,
8.4%; placebo, 5.6%), the SAS (LATUDA, 3.7%; placebo, 1.9%) and the AIMS (LATUDA, 3.4%;
placebo, 1.2%).
All EPS events
bipolar depression
All EPS events,
excluding Akathisia/
9
6
10
6
21
11
23
12
39
22
20
13 Adjunctive Therapy with Lithium or Valproate
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was
Restlessness comparable to placebo-treated patients. The percentage of patients who shifted from normal
Akathisia 3 6 11 12 22 7 to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA,
Dystonia* <1 0 4 5 7 2 8.7%; placebo, 2.1%), the SAS (LATUDA, 2.8%; placebo, 2.1%) and the AIMS (LATUDA, 2.8%;
Parkinsonism** 5 6 9 8 17 11 placebo, 0.6%).
Restlessness 1 1 3 1 3 2 Dystonia
Note: Figures rounded to the nearest integer Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
*Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include:
torticollis, and trismus spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty,
**Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses,
hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor they occur more frequently and with greater severity with high potency and at higher doses of
Bipolar Depression first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and
younger age groups.
Monotherapy
In the short-term, placebo-controlled monotherapy bipolar depression study, for LATUDA-treated Schizophrenia
patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2%
6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for LATUDA-treated of LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg,
patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving
provided in Table 18. placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four
were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day.
Table 18: Incidence of EPS Compared to Placebo in the Monotherapy Bipolar Depression
Study Bipolar Depression
Monotherapy
LATUDA
In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study,
Placebo 20 to 60 mg/day 80 to 120 mg/day
(N=168) (N=164) (N=167)
dystonia occurred in 0.9% of LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20 to 60 mg/day
Adverse Event Term (%) (%) (%) and LATUDA 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No
All EPS events 5 12 20
subject discontinued the clinical study due to dystonic events.
All EPS events, excluding Akathisia/ 2 5 9 Adjunctive Therapy with Lithium or Valproate
Restlessness In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies,
Akathisia 2 8 11 dystonia occurred in 1.1% of LATUDA-treated subjects (20 to 120 mg) compared to 0.6% of
Dystonia* 0 0 2
subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.
Parkinsonism** 2 5 8 Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA
Restlessness <1 0 3
Following is a list of adverse reactions reported by patients treated with LATUDA at multiple doses
of ≥ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia. The
Note: Figures rounded to the nearest integer
*Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm,
reactions listed are those that could be of clinical importance, as well as reactions that are plausibly
torticollis, and trismus drug-related on pharmacologic or other grounds. Reactions listed in Table 14 or those that appear
**Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, elsewhere in the LATUDA label are not included. Although the reactions reported occurred during
glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor treatment with LATUDA, they were not necessarily caused by it.
Reactions are further categorized by organ class and listed in order of decreasing frequency
Adjunctive Therapy with Lithium or Valproate according to the following definitions: those occurring in at least 1/100 patients (frequent) (only
In the short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDA- those not already listed in the tabulated results from placebo-controlled studies appear in this
treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than
8.7% for placebo. The incidence of akathisia for LATUDA-treated patients was 10.8% versus 4.8% 1/1000 patients (rare).
for placebo-treated patients. Incidence of EPS is provided in Table 19.
Blood and Lymphatic System Disorders: Infrequent: anemia
Table 19: Incidence of EPS Compared to Placebo in the Adjunctive Therapy Bipolar
Depression Studies Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris,
bradycardia
Placebo LATUDA
(N=334) 20 to 120 mg/day
Ear and Labyrinth Disorders: Infrequent: vertigo
(%) (N=360) Eye Disorders: Frequent: blurred vision
Adverse Event Term (%) Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis
All EPS events 13 24 General Disorders and Administrative Site Conditions: Rare: sudden death
All EPS events, excluding Akathisia/ 9 14 Investigations: Frequent: CPK increased
Restlessness
Metabolism and Nutritional System Disorders: Frequent: decreased appetite
Akathisia 5 11
Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis
Dystonia* <1 1
Parkinsonism** 8 13 Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria
Restlessness <1 4 Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder
Note: Figures rounded to the nearest integer Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure
*Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast
torticollis, and trismus enlargement, breast pain, galactorrhea, erectile dysfunction
**Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder,
glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor
Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema
Vascular Disorders: Frequent: hypertension
In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was
objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), Clinical Laboratory Changes
the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale Schizophrenia
(AIMS) for dyskinesias. Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum
creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL for placebo-
treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-
treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from 7.2 Potential for LATUDA to Affect Other Drugs
> 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 20). No adjustment is needed for lithium, substrates of P-gp, CYP3A4 (Figure 2) or valproate when
Table 20: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in coadministered with LATUDA.
Schizophrenia Studies Figure 2: Impact of LATUDA on Other Drugs
Placebo LATUDA LATUDA LATUDA LATUDA LATUDA Interacting drug PK Fold Change and 90% CI Recommendation
Laboratory (N=708) 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
P-gp Substrates

For your patients

Parameter (N=71) (N=487) (N=538) (N=291) (N=121)
Serum Creatinine 2% 1% 2% 2% 5% 7% Digoxin Cmax Adjustment
Elevated 0.25 mg SD not required

struggling with
AUC
Bipolar Depression
Monotherapy CYP3A4 Substrates
Serum Creatinine: In the short-term, flexible-dose, placebo-controlled monotherapy bipolar Adjustment

bipolar depression
Midazolam Cmax
depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for 5 mg SD not required
LATUDA-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift AUC
from normal to high occurred in 2.8% (9/322) of LATUDA-treated patients and 0.6% (1/162) on Oral Contraceptive
placebo (Table 21).
Ethinyl Cmax Adjustment
Table 21: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in a Estradiol not required
Monotherapy Bipolar Depression Study AUC
Placebo LATUDA LATUDA Norelgestromin Cmax Adjustment
(N=168) 20 to 60 mg/day 80 to 120 mg/day not required
Laboratory Parameter (N=164) (N=167) AUC
Serum Creatinine Elevated <1% 2% 4% Lithium Adjustment
600mg BID* Ctrough not required
Adjunctive Therapy with Lithium or Valproate 0.0 0.5 1.0 1.5 2.0 2.5 3.0
Serum Creatinine: In short-term, placebo-controlled premarketing adjunctive studies for bipolar Change Relative to Interactive Drug Alone

depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for LATUDA-
*Steady state lithium Ctrough on Day 4 vs Day 8 when lithium was coadministered with lurasidone at steady state
treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from
normal to high occurred in 4.3% (15/360) of LATUDA-treated patients and 1.6% (5/334) on placebo 8 USE IN SPECIFIC POPULATIONS
(Table 22). 8.1 Pregnancy
Table 22: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Pregnancy Category B
the Adjunctive Therapy Bipolar Depression Studies Risk Summary
Placebo LATUDA There are no adequate and well controlled studies of LATUDA use in pregnant women.
(N=334) 20 to 120 mg/day Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk
Laboratory Parameter (N=360) for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of
Serum Creatinine Elevated 2% 4% agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder
7 DRUG INTERACTIONS in these neonates. These complications have varied in severity; while in some cases symptoms
have been self-limited, in other cases neonates have required intensive care unit support and
7.1 Potential for Other Drugs to Affect LATUDA prolonged hospitalization.
LATUDA is predominantly metabolized by CYP3A4. LATUDA should not be used concomitantly LATUDA should be used during pregnancy only if the potential benefit justifies the potential
with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, risk to the fetus.
mibefradil, etc.) or strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John’s wort, phenytoin,
carbamazepine, etc.) [see Contraindications (4)]. The LATUDA dose should be reduced to half of Human Data
the original level when used concomitantly with moderate inhibitors of CYP3A4 (e.g., diltiazem, Safe use of LATUDA during pregnancy or lactation has not been established; therefore, use of
atazanavir, erythromycin, fluconazole, verapamil, etc.). If LATUDA is used concomitantly with a LATUDA in pregnancy, in nursing mothers, or in women of childbearing potential requires that the
moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose [see Dosage and benefits of treatment be weighed against the possible risks to mother and child.
Administration (2.5)]. Animal Data
Lithium: It is not necessary to adjust the LATUDA dose when used concomitantly with lithium No adverse developmental effects were observed in a study in which pregnant rats were given
(Figure 1). lurasidone during the period of organogenesis and continuing through weaning at doses up to
Valproate: It is not necessary to adjust the LATUDA dose when used concomitantly with 10 mg/kg/day, which is approximately half of the maximum recommended human dose (MRHD) of
valproate. A dedicated drug-drug interaction study has not been conducted with valproate and 160 mg/day, based on mg/m2 body surface area.
LATUDA. Based on pharmacokinetic data from the bipolar depression studies valproate levels were No teratogenic effects were seen in studies in which pregnant rats and rabbits were given
not affected by lurasidone, and lurasidone concentrations were not affected by valproate. lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively.
Grapefruit: Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since These doses are 1.5- and 6-times, in rats and rabbits, respectively, the MRHD of 160 mg/day based
these may inhibit CYP3A4 and alter LATUDA concentrations [see Dosage and Administration (2.5)]. on mg/m2 body surface area.
Figure 1: Impact of Other Drugs on LATUDA Pharmacokinetics 8.3 Nursing Mothers
Interacting drug PK Fold Change and 90% CI Recommendation
LATUDA was excreted in milk of rats during lactation. It is not known whether LATUDA or its
metabolites are excreted in human milk. Because of the potential for serious adverse reactions in
Strong CYP3A4 Inhibitor
nursing infants, a decision should be made whether to discontinue nursing or to discontinue the
drug, considering the risk of drug discontinuation to the mother.
Should not be
Ketoconazole
400 mg/day
Cmax
coadministered 8.4 Pediatric Use
AUC
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Moderate CYP3A4 Inhibitor
Clinical studies with LATUDA did not include sufficient numbers of patients aged 65 and older to
Diltiazem Cmax Starting dose = 20 mg determine whether or not they respond differently from younger patients. In elderly patients with
240 mg/day psychosis (65 to 85), LATUDA concentrations (20 mg/day) were similar to those in young subjects.
AUC Maximum dose = 80 mg It is unknown whether dose adjustment is necessary on the basis of age alone.
Strong CYP3A4 Inducer Elderly patients with dementia-related psychosis treated with LATUDA are at an increased risk
of death compared to placebo. LATUDA is not approved for the treatment of patients with dementia-
Rifampin Cmax Should not be
600 mg/day coadministered related psychosis [see Boxed Warning].
AUC

Lithium Cmax Adjustment

600 mg BID not required
AUC

0 2 4 6 8 10
Change relative to lurasidone alone
8.6 Other Patient Factors
The effect of intrinsic patient factors on the pharmacokinetics of LATUDA is presented in Figure 3.
Figure 3: Impact of Other Patient Factors on LATUDA Pharmacokinetics
PK Fold Change and 90% CI Recommendation

Renal impairment
Mild Cmax Adjustment
not required

For your patients

AUC
Moderate Cmax Starting dose = 20 mg
AUC Maximum dose = 80 mg
Severe Cmax Starting dose = 20 mg

Mildstruggling with
Hepatic impairment
AUC

Cmax
AUC
Maximum dose = 80 mg
Adjustment
not required

Severebipolar depression
Moderate Cmax
AUC
Cmax
AUC
Starting dose = 20 mg
Maximum dose = 80 mg
Starting dose = 20 mg
Maximum dose = 40 mg
Population description

Gender
Females Adjustment
Cmax not required
AUC
Race
Adjustment
Asian* Cmax not required
AUC

0 1 2 3 4 5 6
Change relative to reference

*Compare to Caucasian

10 OVERDOSAGE
10.1 Human Experience
In premarketing clinical studies, accidental or intentional overdosage of LATUDA was identified
in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without
sequelae. This patient resumed LATUDA treatment for an additional two months.
10.2 Management of Overdosage
Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific
antidote to LATUDA, therefore, appropriate supportive measures should be instituted and close
medical supervision and monitoring should continue until the patient recovers. Consider the
possibility of multiple-drug overdose.
Cardiovascular monitoring should commence immediately, including continuous
electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered,
disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging
effects when administered in patients with an acute overdose of LATUDA. Similarly, the alpha-
blocking properties of bretylium might be additive to those of LATUDA, resulting in problematic
hypotension.
Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine
and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since
beta stimulation may worsen hypotension in the setting of LATUDA-induced alpha blockade. In
case of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Gastric lavage (after intubation if patient is unconscious) and administration of activated
charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis.

Manufactured for:
Sunovion Pharmaceuticals Inc.
Marlborough, MA 01752 USA

For Customer Service, call 1-888-394-7377.

For Medical Information, call 1-800-739-0565.
To report suspected adverse reactions, call 1-877-737-7226.

Revised: July 2013

901456R10

LATUDA and are registered trademarks of Dainippon Sumitomo Pharma Co., Ltd.
Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of
Dainippon Sumitomo Pharma Co., Ltd.

© 2013 Sunovion Pharmaceuticals Inc.

 THE AMERICAN JOURNAL OF

PSYCHIATRY
EDITOR-IN-CHIEF
Robert Freedman, M.D.

DEPUTY EDITORS
David A. Lewis, M.D. Robert Michels, M.D. Daniel S. Pine, M.D.
Susan K. Schultz, M.D. Carol A. Tamminga, M.D

EDITORIAL STAFF ASSOCIATE EDITORS EDITOR EMERITA

Executive Editor
Michael D. Roy
Senior Editor/Features Writer
Jane Weaver, E.L.S.
Senior Editor
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Production Manager
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Assistant Editors
Katie Duffy
Angela Moore
Editorial Support Services
Manager
Nicole Gray
Editorial Assistant
Linda LaCour
Editorial Assistant/
Permissions Coordinator Jerrold F. Rosenbaum, M.D.
Heidi Koch
Assistants to the Editors
Lois Lilienthal
Laura English
Rachel Hogg Patricia Suppes, M.D., Ph.D.
Russell A. Scholl
David A. Brent, M.D. Nancy C. Andreasen, M.D., Ph.D.
Linda Brzustowicz, M.D.
FORMER EDITORS
Cameron S. Carter, M.D.
Amariah Brigham, M.D.
Graham J. Emslie, M.D. 1844-1849
T. Romeyn Beck, M.D.
1849-1854
Daniel C. Javitt, M.D.
John P. Gray, M.D.
Bankole Johnson, M.D. 1854-1886
Ellen Leibenluft, M.D. G. AIder Blumer, M.D.
1886-1894
Douglas F. Levinson, M.D.
Richard Dewey, M.D.
Constantine G. Lyketsos, 1894-1897
M.D., M.H.S.
Henry M. Hurd, M.D.
Barbara Milrod, M.D. 1897-1904
Maria A. Oquendo, M.D. Edward N. Brush, M.D.
1904-1931
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A. John Rush, M.D. 1931-1965
Larry J. Siever, M.D. Francis J. Braceland, M.D.
1965-1978
John C. Nemiah, M.D.
Eduard Vieta, M.D., Ph.D. 1978-1993

The American Journal of Psychiatry is online at ajp.psychiatryonline.org

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 THE AMERICAN JOURNAL OF

PSYCHIATRY
In This Issue
New Research
A12
Articles
Perspectives
294 A Randomized Controlled Trial of 7-Day
Intensive and Standard Weekly Cognitive
Editorials Therapy for PTSD and Emotion-Focused
249 Alternative Intensive Therapy for PTSD Supportive Therapy
Marylene Cloitre Anke Ehlers, Ann Hackmann, Nick Grey, Jennifer
Wild, Sheena Liness, Idit Albert, Alicia Deale, Richard
252 A Primate Model of the Effects of Childhood
Stott, and David M. Clark Audio
Antidepressant Treatment Clinical Guidance Editorial
David A. Brent, Judy Cameron, and David A. Lewis
305 Results of a Multicenter Randomized
256 Treatment of Psychosis and Risk Assessment
Controlled Trial of the Clinical Effectiveness
for Violence
of Schema Therapy for Personality Disorders
Matthew M. Large
Lotte L.M. Bamelis, Silvia M.A.A. Evers, Philip
259 Increasing Treatment Engagement for Spinhoven, and Arnoud Arntz Audio
Persons With Serious Mental Illness Using 323 Fluoxetine Administered to Juvenile
Personal Health Records Monkeys: Effects on the Serotonin
John C. Fortney and Richard R. Owen
Transporter and Behavior
Stal Saurav Shrestha, Eric E. Nelson, Jeih-San Liow,
Robert Gladding, Chul Hyoung Lyoo, Pam L. Noble,
Commentary Cheryl Morse, Ioline D. Henter, Jeremy Kruger, Bo
262 A Word to the Wise About Ketamine Zhang, Stephen J. Suomi, Per Svenningsson, Victor W.
Alan F. Schatzberg Pike, James T. Winslow, Ellen Leibenluft, Daniel S.
Pine, and Robert B. Innis Audio CME Editorial
332 Association of Violence With Emergence of
Treatment in Psychiatry
Persecutory Delusions in Untreated
265 Behavioral and Psychiatric Symptoms in Schizophrenia
Prion Disease Robert Keers, Simone Ullrich, Bianca L. DeStavola,
Andrew Thompson, Angus MacKay, Peter Rudge, and Jeremy W. Coid Audio Clinical Guidance
Ana Lukic, Marie-Claire Porter, Jessica Lowe, John Editorial
Collinge, and Simon Mead Audio CME
340 Multicenter Voxel-Based Morphometry
Mega-Analysis of Structural Brain Scans in
Images in Psychiatry Obsessive-Compulsive Disorder
Stella J. de Wit, Pino Alonso, Lizanne Schweren,
275 When Affective Disorders Were Considered
David Mataix-Cols, Christine Lochner, José M.
to Emanate From the Heart: The Ebers Menchón, Dan J. Stein, Jean-Paul Fouche, Carles
Papyrus Soriano-Mas, Joao R. Sato, Marcelo Q. Hoexter,
Rami Bou Khalil and Sami Richa Damiaan Denys, Takashi Nakamae, Seiji Nishida, Jun
Soo Kwon, Joon Hwan Jang, Geraldo F. Busatto,
Narcís Cardoner, Danielle C. Cath, Kenji Fukui, Wi
Reviews and Overviews Hoon Jung, Sung Nyun Kim, Euripides C. Miguel, Jin
276 Emotion Dysregulation in Attention Deficit Narumoto, Mary L. Phillips, Jesus Pujol, Peter L.
Remijnse, Yuki Sakai, Na Young Shin, Kei Yamada,
Hyperactivity Disorder
Dick J. Veltman, and Odile A. van den Heuvel
Philip Shaw, Argyris Stringaris, Joel Nigg, and Ellen
Leibenluft Audio 350 Revisiting Schizophrenia Linkage Data in the
NIMH Repository: Reanalysis of Regularized
Data Across Multiple Studies
Veronica J. Vieland, Kimberly A. Walters, Thomas
Lehner, Marco Azaro, Kathleen Tobin, Yungui
Huang, and Linda M. Brzustowicz

Volume 171 Number 3 March 2014

A3
 360 Randomized Trial of an Electronic Personal 375 Correction
Health Record for Patients With Serious
376 Books Received
Mental Illnesses
Benjamin G. Druss, Xu Ji, Gretl Glick, and Silke A. von
Esenwein Audio CME Editorial Other Items of Interest
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Communications and Updates
A5 Officers of the American Psychiatric
Association
Letters to the Editor
A7 Calendar
369 Developmental Lag and Course of Cognitive Deficits
From the Premorbid to Postonset Period in A11 British Journal of Psychiatry Contents
Schizophrenia
Management Issues During Pregnancy in Women
With Bipolar Disorder
Cover
In this issue, Shaw et al.
(p. 276) review emotion
Book Forum dysregulation in ADHD. Cover
372 Working With Families in Medical Settings: A illustration appears in
Multidisciplinary Guide for Psychiatrists and Other Struwwelpeter, written and
Health Professionals illustrated in 1861 by
Clinical Guide to Depression and Bipolar Disorder: Frankfurt physician Dr.
Findings From the Collaborative Depression Study Heinrich Hoffmann (1809–1894).
Comprehensive Care for Complex Patients: The Verse translation by Dr. Colin Blyth. Image courtesy of
Medical-Psychiatric Coordinating Physician Model Iolair Publishing, Kingston, Ontario, Canada.
Management of Treatment-Resistant Major
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 of FETZIMA, 737 patients were exposed to FETZIMA for at least 6 months and 367 were exposed for one year.
In these studies FETZIMA was given at doses ranging from 40-120 mg once daily and was given without
regard to food. Adverse reactions reported as reasons for discontinuation of treatment - In the short-term
placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received FETZIMA (40-
120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated
patients in those studies. The most common adverse reaction leading to discontinuation in at least 1% of the
FETZIMA-treated patients in the short-term placebo-controlled studies was nausea (1.5%). Common ad-
verse reactions in placebo-controlled MDD studies - The most commonly observed adverse events in
FETZIMA-treated MDD patients in placebo-controlled studies (incidence * 5% and at least twice the rate of
placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, tachycardia,
vomiting, and palpitations. Table 3 in the full Prescribing Information shows the incidence of adverse reac-
tions that occurred in * 2% of FETZIMA-treated MDD patients and at least twice the rate of placebo in the
placebo-controlled studies. Values shown in parentheses are shown as FETZIMA 40-120 mg/day (N=1583) %,
followed by Placebo (N=1040) %. Gastrointestinal disorders: Nausea (17, 6); Constipation (9, 3); Vomiting
(5, 1); Cardiac disorders: Tachycardiaa (6, 2); Palpitations (5, 1); Reproductive system and breast disordersb:
Erectile dysfunctionc (6, 1); Testicular paind (4, < 1); Ejaculation disordere (5, < 1); Investigations: Heart rate
increasedf (6, 1); Blood pressure increasedg (3, 1); Renal and urinary disorders: Urinary hesitation (4, 0);
Skin and subcutaneous tissue disorders: Hyperhidrosis (9, 2); Rashh (2, 0); Vascular disorders: Hot flush
(3, 1); Hypotensioni (3, 1); Hypertensionj (3, 1); Metabolism and nutrition disorders: Decreased appetite (3,
1). a: Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndrome; b: Per-
centage is relative to the number of patients in the associated demographic sex category. Fewer than 2% of
FETZIMA-treated MDD female patients in placebo-controlled clinical studies reported adverse events related
to sexual function; c: erectile dysfunction includes: erectile dysfunction, organic erectile dysfunction and psy-
chogenic erectile dysfunction; d: testicular pain includes: testicular pain, epididymitis, and seminal vesiculitis;
e: ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature
ejaculation; f: Heart rate increased also includes: orthostatic heart rate response increased; g: Blood pressure
increased also includes: blood pressure systolic increased, blood pressure diastolic increased and blood pres-
sure orthostatic increased; h: Rash also includes: rash generalized, rash maculopapular, rash erythematous
and rash macular; i: Hypotension also includes: orthostatic hypotension and dizziness postural; j: Hypertension
also includes: labile hypertension; N = number of patients in the Safety Population. Dose-related adverse reac-
tions - In pooled data from the short-term placebo-controlled fixed-dose studies, there were no dose-related
adverse reactions (greater than 2% overall incidence) in patients treated with FETZIMA across the dose range
40-120 mg once daily, with the exception of erectile dysfunction and urinary hesitation. See Table 4 in the full
Prescribing Information which provides the incidence of dose-related adverse reactions reported in at least
2% of the FETZIMA treatment group and at an incidence that was greater than in the placebo group. The first
3 values show adverse reactions in the % of patients in the FETZIMA group that had taken a dose of 40 mg/d
[N=366], 80 mg/d [N=367] and 120 mg/d [N=180] respectively. The fourth value shows adverse reactions in
the % of patients in the placebo group [N=362]. Urinary hesitation (4, 5, 6; 0); Erectile dysfunction a (6, 8,
10; 2). a: Percentage is relative to the number of male patients; N = number of patients in the Safety Population.
Other adverse reactions observed in clinical studies - Other infrequent adverse reactions, not described
elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with FETZIMA were:
Cardiac disorders: Angina pectoris; Supraventricular and Ventricular extrasystoles; Eye disorders: Dry
eye; Vision blurred; Conjunctival hemorrhage; General disorders: Chest pain; Thirst; Gastrointestinal
disorders: Abdominal pain; Flatulence; Investigations disorders: Blood cholesterol increased; Liver
function test abnormal; Nervous System disorders: Migraine; Paraesthesia; Syncope; Extrapyramidal
disorder; Psychiatric disorders: Agitation; Anger; Bruxism; Panic attack; Tension; Aggression; Renal
and Urinary disorders: Pollakiuria; Hematuria; Proteinuria; Respiratory, thoracic and mediastinal dis-
orders: Yawning; Skin and subcutaneous tissue disorders: Dry skin; Pruritus; Urticaria.
DRUG INTERACTIONS: Other than CYP3A4 drug interactions, FETZIMA is predicted, based on in vitro studies,
to have a low potential to be involved in clinically significant pharmacokinetic drug interactions. Monoamine
Oxidase Inhibitors (MAOIs) - [see Dosage and Administration in the full Prescribing Information, Contrain-
dications, and Warnings and Precautions]. Serotonergic Drugs - [see Dosage and Administration in the full
Prescribing Information, Contraindications, and Warnings and Precautions]. Drugs that Interfere with Hemo-
stasis (e.g., NSAIDs, Aspirin, and Warfarin) - Serotonin release by platelets plays an important role in hemo-
stasis. Epidemiological studies of case-control and cohort design have demonstrated an association between
use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal
bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk
of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and
SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored
when FETZIMA is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to
Affect FETZIMA - Dose adjustment is recommended when FETZIMA is co-administered with strong inhibitors
of CYP3A4 (e.g. ketoconazole) [see Dosage and Administration in the full Prescribing Information]. An in vivo
study showed a clinically meaningful increase in levomilnacipran exposure when FETZIMA was co-adminis-
tered with the CYP3A4 inhibitor ketoconazole (see Figure 1). No dose adjustment of FETZIMA is needed when
co-administered with a CYP3A4 inducer or substrate. In vivo studies showed no clinically meaningful change
in levomilnacipran exposure when co-administered with the CYP3A4 inducer carbamazepine or the CYP3A4
substrate alprazolam (see Figure 1). No dose adjustment of FETZIMA is needed when co-administered with in-
hibitors of CYP2C8, CYP2C19, CYP2D6, CYP2J2, P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or
OCT2. In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to
metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3,
OAT1, OAT3, or OCT2 and is a weak substrate of P-gp.
Figure 1 PK Interactions between Levomilnacipran (LVM) and Other Drugs
Drug Interaction PK Fold Change and 90% CI Recommendation
OTHER DRUG ON LVM
CYP3A4 Inhibitor
By Ketoconazole Cmax Maximum 80 mg/d
AUC
CYP3A4 Inducer
By Carbamazepine Cmax No dose adjustment
AUC
CYP3A4 Substrate
By Alprazolam Cmax No dose adjustment
AUC
LVM ON OTHER DRUG
CYP3A4 Substrate
On Carbamazepine Cmax No dose adjustment
AUC
CYP3A4 Substrate
On Alprazolam Cmax No dose adjustment
AUC
0.50 0.75 1.00 1.25 1.50 1.75 2.00
Change relative to reference
Potential for FETZIMA to Affect Other Drugs - No dose adjustment of the concomitant medication is recom-
mended when FETZIMA is administered with a substrate of CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies have shown
that levomilnacipran is not an inhibitor of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,
P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Concomitant use of FETZIMA with alprazolam or carba-
mazepine, substrates of CYP3A4, had no significant effect on alprazolam or carbamazepine plasma con-
centrations (see Figure 1). Central Nervous System (CNS)-Active Agents - The risk of using FETZIMA in
combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is
advised when FETZIMA is prescribed in combination with other CNS-active drugs, including those with a
similar mechanism of action. Alcohol - In an in vitro study, alcohol interacted with the extended-release prop-
erties of FETZIMA. If FETZIMA is taken with alcohol, a pronounced accelerated drug release may occur. It is
recommended that FETZIMA extended-release capsules not be taken with alcohol.
133237_Fetzima_Feb_Brief_Page BW.indd 1
USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C: Risk Summary - There are no adequate
and well-controlled studies of FETZIMA in pregnant women. Neonates exposed to dual reuptake inhibitors of
serotonin and norepinephrine (such as FETZIMA), or selective serotonin reuptake inhibitors late in the third
trimester have developed complications that can arise immediately upon delivery. Levomilnacipran was not
teratogenic in rats or rabbits when given during the period of organogenesis at doses up to 8 or 16 times
the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis, respectively. However, an
increase in early post natal rat pup mortality was seen at a dose equivalent to 5 times the MRHD given during
pregnancy and lactation. FETZIMA should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. Clinical Considerations - Neonates exposed to SSRIs or SNRIs, late in the third
trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypogly-
cemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features
are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation
syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
[see Warnings and Precautions]. A prospective longitudinal study of 201 women with history of major de-
pression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant
medication during pregnancy were more likely to experience a relapse of major depression than women who
continued antidepressant medication. Animal Data - No teratogenic effects were observed when levomilnacip-
ran was administered to pregnant rats or rabbits during the period of organogenesis at oral doses up to
100 mg/kg/day. This dose is 8 and 16 times (in rats and rabbits, respectively) the maximum recommended
human dose (MRHD) of 120 mg on a mg/m2 basis. Fetal body weights were reduced in rats, and skeletal ossi-
fication was delayed in both rats and rabbits at this dose; these effects were not observed in either species at
doses up to 30 mg/kg/day, 2.4 times the MRHD in rats or 5 times the MRHD in rabbits. When levomilnacipran
was administered to pregnant rats at an oral dose of 60 mg/kg/day, 5 times the MRHD, during organogen-
esis and throughout pregnancy and lactation, there was an increase in early postnatal pup mortality; no pup
mortality was seen at 20 mg/kg/day, 1.6 times the MRHD. Among the surviving pups, pre- and post-weaning
pup weight gain was reduced up to at least 8 weeks of age; however, physical and functional development,
including reproductive performance of the progeny, was not affected. The effects on body weight gain were
not seen at 7 mg/kg/day, 0.6 times the MRHD. Nursing Mothers - It is not known if FETZIMA is present in
human milk. Studies have shown that levomilnacipran is present in the milk of lactating rats. Because many
drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants
from FETZIMA, a decision should be made whether to discontinue the drug, taking into account the importance
of the drug to the mother. Pediatric Use - Clinical studies on the use of FETZIMA in pediatric patients have
not been conducted; therefore, the safety and effectiveness of FETZIMA in the pediatric population have not
been established. FETZIMA is not approved for use in pediatric patients [see Boxed Warning and Warnings
and Precautions]. Geriatric Use - No dose adjustment is recommended on the basis of age (see Figure 2).
In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure
(Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years). Of the total number
of subjects in clinical studies of FETZIMA, 2.8% of patients were age 65 or older. Because levomilnacipran is
predominately excreted by the kidney, renal clearance of levomilnacipran should be considered when deter-
mining the dose [see Dosage and Administration in the full Prescribing Information]. SSRIs and SNRIs, includ-
ing FETZIMA, have been associated with cases of clinically significant hyponatremia in elderly patients, who
may be at greater risk for this adverse event [see Warnings and Precautions]. Hepatic Impairment - Hepatic
elimination of levomilnacipran is low. Dose adjustment is not recommended in subjects with mild (Child-Pugh
score of 1-6), moderate (Child-Pugh score of 7-9), or severe (Child-Pugh score of 10-13) hepatic impairment
(see Figure 2). Renal Impairment - Renal excretion plays a predominant role in the elimination of levomil-
nacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60-89 ml/min)
renal impairment. Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30
- 59 ml/min) or severe (creatinine clearance of 15-29 ml/min) renal impairment (see Figure 2). FETZIMA is not
recommended for patients with end stage renal disease [see Dosage and Administration in the full Prescribing
Information]. Gender - Dose adjustment based on gender is not recommended (see Figure 2).
Figure 2 Effect of Intrinsic Factors on Levomilnacipran PK
Population Description PK Fold Change and 90% CI Recommendation
AGE
>65 years Cmax No dose adjustment
AUC
GENDER
Females Cmax No dose adjustment
AUC
RENAL IMPAIRMENT
Mild Cmax No dose adjustment
AUC
Moderate Cmax Maximum 80 mg/d
AUC
Severe Cmax Maximum 40 mg/d
AUC
HEPATIC IMPAIRMENT
Mild Cmax No dose adjustment
AUC
Moderate Cmax No dose adjustment
AUC
Severe Cmax No dose adjustment
AUC
0 1 2 3 4
Change relative to reference
The data shown for elderly subjects (>65 years) are relative to younger subjects (18-45 years).
The data shown for female subjects are relative to male subjects.
The data shown for renal and hepatic impairment are relative to subjects with normal renal and hepatic function, respectively.
DRUG ABUSE AND DEPENDENCE: Controlled Substance - FETZIMA is not a controlled substance. Abuse -
FETZIMA has not been systematically studied in animals or humans for its potential for abuse. There was no
evidence suggestive of drug-seeking behavior in the clinical studies. It is not possible to predict on the basis
of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once
marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow
such patients closely, observing them for signs of misuse or abuse of FETZIMA (e.g., development of tolerance
or drug-seeking behavior). Dependence - FETZIMA has not been systematically studied in animals or humans
for its potential for dependence.
OVERDOSAGE: Human Experience - There is limited clinical experience with FETZIMA overdose in humans.
In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal. Management
of Overdose - No specific antidotes for FETZIMA are known. In managing overdose, provide supportive care,
including close medical supervision and monitoring, and consider the possibility of multiple drug involvement.
In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance
and advice. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in
reducing levomilnacipran plasma concentrations.
Distributed by: Licensed from Pierre Fabre Medicament
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045 USA
© 2013 Forest Laboratories, Inc.
Revised: July 2013 039-14000099 – A – RMC19200 – 08/13
Please also see full Prescribing Information at www.fetzima.com
1/6/14 9:49 AM
 Editor-in-Chief
Arshya Vahabzadeh, M.D.
(MGH/Harvard)

Deputy Editor
Misty Richards, M.D., M.S.
January 2014 Volume 9 Issue 1
(UCLA)

Inside In This Issue

Associate Editor
2 The Judicial-Mental Health David Hsu, M.D.
Partnership: Opportunities
and Risks
(McLean/Harvard)
Katherine C. Michaelsen, M.D.

5 A Relevant Review of
The Residents’ Journal accepts manuscripts
Violence Risk for the
Psychiatric Trainee
Tobias D. Wasser, M.D.
authored by medical students, resident
8 Outpatient Commitment and physicians, and fellows. To submit your paper,
Statutory Law
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Clinical and Legal Issue
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14 Psychiatry and Its Importance
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From the Perspective of an
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Electronic Personal Health Records for
Patients With Mental Illness
A web-based personal health record (figure) improved the
quality of medical care and increased use of medical
services among patients with serious mental illness and
comorbid medical conditions. Among 170 patients stud-
ied by Druss et al. (CME, p. 360) at a community mental
health center, the proportion of recommended services
received at 1-year follow-up was 40% for patients given
personal health records with computer training and 18%
for those receiving usual care. The group with personal
health records also had greater improvement in care for
hypertension but not for diabetes or hyperlipidemia. The
improved outcomes were largely related to the greater
number of outpatient medical visits. The editorial by
Fortney and Owen (p. 259) points out the marked dose-
response relationship between the amount of technical
support provided the patients and their success in using
the electronic record.
Clinical Guidance: Violence and
Persecutory Delusions
Individuals with schizophrenia who have been im-
prisoned for violent crimes but not treated are more
likely to commit violent acts after release from prison
than are those without psychosis or those with schizo-
phrenia who are treated in prison or after release.
Keers et al. (p. 332) followed 967 released prisoners
in the United Kingdom for a mean of 39 weeks. In the
United Kingdom Prisoner Cohort, 22% of those with
schizophrenia reported that they had not received
any treatment in prison or after release. The higher
risk for violence is related to persecutory delusions but
not to hallucinations or other psychotic experiences.
In an editorial, Large (p. 256) underscores the value of
antipsychotic treatment for violent prisoners with
schizophrenia to prevent further violent crimes.
A12
Patients with mental illness
and comorbid medical
conditions received more
preventive medical services
when given electronic
personal health records
(Druss et al., p. 360)
Fluoxetine’s Long-Term Effects in a Juvenile
Primate Model
Shrestha et al. (CME, p. 323) report that fluoxetine increased
the activity of a key component of serotonin neurotransmis-
sion in the brains of monkeys at an age corresponding to
prepuberty childhood in humans. The increase in serotonin
transporter protein (SERT) was apparent 1.5 years after drug
discontinuation. The behavior of the monkey was assessed
and not found to change significantly. Fluoxetine’s effects on
SERT have not been similarly tested in humans. An editorial
by Brent et al. (p. 252) reminds clinicians and parents, who
might interpret these new findings as contraindicating treat-
ment, to recognize that untreated depression carries sub-
stantial risk for adolescents and to continue to consider both
pharmacotherapy and psychotherapy.
Clinical Guidance: Intensive Cognitive
Therapy Speeds PTSD Response
Standard once-weekly cognitive therapy and 7-day
intensive cognitive therapy are both effective in reducing
symptoms of posttraumatic stress disorder (PTSD), but
intensive treatment does so faster. Three weeks after the
beginning of treatment, Ehlers et al. (p. 294) found lower
levels of PTSD symptoms in patients receiving intensive
therapy, and outcomes were similar at 14 weeks. No
patients dropped out of intensive treatment, and few
discontinued standard cognitive therapy. A comparison
treatment, emotion-focused supportive therapy, reduced
symptoms more than a waiting list control condition but
not as much as the two cognitive therapies. The rates of
recovery at 14 weeks were 73% and 77% for intensive
and standard cognitive therapy, respectively, 43% for
supportive therapy, and 7% for the waiting list. Edi-
torialist Cloitre (p. 249) highlights the potential for
more personalized treatment of PTSD: intensive cog-
nitive therapy could increase some patients’ involvement
in treatment, and supportive therapy might engage
patients who do not want trauma-focused treatment.
 Editorial

Alternative Intensive Therapy for PTSD

A n important emerging goal in mental health services is the development of

patient-centered care. This includes providing patients with options regarding how
their care is delivered and which treatments they should receive based on their needs
and preferences. In this issue, Ehlers and colleagues (1) report on a randomized
controlled trial that evaluates the acceptability and efficacy of a rapid, intensive
cognitive therapy delivered over a 7-day period compared with its established
version, which involves once weekly therapy over approximately 3 months. In
addition, the study evaluates the efficacy of these two cognitive therapies against
a credible alternative treatment of emotion-focused supportive therapy. The study
has four treatment arms: a 7-day intensive version of cognitive therapy, standard
cognitive therapy, emotion-focused supportive therapy, and a waiting list.
Three important findings are reported. First, cognitive therapy delivered in-
tensively over little more than a week was as effective as cognitive therapy delivered
over 3 months. Second, both intensive cognitive therapy and standard cognitive
therapy were superior to emotion-focused supportive therapy. Third, emotion-
focused supportive therapy was supe-
rior to the waiting list condition. The The success of intensive cognitive
inclusion of the emotion-focused sup-
portive therapy and waiting list con-
therapy increases service options for
ditions is of theoretical and practical patients with PTSD.
importance. It is occasionally argued
that waiting list should no longer be included in posttraumatic stress disorder
(PTSD) trials because so many efficacious treatments for PTSD exist that the use
of a waiting list is an expense with little scientific benefit or ethical justification.
However, there is growing interest in evaluating the potential benefits of PTSD ther-
apies that do not necessarily focus directly on traumatic memories or experiences,
particularly for patients who refuse or who prefer not to engage in trauma-focused
treatment. Thus, knowledge about the efficacy of emotion-focused supportive ther-
apy relative to no therapy is important. The use of the waiting list condition allowed
direct evaluation of the efficacy of emotion-focused supportive therapy while con-
trolling for confounds such as the potential therapeutic effects of contact with a
clinic and periodic assessments. The response rate in emotion-focused supportive
therapy, defined as loss of PTSD diagnosis, was substantially superior to the waiting
list response.
The intensive therapy did not differ from the standard therapy with regard to
PTSD symptom reduction, as measured by within-group pre- to posttreatment
effect sizes and as compared with emotion-focused supportive therapy at
posttreatment. Participants in both the intensive and standard cognitive therapy
received approximately 18 hours of therapy. However, intensive therapy par-
ticipants completed these hours over a period of 5–7 working days. Treatment
days were usually comprised of two sessions, one in the morning and one in the
afternoon, each lasting from 90 minutes to 2 hours. Of note, treatment credibility
and therapeutic alliance was as high in the intensive therapy as in the standard

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 249

EDITORIAL

treatment. Intensive treatment of this kind has also been shown to be effective for
panic disorder (2), suggesting the generalizability of this approach for some dis-
orders, perhaps for individuals who have a phobia as a core component. The
success of intensive cognitive therapy increases service options for patients with
PTSD. Certain individuals, as a result of circumstances or by predisposition, may
prefer a “total immersion” experience. Those individuals who have work or home
responsibilities may find it easier to manage a brief period away from their day-to-
day demands. Others may be in a state of “psychological readiness” and will be
more motivated for and engaged in an intensive treatment. However, the ease of
disseminating intensive forms of treatment remains to be seen. Challenges in the
transition from a randomized controlled trial to community implementation
need to be considered, and they include the cost of this approach to the community
clinic as well as the willingness and availability of therapists to conduct intensive
work.
Both intensive and standard cognitive therapies were superior to emotion-focused
supportive therapy in reducing PTSD. Many variations of supportive therapy have
been used in PTSD clinical trials (3–5). The investigators of this study formulated
emotion-focused supportive therapy in a way that was distinct from cognitive
therapy so that inferences regarding the underlying mechanisms of action might be
considered. The cognitive therapies focused on identifying and modifying excessively
negative appraisals of the trauma, identifying triggers of intrusive re-experiencing,
and reducing the use of cognitive strategies and behaviors (e.g., safety seeking) that
are believed to maintain PTSD. The supportive therapy was a patient-directed treat-
ment that provided psychoeducation about the role of unprocessed emotions in
PTSD, explored emotional reactions rather than cognitions, and provided inter-
ventions that clarified emotions as a means to problem solving. The results suggest
that cognitive reappraisal is an important mechanism of action in recovery from
PTSD and that attention to emotions in the absence of cognitive reappraisal
produces less than optimal results.
Nevertheless, the effectiveness of emotion-focused supportive therapy relative to
waiting list supports the potential benefit of exploring and building more patient-
directed therapies that do not necessarily require sustained attention to trauma-
related memories. While research to date suggests that PTSD recovery associated
with these therapies is inferior to recovery with cognitive therapies or cognitive-
behavioral therapies, studies have nevertheless consistently reported their benefits
(3–5) and they may be an acceptable option or an engagement strategy for patients
who would otherwise refuse treatment.
Dropout from intensive or standard cognitive therapy was extremely low (0% and
3%, respectively) and differs from a previous cognitive therapy trial by this group of
investigators (6) and from the more common dropout rate seen in meta-analyses of
PTSD treatment studies, which hovers around 20% (7). It may be that the innovative
nature of the study engaged participants who were highly motivated for this type of
treatment. No adverse effects were identified in any of the treatment conditions.
Symptom deterioration at posttreatment was low in all of the active treatment
conditions and significantly lower in the intensive and standard cognitive therapies
than for waiting list. This result is important, as it indicates that delivering cognitive
therapy in an intensive format did not increase symptoms. Some cautions about the
generalizability of the therapy to more impaired populations should be noted.
Participants’ PTSD had to be related to discrete traumatic events in adulthood, and
individuals with current substance abuse or borderline personality disorder were

250 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 EDITORIAL

excluded. Thus, the efficacy of intensive cognitive therapy for PTSD in individuals with
certain types of comorbidities or PTSD related to chronic or repeated traumas, such as
childhood sexual abuse or domestic violence, remains unknown.
This study tested an innovative approach for treating PTSD that, given the results,
increases service delivery options for patients. The study also provides a model for
conducting clinical trial research that contributes to patient-centered care.
References
1. Ehlers A, Hackmann A, Grey N, Wild J, Liness S, Albert I, Deale A, Stott R, Clark DM: A randomized controlled
trial of 7-day intensive and standard weekly cognitive therapy for PTSD and emotion-focused supportive therapy.
Am J Psychiatry 2014; 171:294–304
2. Bitran S, Morissette SB, Spiegel DA, Barlow DH: A pilot study of sensation-focused intensive treatment for
panic disorder with moderate to severe agoraphobia: preliminary outcome and benchmarking data. Behav
Modif 2008; 32:196–214
3. Schnurr PP, Friedman MJ, Engel CC, Foa EB, Shea MT, Chow BK, Resick PA, Thurston V, Orsillo SM, Haug R,
Turner C, Bernardy N: Cognitive-behavioral therapy for posttraumatic stress disorder in women: a randomized
controlled trial. JAMA 2007; 297:820–830
4. Surís A, Link-Malcolm J, Chard K, Ahn C, North C: A randomized clinical trial of cognitive processing therapy for
veterans with PTSD related to military sexual trauma. J Trauma Stress 2013; 26:28–37
5. Ford JD, Steinberg KL, Zhang W: A randomized clinical trial comparing affect regulation and social problem-
solving psychotherapies for mothers with victimization-related PTSD. Behav Ther 2011; 42:560–578
6. Duffy M, Gillespie K, Clark DM: Posttraumatic stress disorder in the context of terrorism and other civil conflict
in Northern Ireland: randomized controlled trial. BMJ 2007; 334:1147–1150
7. Bradley R, Greene J, Russ E, Dutra L, Westen D: A multidimensional meta-analysis of psychotherapy for PTSD.
Am J Psychiatry 2005; 162:214–227
MARYLENE CLOITRE, PH.D.

From the Division of Training and Dissemination, the National Center for PTSD, Palo Alto, Calif., and the NYU
Langone School of Medicine, New York. Address correspondence to Dr. Cloitre (marylene.cloitre@nyumc.org).
Editorial accepted for publication December 2013 (doi: 10.1176/appi.ajp.2013.13121695).

Dr. Cloitre reports no financial relationships with commercial interests.

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 251

 Editorial

A Primate Model of the Effects of Childhood

Antidepressant Treatment

A ll pharmacological treatments for human disease carry the risk of unintended,

adverse effects that may only become evident upon long-term follow-up. The
concern about such long-term effects is particularly heightened when medica-
tions that affect the CNS are administered to children or adolescents. As a result
of the substantial and protracted developmental changes in the molecular and
structural features of the human brain, children and adolescents may be par-
ticularly susceptible to the eventual development of adverse effects of med-
ications. However, detecting such long-term effects can be particularly problematic
in human studies because patients receive the medications for illnesses that
themselves may have long-term adverse effects on brain development. Other
confounding factors are the long follow-up period required for children to
reach adulthood, the potential for the same medication administered at different
ages to have different (or no) long-term effects, and the multiple other potentially
confounding factors (e.g., use of other medications, illicit substance use, exposure
to environmental stress or abuse, or other illnesses) that may occur in the interim.
One strategy for addressing these challenges is conducting experimental drug
administration studies in nonhuman primates. Macaque monkeys provide a
particularly informative resource, as the behavioral repertoire, structure of brain
circuitry, neuronal cell types, molecular features, and protracted postnatal de-
velopment of the macaque brain are more similar to those of the human brain than
any other available animal model. In addition, many medications can be ad-
ministered to macaque monkeys in a manner that is similar to their clinical use in
humans in terms of route of administration, dosing frequency, length of exposure,
and serum drug levels. Moreover, studies in monkeys, as in other animal models,
provide the unique ability to control for individual and environmental factors that
can confound the identification of medication effects on the brain and behavior.
Additionally, early life adversity leading to long-term behavioral changes, similar to
those characteristic of several mental health disorders including anxiety, affective
disorders, and addictive disorders, can also be modeled well in macaques. These
include early separation of infant monkeys from their mothers and rearing in an
unpredictable environment.
The study by Shrestha et al. (1) published concurrently with this editorial employs
this approach to examine the possible long-term impact of fluoxetine treatment
during adolescence. In this study, 32 male rhesus monkeys were randomly assigned
to one of four conditions in a balanced two-by-two design. Half of the monkeys
were separated from their mothers whereas the others were reared with their
mothers, and half of each group were treated for 1 year with fluoxetine at 3 mg/kg
beginning at 2 years of age (roughly equivalent to late childhood in humans), while
the other half received placebo; thus each combination of rearing and treatment
condition had eight primates assigned. At a minimum of 1.5 years after the end of
treatment, when monkeys were fully adult, all monkeys were assessed behaviorally
and underwent positron emission tomography (PET) imaging to examine serotonin

252 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 EDITORIAL

transporter (SERT) and serotonin 1A (5-HT1A) receptor binding. After correcting for
multiple comparisons, no imaging or behavioral effects of rearing condition re-
mained, nor were there any behavioral effects of fluoxetine treatment. However,
monkeys treated with fluoxetine showed increased SERT binding compared with
those treated with placebo, with no treatment differences for 5-HT1A receptor binding.
The authors are frank about the limitations of the study. The design was
underpowered to be able to detect any but the largest of effect sizes, especially
interactions between treatment and rearing. No PET or behavioral data were
obtained prior to treatment, so baseline differences across groups cannot be
excluded. The combined level of fluoxetine and norfluoxetine was lower than in
therapeutic studies in humans, and in fact, the percent binding for SERT was below
the accepted therapeutic level for treatment response, which is 80% (2). Finally,
fluoxetine is primarily a serotonergic agent, but norfluoxetine has strong noradren-
ergic properties. Therefore, it is likely that treatment affected multiple neurotrans-
mitter systems, making it difficult to speculate about the possible implications of an
increase in SERT binding in isolation from more detailed information about the
status of the noradrenergic system, which was not examined in this study.
In fact, clinical studies in humans are decidedly mixed with regard to the
significance of SERT binding in depression, with some studies finding de-
creased binding, some no change,
and some finding increased bind-
ing, although the most support is The field waits for a convergence of
for increased SERT binding associ- findings from well-designed and
ated with depression (3). Meyer (2) controlled studies in animals and from
reported that while SERT binding per
se was not associated with depres-
longitudinal studies in humans in
sion, greater binding was correlated order to truly understand the impact of
with a measure of cognitive distor- antidepressant treatments in
tion and pessimism, which in turn adolescents, and thus inform their use.
could predispose to future depressive
episodes. In humans, we do not know
if an increase in SERT binding predicts future episodes of depression, as has been
demonstrated for greater monoamine oxidase A binding (2).
Nevertheless, the idea that a treatment for a circumscribed period of time results
in long-term changes in function of the serotonin system, even without clear
behavioral changes, is unsettling. This study should be replicated with behavioral
and PET data in primates obtained prior to and after treatment, with a larger
number of monkeys, and with measures of the noradrenergic system. In humans,
follow-up studies of adolescents treated with antidepressants compared with
psychotherapy should be conducted to look for any specific, enduring changes in
brain function and receptor binding and whether those changes are related to
changes in behavior and long-term outcome. We should also learn, in controlled
studies, to what extent medication compared with psychotherapy protects against
recurrent depression. In adults, some evidence indicates that depressed patients
treated with cognitive-behavioral therapy (CBT) are less likely to relapse than pa-
tients treated with antidepressants (4), but the existing evidence in adolescents, at
least with relatively brief interventions, does not support a similar protective effect
of CBT compared with antidepressants (5, 6). The British National Institute for
Health and Care Excellence guidelines, with regard to concern about suicidal events
and antidepressants in adolescents, firmly recommend a trial with psychotherapy

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 253

EDITORIAL

before the use of medication. However, given the much slower response to CBT for
adolescent depression than to antidepressants that was found in the Treatment of
Adolescent Depression Study, American guidelines recommend antidepressants
as a first-line treatment for adolescent depression (7, 8). It is also important not to paint
recommendations about antidepressant use in adolescents with too broad a brush,
since the risk-benefit ratio is even more favorable for the treatment of anxiety than for
the treatment of depression, as a result of greater efficacy (9).
What should clinicians say to their adolescent patients and to their patients’
parents in light of this study? We think the honest answer is that although these
findings and some other animal studies have shown long-acting effects on the brain
as a result of antidepressants, we do not know the clinical meaning of these
findings. Indeed, the field waits for a convergence of findings from well-designed
and controlled studies in animals and from longitudinal studies in humans in order
to truly understand the impact of antidepressant treatments in adolescents, and
thus inform their use.
In the meantime, although current clinical data suggest that the risk-benefit ratio
for antidepressants is acceptable, and that antidepressants may work more quickly
than psychotherapy, effective psychotherapeutic treatments are available for ado-
lescent depression, namely CBT and interpersonal therapy (8, 9). Already, concern
about the possible negative effects of antidepressants in adolescents has resulted in
a decline in their use for the treatment of depression, without an offsetting increase
in referral for psychotherapy (10). While we need more research to understand
the long-term effects of antidepressants, we must also recognize that untreated
depression carries substantial risk, and that beginning with one of the indicated
treatments—either psychotherapy or antidepressant medication—is better than
succumbing to unjustified therapeutic nihilism.

References
1. Shrestha SS, Nelson EE, Liow J-S, Gladding R, Lyoo CH, Noble PL, Morse C, Henter ID, Kruger J, Zhang B,
Suomi SJ, Svenningsson P, Pike VW, Winslow JT, Leibenluft E, Pine DS, Innis RB: Fluoxetine administered
to juvenile monkeys: effects on the serotonin transporter and behavior. Am J Psychiatry 2014; 171:
323–331
2. Meyer JH: Neuroimaging markers of cellular function in major depressive disorder: implications for thera-
peutics, personalized medicine, and prevention. Clin Pharmacol Ther 2012; 91:201–214
3. Savitz JB, Drevets WC: Neuroreceptor imaging in depression. Neurobiol Dis 2013; 52:49–65
4. Cuijpers P, Hollon SD, van Straten A, Bockting C, Berking M, Andersson G: Does cognitive behavior therapy
have an enduring effect that is superior to keeping patients on continuation pharmacotherapy? a meta-
analysis. BMJ Open 2013; 3:e002542
5. Birmaher B, Brent DA, Kolko D, Baugher M, Bridge J, Holder D, Iyengar S, Ulloa RE: Clinical outcome after short-
term psychotherapy for adolescents with major depressive disorder. Arch Gen Psychiatry 2000; 57:29–36
6. Curry J, Silva S, Rohde P, Ginsburg G, Kratochvil C, Simons A, Kirchner J, May D, Kennard B, Mayes T, Feeny N,
Albano AM, Lavanier S, Reinecke M, Jacobs R, Becker-Weidman E, Weller E, Emslie G, Walkup J, Kastelic E,
Burns B, Wells K, March J: Recovery and recurrence following treatment for adolescent major depression.
Arch Gen Psychiatry 2011; 68:263–269
7. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J;
Treatment for Adolescents With Depression Study (TADS) Team: Fluoxetine, cognitive-behavioral therapy,
and their combination for adolescents with depression: Treatment for Adolescents With Depression Study
(TADS) randomized controlled trial. JAMA 2004; 292:807–820
8. Birmaher B, Brent D, Bernet W, Bukstein O, Walter H, Benson RS, Chrisman A, Farchione T, Greenhill L,
Hamilton J, Keable H, Kinlan J, Schoettle U, Stock S, Ptakowski KK, Medicus J; AACAP Work Group on Quality
Issues: Practice parameter for the assessment and treatment of children and adolescents with depressive
disorders. J Am Acad Child Adolesc Psychiatry 2007; 46:1503–1526
9. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA: Clinical response and risk
for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of
randomized controlled trials. JAMA 2007; 297:1683–1696
10. Libby AM, Orton HD, Valuck RJ: Persisting decline in depression treatment after FDA warnings. Arch Gen
Psychiatry 2009; 66:633–639

254 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 EDITORIAL

DAVID A. BRENT, M.D.

JUDY CAMERON, PH.D.
DAVID A. LEWIS, M.D.

From the Department of Psychiatry, University of Pittsburgh, Pittsburgh. Address correspondence to Dr. Lewis
(lewisda@msx.upmc.edu). Editorial accepted for publication December 2013 (doi: 10.1176/appi.ajp.2013.
13121575).

Dr. Brent has received research support from NIMH grants; royalties from Guilford Press and eResearchTechnology
for the Columbia Suicide Severity Rating Scale; and honoraria for presenting at CME events. Dr. Lewis has received
investigator-initiated research support from Bristol-Myers Squibb, Curridium Ltd, and Pfizer and served as a
consultant in the areas of target identification and validation and new compound development for Bristol-Myers
Squibb and Concert Pharmaceuticals. Dr. Cameron reports no financial relationships with commercial interests.
Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 255

 Editorial

Treatment of Psychosis and Risk

Assessment for Violence

I n the trial of Daniel M’Naghten for the 1843 shooting of the British Prime Minister’s
secretary, Edward Drummond, the jury accepted that the defendant was not guilty
because he was suffering from a “disease of the mind” and that a resulting “delusion
carried him away beyond the power of his own control … over acts which had
connexion with his delusion” (1). While this verdict excited considerable controversy
at the time and not all contemporary jurisdictions accept a legal defense of mental
illness, it remains conventional wisdom that severe mental illnesses in general
and delusions in particular are causally associated with violence. However, not all
empirical studies support this association, and the role of delusions remains
controversial. For example, a well-known meta-analysis by Bonta et al. (2) found that
violent recidivism was less common among those with psychosis than among other
released prisoners. In the MacArthur Violence Risk Assessment Study, delusions did
not increase the overall probability of violence among patients released from
psychiatric hospitals (3).
In this issue of the Journal, Robert Keers, Ph.D., et al. (4) report the findings of an
elegant, longitudinal prospective study of 967 British prisoners, incarcerated for a
sexual or violent offense, who were followed up for a mean of 39.2 weeks (SD533.0)
after their release. Most were men, and almost a quarter suffered from a psychosis
defined as schizophrenia, delusional disorder, or drug-induced psychosis. The
authors asked the following three related questions:
1. Is psychosis a risk factor for violent offending after release?
2. Is treatment for psychosis important in the relationship between symptoms
and violence?
3. Which symptoms of psychosis are associated with violence?
In answer to the first question, they found that, before and after statistical ad-
justment for factors such as age, gender, and substance use, schizophrenia and
delusional disorder were not significantly associated with later violence. Further-
more, drug-induced psychosis was not associated with violence after substance
use was taken into account. Second, they found that patients with untreated
schizophrenia were almost four times more likely to be violent than those with
treated schizophrenia or no psychosis. Third, the data suggest that the emergence
of persecutory delusions partially explained the association between untreated
schizophrenia and violence.
Viewed alone, this study may not change the views of those who believe the
association between psychosis and violence is important, trivial, spurious, or non-
existent. Like earlier studies, this one has limitations. The comparator group for
those with psychosis consisted of previously violent offenders without psychosis
who may have had other risk factors for violence other than psychosis, thus
reducing the possibility of finding an association between psychosis and violence.
Furthermore, the small number of individuals who had untreated psychosis
increased the possibility of a chance association between delusions and violence in
this subgroup.

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However, a number of observations emerge when this study is seen in the context
of other recent research. First, it is likely that the negative finding with respect to
psychosis and violence was a result of the nature of the comparator group of
released prisoners. Meta-analyses of studies of the violence risk of patients with
psychosis using community comparisons have fairly consistently suggested a mod-
est but significant association between psychosis and violence (5, 6).
Second, the finding that nontreatment for psychosis is associated with vio-
lence is consistent with recent research. Most studies of violence risk have
examined the violent acts by patients who had been previously diagnosed and
treated. Few studies have compared the violence risk of treated people with
psychosis with the violence risk of people with untreated psychosis. However,
a meta-analysis found that patients with never-treated psychosis had a much
higher rate of homicide compared with people who had received earlier treat-
ment for psychosis (7).
Third, the finding of an association between persecutory ideas and violence
among untreated patients also aligns in a broad way with the results of recent
studies that used detailed approaches to considering how and when delusions
might lead to violence. For example, one recent study found that the interval be-
tween the recording of the delusions and the act of violence mediated the strength
of the association (8). On the other
hand, a second study found that per-
secutory delusions were associated
If risk assessment is to prove its worth
with violence only when they were as a rational way of making treatment
also associated with an angry affec- decisions about psychosis, future
tive state (9). improvements would need to be
The most important implications of
the Keers et al. study are that in some dramatic.
circumstances, delusions might well
be associated with violence and that the use of antipsychotic treatment, at least
among released prisoners with psychosis, is likely to prevent some acts of violence.
The study does not mean that other factors are unimportant. Male sex, young age,
prior offending, and substance abuse are the most well-established risk factors for
violence; this also applies to those with psychosis. However, the study does point to
the complexity of the antecedents to violence in psychosis. Complex interactions
between substance use and psychosis (10) and between delinquency and positive
symptoms (11) are known to influence violence risk. Here, too, the message
appears to be that the association between mental illness and violence is complex,
with multiple interacting risk factors.
Simple explanations, such as the flow of events leading from untreated men-
tal illness to delusions to anger to violence, are plausible and easy to understand
in retrospect. However, when viewed prospectively, apparently simple events
are more complex and involve subtle interplays between patients’ personal-
ity, their illness and its treatment, their community, and their own decision
making.
The complex nature of violence risk factors should not be underestimated. As
currently formulated, violence risk assessment instruments generally do not con-
sider interactions between risk factors. They operate by simply adding risk factor
items to obtain an overall risk score. It remains to be seen whether future risk as-
sessment instruments can be improved by methods that acknowledge the com-
plexity of violence risk factors.

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EDITORIAL

If risk assessment is to prove its worth as a rational way of making treatment

decisions about psychosis, future improvements would need to be dramatic. One
study examined the utility of a hypothetically excellent risk assessment instrument
that could define a high-risk group with 16 times the probability of violence than
a low-risk group (12). It concluded, as have other studies, that even under highly
optimal conditions, the proportion of true positive cases among high-risk groups
was far too low to serve as a rational basis for treatment (13) and that risk as-
sessment is insufficiently sensitive to provide a basis for the protection of the public
(14).
Finally, the findings of Keers et al. suggest another problem if a risk assessment is
to be used as a basis for deciding who will be treated for psychosis. In replication
studies, existing risk instruments can identify groups of high-risk patients who are
approximately three times more likely to be violent than low-risk patients (15).
However, Keers et al. found that untreated patients were four times more likely to
be violent than treated patients. These figures suggest that if risk assessment is used
to define a high-risk group of individuals who need treatment and a low-risk group
of individuals who do not need treatment, then the failure to treat low-risk people
with psychosis will inevitably result in some violent events.
References
1. United Kingdom House of Lords Decisions: M’Naghten’s case; 8 ER 718, UKHL J16 (1843)
2. Bonta J, Law M, Hanson K: The prediction of criminal and violent recidivism among mentally disordered
offenders: a meta-analysis. Psychol Bull 1998; 123:123–142
3. Appelbaum PS, Robbins PC, Monahan J: Violence and delusions: data from the MacArthur Violence Risk
Assessment Study. Am J Psychiatry 2000; 157:566–572
4. Keers R, Ullrich S, DeStavola BL, Coid JW: Association of violence with emergence of persecutory delusions in
untreated schizophrenia. Am J Psychiatry 2014; 171:332–339
5. Fazel S, Gulati G, Linsell L, Geddes JR, Grann M: Schizophrenia and violence: systematic review and meta-
analysis. PLoS Med 2009; 6:e1000120
6. Large M, Smith G, Nielssen O: The relationship between the rate of homicide by those with schizophrenia
and the overall homicide rate: a systematic review and meta-analysis. Schizophr Res 2009; 112:123–129
7. Nielssen O, Large M: Rates of homicide during the first episode of psychosis and after treatment: a systematic
review and meta-analysis. Schizophr Bull 2010; 36:702–712
8. Coid JW, Ullrich S, Kallis C, Keers R, Barker D, Cowden F, Stamps R: The relationship between delusions and
violence: findings from the East London First Episode Psychosis Study. JAMA Psychiatry 2013; 70:465–471
9. Ullrich S, Keers R, Coid JW: Delusions, anger, and serious violence: new findings from the MacArthur Violence
Risk Assessment Study. Schizophr Bull (Epub ahead of print, Sept 18, 2013)
10. Elbogen EB, Johnson SC: The intricate link between violence and mental disorder: results from the National
Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2009; 66:152–161
11. Winsper C, Singh SP, Marwaha S, Amos T, Lester H, Everard L, Jones P, Fowler D, Marshall M, Lewis S, Sharma
V, Freemantle N, Birchwood M: Pathways to violent behavior during first-episode psychosis: a report from
the UK National EDEN Study. JAMA Psychiatry 2013; 70:1287–1293
12. Large MM, Ryan CJ, Singh SP, Paton MB, Nielssen OB: The predictive value of risk categorization in schizo-
phrenia. Harv Rev Psychiatry 2011; 19:25–33
13. Szmukler G, Everitt B, Leese M: Risk assessment and receiver operating characteristic curves. Psychol Med
2012; 42:895–898
14. Mossman D: The imperfection of protection through detection and intervention: lessons from three decades
of research on the psychiatric assessment of violence risk. J Leg Med 2009; 30:109–140
15. Singh JP, Grann M, Fazel S: Authorship bias in violence risk assessment? a systematic review and meta-
analysis. PLoS ONE 2013; 8:e72484
MATTHEW M. LARGE, F.R.A.N.Z.C.P.

From the School of Psychiatry, University of New South Wales, Sydney, Australia. Address correspondence to
Dr. Large (mmbl@bigpond.com). Editorial accepted for publication November 2013 (doi: 10.1176/appi.ajp.
2013.13111479).

Dr. Large has received speaker’s fees from AstraZeneca to discuss risk assessment, and he has served as an
expert witness in cases involving violence risk. Dr. Freedman has reviewed this editorial and found no evidence
of influence from these relationships.

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 Editorial

Increasing Treatment Engagement for

Persons With Serious Mental Illness Using
Personal Health Records

I ndividuals living with serious mental illnesses experience a number of challenges

to achieving optimal health outcomes. This population has high rates of problem-
atic health behaviors, such as tobacco use (1), as well as high rates of medical
comorbidities, including obesity, diabetes, and cardiovascular disease (2–4). Partly
because of these factors, persons with serious mental illnesses are likely to die
prematurely compared with the general population (5, 6). The excess morbidity and
mortality associated with serious mental illnesses also result from disparities in health
care due to problems with health care access, continuity of care, and coordination
among mental health, primary care, and specialty physical health providers (5–7).
Few randomized trials have successfully improved the quality of medical care
delivered to individuals with serious mental illnesses (8–10). Druss et al. have been
at the forefront of this important area of research for a number of years and have
been able to effectively improve the
physical health services delivered to
patients with serious mental illnesses [I]ncreasing digital access to care can
using a variety of approaches, includ- substantially improve patients’
ing peer support (11) and care man- engagement in physical health services,
agement (12, 13). In their article in this even for those with limited resources,
issue of the Journal, Druss et al. (14)
report the results of a technology-based computer skills, and health literacy.
patient-activation approach to improv-
ing physical health service delivery that builds upon their earlier achievements.
Patients with serious mental illnesses were recruited from a community men-
tal health center, and one-half were randomly assigned to be given access to a
community-based personal health record. Theoretically, improving “digital access”
(i.e., connectivity that enables patients to interact with providers, caregivers, peers,
and computer applications such as personal health records) should improve
treatment engagement, just as online shopping (e.g., Amazon) has increased mar-
ket share in the retail industry (15). And in fact, patients given access to the personal
health record received nearly twice the number of preventive services during
the intervention period than they did the year before. These findings represent
a major victory in the war against health disparities among individuals with
serious mental illnesses. Importantly, a post hoc mediation analysis found that
improvements in the quality of medical care were achieved through a substantial
increase in the number of physical health outpatient encounters (14.9 visits) in
the personal health record group. This finding suggests that increasing digital
access to care can substantially improve patients’ engagement in physical health
services, even for those with limited resources, computer skills, and health
literacy.
This is a timely study given the rapid development and deployment of personal
health records in large health systems and in the context of health care reform. For

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EDITORIAL

example, the personal health record evaluated in this study has many of the same
features as the “My HealtheVet” personal health record. My HealtheVet was in-
troduced 10 years ago by the Veterans Health Administration, but its impact has
not been rigorously evaluated (16). My HealtheVet includes fields for self-entered
health information and self-management goals, information from the Veterans
Health Administration electronic health record, health education materials, and
other resources, as well as the capability for secure messaging between patients and
providers (16). My HealtheVet was also adapted specifically for persons with serious
mental illnesses (e.g., adding a mental health advance directive section). It is en-
couraging to note that veterans receiving mental health services are equally as likely
to use My HealtheVet as those using only physical health services, although per-
sonal health record use is low in both groups (17).
While continued research and development will be needed to guide improve-
ments in personal health records for patients with serious mental illnesses, based
on the results of the Druss et al. study, implementation researchers should begin to
examine how personal health records can best be deployed, especially in the
context of behavioral health homes. The behavioral health home model rapidly
being adopted by community mental health centers across the country is a patient-
centered approach to care and focuses on providing integrated and coordinated
health care. One of the core components of the behavioral health home is to en-
sure access to and coordination of care across the prevention, primary care, and
specialty health care service sectors. The Druss et al. study clearly indicates that the
deployment of a personal health record can facilitate the implementation of this core
behavioral health home component.
Currently, there is a paucity of information reported in the scientific literature
about the uptake of personal health records among persons with serious mental
illnesses (18). And there may be strong headwinds impeding large numbers of
patients with these illnesses using personal health records in routine care. In-
clusion criteria for the Druss et al. trial included having both a regular mental
health provider and a regular primary care provider, and only about one-half of
those patients approached for the study met these two criteria. This suggests that
up to one-half of patients with serious mental illnesses may not benefit from us-
ing a personal health record, although future research might prove otherwise. In
addition, patients in this trial received 4 hours of initial training to use the personal
health record and 14.8 technical support visits. This represents a substantial in-
vestment in manpower for under-resourced mental health clinics and may present
a barrier to adoption. However, this high level of support is likely necessary because
previous studies relying on less technical support found significantly lower levels
of personal health record use (18, 19). Thus, there appears to be a dose-response
relationship between technical support and use that should not be ignored during
the rollout of a personal health record. Moreover, because most personal health
records are linked with electronic health records, another barrier to implementing
a personal health record for patients with serious mental illnesses is that mental
health clinics lag in the adoption of electronic health records compared with physical
health clinics (20). Despite these headwinds, the highly promising results of the trial
presented in this issue suggest that the field should be poised to move forward with
implementation trials, demonstration projects, and quality improvement pilot
studies. Community mental health centers in the process of obtaining recognition as
a behavioral health home may particularly benefit from investing in a personal
health record for their clients.

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 EDITORIAL

References
1. Substance Abuse and Mental Health Services Administration: Results from the 2011 National Survey on Drug
Use and Health: Mental Health Findings (NSDUH Series H-45, HHS publication number, 12-4725). Rockville,
Md, Substance Abuse and Mental Health Services Administration, 2012
2. Jones DR, Macias C, Barreira PJ, Fisher WH, Hargreaves WA, Harding CM: Prevalence, severity, and co-
occurrence of chronic physical health problems of persons with serious mental illness. Psychiatr Serv 2004;
55:1250–1257
3. Dalmau A, Bergman B, Brismar B: Somatic morbidity in schizophrenia: a case control study. Public Health
1997; 111:393–397
4. Newcomer JW, Hennekens CH: Severe mental illness and risk of cardiovascular disease. JAMA 2007; 298:
1794–1796
5. Druss BG, Zhao L, von Esenwein S, Morrato EH, Marcus SC: Understanding excess mortality in persons with
mental illness: 17-year follow up of a nationally representative US survey. Med Care 2011; 49:599–604
6. Kilbourne AM, Welsh D, McCarthy JF, Post EP, Blow FC: Quality of care for cardiovascular disease-related
conditions in patients with and without mental disorders. J Gen Intern Med 2008; 23:1628–1633
7. Druss BG, Bornemann TH: Improving health and health care for persons with serious mental illness: the
window for US federal policy change. JAMA 2010; 303:1972–1973
8. Druss BG, von Esenwein SA: Improving general medical care for persons with mental and addictive disorders:
systematic review. Gen Hosp Psychiatry 2006; 28:145–153
9. Bradford DW, Slubicki MN, McDuffie J, Kilbourne A, Willams JW: Effects of Care Models to Improve General
Medical Outcomes for Individuals With Serious Mental Illness. Washington, DC, Department of Veterans
Affairs, 2011
10. Cohen AN, Chinman MJ, Hamilton AB, Whelan F, Young AS: Using patient-facing kiosks to support quality
improvement at mental health clinics. Med Care 2013; 51(suppl 1):S13–S20
11. Druss BG, Zhao L, von Esenwein SA, Bona JR, Fricks L, Jenkins-Tucker S, Sterling E, Diclemente R, Lorig K: The
Health and Recovery Peer (HARP) Program: a peer-led intervention to improve medical self-management for
persons with serious mental illness. Schizophr Res 2010; 118:264–270
12. Druss BG, von Esenwein SA, Compton MT, Rask KJ, Zhao L, Parker RM: A randomized trial of medical care
management for community mental health settings: the Primary Care Access, Referral, and Evaluation
(PCARE) study. Am J Psychiatry 2010; 167:151–159
13. Druss BG, Rohrbaugh RM, Levinson CM, Rosenheck RA: Integrated medical care for patients with serious
psychiatric illness: a randomized trial. Arch Gen Psychiatry 2001; 58:861–868
14. Druss BG, Ji X, Glick G, von Esenwein SA: Randomized trial of an electronic personal health record for patients
with serious mental illnesses. Am J Psychiatry 2014; 171:360–368
15. Fortney JC, Burgess JF, Bosworth HB, Booth BM, Kaboli PJ: A re-conceptualization of access for 21st century
healthcare. J Gen Intern Med 2011; 26(suppl 2):639–647
16. Nazi KM, Hogan TP, Wagner TH, McInnes DK, Smith BM, Haggstrom D, Chumbler NR, Gifford AL, Charters KG,
Saleem JJ, Weingardt KR, Fischetti LF, Weaver FM: Embracing a health services research perspective on
personal health records: lessons learned from the VA My HealtheVet system. J Gen Intern Med 2010; 25(suppl
1):62–67
17. Tsai J, Rosenheck RA: Use of the Internet and an online personal health record system by US veterans:
comparison of Veterans Affairs mental health service users and other veterans nationally. J Am Med Inform
Assoc 2012; 19:1089–1094
18. Druss BG, Dimitropoulos L: Advancing the adoption, integration and testing of technological advancements
within existing care systems. Gen Hosp Psychiatry 2013; 35:345–348
19. Warner JP, King M, Blizard R, McClenahan Z, Tang S: Patient-held shared care records for individuals with
mental illness: randomised controlled evaluation. Br J Psychiatry 2000; 177:319–324
20. Rosenberg L: HIT: time to end behavioral health discrimination. J Behav Health Serv Res 2012; 39:336–338
JOHN C. FORTNEY, PH.D.
RICHARD R. OWEN, M.D.

From the Central Arkansas Veterans Healthcare System, Little Rock, Ark., and the Department of Psychiatry,
University of Arkansas for Medical Sciences, Little Rock, Ark. Address correspondence to Dr. Fortney
(fortneyjohnc@uams.edu). Editorial accepted for publication December 2013 (doi: 10.1176/appi.ajp.2013.
13121701).

The authors report no financial relationships with commercial interests.

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 261

 Commentary

A Word to the Wise About Ketamine

R ecent reports of an acute antidepressant effect for intravenous ketamine,

a schedule III agent used in anesthesia and pain clinics, have generated con-
siderable hope and enthusiasm among both researchers and clinicians (1–4). The
response partly reflects hope that a new mechanism of antidepressant action has
been discovered and highlights the scarcity of agents that clinicians can administer
to produce immediate effects on mood. Positive initial research reports (including
the recent article in the Journal by Murrough et al. [4]) have unintentionally en-
gendered growing off-label clinical use of ketamine in emergency rooms, specialty
pain clinics and, most recently, free-standing private psychiatry clinics. If ketamine
were a new drug, then the Food and Drug Administration would have required
hundreds more patients to be rigorously studied before an approval for general
distribution. However, because ketamine was already approved as an anesthe-
tic, any physician can legally prescribe it. Some practitioners have even com-
missioned pharmacists to compound intranasal and other formulations. This
unbridled enthusiasm needs to be tempered by a more rational and guarded
perspective.
We Need To Know More About Acute and Longer-Term Efficacy and Risks
The data on clinical response to ketamine as an antidepressant are still rela-
tively limited. The study by Murrough et al. (4) was the largest to date but still
included only 47 patients treated with the drug. Will the data hold up in other
controlled trials? The antidepressant effects of ketamine are generally short lived,
lasting less than 1 week, although longer than its half-life. Unfortunately, to date
we have no idea what we should do for follow-up therapy. In a recent report (3),
repeated ketamine administration every few days appeared to be effective
over a 2-week period with no clear tachyphylaxis to either the antidepressant
or depersonalization effect, but that does not address what to do beyond 2
weeks, including dealing with the risk for dependence since ketamine is a drug of
abuse.
Ketamine produces feelings of depersonalization and even psychosis (1–4), and
it was previously used to test hypotheses regarding dopamine and glutamate in
schizophrenia. In their study, Murrough et al. (4) undertook stringent patient eval-
uations to decrease the risk of psychotic reactions, but such evaluations may not be
occurring in other settings. Clinicians outside a research setting generally do not
have the resources to screen patients similarly.
We Need To Know More About the Mechanism of Action of the Mood-Elevating Effects
The antidepressant effect has been thought to reflect ketamine’s glutamatergic
properties, specifically its blocking of N-methyl-d-aspartic acid (NMDA) receptors,
which should be a clue for follow-up therapy. However, other currently available
agents (covering a variety of glutamatergic actions) have proven unsuccessful in
antidepressant trials either as monotherapy or in combination with ketamine
(5–7). Investigational agents have been mixed in their effects, with glycine par-
tial or full agonists that act essentially as NMDA agonists also being effective
for depression (unpublished 2012 report by R.M. Burch; 8, 9). This suggests

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that NMDA antagonism may not be the primary mechanism of action for
ketamine in major depression. Recent reports have indicated that ketamine
has effects on intracelluar mTor that could account for its antidepressant
properties (10).
Stimulants and opiates have long been associated with short-term, although
generally clinically ineffective, therapeutic effects and problems with abuse.
Ketamine has both opiate and stimulant effects (11, 12). It is a strong promoter
of catecholamine, particularly dopamine, turnover (12), and its monoaminergic
properties are similar to cocaine or amphetamine. Ketamine also has mu opioid
receptor properties, consistent with its use for anesthesia and treatment of pain.
This mechanism may be similar to the antidepressant effects of buprenorphine
(13), although a study in healthy individuals did indicate that the effects of
ketamine on responses to alcohol were not blocked by the mu antagonist nal-
trexone (14). To our knowledge, such a study has not been conducted in
depressed patients. It is interesting that Rodriguez et al. (15) recently reported
that ketamine given intravenously was similarly effective in refractory obsessive-
compulsive disorder (OCD). This was reminiscent of a double-blind, placebo-
controlled study by Koran et al. (16)
a few years ago that reported that oral Until we know more, clinicians
morphine improved OCD symptoms
1 day after administration—an effect
should be wary about embarking
that lasted 5 days. Comparison studies on a slippery ketamine slope.
against stimulants and opioids would
be helpful for assessing ketamine’s mechanism of action for acutely elevating mood
and its potential for providing overall benefit in the treatment of depression.
Should Clinicians Prescribe Ketamine for Patients With Refractory Depression?
Without more data on what ketamine can do clinically, except to produce brief
euphoriant effects after acute administration, and knowing it can be a drug of
abuse, it is difficult to argue that patients should receive an acute trial of ketamine
for refractory depression. Some ketamine investigators have argued for not using it
outside of a hospital setting (17), but without extensive experience and a follow-up
strategy, is even that the most prudent strategy? I would argue that waiting until we
understand more about its effects and risks makes most sense. Patients have not
benefitted in the past from the overuse of short-term treatments such as stimulants
and opiates. The results have been toxicity and dependence from the immediate
treatment and a failure to recommend and follow through with more definitive
longer-term treatments required for patients with depression. The recent ketamine
studies are exciting, and they open up important avenues for investigation that
should be supported; however, until we know more, clinicians should be wary
about embarking on a slippery ketamine slope.

References
1. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK: A ran-
domized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen
Psychiatry 2006; 63:856–864
2. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z,
Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr: A randomized add-on trial of an
N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67:
793–802
3. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS,
Iosifescu DV: Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-
resistant major depression. Biol Psychiatry 2013; 74:250–256

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4. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A,
Charney DS, Mathew SJ: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-
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5. Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, Caloro M, Telesforo CL, Caltagirone SS,
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6. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, Moaddel R, Wainer I,
Luckenbaugh DA, Manji HK, Zarate CA Jr: Course of improvement in depressive symptoms to a single in-
travenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled
study. Neuropsychopharmacology 2012; 37:1526–1533
7. Barbee JG, Thompson TR, Jamhour NJ, Stewart JW, Conrad EJ, Reimherr FW, Thompson PM, Shelton RC: A
double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-
refractory unipolar depression. J Clin Psychiatry 2011; 72:1405–1412
8. Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA,
Luckenbaugh DA: A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker
in major depression. Biol Psychiatry 2013; 74:257–264
9. Huang CC, Wei IH, Huang CL, Chen KT, Tsai MH, Tsai P, Tun R, Huang KH, Chang YC, Lane HY, Tsai GE:
Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry
2013; 74:734–741
10. Li N, Lee B, Liu R-J, Banasr M, Dwyer JM, Iwata M, Li X-Y, Aghajanian G, Duman RS: mTOR-dependent synapse
formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329:959–964
11. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant effects of
ketamine in depressed patients. Biol Psychiatry 2000; 47:351–354
12. Tan S, Lam WP, Wai MS, Yu WH, Yew DT: Chronic ketamine administration modulates midbrain dopamine
system in mice. PLoS ONE 2012; 7:e43947
13. Bodkin JA, Zornberg GL, Lukas SE, Cole JO: Buprenorphine treatment of refractory depression. J Clin Psy-
chopharmacol 1995; 15:49–57
14. Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D’Souza DC: Potentiation of
low-dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.
Neuropsychopharmacology 2006; 31:1793–1800
15. Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, Flood P, Simpson HB: Randomized
controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuro-
psychopharmacology 2013; 38:2475–2483
16. Koran LM, Aboujaoude E, Bullock KD, Franz B, Gamel N, Elliott M: Double-blind treatment with oral mor-
phine in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry 2005; 66:353–359
17. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ: Ketamine for depression: where do we go from here?
Biol Psychiatry 2012; 72:537–547
ALAN F. SCHATZBERG, M.D.

From Stanford University School of Medicine, Stanford, Calif. Address correspondence to Dr. Schatzberg
(afschatz@stanford.edu). Commentary accepted for publication January 2014 (doi: 10.1176/appi.ajp.2014.
13101434).

Dr. Schatzberg has received consulting fees from Bay City Capital, BrainCells, CeNeRx, Cervel, Eli Lilly,
Genentech, Gilead, Jazz, Lundbeck/Takeda, McKinsey, Merck, MSI, Naurex, Neuronetics, Novadel, Pharma-
NeuroBoost, Sunovion, Synosia, and Xhale. He has equity in Amnestix, BrainCells, CeNeRx, Cervel, Corcept (co-
founder), Delpor, Forest Labs, Merck, Neurocrine, Novadel, Pfizer, PharmaNeuroBoost, Somaxon, Synosia,
Titan, and Xhale. He is a named inventor on pharmacogenetic use patents on prediction of antidepressant
response and glucocorticoid antagonists in psychiatry, and he has received speakers’ honoraria from Merck.
Dr. Freedman has reviewed this commentary and found no evidence of influence from these relationships.

264 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 Treatment in Psychiatry

Behavioral and Psychiatric Symptoms in Prion Disease

Andrew Thompson, B.Sc., The prion diseases are rare neurodege-
nerative conditions that cause complex
M.R.C.P. and highly variable neuropsychiatric syn-
dromes, often with remarkably rapid
Angus MacKay, Ph.D., progression. Prominent behavioral and
F.R.C.Psych. psychiatric symptoms have been recog-
nized since these diseases were first de-
Peter Rudge, F.R.C.P. scribed. While research on such symptoms
in common dementias has led to major
Ana Lukic, B.Sc., M.R.C.P. changes in the way these symptoms are
managed, evidence to guide the care of
patients with prion disease is scarce. The
Marie-Claire Porter, B.Sc., authors review the published research and
M.R.C.P. draw on more than 10 years’ experience at
the U.K. National Prion Clinic, including
Jessica Lowe, B.Sc. two large prospective clinical research
studies in which more than 300 patients
John Collinge, F.R.C.P., F.R.S. with prion disease have been followed up
from diagnosis to death, with detailed
Simon Mead, Ph.D., F.R.C.P. observational data gathered on symptom-
atology and symptomatic treatments.
The authors group behavioral and psychi-
atric symptoms into psychotic features,
agitated features, and mood disorder
and describe their natural history, showing
that they spontaneously improve or re-
solve in many patients and are short-
lived in many others because of rapid
progression of global neurological dis-
ability. Diagnostic category, disease se-
verity, age, gender, and genetic variation
are or may be predictive factors. The
authors review the observational data
on pharmacological treatment of these
symptoms in the U.K. clinical studies and
make cautious recommendations for
clinical practice. While nonpharmaco-
logical measures should be the first-line
interventions for these symptoms, the
authors conclude that there is a role for
judicious use of pharmacological agents
in some patients: antipsychotics for se-
vere psychosis or agitation; benzodiaze-
pines, particularly in the late stages of
disease; and antidepressants for mood
disorder.

(Am J Psychiatry 2014; 171:265–274)

T he human prion diseases are a group of rare neuro-

degenerative conditions. They share a common molecular
pathological process, characterized by conversion of the
normal cellular prion protein (PrPc) into abnormal disease-
associated forms (PrPSc), but their etiologies vary. They in-
clude sporadic Creutzfeldt-Jakob disease (sCJD), the inherited
prion diseases (IPD), and the acquired prion diseases: var-
iant CJD (vCJD), iatrogenic CJD (iCJD), and kuru (1).
Clinically, these diseases are remarkably heterogeneous,
both within and between the different disease types. As
illustrated in the composite case vignette, they often cause
complex neuropsychiatric syndromes that evolve rapidly
through the course of the disease. Various factors have been
shown to contribute to clinical heterogeneity in prion
disease, including etiological disease type, prion strain,
genotype at the polymorphic codon 129 of the prion protein
gene (PRNP), and demographic factors such as age (2).
Behavioral and Psychiatric Features of
Prion Disease
Behavioral and psychiatric symptoms have been recog-
nized since the earliest clinical descriptions of prion disease
(3), but there has been relatively little research into their
prevalence, phenomenology, natural history, and treat-
ment. When vCJD first arose in the United Kingdom dur-
ing the 1990s, early psychiatric symptoms were noted
(4, 5), and they are included in the World Health Organi-
zation diagnostic criteria for this disease (6). A review of 106
pathologically confirmed cases of vCJD concluded that
behavioral and psychiatric symptoms were present in 92%
(7). In 2005, Wall et al. (8) reported a retrospective study of
126 sCJD cases evaluated at the Mayo Clinic over 25 years
and found that psychiatric symptoms (excluding sleep
disturbance) were present in 26% of cases at presentation,
in 80% within the first 100 days after onset, and in 89% at
any stage of their illness. Appleby et al. used retrospective
case note review (9) and meta-analysis of published cases
(10) to investigate patterns of symptoms in sCJD, and they
suggest that there is a distinct “affective sCJD variant.”
Published experience of pharmacological treatments in
prion disease has focused on putative disease-modifying
agents. Interestingly, chlorpromazine and the tricyclic anti-
depressants are among a number of agents that have been
found to inhibit prion replication in vitro (11, 12), and their
use in patients with prion disease has been described in
a handful of case reports (13–16), but the reports address the

This article is featured in this month’s AJP Audio and is the subject of a CME course (p. 377).

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TREATMENT IN PSYCHIATRY
A 62-year-old man with agitation, hallucinations, myoclonus, and cognitive decline is hospitalized.
A recently retired 62-year-old man had become withdrawn,
apathetic, and taciturn over 2 months, and was sleeping
poorly. His general practitioner started treatment with
citalopram for a suspected depressive illness. Over the next
few weeks, the patient became increasingly confused and
agitated and reported seeing frightening people and
animals. On several occasions, he left the house to chase
these intruders away and became lost. He also developed
involuntary muscle jerks of the limbs, and his balance
deteriorated. During one episode of wandering, a bystander
contacted the police, who found him to be “incoherent and
unsteady” and took him to the hospital. Citalopram was
stopped in case his symptoms represented an adverse drug
reaction, but this did not lead to any improvement.
During a 2-week inpatient stay in the hospital, extensive
investigations were undertaken, and a diagnosis of pro-
bable sporadic Creutzfeldt-Jakob disease (CJD) was made.
Sequencing of the prion protein gene (PRNP) showed
methionine/valine heterozygosity at the codon 129 poly-
morphism and no pathogenic mutations. Visual hallu-
cinosis with some associated agitation and behavioral
disturbance continued, and the patient had several falls
on the ward as a result of attempts to move around despite
increasing ataxia and apraxia. Risperidone was initiated at
a low dosage, and within a few days the patient’s agitation
had lessened. Although hallucinations persisted, they were
less intense and frightening; the patient had some limited
insight and was able to contribute to end-of-life-care plan-
ning. By the time he was discharged home, he needed
failure of these agents to halt the progression of the disease
rather than any usefulness in treating psychiatric symptoms.
Beyond this, there has been no published evidence on which
to base the symptomatic treatment of behavioral and psy-
chiatric symptoms in patients with prion disease.
In contrast, behavioral and psychiatric symptoms in the
common dementias have received increasing clinical and
scientific attention in recent years. They are a major cause
of morbidity in themselves, and they are associated with
poorer outcomes for patients and more stress for caregivers
(17, 18). Large-scale research on their treatment has pro-
duced unexpected and important results in terms of both
efficacy and safety (19–22) and has had a major impact on
clinical practice. Several studies have used factor analysis to
show that behavioral and psychiatric symptoms in Alz-
heimer’s disease tend to occur in a small number of clusters
or “subsyndromes” (23, 24). All studies have reported psy-
chosis, mood disorder, and agitation/hyperactivity clusters.
In comparison with the more common dementias, there
are a number of particular challenges to studying behav-
ioral and psychiatric symptoms in prion diseases. Their
rarity, their typically rapid progression, and a tendency for
266 ajp.psychiatryonline.org
substantial assistance to transfer and mobilize, and his
speech output was markedly reduced.
Back at home, the patient’s mobility and cognitive
function continued to steadily decline, and he became
increasingly dependent on his family and caregivers. He
also had increasing periods of daytime somnolence. His
minimal speech output made assessment of his mental
state difficult, but he appeared less agitated than pre-
viously. A decision was made to discontinue risperidone
(after a total treatment duration of 4 weeks). There was no
clear improvement in his daytime somnolence, but no
deterioration in agitation or behavior.
Over the next 6 weeks, the patient became bedbound
and mute. He was noted to have a “wide-eyed, scared”
expression at times, and when personal care was being
administered, he appeared agitated and had dramatic
stimulus-sensitive myoclonus, which had an impact on his
nursing care. Clonazepam was started at a low dosage, and
both the agitation and the myoclonus decreased.
The patient became unable to swallow, and he was
admitted to a hospice for end-of-life care. He continued to
have periods of wide-eyed agitation, and myoclonus
became troublesome. Midazolam was administered sub-
cutaneously in low doses, with good effect. The patient’s
conscious level steadily declined over a week, and his
breathing became irregular and labored.
He died 8 months after the onset of the first symptoms
of withdrawal and apathy. Postmortem examination of the
brain confirmed the diagnosis of sporadic CJD.
late diagnosis all make prospective study challenging.
Expressive language dysfunction is a hallmark of prion
disease, and this limits patients’ ability to describe the
internal experience of psychiatric symptoms.
Prospective Data From U.K. Clinical
Studies
The National Health Service’s National Prion Clinic
offers specialist clinical assessment and follow-up for all
cases of suspected prion disease in the United Kingdom.
Over the past 10 years the clinic has also conducted two
large clinical studies: the PRION-1 study and the ongoing
National Prion Monitoring Cohort, which have achieved
high levels of enrollment (.95% of eligible patients were
enrolled in the Cohort). The PRION-1 study was an open-
label patient preference trial of quinacrine for all types
of prion disease, and the study showed no effect of
quinacrine on survival or any of the rating scales used
as secondary outcome measures (25, 26); for our pur-
poses here, the clinical data from the PRION-1 study are
therefore regarded as natural history data. The National
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 TREATMENT IN PSYCHIATRY

Prion Monitoring Cohort is a prospective natural history visual distortion and agnosia) and as an isolated phenom-
study. Full details of these studies have been published enon. Distressing visual distortions and illusions were also
elsewhere (25–27). common. Several patients described unpleasant splitting
In both the PRION-1 and National Prion Monitoring and twisting of faces and other objects, “like a Picasso.”
Cohort studies, details of symptoms at illness onset and at In terms of hallucination content, there was a striking
the time of each study assessment, along with the in- abundance of animals, and also human figures. In a few
dications for any medication prescribed during the study instances, patients described multimodal hallucinations
period, were systematically recorded. The clinical case (e.g., seeing, hearing, feeling, and smelling rats crawling
notes of selected patients identified from the research over the body), but this was rare and was always associated
data, including all those for whom medication was pre- with a particularly florid visual hallucinosis. In patients
scribed for behavioral and psychiatric symptoms, were with more advanced disease, episodes characterized by
reviewed in detail. These studies provide valuable data on a wide-eyed, staring, or fearful expression were frequently
the psychiatric and behavioral features of the diseases, as observed. Some of these patients had previously reported
well as systematically collected prospective clinical data visual hallucinations at an earlier stage. A smaller number
on more than 350 patients (see Table 1). Here we combine of patients were noted to have delusions, which tended
this experience with the previously published work to to be relatively simple (e.g., theft or infidelity). Several pa-
review the clinical characteristics, natural history, and in tients reported vivid sensory experiences outside the limits
particular the treatment of these important symptoms of of their real sensory field, such as “seeing” someone in another
prion disease. Using other clinical and demographic data part of the house or a distant location—“extracampine”
collected in these studies, we also assessed factors that hallucinations—which were often associated with de-
predict the presence of particular lusional thought content. Possible
behavioral and psychiatric symp- Schneiderian first-rank symptoms
toms, offering some insight into the Behavioral and psychiatric were noted in two patients with
pathophysiology underlying these
clinical features.
features are common in all vCJD. A 54-year-old man with irri-
tability, agitation, visual halluci-
As has been found previously in types of prion disease, and nations, and myoclonus reported
work on behavioral and psychiatric there is significant feeling “as if someone is taking over
symptoms in dementia (23, 24), my mind,” and a 30-year-old man
clinical features occurring together heterogeneity both within was noted to have “thought inter-
in individual patients seemed to be and between disease types. ference, delusional thinking, and
divisible into three main groups: possible hallucinations” before the
psychotic features (e.g., hallucina- onset of any frank neurological symp-
tions, delusions); agitated features (e.g., agitation, aggres- toms. Six of the 204 patients with sCJD had purely visual
sion, behavioral disturbance); and mood disorder (e.g., symptoms at onset (and could therefore be classified as
low mood, emotional lability, apathy, withdrawal). having the Heidenhain variant of sCJD [28]). They had
symptoms such as loss of acuity, blurring, or distortions
initially, but several developed hallucinations as the
Psychotic Features
disease progressed. Another 29 sCJD patients had visual
Prevalence and Pathophysiology symptoms at onset (in combination with other symp-
In our series, 36.9% of patients had psychotic features at toms), including hallucinations in 13 patients.
any stage of their illness. Table 2 summarizes the prevalence Figure 1 shows the proportion of assessments at which
across different disease types. Psychotic features were par- hallucinations were noted at different stages of disease
ticularly common in vCJD and sCJD. Using logistic re- progression, as assessed by the Medical Research Council
gression analysis (with age at onset, gender, disease type, Prion Disease Rating Scale (MRC-PDRS) (27). Hallucina-
and PRNP codon 129 genotype as covariates), presence of tions were not observed in the most mildly impaired, and
psychotic symptoms at any stage was independently pre- they became more prevalent as impairment increased. In
dicted by specific disease types (sCJD . IPD) and codon 129 keeping with this, logistic regression showed a highly
genotypes (MV . MM) with high levels of significance significant effect of MRC-PDRS score on the odds of
(p values ,0.01) (see the data supplement that accom- hallucinations being present (p,0.001), adjusted for disease
panies the online edition of this article). type. To assess the natural history of these symptoms in
individual patients, Figure 1 also shows the severity of
Phenomenology and Natural History hallucinations recorded at the assessment following one at
Psychotic features occurred with and without associated which they were rated “often” or “always.” The symptoms
agitation or behavioral disturbance. By far the most com- had improved in about 40% of cases, and in about 20% of
mon was visual hallucinosis, which occurred both in the cases, symptoms could no longer be assessed because of
context of other progressive visual symptoms (such as progression of the disease.

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TREATMENT IN PSYCHIATRY

TABLE 1. Summary of Patient Diagnoses in the PRION-1 and Pharmacological Treatment

National Prion Monitoring Cohort Studies
Table 3 summarizes the observed pharmacological
Number of Patients treatment of patients with behavioral and psychiatric
Diagnosis Symptomatic At Risk symptoms in the PRION-1 and National Prion Monitoring
Sporadic CJD 204 Cohort studies.
Definite 102 A total of 31 prescriptions were written for antipsy-
Probable 82 chotics for psychotic symptoms. The choice of specific
Possible 20 agents was influenced by the risk of extrapyramidal side
PRNP codon 129 MM 89 effects; quetiapine was the most frequently prescribed,
PRNP codon 129 MV 48
and very few first-generation antipsychotics were used.
PRNP codon 129 VV 32
Most treatment courses were short (median561 days). In
Not genotyped 35
nine cases (29%), antipsychotics were noted to have
Variant CJD 25 10
Definite 18 apparent clinical benefit. Sedation was noted as an
Probable 7 apparent adverse effect in six cases (19%); this often
PRNP codon 129 MM 24 4 occurred in the context of severe neurological disability,
PRNP codon 129 MV 1 2 and in no case was it recorded as a reason for discontin-
Not genotyped 0 4 uation of the prescription.
Iatrogenic CJD (treatment with 8 There were 32 prescriptions of benzodiazepines for
human growth hormone)
psychotic symptoms. Most were in the context of late-
Definite 4
stage disease and were prompted by severe agitation or
Probable 4
PRNP codon 129 MM 1 distress that seemed to be driven by psychotic symptoms.
PRNP codon 129 MV 5 In a number of cases, myoclonus was noted as a joint
PRNP codon 129 VV 1 indication. Most treatment courses were short (median542
Not genotyped 1 days). In seven cases (22%), benzodiazepines were noted
Inherited prion disease (IPD) 80 30 to have apparent clinical benefit. Sedation was noted as
Insertion mutations: IPD-OPRI an apparent adverse effect in four cases (13%) but was
4-OPRI 3 0 never recorded as a reason for discontinuation of the
5-OPRI 8 1
prescription.
6-OPRI 19 2
Five prescriptions were written for acetylcholinesterase
Point mutations: IPD-point
P102L 24 11
inhibitors for psychotic symptoms. The decision to use
A117V 7 2 these agents was based on overlap between the neuro-
E200K 8 8 psychiatric symptomatology of some prion disease cases
D178N-129M 1 3 with that of Lewy body disease, in which these drugs are
D178N-129V 2 2 known to be effective in treating behavioral and psychi-
D178N (129 haplotype 1 1 atric symptoms (29, 30). Prescriptions were started in
unknown)
patients with moderately advanced disease, all of whom
Y1633 3 0
had hallucinations, and courses were relatively long
Others (P105L, Q212P, 4 0
V210I, E211Q) (median5236 days). Three of the five (60%) prescriptions
a
CJD5Creutzfeldt-Jakob disease; OPRI5octapeptide repeat insertion. were noted to have apparent clinical benefit, and no
adverse effects were recorded.

TABLE 2. Prevalence of Behavioral and Psychiatric Symptoms (BPS) in All Symptomatic Patients and in Individual Prion
Disease Types, at Illness Onset and at Any Stage of Disease, in the PRION-1 and National Prion Monitoring Cohort Studiesa
At Illness Onset At Any Stage
Any BPS Only BPS Any BPS Psychotic Agitated Mood
Patient Group N N % N % N % N % N % N %
All patients 317 141 44.5 28 8.8 253 79.8 117 36.9 57 18.0 132 41.6
sCJD 204 88 43.1 15 7.4 161 78.9 87 42.6 33 16.2 68 33.3
vCJD 25 23 92.0 6 24.0 24 96.0 12 48.0 7 21.9 16 64.0
iCJD 8 2 25.0 0 0.0 6 75.0 2 25.0 0 0.0 4 50.0
IPD (all) 80 28 35.0 7 8.8 62 77.5 16 20.0 17 21.3 44 55.0
IPD-OPRI 30 16 53.3 5 16.7 26 86.7 7 23.3 10 33.3 15 50.0
IPD-point 50 12 24.0 2 4.0 36 72.0 9 18.0 7 14.0 29 58.0
a
sCJD5sporadic Creutzfeldt-Jakob disease; vCJD5variant Creutzfeldt-Jakob disease; iCJD5iatrogenic Creutzfeldt-Jakob disease; IPD5inherited
prion diseases; OPRI5octapeptide repeat insertion.

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 TREATMENT IN PSYCHIATRY

FIGURE 1. Natural History of Hallucinations and Depressive Symptoms in Prion Diseasea

Hallucinations
Severity at Follow-Up After
a Rating of Often or Always
Symptoms Present (N=58)
100 100

Absent
80 80
Percent of Assessments

60 60 Not assessable

Rare
40 40

20 20 Often or always

0 0
0 1–3 4–7 8–11 12–15 16–19 20
MRC-PDRS Score

Depressive Symptoms
Severity at Follow-Up After
a Rating of Often or Always
Symptoms Present (N=95)
100 100
Absent

80 80
Not assessable
Percent of Assessments

60 60

Rare

40 40

20 20
Often or always

0 0
0 1–3 4–7 8–11 12–15 16–19 20
MRC-PDRS Score
a
The panels on the left present the prevalence of hallucinations and depressive symptoms (at all assessments), grouped by stage of disease
progression; the panels on the right summarize severity ratings of hallucinations and depressive symptoms at the assessment following one in
which these symptoms were rated “often” or “always.” Disease progression was assessed by score on the Medical Research Council Prion
Disease Rating Scale (MRC-PDRS), on which 05maximal impairment, akinetic and mute, and 205no functional impairment.

Agitated Features onset and symptoms requiring pharmacological treat-

Prevalence and Pathophysiology
Agitated (nonpsychotic) features were not systemati-
cally recorded at all study assessments, so the prevalences
in Table 2 are derived only from symptoms present at
ment, and they are therefore likely to be significantly
underestimated.
In logistic regression analysis, younger age at onset
approached significance (in light of multiple testing
involved) as an independent predictor of agitated features

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TREATMENT IN PSYCHIATRY

TABLE 3. Drug Treatment of Behavioral and Psychiatric Symptoms in the PRION-1 and National Prion Monitoring Cohort
Studiesa
Duration of Treatment (days) Reason for Discontinuation
Clinical Adverse Death or Ongoing at
Benefit Effects Adverse Lack of Advanced Last
Median Noted Noted Effects Benefit Disease Follow-Up
Course
Features and Agent Nb Total Length N % N % N % N % N % N % Side Effects Noted
Agitated features
Benzodiazepinesc 39 5,683 23 6 15.4 4 10.3 0 0.0 0 0.0 24 61.5 8 20.5 Sedation (N54)
Antipsychoticsd 23 7,253 149 10 43.5 3 13.0 0 0.0 0 0.0 14 60.9 7 30.4 Extrapyramidal
symptoms (N52),
sedation (N51)
Antidepressantse 6 3,995 750.5 1 16.7 2 33.3 1 16.7 1 16.7 0 0.0 4 66.7 Weight gain (N51),
headache (N51)
Psychotic features
Benzodiazepinesf 32 3,280 42 7 21.9 4 12.5 0 0.0 0 0.0 26 81.3 1 3.1 Sedation (N54)
Antipsychoticsg 31 6,266 61 9 29.0 6 19.4 0 0.0 1 3.2 22 71.0 4 12.9 Sedation (N56)
Acetylcholinesterase 5 2,027 236 3 60.0 0 0.0 0 0.0 0 0.0 2 40.0 3 60.0 None
inhibitorsh
Mood disorder
Antidepressantsi 45 18,315 301.5 16 35.6 4 8.9 1 2.2 2 4.4 22 48.9 13 28.9 Sedation (N51),
agitation (N51),
weight gain (N51),
unpleasant
taste (N51)
a
Observational data for all drug classes prescribed five or more times for each symptom group. Some patients received more than one agent
(most commonly an antipsychotic and a benzodiazepine), but in most cases the two agents were not started simultaneously. As far as
possible, the relative clinical benefit and adverse effects of each were determined from careful review of the clinical notes. If this was not
clear, the benefit or adverse effect was attributed to both.
b
Number of prescriptions studied.
c
Midazolam (N516), diazepam (N512), lorazepam (N57), clonazepam (N54).
d
Quetiapine (N511), haloperidol (N56), risperidone (N54), olanzapine (N52).
e
Amitriptyline (N52), mirtazapine (N52), fluoxetine (N51), sertraline (N51).
f
Lorazepam (N512), diazepam (N56), midazolam (N56), clonazepam (N54), temazepam (N53), alprazolam (N51).
g
Quetiapine (N514), olanzapine (N58), risperidone (N56), haloperidol (N52), levomepromazine (N51).
h
Donepezil (N54), rivastigmine (N51).
i
Citalopram (N521), fluoxetine (N57), mirtazapine (N56), sertraline (N53), amitriptyline (N52), escitalopram (N52), clomipramine (N51),
paroxetine (N51), trazodone (N51), venlafaxine (N51).

(odds ratio50.966 per year, p50.03) (see the online data
supplement).
Phenomenology and Natural History
Agitation and behavioral disturbance frequently oc-
curred in the absence of psychotic features. Typical
descriptions included “irritability,” “resistiveness,” and
“hostility.” Other overactive behaviors, such as wandering
and repetitive vocalizations, were also included. These
symptoms were commonly noted to occur in response to
external stimuli (most commonly administration of per-
sonal care). In some patients in the earlier stages of
disease, nonpsychotic behavioral disturbance occurred in
the context of disinhibition, impulsivity, and other signs of
frontal lobe dysfunction. Patients with advanced disease
often showed evidence of agitation without any behavioral
evidence of hallucinations. Agitation was often reactive to
stimulus and often coexisted with stimulus-sensitive myo-
clonus and an exaggerated startle response, which are com-
mon features in the late stages of all prion diseases. This was
observed in some patients in whom agitated features had
been noted earlier in the disease course, but also in many
who did not have earlier agitation.
Pharmacological Treatment
A total of 23 prescriptions were written for antipsy-
chotics to treat agitation (see Table 3). These included very
short treatment courses at the end stage of sCJD (minimum,
7 days) and much longer courses in slowly progressive IPD
(maximum, 1,506 days). In 10 cases (43%), antipsychotics
were noted to have apparent clinical benefit. Apparent
adverse effects were noted in three cases (13%): extrapyra-
midal symptoms in two cases and sedation in one. None of
these symptoms was severe, and they were not recorded as
a reason for discontinuation.
There were 39 prescriptions for benzodiazepines for
agitation, most initiated in late-stage disease. In a number
of cases, myoclonus was noted as a joint indication. Most
treatment courses were short (median523 days). Six (15.4%)
prescriptions were noted to have apparent clinical benefit.
Sedation was noted as an apparent adverse effect in four
cases (10.3%). This often occurred in the context of severe
neurological disability, and it was not recorded as a reason
for discontinuation of the prescription in any of the cases.
There were six prescriptions for antidepressants for
agitation, in five patients with IPD treated at relatively

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early stages of disease, and treatment courses were long
(median5750.5 days). Only one (17%) was noted to have
apparent clinical benefit. Apparent adverse effects were
noted in two cases (33%): weight gain and headache. The
headache led to discontinuation of treatment.
Mood Disorder
Prevalence and Pathophysiology
Symptoms of mood disorder were noted in 41.6% of
patients at any stage of disease. Table 2 summarizes the
variation in prevalence across disease types.
In logistic regression analysis, female gender approached
significance as an independent predictor of mood
disorder at any stage (odds ratio51.68, p50.049), but
there were no other significant predictors (see the online
data supplement).
Phenomenology and Natural History
Some patients who were studied in the early stages of
disease had symptoms of low mood combined with typical
biological symptoms consistent with a “classical” de-
pressive illness. Patients in the early stages of vCJD were
often noted to have predominant symptoms of social
withdrawal, irritability, anxiety, and low mood. Patients in
the early to middle stages of disease were more commonly
noted to have emotional lability. Patients in these stages
were also often noted to have social withdrawal and
apathy, albeit in the context of deteriorating expressive
language and frontal executive function. Affective symp-
toms in patients in the late stages of disease could rarely be
characterized.
Suicidal ideation was noted in a few cases, all in the early
to middle stages of IPD. This varied from a patient with
minimal cognitive impairment making inquiries regarding
physician-assisted suicide to a patient with marked frontal
deficits voicing suicidal intent impulsively and with in-
congruous affect. Only one suicide attempt was identified
from the clinical case notes reviewed (a patient in the early
stages of IPD), and there were no completed suicides.
As shown in Figure 1, depressive symptoms were
observed at a similar rate across the range of functional
impairment until the very severely impaired range, where
they often could not be assessed. There was no significant
effect of MRC-PDRS score on the odds of depressive symp-
toms being present. Figure 1 also shows the severity of de-
pressive symptoms at the assessment following one at
which they were rated “often” or “always.” The symptoms
had improved in about 40% of cases, and in about 20% of
cases, symptoms could no longer be assessed because of
progression of the disease.
Pharmacological Treatment
A total of 45 prescriptions were written for antidepres-
sants for mood disorder (see Table 3). Most of these were
either in sCJD cases, where treatment courses tended to be
Am J Psychiatry 171:3, March 2014
TREATMENT IN PSYCHIATRY
shorter (median5111 days), or in IPD cases, where courses
were longer (median5565 days). Sixteen prescriptions
(36%) were noted to have apparent clinical benefit.
Apparent adverse effects were noted in four cases (9%):
agitation, sedation, weight gain, and a persistent un-
pleasant taste. None of these symptoms were severe, and
in only one case (unpleasant taste) did the symptom lead
to discontinuation.
Other Symptoms
Almost all symptoms noted could be classified into the
three groups described above, but a few others did occur.
Obsessive thoughts were reported in a handful of patients.
Compulsive or repetitive behaviors were included in
the agitated features group. One patient with IPD due to
D178N mutation had a diagnosis of obsessive-compulsive
disorder that predated onset of cognitive and neurological
symptoms by many years. A recurrent sensation of “déjà
vu” and a strong sensation of derealization were reported
by two patients in the very early stages of sCJD.
Symptoms at the Onset of Illness
Behavioral and psychiatric symptoms arising very early
in the disease course deserve particular attention. They are
used as specific diagnostic markers for vCJD; patients may
present to psychiatric services before they exhibit frank
evidence of neurological disease and may be given an
initial diagnosis of a primary psychiatric condition, as in
our case vignette. In our series, 44.5% of patients had
behavioral and psychiatric symptoms as part of their first
symptoms of the disease, but only in 8.8% were they the
only symptoms at this stage (see Table 2). This highlights
the importance of thorough assessment for neurologi-
cal symptoms and signs in patients presenting to psy-
chiatric services: the presence of neurological features
should prompt further investigation for an organic cause,
including prion disease and other neurodegenerative
conditions.
As expected, early behavioral and psychiatric symptoms
were particularly common in vCJD, with 92% of patients
having such symptoms at illness onset (and 24% having
only such symptoms at onset), and vCJD diagnosis was an
independent predictor of the presence of behavioral and
psychiatric symptoms at illness onset in logistic regression
analysis (odds ratio59.7, p50.01). However, as sCJD is far
more common than vCJD, most of the patients in the
series with behavioral and psychiatric symptoms at onset
had sCJD.
Analyzing sCJD patients separately using logistic re-
gression (with age at onset, gender, PRNP codon 129
genotype, and distribution of pathological signal change
on MR brain imaging as covariates), the presence of
behavioral and psychiatric symptoms at onset was in-
dependently predicted by younger age at onset (odds
ratio50.935 per year, p50.01), and no other strongly
ajp.psychiatryonline.org 271
TREATMENT IN PSYCHIATRY
significant predictors were found. In a study using pooled
data from a large number of published clinical cases,
Appleby et al. (10) also concluded that younger sCJD
patients were more likely to present with particular
symptoms, including affective symptoms and behavioral
disturbance.
These findings raise the possibility that the presence of
psychiatric symptoms at onset may (to some extent at
least) be a feature of prion disease in younger people, as
opposed to being primarily a feature of the vCJD
etiological disease type. As the presence of early psychi-
atric features is currently used as a criterion for diagnosing
vCJD (7), this may have important implications: if older
vCJD patients were less likely to exhibit this feature, it
would be more difficult to distinguish them from the more
numerous sCJD cases. This is of particular interest in the
context of the evolving vCJD epidemic in the United
Kingdom, where future patients presenting with longer
incubation periods will tend to be older.
Safety of Antipsychotics
The use of antipsychotic medication in patients with
dementia has been shown to be associated with a signif-
icant increase in mortality, partly explained by an excess of
cerebrovascular events (22, 31). It is important that we
consider whether the same risks exist in patients with
prion disease. Most antipsychotic treatment courses in our
patients were relatively short, principally because of the
rapid progression of disease. However, in an important
minority of patients (mostly with IPD), progression is
slower and treatment courses longer. Patients with prion
disease are also younger than the dementia population in
whom the risk has been demonstrated (the mean age of
patients treated with antipsychotics in our series was 51.2
years). The baseline risk of cerebrovascular disease is
therefore likely to be lower, and it seems likely that this
would reduce the risk of this type of adverse event.
However, our study was not powered to demonstrate
a small change against the very high background mortality
of a prion disease population, so a similar risk cannot be
ruled out.
Recommendations
Behavioral and psychiatric features are common in all
types of prion disease, and there is significant heteroge-
neity both within and between disease types. This should
inform clinical care, as these symptoms represent a signif-
icant burden of morbidity for patients and caregivers but
may easily go unreported and unrecognized unless clin-
icians are vigilant about them. The first step toward treat-
ing a symptom is to ask about it.
Most clinical features of prion disease result from the
irreversible loss of brain functions and do not resolve once
they have appeared. Our data show that behavioral and
psychiatric symptoms, in contrast, fluctuate and improve
272 ajp.psychiatryonline.org
in a substantial proportion of patients (in addition to many
in whom manifest symptoms are short-lived because of
rapid progression to akinetic mutism). This suggests that
improving these symptoms with pharmacological or other
interventions may be feasible, but also that improvement
may occur without any specific intervention. It is impor-
tant to bear this in mind when making decisions about
treatment, interpreting the apparent effects of treatments,
and designing clinical trials.
There has been no systematic study of nonpharmaco-
logical interventions for behavioral and psychiatric symp-
toms in prion disease, but from the case notes reviewed
for our study and our clinical experience more generally,
it is clear that such interventions play a vital role. The
involvement of suitably trained and experienced care-
givers and the care of patients in appropriate, calm, and
containing settings seem to be particularly valuable.
Providing full-time family caregivers with respite periods
can greatly reduce levels of caregiver stress, and this
should be offered if possible.
Although it is important to bear in mind that behavioral
and psychiatric symptoms may respond to nonpharmaco-
logical measures and may improve spontaneously, we feel
that there is a role for the judicious use of pharmacological
treatments in some patients.
For more severe psychotic symptoms or agitation, short
courses of antipsychotic medication appear to be effective
in some cases. These cases should be reviewed regularly,
and prescribers should be vigilant about adverse effects,
such as sedation and extrapyramidal dysfunction, although
in our experience adverse effects do not limit treatment
in most cases. Longer treatment courses in slowly pro-
gressive forms of prion disease should be avoided if pos-
sible, in light of the safety concerns discussed above, and
also because longer courses are not usually necessary.
Benzodiazepines may be an appropriate option in the later
stages of disease, where psychotic features often coexist
with significant neurological disability and other distressing
symptoms, such as myoclonus. Our limited experience of
using acetylcholinesterase inhibitors for psychotic symp-
toms in prion disease seems promising, but the numbers
are too small to allow any strong conclusions to be drawn.
The symptoms grouped as mood disorder above are
likely to include several distinct clinical presentations—
for example, patients in early disease stages who have
a coexisting depressive illness and patients with more
advanced dementia causing symptoms of emotional
lability, apathy, or social withdrawal. The former may
respond to standard treatments for depression, although
cognitive impairment may limit patients’ ability to partic-
ipate in standard talking therapies. Antidepressants may
have a role in both situations, and our experience suggests
that they are well tolerated in these patients.
It is important to note the limitations of the evidence
presented here: the data related to treatment of symptoms
is purely observational, the numbers are small, and the
Am J Psychiatry 171:3, March 2014

clinicians collecting the data were often the same people
making treatment decisions. Nevertheless, in the absence
of more definitive research, we hope our experience will
provide a starting point for clinicians making treatment
decisions with patients and caregivers and inspire further
research into these challenging and distressing clinical
features.
Received Nov. 23, 2012; revision received May 19, 2013; accepted
May 28, 2013 (doi: 10.1176/appi.ajp.2013.12111460). From the
National Health Service (NHS) National Prion Clinic, National Hospital
for Neurology and Neurosurgery, University College London Hospitals
NHS Foundation Trust, London; the NHS Highland Mental Health
Services, Argyll and Bute Hospital, Blarbuie Road, Lochgilphead,
Scotland; and the Medical Research Council (MRC) Prion Unit,
Department of Neurodegenerative Disease, University College Lon-
don Institute of Neurology, London. Address correspondence to Dr.
Mead (s.mead@prion.ucl.ac.uk).
Prof. Collinge is a director and shareholder of D-Gen Limited, an
academic spinout company working in the field of prion disease
diagnosis, decontamination, and therapeutics. The other authors
report no financial relationships with commercial interests.
Supported by the MRC and the Department of Health (England).
This research was undertaken at University College London Hospitals/
University College London, which received a proportion of funding
from the Department of Health’s National Institute for Health
Research Biomedical Research Centre’s funding scheme. The MRC
and the Department of Health funded the PRION-1 trial (G0400713).
The authors thank all the individuals, their carers, and their
families, who took part in the PRION-1 and Cohort studies, and U.K.
neurologists and the National CJD Research and Surveillance Unit for
referring patients. The authors gratefully acknowledge the contribu-
tion of current and past members of the National Prion Clinic,
particularly Drs. Harpreet Hyare, Steve Wroe, Tom Webb, Suvankar
Pal, Durre Siddique, Dilip Gajulapalli, Diego Kaski, and Christopher
Carswell. They also thank Ray Young and Richard Newton for
assistance with preparation of the figure and tables.
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MA, Stewart GE, Zeidler M, MacKenzie JM, Ironside JW, Summers
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8. Wall CA, Rummans TA, Aksamit AJ, Krahn LE, Pankratz VS:
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11. Korth C, May BC, Cohen FE, Prusiner SB: Acridine and pheno-
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Am J Psychiatry 171:3, March 2014
 Images in Psychiatry
When Affective Disorders Were Considered to Emanate From
the Heart: The Ebers Papyrus
A mong the oldest and most important medical papyri of
ancient Egypt, the Ebers Papyrus, contains a “book of hearts”
constituting a collection of extracts from different existing sources
dating as far back as 3400 B.C.E. The Ebers Papyrus was obtained
by Georg Ebers at Thebes in 1872. The papyrus was written in about
1500 B.C.E. in hieratic Egyptian writing and preserves for us the
most voluminous record of ancient Egyptian medicine known. In
the book, the unknown author notes three types of healers:
physicians, surgeons, and sorcerers. Among the medicines men-
tioned in the papyrus figure treatments such as pomade for
baldness, consisting of equal parts of lion, hippopotamus, crocodile,
serpent, and ibex fats. The manuscript describes a few mental
disorders as well as many organic diseases, mainly relating them to
different dysfunctions in the heart, which is “the center of the blood
supply with vessels attached for every member of the body” (1).
In the book’s chapter related to disorders and remedies of the
nervous system, no mention is made of any of the mental
disorders known in the contemporary medical nosology. How-
ever, in the book’s chapter on disorders of the heart and the
circulatory system, some of the conditions described in the
papyrus are believed to correspond to affective disorders. The
following quotations are taken from the papyrus as they were
translated to English by Cyril P. Bryan in 1930 (1):
When the heart is sad, behold it is the moroseness of the
heart, or the vessels of the heart are closed up in so far as they
are not recognizable under thy hand.
When the heart is miserable and is beside itself, behold it is
the breath of the heb-xer priest that causes it through the
hollow of his hand. It penetrates right down to the rectum in
such a manner that the heart comes forth and loses its way
under the disease.
When his heart is afflicted and has tasted sadness, behold
his heart is closed in and darkness is in his body because of
anger which is eating up his heart.
Am J Psychiatry 171:3, March 2014
In these passages, the author tends to relate the occurrence of
affective disorders to a dysfunction in the cardiovascular system.
While the contemporary medical community has related the
occurrence of affective disorders to dysfunctions in brain areas
such as the hippocampus, the amygdala, and the prefrontal
cortex, the medical literature points to the presence of a cross-
talk between affective and cardiovascular regulatory systems (2).
On one hand, affective disorders, such as major depressive
disorder, have been shown to be associated with an increased
risk of cardiovascular disease through direct biological mech-
anisms as well as many indirect influences related to the pa-
tient’s lifestyle, and on the other hand, patients already having
cardiovascular diseases have been found to be at a higher risk
of developing affective disorders (3). Accordingly, our Egyp-
tian ancestors were not completely wrong when they acciden-
tally assessed and treated the heart in patients with affective
disorders.
References
1. Bryan CP (translator): The Papyrus Ebers. London, Geoffrey Bles,
1930
2. Palazidou E: The neurobiology of depression. Br Med Bull 2012;
101:127–145
3. Chauvet-Gélinier JC, Trojak B, Vergès-Patois B, Cottin Y, Bonin B:
Review on depression and coronary heart disease. Arch Car-
diovasc Dis 2013; 106:103–110
RAMI BOU KHALIL, M.D.
SAMI RICHA, M.D., PH.D.
From the Department of Psychiatry, Saint Joseph University, Beirut;
the Psychiatric Hospital of the Cross, Jalledib, Lebanon; and the Depart-
ment of Psychiatry, Hotel Dieu de France, Beirut. Address correspon-
dence to Dr. Bou Khalil (ramiboukhalil@hotmail.com). Image accepted
for publication August 2013 (doi: 10.1176/appi.ajp.2013.13070860).
Photograph used by permission of University Library Leipzig,Leipzig,
Germany.
ajp.psychiatryonline.org 275
 Reviews and Overviews

Mechanisms of Psychiatric Illness

Emotion Dysregulation in Attention Deficit

Hyperactivity Disorder
Philip Shaw, M.B.B.Ch., Ph.D.
Argyris Stringaris, M.D., Ph.D.
Joel Nigg, Ph.D.
Ellen Leibenluft, M.D.
Although it has long been recognized that
many individuals with attention deficit
hyperactivity disorder (ADHD) also have
difficulties with emotion regulation, no
consensus has been reached on how to
conceptualize this clinically challenging
domain. The authors examine the current
literature using both quantitative and
qualitative methods. Three key findings
emerge. First, emotion dysregulation is
prevalent in ADHD throughout the lifespan
and is a major contributor to impairment.
Second, emotion dysregulation in ADHD
may arise from deficits in orienting toward,
recognizing, and/or allocating attention to
emotional stimuli; these deficits implicate
dysfunction within a striato-amygdalo-medial
prefrontal cortical network. Third, while
current treatments for ADHD often also
ameliorate emotion dysregulation, a fo-
cus on this combination of symptoms
reframes clinical questions and could
stimulate novel therapeutic approaches.
The authors then consider three models
to explain the overlap between emotion
dysregulation and ADHD: emotion dysre-
gulation and ADHD are correlated but
distinct dimensions; emotion dysregula-
tion is a core diagnostic feature of ADHD;
and the combination constitutes a noso-
logical entity distinct from both ADHD and
emotion dysregulation alone. The differing
predictions from each model can guide
research on the much-neglected popula-
tion of patients with ADHD and emotion
dysregulation.

(Am J Psychiatry 2014; 171:276–293)

I t has long been recognized that emotion dysregulation

is common in individuals with neurodevelopmental
disorders, including attention deficit hyperactivity disor-
der (ADHD). Indeed, in the early conceptualization of
ADHD as reflecting “minimal brain damage,” emotion
dysregulation was placed along with inattention among
the cardinal symptoms (1). Only with the publication of
DSM-III did emotional symptoms became an “associated
feature” rather than a diagnostic criterion of ADHD.
Renewed interest in this area makes timely a review of the
overlap of emotion dysregulation with ADHD, focusing on
prevalence, pathophysiology, and treatment.
In line with previous theorists, we define emotion reg-
ulation as an individual’s ability to modify an emotional
state so as to promote adaptive, goal-oriented behaviors
(2). It encompasses the processes that allow the individual
to select, attend to, and appraise emotionally arousing stim-
uli, and to do so flexibly. These processes trigger behavioral
and physiological responses that can be modulated in line
with goals. Emotion dysregulation arises when these adap-
tive processes are impaired, leading to behavior that defeats
the individual’s interests. It encompasses 1) emotional ex-
pressions and experiences that are excessive in relation
to social norms and are context inappropriate; 2) rapid,
poorly controlled shifts in emotion (lability); and 3) the
anomalous allocation of attention to emotional stimuli.
Here, we focus on the clinical expression of emotion dys-
regulation as irritability, which is often linked with re-
active aggression and temper outbursts (3–5).
Emotion dysregulation is a dimensional trait that is not
unique to ADHD; rather, it undercuts the traditional divide
between internalizing and externalizing diagnoses and,
indeed, may partly explain their high correlation (6). For
example, a study that contrasted 105 irritable, emotionally
dysregulated children with ADHD and 395 nonirritable
children with ADHD found higher rates not only of
oppositional defiant disorder but also of depression
and dysthymia in the group with irritability (7).
Emotion dysregulation is also not synonymous with any
single DSM-5 disorder. For example, of the three symptom
clusters in oppositional defiant disorder—angry/irritable
mood, defiant behavior, and vindictiveness—only the first
plausibly reflects dysregulated emotions (8). In its extreme
form, emotion dysregulation is likely to emerge as a major
etiological factor behind the frequent, severe temper out-
bursts and irritability of the new DSM-5 diagnosis of dis-
ruptive mood dysregulation disorder. However, emotion
dysregulation is a dimensional entity, not a categorical
diagnosis, and here we consider the full spectrum of emotion
dysregulation within ADHD, not just extremes. Thus, we

This article is featured in this month’s AJP Audio

276 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


include individuals with emotion dysregulation who do
not meet criteria for any DSM diagnoses beyond ADHD.
We focus on emotion dysregulation itself, rather than on
diagnoses that may include emotion dysregulation and be
comorbid with ADHD, because it is a simpler symptom
construct that is familiar to clinicians and, consistent with
the Research Domain Criteria initiative, may be more
readily tied to underlying neurobiological mechanisms.
Method
We conducted a literature search for relevant articles published
before January 1, 2013 (details of the search are available in the data
supplement that accompanies the online edition of this article). We
summarized data quantitatively where possible. Meta-analyses were
possible for studies of aggressive behavior (9–20), emotion recogni-
tion (12, 21–36), and delay aversion/reward valuation (35, 37–50). As
all the outcomes included in the meta-analysis were continuous, we
calculated standardized mean differences. We used a random-
effects model to generate a pooled effect size and confidence
intervals with the inverse variance method. The remaining studies
are reviewed qualitatively under the headings of prevalence,
pathophysiology, and treatment.
Results
Prevalence
Childhood. Most epidemiological research has focused on
children and has found a strong association between ADHD
and emotion dysregulation (35, 51–56) (Table 1). A popula-
tion study of 5,326 youths (51) found mood lability in 38% of
children with ADHD, ten times the population rate. Elevated
rates were observed in children without comorbid ADHD,
and similar rates were seen in children with noncomorbid
oppositional defiant disorder. Research on the Child Be-
havior Checklist “dysregulation profile” based on parent-
reported problems with mood and aggression in youths
who also have attention problems shows community rates
of 1%25%, compatible with high rates of emotion dysregu-
lation among those likely to have ADHD (62). Clinic-based
studies in youths with ADHD similarly report prevalence
estimates of emotion dysregulation between 24% and 50%.
Reactive aggression may reflect emotion dysregulation
(5). Our meta-analysis found consistent elevation in mea-
sures of aggressive behavior in ADHD compared with non-
ADHD populations, associated with a large effect size
(1.92, 95% CI=0.95–2.89) (Figure 1A). In the general pop-
ulation, the correlation is higher between aggression and
hyperactivity-impulsivity (0.60–0.83) than between aggres-
sion and inattention (0.20–0.56) (6). In clinical popula-
tions, emotion dysregulation is commonly associated with
either symptom domain (52, 56).
Notably, behaviors reflecting emotion dysregulation
can be reliably provoked among those with ADHD using
paradigms that induce frustration (see Table S1 in the
online data supplement). Children with ADHD show more
negative affect and temper outbursts than do comparison
Am J Psychiatry 171:3, March 2014
SHAW, STRINGARIS, NIGG, ET AL.
subjects during challenging tasks. This consistency among
studies is also notable, as different paradigms and behav-
ioral measures were employed.
Infancy and early childhood. Modest correlations (0.10–0.37)
are reported between difficult infantile temperamental
characteristics, such as being fussy, angry, or difficult
to control, and ADHD arising later in childhood (63–67)
(Figure 2; see also Table S2 in the online data supplement).
A longitudinal study of 7,140 children found that while
temperamental emotionality at age 3 predicted comorbid
ADHD and internalizing disorders at age 7, activity level
predicted comorbid ADHD and oppositional defiant dis-
order (68). A second longitudinal study found that infants
who developed hyperactive symptoms alone did not differ
temperamentally from typical infants, whereas those who
ultimately developed both ADHD and aggressive symptoms
were uncooperative and irritable from infancy onward (69).
In short, a difficult early temperament with prominent
negative emotionality is modestly linked with later ADHD
combined with emotion dysregulation.
Longitudinal studies. Most studies following children with
ADHD into adulthood have focused on DSM-IV diag-
noses, without considering emotion dysregulation per se,
and have found elevated rates of adult disruptive and
antisocial disorders and, less consistently, mood and
anxiety disorders (70). One study defined emotion dys-
regulation as a moderate elevation (one to two standard
deviations above the mean) on the combined Child Be-
havior Checklist subscales for attention problems, ag-
gressive behavior, and anxious/depressed (71). In that
study, such emotion dysregulation in 79 children with
ADHD was associated 4 years later with more psychiatric
comorbidities, greater social impairment, and ADHD per-
sistence, compared with 98 children with ADHD without
emotion dysregulation and 204 children without ADHD. A
population-based study of 2,076 children (72) found that
those matching the Child Behavior Checklist dysregula-
tion profile had higher rates of anxiety disorders and dis-
ruptive behavior disorders in adulthood compared with
those who did not match the dysregulation profile (72).
Adult studies. Earlier concepts of adult ADHD included
emotion dysregulation as a defining feature (73). This
model has been supported to some extent by recent
clinic-based studies reporting impairing emotion dys-
regulation in 34%270% of adults with ADHD (57–61),
although population-based studies are needed (Table 1).
Aggressive behaviors are also prominent. In a population
study contrasting 950 adults with diagnosed or likely
ADHD and 20,000 unaffected adults (57), the ADHD
group had higher self-ratings of interpersonal conflict
and negative, conflictual social ties. Other cross-sectional
studies have compared adults whose childhood ADHD
has remitted and those whose ADHD has persisted. In
one such comparison (58), 55 adults with persistent
ADHD showed higher rates of emotion dysregulation
ajp.psychiatryonline.org 277
EMOTION DYSREGULATION IN ADHD

TABLE 1. Prevalence Estimates of Emotion Dysregulation in Children and Adults With ADHDa
Definition of “Emotion
Study Participants Dysregulation” Impairment Criterion Findings
Children and adolescents
Stringaris and Population based; N=5326 Parent and self-report of Severity ratings of Parent rating of impairing
Goodman (51) emotional lability symptoms emotional lability: ADHD
occurring “a lot” alone, 38% (RRR=12
compared with
unaffected); ODD alone,
42% (RRR=14.7); self-
report: ADHD alone, 27%
(RRR=6.9); ODD alone,
14% (RRR=3.0)
Sobanski Family based; ADHD, Conners emotional lability index, 3 SD above population 25% of ADHD probands had
et al. (52) N=216; siblings, N=142 parent and teacher ratings of norms emotional lability .3 SD
unpredictable mood changes, above population norms
temper tantrums; tearfulness;
low frustration tolerance
Anastopoulos Family based; ADHD, Conners emotional lability index Above 65th Elevated levels: ADHD, 47%;
et al. (53) N=216; siblings, N=142 (see above) percentile of unaffected, 15%
population norms
Spencer Clinic based; ADHD, Parent report of “dysregulation Scores 1–2 SD above ADHD, 44% with
et al. (54) N=197; controls, N=224 profile” based on Child Behavior norms (above 2 SD, dysregulation profile;
Checklist subscales of attention considered bipolar controls, 2%
problems, anxiety/depression, phenotype and
and aggression excluded)
Sjöwall Clinic based; ADHD, N=102; Parent report of child’s ability to Not given ADHD showed significant
et al. (35) controls, N=102 regulate specific emotions impairment compared
with controls in regulating
all emotions
Strine Population based; history of Strength and Difficulties Parent rating of each Emotional problems: history
et al. (55) ADHD, N=512; no history Questionnaire, parent report symptom’s impact of ADHD, 23%; no history
of ADHD, N=8,169 of emotional and conduct of ADHD, 6.3%
problems, including: often
loses temper, often unhappy
(also clingy, fearful, somatic
complaints, and having worries)
Becker Clinic based; ADHD, Strength and Difficulties Based on U.K. 40% of boys and 49% of
et al. (56) N=1,450 Questionnaire, parent report population norms girls had abnormally
of emotional problems (see high levels of emotional
above) problems
Adult studies
Able et al. (57) Population based (N=21,000); Self-report of tendency to become Not given Both diagnosed and likely
diagnosed ADHD, N=198; angry, disagree, or be critical ADHD subjects more likely
likely ADHD (based on of others; self-report of degree to express anger, to
self-report scale), N=752; to which others evoke feelings engage in conflict, and
controls, N=199 of anger to have been the target
of anger or intimidating
behavior
Barkley and Clinic based; ADHD, N=55; Self-report of items reflecting Symptom occurs “often” Impatient: ADHD, 72%;
Fischer (58) controls, N=75 emotional impulsivity (taken controls, 3%; quick to
from the Behavior Rating of anger: ADHD, 65%;
Executive Functioning) controls, 6%; easily
frustrated: ADHD, 85%;
controls, 7%; emotionally
overexcitable: ADHD, 70%;
controls, 6%; easily
excitable: ADHD, 73%;
controls, 14%
Reimherr Clinic based; ADHD, N=536 Self-report of items from the 2 SD above population 32% met criteria for
et al. (59) (enrolled in treatment Wender-Reimherr Adult norms emotion dysregulation
trials) Attention Disorder Rating
Scale: irritability and outbursts;
short, unpredictable mood shifts;
emotional overreactivity
Reimherr Clinic based; ADHD, N=47 Wender-Reimherr Adult 2 SD above population 78% met criteria for
et al. (60) (enrolled in treatment trial) Attention Disorder Rating norms emotion dysregulation
Scale (see above)
continued

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 SHAW, STRINGARIS, NIGG, ET AL.

TABLE 1. Prevalence Estimates of Emotion Dysregulation in Children and Adults With ADHDa (continued)
Definition of “Emotion
Study Participants Dysregulation” Impairment Criterion Findings
Adult studies
Surman Clinic based; ADHD, N=206; Barkley’s self-report scale: quick Above 95th Met criteria for emotion
et al. (61) controls, N=123 to anger, loses temper, percentile on dysregulation:
argumentative, angry; easily population norms ADHD, 55%; controls, 3%
frustrated, touchy; overreactive
emotionally, easily excited
a
ADHD=attention deficit hyperactivity disorder; ODD=oppositional defiant disorder; RRR=relative risk ratio.

(42%272%, depending on specific symptoms) than 80
adults with remitted ADHD (23%245%), although both
groups differed from healthy subjects. This suggests a
degree of developmental coherence: as symptoms of
ADHD improve, so may emotion dysregulation.
Impairment. The combination of ADHD and emotion
dysregulation represents a major source of impairment.
In a study of 1,500 children (74), emotional problems
were found to have a greater impact than hyperactivity
and inattention on well-being and self-esteem. Individ-
uals with ADHD and emotion dysregulation were sig-
nificantly more impaired in peer relationships, family
life, occupational attainment, and academic perfor-
mance than those with ADHD alone (75), and this result
held after controlling for comorbid disorders, including
oppositional defiant disorder (76).
In summary, emotion dysregulation is found in some
25%245% of children and 30%270% of adults with
ADHD. It represents a major source of impairment and
presages a poor clinical outcome.
Pathophysiology
Several psychological and neural processes may un-
derpin the overlap between ADHD and emotion dysreg-
ulation. Recent models describe both “bottom-up”
processes that support or influence emotion regulation
and “top-down” processes, such as the allocation of
attention to emotionally arousing stimuli (77, 78). Most
studies reviewed in this section have either excluded
individuals with comorbid diagnoses (including opposi-
tional defiant disorder) or controlled for comorbidities,
ensuring that the anomalies pertain to ADHD rather than
to other disorders (Table 2).
Bottom-up psychological mechanisms. Two basic processes
affect emotion regulation: orienting to emotionally salient
stimuli, and the evaluation of signals for reward. In order for
emotion to be regulated, posterior attention systems must
both detect salient stimuli and signal that control is
needed (77, 90). Evidence suggests anomalies in early
orienting to emotional stimuli in ADHD. In healthy
individuals, affectively charged stimuli receive enhanced
early sensory encoding, detectable by electrophysiological
markers. Two studies (91, 92) found that this effect is
reduced in adults with ADHD when viewing positive, but
not negative stimuli; this would be expected to cause
overperception of negative stimuli. The studies further
linked these early processing deficits with self-rated emo-
tional lability. Additionally, whereas the startle reflex is
typically accentuated by precursive positive stimuli and
attenuated by negative stimuli, this effect is lost in adults
with ADHD, which constitutes further evidence of abnor-
mal early processing of emotional stimuli in ADHD (93).
Likewise, the rapid and accurate recognition of emotions
in human faces or voices is central to well-regulated
behavior; emotional misperception is linked with aberrant
emotional responses, and misperception can itself result
from emotion dysregulation (94, 95). Studies of emotion
labeling have found moderate impairments in ADHD, with
our meta-analysis producing an effect size of 0.65 (95%
CI=0.48–0.81) (Figure 1B).
The evaluation of emotionally salient stimuli has also
been studied in relation to the evaluation of signals for
potential reward. A preference for immediate small re-
wards over larger delayed ones, even when such choice
defeats one’s own goals and desires, is held to be a hall-
mark of impulsivity, reflecting an aversion to delayed
reward (96, 97). Our meta-analysis found that ADHD was
also moderately associated with this preference (effect
size, 0.6, 95% CI=0.40–0.79), albeit with considerable
heterogeneity in results (35, 37) (Figure 1C). This style of
reward processing can be construed as a contributor to
emotion dysregulation, as it may reflect anomalous
activity in limbic regions that are pivotal in emotion
processing. Equally, the preference for immediate
small rewards might also reflect failures in top-down
regulatory mechanisms, such as the ability to hold longer-
term goals in mind or to exert cognitive control to suppress
the arousing value of immediate incentives (78, 98, 99).
Thus, anomalies in reward evaluation provide further,
albeit indirect, evidence for dysregulation of emotion
systems in ADHD.
Top-down regulatory processes. Parasympathetic response
is considered one gauge of regulatory functioning (100). In
typically developing children, autonomic nervous system
function tracks the valence of emotional stimuli and task
demands, with greater top-down regulatory activity when
stimuli are negative rather than positive (100). In children
with ADHD, this ability to adjust top-down regulation in
response to different emotional stimuli was partially lost,
based on physiological indicators of regulation.

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EMOTION DYSREGULATION IN ADHD

FIGURE 1. Forest Plots With Standardized Mean Difference Between ADHD and Comparison Groups in Measures of
Aggression, Emotion Recognition, and Reward Processinga
A. Aggression B. Emotion Recognition
Study or Subgroup SMDb Study or Subgroup SMDb
Abikoff (boys) (9) Yuill (31)
Abikoff (girls) (9) Corbett (30)
Matthys (16) Malisza (29)
Ohan (17) Da Fonseca (28)
Greene (15) Boakes (21)
Mikami (girls) (11) Cadesky (12)
Mikami (boys) (11) Seymour (32)
Buhrmester (14) Shin (27)
Zalecki (combined) (18) Rapport (23)
King (19) Dyck (25)
McQuade (13) Pelc (26)
Cadesky (12) Downs (33)
Zalecki (inattentive) (18) Greenbaum (34)
Hoza (10) Sjöwall (boys) (35)
Waschbusch (20) Sjöwall (girls) (35)
Total (95% CI) Sinzig (22)
–4 –2 0 2 4 Miller (inattentive) (36)
ADHD aggression Herpertz (24)
Heterogeneity: tau2=3.61; χ2=1652.89, df=14 (p<0.00001); I2=99% Miller (combined) (36)
Test for overall effect: Z=3.87 (p=0.0001) Total (95% CI)
–2 –1 0 1 2
ADHD impaired
Heterogeneity: tau2=0.06; χ2=32.53, df=18 (p=0.02); I2=45%
Test for overall effect: Z=7.47 (p=0.00001)

C. Reward Processing
Study or Subgroup SMDb
Plichta (38)
Kuntsi (44)
Marx (adult) (46)
Solanto (48)
Dalen (42)
Marco (child) (45)
Antrop (39)
Marx (child) (46)
Vloet (49)
Bitsakou (child) (41)
Marco (adolescent) (45)
Marx (adolescent) (46)
Yang (50)
Banaschewski (37)
Karalunas (43)
Sjöwall (boys) (35)
Bitsakou (adolescent) (41)
Bidwell (40)
Solanto (inattentive) (47)
Solanto (combined) (47)
Sjöwall (girls) (35)
Total (95% CI)
–2 –1 0 1 2
Heterogeneity: tau2=0.15; χ2=103.43, df=20 (p<0.00001); I2=81%
Test for overall effect: Z=6.03 (p=0.00001)

a
In panel A, more aggressive behavior is seen in the ADHD groups (the effect size for boys in the Abikoff study [9] was 14). In panel B, emotion
recognition deficits are seen in ADHD. In panel C, reward processing is measured by the tendency to prefer immediate small rewards over
larger delayed ones; the ADHD participants show a tendency to prefer immediate, small rewards. Further details are provided in the online
data supplement.
b
SMD=standardized mean difference, inverse variance, random effects, with 95% confidence intervals.

Another way to assess the recruitment of regulatory the ability to direct attention toward or away from emo-
resources is to consider the allocation of attention itself to tional stimuli so as to maintain emotional homeostasis or
emotional stimuli. Just as emotion regulation requires the maintain focus on a goal (101). This ability can be assessed
ability to recruit autonomic responses, it also relies on by incorporating an affective dimension in a cognitive

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 SHAW, STRINGARIS, NIGG, ET AL.

FIGURE 2. Correlations Between Infantile Temperament and Later Externalizing and ADHD Symptomsa

Study Author Design Early Temperament Correlation Outcome

Goldsmith Longitudinal Anger (infancy) 0.14 * ADHD symptoms (age 4)

et al. (64)
High approach (infancy) 0.19 * ADHD symptoms (age 4)

Bates Longitudinal Resistance to control (6 months) 0.30 ** Externalizing symptoms (age 8)

et al. (65)

Bates Mixed design Resistance to control (6 months) 0.32 ** Externalizing symptoms (age 8)
et al. (65)

Carlson Longitudinal Infant adaptability (3 months) 0.10 (n.s.) Hyperactivity (age 8)

et al. (66)
0.06 (n.s.) Hyperactivity (age 11)

Olson Longitudinal Fussy/difficult (6 months) 0.01 (n.s.) Behavioral control (age 8)

et al. (67)
0.15 (n.s.) Inhibitory control (age 8)

a
n.s.=not significant.
*p,0.05. **p,0.01.

paradigm. For example, in the emotional Stroop task,
individuals must deflect attention away from the emo-
tional properties, such as emotional expression, and at-
tend to a nonemotional feature, such as eye color. This
manipulation exacerbates the performance deficits al-
ready evident in ADHD, suggesting that performance
drops off more steeply than it does in typical individuals
under emotional challenge (87, 89).
Finally, given that ADHD is associated with poor higher-
order cognitive control even in the absence of emotionally
salient stimuli, what role does poor cognitive control play
in emotion dysregulation in ADHD? Evidence suggests
a modest connection but not isomorphism. For example,
in 49 boys with and without ADHD, cognitive control,
indexed by response inhibition, accounted for 11% of the
variance in “dysregulated” behavior during a frustrating
task (102). A larger study of 424 children with ADHD and
their siblings (37) found that while a range of neuro-
psychological variables correlated with emotional lability,
this link was not direct but was mediated almost entirely
by the severity of ADHD symptoms.
In summary, emotion dysregulation in ADHD may
arise from deficits at multiple levels. At the most basic
level, there are anomalies in orienting to emotional stimuli
and reward valuation. This is combined with failings in top-
down psychological processes, such as the allocation
of attention to emotional stimuli. Meanwhile, deficits
in cognitive processes, including working memory and
response inhibition, may contribute to emotion dysregu-
lation, but by themselves they do not seem to explain its
presence in ADHD.
Neural mechanisms. It is useful to distinguish between
regions mediating bottom-up responses to emotional
stimuli—specifically the amygdala, ventral striatum, and
orbitofrontal cortex—and top-down cortical regions con-
trolling the allocation of attentional resources in emotionally
arousing contexts (77, 103). In ADHD, functional imag-
ing studies have yielded disparate findings, possibly
because of differences in tasks and sample characteristics
and limited power to detect effects in smaller studies,
but nonetheless some themes emerge (Table 2 and
Figure 3).
Amygdala activation during emotion processing in
ADHD has received some research attention. The larger
studies find amygdala hyperactivation in ADHD, during
both the subliminal perception of fearful expressions and
while subjects rated their fear of neutral faces, although
results are mixed (24, 29, 79–82) (Table 2; see also the
online data supplement). Amygdala hyperactivation has
also been reported in ADHD during the processing of
delayed rewards, perhaps consistent with the delay
aversion found in some behavioral studies (38, 83–85).
Deficits in early processing of visual emotional stimuli and
in the modulation of the startle reflex, described above, also
suggest amygdala dysfunction in ADHD. These functional

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EMOTION DYSREGULATION IN ADHD
TABLE 2. Summary of Functional MRI Studies of Emotion Perception, Reward Processing, and the Allocation of Attention
to Emotional Stimulia
Study Participants
Emotion perception and recognition
Brotman ADHD with no comorbidity,
et al. (79) N=18; severe mood
dysregulation, N=29 (24 with
ADHD); bipolar affective
disorder, N=43 (20 with
ADHD); healthy, N=37
Marsh ADHD with no comorbidity,
et al. (80) N=12; callous-unemotional
traits, N=12; healthy, N=12
Posner ADHD, N=15 (mix of
et al. (81) medication
naive and receiving
psychostimulants; some
had ODD, although the
number is unclear);
healthy, N=15
Herpertz ADHD without comorbidity,
et al. (24) N=13; conduct disorder,
N=22 (16 with ADHD);
healthy, N=22
Schlochtermeier Adults treated in childhood
et al. (82) for ADHD with no
comorbidity, N=10; adults
with childhood ADHD,
medication naive, N=10;
healthy, N=10
Malisza ADHD, N=9; autism, N=9;
et al. (29) healthy, N=9
Reward processing
Ströhle Adult ADHD without
et al. (83) comorbidity, N=10;
controls, N=10
Plichta Adult ADHD without
et al. (38) comorbidity, N=14;
controls, N=12
Scheres Adolescent ADHD, N=11;
et al. (84) controls, N=11
Stoy et al. (85) Adult ADHD, N=24 (analyzed
as remitted versus persistent,
and as history of childhood
treatment with
psychostimulants versus
medication naive);
controls, N=12
282 ajp.psychiatryonline.org
Task Behavioral results fMRI results
Rating of fear, nose width, Rating of fear in neutral Left amygdala activity
and passive viewing of faces: severe mood during fear ratings: ADHD
neutral, fearful, happy, dysregulation = bipolar . healthy = bipolar .
and angry faces . healthy; ADHD did not severe mood
differ from any group dysregulation
Gender judgments No group differences in Amygdala activity in ADHD
on fearful, neutral, accuracy; ADHD had during fear processing
and angry faces slower reaction times did not differ from healthy
Subliminal presentation No group differences Greater activity in
of fearful face followed medication-naive ADHD
by supraliminal in amygdala and stronger
presentation of neutral functional connectivity
expression on the same with lateral prefrontal
face; postscan face cortex (BA47)
memory test
Passive viewing of Subjects with conduct Increased left amygdala
negative, positive, disorder rated emotional activation in conduct
and neutral scenes pictures as less arousing disorder with ADHD,
than did other groups not ADHD alone; ADHD
alone had decreased
insula activation to
negative faces
Rating of positive and Adults with ADHD treated Decreased ventral striatum
negative pictures in childhood rated and subgenual cingulate
neutral pictures as more activation in medication-
pleasant than medication naive adults with history
naive and healthy subjects of ADHD; ADHD treated
in childhood did not
differ from healthy
View happy and angry Accuracy: autism ADHD had less fusiform,
faces and respond to , ADHD = healthy temporal poles activity
happy than healthy; ADHD
showed same amygdala
activity as healthy;
autism showed less
amygdala activity than
other two groups
Monetary incentive delay No group differences Decreased ventral striatum
activation in ADHD
during reward
anticipation, and
increased orbitofrontal
activation during
reward receipt
Delayed discounting task No group differences Decreased ventral striatum
(choose between activation in ADHD
immediate during processing of
small and delayed both immediate and
large rewards) delayed rewards; within
subjects, delayed reward
in ADHD associated with
increased activity of
amygdala and caudate
Monetary incentive delay No group differences Decreased ventral striatal
activity in ADHD during
reward anticipation
Monetary incentive delay No group differences Decreased insula activation
during outcome of loss
avoidance in medication-
naive adults compared
with other groups
continued
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 SHAW, STRINGARIS, NIGG, ET AL.

TABLE 2. Summary of Functional MRI Studies of Emotion Perception, Reward Processing, and the Allocation of Attention
to Emotional Stimulia (continued)
Study Participants
Reward processing
Rubia Childhood ADHD on and
et al. (86) off psychostimulants,
N=13 (1 with comorbid
ODD); healthy, N=13
Control of attention to emotional stimuli
Passarotti Adolescent ADHD without
et al. (87) comorbidity (N=14);
bipolar disorder, N=23;
healthy, N=19
Passarotti Adolescent ADHD without
et al. (88) comorbidity (N=15); bipolar
disorder, N=17;
healthy, N=15
Posner Adolescent ADHD, on and
et al. (89) off psychostimulants,
N=15; healthy, N=15
a
ADHD=attention deficit hyperactivity disorder; ODD=oppositional defiant disorder.
Task
Rewarded continuous
performance task
Working memory task
using angry, happy,
and neutral faces
Emotional Stroop test
Emotional Stroop test
Behavioral results fMRI results
No difference between Unmedicated ADHD showed
medicated ADHD and orbitofrontal
healthy; trend to worse hyperactivation during
performance in reward receipt,
unmedicated ADHD normalized by
psychostimulants
Accuracy: healthy . ADHD compared with
ADHD . bipolar healthy: decreased
prefrontal and striatal
activation to angry faces,
increased to happy;
ADHD compared with
bipolar: similar cortical
anomalies, more
prominent subcortical
anomalies in bipolar
Bipolar and ADHD slower For negative versus neutral
than healthy; more words: gradient of
interference from ventrolateral prefrontal
positive distractors in cortical activation: ADHD
bipolar and from , healthy , bipolar; both
negative distractors ADHD and bipolar showed
in ADHD more dorsolateral
prefrontal and parietal
activation than healthy
Medication-free ADHD
showed medial
prefrontal hyperactivity
with positive and
hypoactivity with
negative distractors;
normalized on
psychostimulants

deficits align with reports of amygdala structural abnormali-
ties in ADHD, including surface morphology and dopamine
receptor density (104).
The orbitofrontal cortex, which has rich interconnec-
tions with the amygdala, the thalamus, and multiple
cortical regions, is pivotal in emotion regulation and re-
ward representations (77, 105). Some data suggest orbito-
frontal anatomic anomalies (106) and abnormal activation
during the anticipation and receipt of rewards in ADHD.
There is also decreased connectivity between the amyg-
dala and the orbitofrontal cortex, reflected in a loss of the
typical correlation between the volumes of these struc-
tures (104).
The ventral striatum is the third important hub in the
bottom-up circuitry, partly by virtue of its role in mediat-
ing positive affect and reward processing (107). Functional
neuroimaging studies find reduced ventral striatum re-
sponsiveness in ADHD during the anticipation (and re-
ceipt) of rewards, thus contributing to aversion to delay
(Table 2). By examining brain activity at rest in ADHD, two
groups have reported both increased functional connectiv-
ity between the ventral striatum and the orbitofrontal/
ventromedial prefrontal cortex and decreased connectivity
between these regions and cortical attentional control
regions (108, 109). Thus, evidence suggests dysfunction in
a network encompassing the amygdala, ventral striatum,
and orbitofrontal cortex that processes emotional stimuli
and is implicated in emotion regulation.
With regard to cortical regions, in healthy subjects the
addition of an emotional dimension to cognitive tasks
usually boosts top-down prefrontal cortical activation
(particularly in ventrolateral, medial prefrontal, and
anterior cingulate cortical regions) and diminishes sub-
cortical activity (77). These patterns are partly lost in
ADHD. Specifically, when negative stimuli are added to a
working memory task, performance deficits in ADHD
are associated with hypoactivation in prefrontal control
regions, including the ventrolateral, orbitofrontal, and
medial prefrontal cortices. However, when positive
stimuli are used, ADHD patients show hyperactivation
in these regions (87). Similarly, two independent studies
using the emotional Stroop task (88, 89) found hypoacti-
vation in ADHD in the right medial and ventrolateral
prefrontal cortex while processing negative distractors but
hyperactivation in the left medial prefrontal cortex while
processing positive distractors. Such work represents the

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EMOTION DYSREGULATION IN ADHD
FIGURE 3. Neural Circuits Implicated in Emotion Dysregulation in ADHDa
C
l PF
ra
te
ola
rs
Do
al
M edi
VL
PF
pOFC
C
a
The circuitry that underpins deficits in early orienting to emotional stimuli and their perception is shown in red. Regions that interface
between emotional and cognitive circuits, allocating attention to emotional stimuli, are shown in yellow. Circuitry implicated in cognitive
control, motor planning, and attention is shown in blue. ACC=anterior cingulate cortex; pOFC=posterior orbitofrontal cortex; PFC=prefrontal
cortex; VLPFC=ventrolateral prefrontal cortex.
first stage in charting the neural basis of dysregulated
attentional control in ADHD in the presence of emotional
stimuli.
In summary, emotion dysregulation in ADHD impli-
cates dysfunction in the amygdala, ventral striatum, and
orbitofrontal cortex, which could be regarded as the
bottom-up contributor. Regions at the interface of cog-
nition and emotion (the medial and ventrolateral pre-
frontal cortex) may underpin the abnormal allocation
of attention to emotional stimuli and could thus
be regarded as the major top-down contributor to
emotion dysregulation in ADHD (Figure 2). Higher
cortical centers involved in motor control (supplemen-
tary motor areas, motor cortex), monitoring for salient
stimuli (temporoparietal junction, frontal operculum),
and shifting attention flexibly (frontal eye fields, intra-
parietal sulcus) may play a less direct role (110). The exact
balance of symptoms stemming from ADHD and emotion
dysregulation in an individual may depend on the degree
to which each neural network or level is compromised. We
predict that dysfunction at the cortical nexus between
cognition and emotion (the medial and ventrolateral
prefrontal cortex) is strongly associated with symptoms
of both ADHD and emotion dysregulation. If, however, an
individual has dysfunction that is more focused in higher,
more lateral prefrontal/parietal cortical regions, then in
that individual symptoms of ADHD such as inattention
284 ajp.psychiatryonline.org
Parie
tal Co
rtex
C
/AC
PFC
Ventral
Striatum Early
Visual
Regions
ala
ygd
Am
would predominate over emotion dysregulation. Con-
versely, an individual with predominantly (para)limbic
dysfunction may exhibit mainly symptoms stemming
from emotion dysregulation.
Etiological factors. It has been proposed that the combi-
nation of ADHD and emotion dysregulation defines a
distinct genetic group. In support of this view, one group
found that the siblings of probands with both ADHD and
emotion dysregulation also had significantly elevated rates
of this combination, although this has not been replicated
(52, 111, 112). The Child Behavior Checklist-defined dys-
regulation profile is highly heritable (67%) (113), and stud-
ies have suggested candidate genes (114).
Among possible environmental factors, high levels of
parental criticism and hostility have been linked both with
the development of conduct problems in children with
ADHD and with the development of childhood ADHD in
preschoolers with behavioral problems (115, 116). A
plausible hypothesis is that failures of parental emotion
regulation, reflected by high expressed hostility, contrib-
ute to the development of emotion dysregulation in
children with ADHD.
Treatment
The management of emotion dysregulation in ADHD
presents formidable therapeutic challenges, partly be-
cause clinical trials in ADHD either fail to assess change in
Am J Psychiatry 171:3, March 2014

emotion regulation or do so as a secondary outcome
measure. Psychostimulants are highly effective in treat-
ing oppositional defiant disorder comorbid with ADHD
(meta-analyses are available at http://www.nice.org.uk/
CG72). However, evidence for psychostimulant effi-
cacy in treating emotion dysregulation in ADHD is
more limited (Table 3). A review found that two
randomized placebo-controlled studies in children with
ADHD reported that psychostimulants reduced emotional
lability and irritability (127). In adults, several studies found
that the beneficial effects of psychostimulants on emotion
dysregulation parallel the improvement seen in hyperac-
tivity and impulsivity. However, two randomized con-
trolled trials comparing amphetamine and placebo found
no beneficial medication impact on a broad range of
emotional problems, and some studies have found that
amphetamine preparations increase irritability and la-
bility (127).
Among individuals with ADHD, psychostimulants also
improve emotion recognition (91) and normalize both the
startle modulation by affective stimuli (93) and perfor-
mance on the emotional Stroop task (89). This behavioral
normalization is accompanied by normalization of un-
derlying neural activity (89, 91, 93).
Among the non-stimulant treatments, improvement of
emotion regulation on atomoxetine paralleled improve-
ment in core symptoms of ADHD among adults (59). Mood
stabilizers have yielded mixed results. A trial of lithium for
children with severe mood dysregulation, most of whom
had ADHD, was negative (128). However, a comparison of
behavioral therapy combined with either divalproex or
stimulants found that the use of divalproex was more
efficacious in children with severe aggressive behavior,
most of whom also had ADHD (129). Another study found
that among 30 children with ADHD whose aggression
did not respond to open-label psychostimulant treat-
ment and behavioral therapy, the addition of divalproex
resulted in significantly higher rates of remission com-
pared with placebo (130). The use of atypical antipsychotic
medications for the combination of ADHD, emotion dys-
regulation, and aggression still lacks a clear evidence
base.
While cognitive and behavioral psychotherapies have
a limited impact on core symptoms of ADHD, there is
preliminary evidence that interventions that specifically
target emotion dysregulation are efficacious (131, 132). We
consider such interventions to be a promising future direc-
tion for research.
The current literature suggests the following treat-
ment approach. Psychostimulant treatment of the core
symptoms of ADHD is often linked to a beneficial effect
on emotion dysregulation and should be considered
first-line treatment. Atomoxetine also appears effective
for symptoms of ADHD and emotion dysregulation. Use
of adjunctive behavioral modification in children is
reasonable, as this combination is effective in those with
Am J Psychiatry 171:3, March 2014
SHAW, STRINGARIS, NIGG, ET AL.
mixed internalizing and externalizing symptoms, many
of whom have emotional dysregulation (51, 133). Group-
based psychotherapy in adults with ADHD to bolster
emotion regulation skills shows promise but requires
replication (132). Lacking an evidence base for second-
line pharmacological approaches to emotion dysregula-
tion in ADHD, treatment will be guided largely by the
presence of comorbid disorders. For example, for
patients with ADHD and depression, in whom emotion
dysregulation is often prominent, use of serotonin re-
uptake inhibitors combined with psychostimulants is
reasonable (134).
Conceptual Models
Three models have been proposed, whose proponents
can be characterized as “lumpers,” who view emotion
dysregulation as an integral component of ADHD; “split-
ters,” who view the combination as defining a distinct
entity; and “diplomats,” who view symptoms of ADHD
and emotion dysregulation as correlated but ultimately
dissociable dimensions (Table 4). The current evidence is
insufficient to choose decisively among these models,
partly because few studies have been designed to
address specifically the question of why emotion dysreg-
ulation is so prominent in ADHD. However, this frame-
work generates testable hypotheses that can stimulate
future research.
The first model, which harks back to earlier conceptu-
alizations of ADHD, posits that emotion dysregulation is
a core defining feature of ADHD that is as central to the
disorder as hyperactivity, impulsivity, and inattention (135).
Emotion dysregulation is seen as an expression of the same
neurocognitive deficits that underpin other symptoms of
ADHD, and Occam’s razor dictates that it is unnecessary to
invoke additional emotion processing deficits. The model
is parsimonious and recognizes the close associations be-
tween cognitive and emotional regulation systems. However,
as noted above, the overlap between ADHD and emotion
dysregulation is far from complete: many ADHD pa-
tients do not exhibit impairing levels of emotion dysreg-
ulation (55%275% of children and 30%270% of adults
with ADHD). Additionally, the evidence for widespread
(para)limbic dysfunction in ADHD and associated def-
icits in emotional processes might argue against a re-
ductionist model of emotion dysregulation in ADHD as
another expression of purely cortico-striatal-cerebellar
dysfunction. This model also predicts that treatments
that ameliorate core symptoms would have an almost
equal impact on emotion dysregulation, which seems to
occur in adulthood but does so less clearly in childhood.
The second model holds that the combination of
ADHD and emotion dysregulation defines a distinct en-
tity (111, 112). This model has been generated largely on
the basis of genetic findings of familial cosegregation of
ADHD and emotion dysregulation, although evidence on
this point is mixed (52, 111). This model could imply both
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EMOTION DYSREGULATION IN ADHD

TABLE 3. Randomized Controlled Treatment Studies in Children and Adults With ADHD in Which Change in Measures
Reflecting Emotion Dysregulation Was Measureda
Study Participants
Children
Childress Lisdexamphetamine versus placebo
et al. (117) for 4 weeks, N=283; at baseline
179 had prominent emotional
lability
Ahmann Crossover design; treated with
et al. (118) placebo or low-dosage (0.3 mg/kg)
and higher-dosage (0.5 mg/kg)
methylphenidate; N=234
Gillberg Amphetamine versus placebo
et al. (119) for 6 months, N=56
Kratochvil Atomoxetine versus placebo,
et al. (120) for 8 weeks, N=179
Coghill et al. (121) Crossover methylphenidate
0.3 mg/kg and 0.6 mg/kg
versus placebo for 12 weeks,
N=75
Herbert et al. (122) Randomized to waiting list or
parent training to boost child’s
emotion regulation and
socialization, N=31
Webster-Stratton Randomized to waiting list or
et al. (123) parenting program boosting
positive and consistent
parenting style, N=99
Adults
Reimherr Crossover trial of extended-release
et al. (60) methylphenidate versus placebo
(4 weeks each arm), N=47
Reimherr Post hoc analyses of trials comparing
et al. (59) atomoxetine and placebo;
ADHD only, N=359; ADHD and
emotion dysregulation, N=170
Marchant Crossover trial of transdermal
et al. (124) methylphenidate versus placebo
(4 weeks each arm); ADHD alone,
N=21; ADHD and emotion
dysregulation, N=28; ADHD and
oppositional defiant disorder, N=9;
ADHD, oppositional defiant
disorder, and emotion
dysregulation, N=32
Rösler et al. (125) Methylphenidate versus
placebo with 24-week
double-blind phase, N=363
Emilsson Cognitive behavioral therapy and
et al. (126) medication versus medication
alone, N=54
a
All medication studies were randomized, placebo-controlled, double-blind trials.
Measures
Conners Parent Rating Scale of emotional For those with prominent
lability (angry/resentful, losing temper, emotional lability, medication
and irritability); prominent emotional
lability defined as having at least one
symptom “pretty much” or “very much”
Side effect questionnaire including items Decreased irritability on
on dysthymia, euphoria, irritability,
and anxiety
Side effect questionnaire including
items on dysthymia, euphoria,
irritability, and anxiety
Emotion and Expression Scale
for Children
Conners’ emotional lability subscale
Emotion Regulation Checklist
Emotion regulation scale
Wender-Reimherr adult ADHD scale,
emotion dysregulation items
Wender-Reimherr adult ADHD scale,
emotion dysregulation items
Wender-Reimherr adult ADHD scale,
emotion dysregulation items
Wender-Reimherr adult ADHD scale,
emotion dysregulation items
Self-report scale of emotional control
Results
was associated with a significant
reduction in emotional
symptoms; no change in
emotionality seen in those
with low emotional lability
methylphenidate (odds
ratio=0.33, 95% CI=0.18–0.61)
No differences between treated
and placebo groups
No difference between
atomoxetine and placebo
Significant reduction in
emotional lability for both
low-dosage (parent-report
effect size, 0.46; teacher-report
effect size, 0.45) and
high-dosage methylphenidate
(parent-report effect size, 0.42;
teacher-report effect size, 0.79)
Parent training linked with
moderate reduction of child’s
emotional lability (effect size,
0.27–0.45).
Moderate effect of intervention
on emotion regulation
(effect size, 0.25)
Decrease in emotion dysregulation
on methylphenidate (effect
size, 0.7)
Decrease in emotion dysregulation
on atomoxetine (effect size, 0.66)
All groups showed benefit on
psychostimulants; trend for
those with emotion
dysregulation to improve most
Methylphenidate reduced
emotional lability (effect
size, 0.28–0.4)
Combination group did not
show significantly better
emotional control at end
of intervention but did 3
months following intervention
(d=1.12)

a distinct neurocognitive etiology and a distinct clinical The third model holds that symptoms of ADHD and
course for those with the combination of ADHD and emotion dysregulation are distinct but correlated di-
emotion dysregulation, a possibility that warrants further mensions, each underpinned by partly overlapping but
testing. dissociable neurocognitive deficits. This model has much

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 SHAW, STRINGARIS, NIGG, ET AL.

TABLE 4. Three Models to Explain the Overlap Between ADHD and Emotion Dysregulation
Phenomenology Pathophysiology
Correlations
Between ADHD
and Emotion
Model Dysregulation Clinical Course Psychological Basis Neural Basis Genetic Treatment
Emotion Extremely high Yoked clinical Deficits in behavioral Anomalies Same genetic Treatments that
dysregulation is courses for inhibition and confined to basis for improve
integral to symptoms of working memory fronto-striatal- ADHD with ADHD will
ADHD ADHD and mediate both core cerebellar circuits emotion improve
emotion ADHD symptoms dysregulation emotion
dysregulation and emotion and ADHD dysregulation
dysregulation alone
Combined ADHD subgroup Distinct clinical Distinct cognitive Distinct neural Distinct genetic Existing
ADHD and exists that is course for deficits in bases for bases for ADHD treatments
emotion high on both ADHD with ADHD with ADHD with with emotion for ADHD
dysregulation symptom emotion emotion emotion dysregulation may be less
defines a domains dysregulation dysregulation dysregulation and ADHD effective for
distinct entity and ADHD alone and ADHD alone and ADHD alone ADHD with
alone emotion
dysregulation
Symptoms Modest Similar but Deficits in emotion Anomalies extend Some genes Treating “core”
of ADHD dissociable processing mediate beyond fronto- shared between ADHD
and emotion clinical courses dysregulation and striato-cerebellar ADHD alone symptoms
dysregulation for symptoms correlate with circuits to and ADHD with benefits
are correlated of ADHD deficits mediating (para)limbic emotion emotion
but distinct and emotion core ADHD regions dysregulation dysregulation,
dimensions dysregulation symptoms but separate
treatment
may also
be needed

in common with the concept of multiple but overlapping
pathways to ADHD (103, 110). It is supported by the sig-
nificant but modest correlations between symptoms of
ADHD and emotion dysregulation reviewed earlier; the
symptom domains commonly coexist but are far from com-
pletely overlapping. Similarly, modest correlations have
been reported between deficits in emotional processes—
such as deficits in emotion recognition and frustration
tolerance—and the executive dysfunction often held to be
a core feature of the disorder (35, 37). Longitudinal data
reviewed earlier also suggest modest links between the
course of ADHD symptoms and emotion dysregulation in
early childhood, and perhaps in adulthood, consistent with
a model of correlated but distinct symptom dimensions.
Future Research Directions
Phenomenology and Pathophysiology
Refinement of the phenotype is needed, as emotion
dysregulation in individuals with ADHD is likely to have
a number of clinically important components, such as
irritability and mood lability (4, 51). It will be important to
operationalize each component, develop consensus mea-
surement techniques, and conduct longitudinal studies to
define how the developmental trajectories of the compo-
nents interact with each other and with the dimensions
of ADHD. Pathophysiological studies should include
individuals lying along the spectrum of emotion regulation
abilities, but perhaps oversample those most in clinical
need, lying at the extreme of dysregulation. Such work would
allow direct links to be made between emotion dysregula-
tion in ADHD and the underlying neural anomalies—a link
that has been made in relatively few studies.
Functional imaging studies should include a broad
range of tasks of emotion regulation, defining the neural
bases of the ability to reinterpret the meaning of emotional
stimuli, the adaptive suppression of ongoing emotional
responses, and the ability to employ strategies such as
distancing oneself from emotionally arousing materials
(77). We predict that emotionally dysregulated individuals
with ADHD would lose the coordinated increase in medial
prefrontal/anterior cingulate cortex activation and altered
amygdala activation that underpins many forms of emotion
regulation.
To what extent do individuals with ADHD develop
emotion dysregulation for reasons different from those of
individuals with other disorders? Could ADHD-specific
symptoms or cognitive aberrations be related to emotion
dysregulation? “Mind wandering” is one candidate cogni-
tive mechanism. It is typically measured as interference in
tasks of cognitive control and appears to be related to
a failure to deactivate the so-called default mode network
of the brain, a deficit also found in ADHD (136). Notably,
mind wandering appears to lead to transient dysphoric
mood and vice versa (137). Testing the links between

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EMOTION DYSREGULATION IN ADHD
attentional lapses and emotion dysregulation and the
possible mediating role of the default mode network may
be a promising research avenue.
There is evidence in ADHD of an altered structural and
functional maturation of the prefrontal cortical regions
that support top-down emotion regulation (138). Could
disrupted developmental trajectories be particularly pro-
nounced among those with both ADHD and impaired
emotion regulation? Our model predicts a disruption of
white matter tracts such as the uncinate fasciculus that
connect limbic regions, including the amygdala, hippo-
campus, and orbitofrontal cortex; these tracts can be
assessed using diffusion tensor imaging.
Behavioral genetic data on twins could parse out the
degree to which ADHD and emotion dysregulation share
genetic or environmental risk factors. This could be
achieved by reanalysis of existing data sets that include
measures of irritability and other relevant traits. Studies
of environmental risk factors have focused on familial
characteristics but could also define the characteristics of
a child’s peer group that confer vulnerability to emotion
dysregulation.
Treatment
Is a two-pronged pharmacological approach targeting
both the symptoms of ADHD and those of emotion
dysregulation more effective than use of psychostimulants
alone? This question is being examined in children with
severe mood dysregulation (most of whom have ADHD)
in trials that use both psychostimulants and selective
serotonin reuptake inhibitors (SSRIs) (clinicaltrials.gov
identifiers NCT00794040, NCT01714310). The use of SSRIs
is grounded in preclinical studies showing that the modu-
lation of serotonergic tone affects the processing of emotion-
ally charged stimuli and clinical studies showing efficacy in
promoting emotion regulation in other disorders (139).
Other agents show promise. Postsynaptic alpha-2 adre-
noceptor agonists such as guanfacine treat core symptoms
of ADHD and oppositionality (140). In healthy adults,
guanfacine reverses the bias to respond less accurately to
negative compared with positive emotional stimuli, partly
by boosting activation of the left dorsolateral prefrontal
cortex (141). Given the interactions between the lateral
prefrontal cortex and the ventral/medial prefrontal corti-
cal regions linked to emotion regulation, guanfacine
emerges as a potential emotion regulator in ADHD.
Modafinil, which inhibits dopamine and norepinephrine
transporters and decreases GABA, also shows promise as
a treatment for ADHD (142). In healthy adults, modafinil
decreases amygdala activation during the viewing of
fearful stimuli and boosts prefrontal cortical activation
during executive functions (143). Again, this profile points
to a possible benefit for ADHD and associated emotion
dysregulation. Dietary interventions can be considered,
as there appears to be benefit from omega-3 fatty acid
supplementation in ADHD (131). Given that low levels of
288 ajp.psychiatryonline.org
omega-3 fatty acids are associated with electrophysiolog-
ical anomalies during emotion processing in ADHD (144),
might emotion dysregulation in ADHD also benefit from
supplementation?
Which psychotherapies are promising? Cognitive ther-
apy can help individuals with ADHD recognize and label
emotions accurately, challenge emotions that are not
context appropriate, and cope with intense negative
emotional reactions (132). These skills have been aug-
mented with mindfulness training that promotes a non-
judgmental, present-centered focused awareness of
emotions. This approach, derived partly from dialectical
behavior therapy for disorders with prominent emotion
dysregulation, such as borderline personality disorder, is
currently being assessed in adults with ADHD (73).
Improving executive functions such as working memory
and planning abilities helps core ADHD symptoms in
adults, but future studies should also ask if these cognitive
interventions also improve emotion regulation (132).
Similarly, it has been argued that parent-led games can
boost a preschooler’s executive skills and might prevent
later ADHD (145, 146). Might such early intervention also
promote emotion regulation?
What of interventions that target not just the individual
with ADHD but also the individual’s social context? For
example, there is a strong rationale for family-based
interventions to decrease negative family dynamics and
thus perhaps enhance emotion regulation in both the
parent and the child with ADHD (115). A novel approach
leverages a child’s peer group as a therapeutic ally (147).
Children with ADHD often form cliques with disruptive
others, and classroom interventions might promote alli-
ances with less disruptive children who can perhaps better
model emotion regulation.
Conclusions
Since Still described the “morbid excitability” of children
with ADHD (148), the presence of emotion dysregulation
in ADHD has been well recognized. Recent advances in the
behavioral, neuroimaging, and genomic sciences hold the
promise that our renewed focus on this overlap will result
in an understanding of the underlying pathophysiological
mechanisms and stimulate novel treatment approaches.
Received July 23, 2013; revision received Oct. 21, 2013; accepted
Nov. 18, 2013 (doi: 10.1176/appi.ajp.2013.13070966). From the
Section on Neurobehavioral Clinical Research, Social and Behavioral
Research Branch, Division of Intramural Research Programs, National
Human Genome Research Institute, Bethesda, Md.; the Section on
Bipolar Spectrum Disorders, Emotion and Development Branch,
Division of Intramural Research Programs, NIMH, Bethesda; the
NIMH Intramural Program, Bethesda; the Institute of Psychiatry,
King’s College London; and the Division of Psychology, Department
of Psychiatry, Oregon Health and Science University, Portland.
Address correspondence to Dr. Shaw (shawp@mail.nih.gov).
Dr. Stringaris is a Wellcome Trust Fellow and also receives funding
from the U.K. Department of Health and the Biomedical Research
Centre of the National Institute of Health Research, U.K.; he receives
Am J Psychiatry 171:3, March 2014

royalties from Cambridge University Press. The other authors report
no financial relationships with commercial interests.
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 Article

A Randomized Controlled Trial of 7-Day Intensive and

Standard Weekly Cognitive Therapy for PTSD and
Emotion-Focused Supportive Therapy
Anke Ehlers, Ph.D.
Ann Hackmann, D.Clin.Psy.
Nick Grey, D.Clin.Psy.
Jennifer Wild, D.Clin.Psy.
Sheena Liness, M.A.
Idit Albert, D.Clin.Psy.
Alicia Deale, Ph.D.
Richard Stott, D.Clin.Psy.
David M. Clark, D.Phil.
Objective: Psychological treatments for
posttraumatic stress disorder (PTSD) are
usually delivered once or twice a week
over several months. It is unclear whether
they can be successfully delivered over a
shorter period of time. This clinical trial had
two goals: to investigate the acceptability
and efficacy of a 7-day intensive version of
cognitive therapy for PTSD and to investigate
whether cognitive therapy has specific treat-
ment effects by comparing intensive and
standard weekly cognitive therapy with an
equally credible alternative treatment.
Method: Patients with chronic PTSD
(N=121) were randomly allocated to 7-
day intensive cognitive therapy for PTSD, 3
months of standard weekly cognitive ther-
apy, 3 months of weekly emotion-focused
supportive therapy, or a 14-week waiting
list condition. The primary outcomes were
change in PTSD symptoms and diagnosis
as measured by independent assessor
ratings and self-report. The secondary out-
comes were change in disability, anxiety,
depression, and quality of life. Evaluations
were conducted at the baseline assessment
and at 6 and 14 weeks (the posttreatment/
wait assessment). For groups receiving treat-
ment, evaluations were also conducted at 3
weeks and follow-up assessments at 27 and
40 weeks after randomization. All analyses
were intent-to-treat.
Results: At the posttreatment/wait as-
sessment, 73% of the intensive cognitive
therapy group, 77% of the standard cogni-
tive therapy group, 43% of the supportive
therapy group, and 7% of the waiting list
group had recovered from PTSD. All treat-
ments were well tolerated and were
superior to waiting list on nearly all out-
come measures; no difference was ob-
served between supportive therapy and
waiting list on quality of life. For primary
outcomes, disability, and general anxiety,
intensive and standard cognitive therapy
were superior to supportive therapy. In-
tensive cognitive therapy achieved faster
symptom reduction and comparable over-
all outcomes to standard cognitive therapy.
Conclusions: Cognitive therapy for PTSD
delivered intensively over little more than
a week was as effective as cognitive therapy
delivered over 3 months. Both had specific
effects and were superior to supportive
therapy. Intensive cognitive therapy for
PTSD is a feasible and promising alterna-
tive to traditional weekly treatment.

(Am J Psychiatry 2014; 171:294–304)

A range of trauma-focused psychological treatment

programs are effective for posttraumatic stress disorder
(PTSD) (1–3). Such treatments are usually delivered once
or twice per week over the course of several months. While
this is a conventional psychotherapy format, it has some
potential disadvantages from a patient perspective. PTSD
interferes with social and occupational functioning and it
could be desirable to make more rapid progress. Further-
more, some patients find it difficult to commit to protracted
psychological treatment (2). This raises the question of
whether trauma-focused psychological treatment for
PTSD is effective and acceptable if condensed into a
shorter period of time. There is some evidence that
intensive cognitive-behavioral therapy is effective in other
anxiety disorders (4, 5), but it remains unclear whether it
is feasible for PTSD. Some clinicians are concerned about
the risk of symptom exacerbation in the treatment of PTSD
(6, 7), and it is conceivable that a concentrated treat-
ment delivery could enhance the risk of possible adverse
effects.
This clinical trial had two goals. First, we investigated the
acceptability and efficacy of an intensive 7-day version of
cognitive therapy for PTSD (8). Standard weekly cognitive
therapy for PTSD over 3 months has been shown to be
highly effective and acceptable to patients (9–13). A pilot
study suggested that intensive cognitive therapy for
PTSD may also be effective (8). Second, we tested
whether cognitive therapy for PTSD has specific treat-
ment effects by comparing intensive and standard weekly
cognitive therapy with an alternative active treatment,

This article is featured in this month’s AJP Audio, is an article that provides Clinical Guidance (p. A12),
and is discussed in an Editorial by Dr. Cloitre (p. 249)

294 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 EHLERS, HACKMANN, GREY, ET AL.

FIGURE 1. Flow Diagram of Patient Recruitment and Trial Progress in a Study of Cognitive and Supportive Therapies for PTSD

Assessed for eligibility (N=253)

(London=173, Oxford=80)

Not suitable (N=110)

Did not have PTSD (N=40)
Did not meet trauma inclusion criteria (N=11)
Other disorder primary problem (e.g., borderline
personality disorder, substance dependence,
immediate suicide risk) (N=48)
Treatment not possible at this time (e.g., serious
ongoing threat, imprisonment) (N=9)
Did not speak English (N=2)

Eligible for trial (N=143)

(London=100, Oxford=43)

Self-excluded (N=22)
Opted for treatment elsewhere (N=14)
Did not want treatment (N=6)
Lost contact (N=2)

Consented and randomly allocated (N=121)

(London=81, Oxford=40)

Intensive cognitive therapy (N= 30)
(London=21, Oxford=9)
Completers (N=29)
Dropouts (N=1)
Posttreatment data (N=30)
Weekly cognitive therapy (N=31)
(London=21, Oxford=10)
Completers (N=30)
Dropouts (N=1)
Posttreatment data (N=31)
Weekly supportive therapy (N=30) Waiting list (N=30)
(London=20, Oxford=10) (London=19, Oxford=11)
Completers (N=27) Completers (N=30)
Dropouts (N=3) Dropouts (N=0)
Posttreatment data (N=30) Post-waiting period data
(N=30)

Completed first follow-up (N=29) Completed first follow-up (N=31) Completed first follow-up (N=27)
Lost to follow-up Lost to follow-up Lost to follow-up
Completers (N=0) Completers (N=0) Completers (N=1)
Dropouts (N=1) Dropouts (N=0) Dropouts (N=2)

Completed second follow-up Completed second follow-up Completed second follow-up

(N=27) (N=31) (N=24)
Lost to follow-up Lost to follow-up Lost to follow-up
Completer (N=2) Completers (N=0) Completers (N=3)
Dropouts (N=1) Dropouts (N=0) Dropouts (N=3)

Analyzed=30 Analyzed=31 Analyzed=30 Analyzed=30

emotion-focused supportive psychotherapy, using a broad Method

range of outcomes including PTSD symptoms, disability,
anxiety, depression, and quality of life. Cognitive therapy
for PTSD has been shown to be superior to self-help in-
terventions with limited therapist contact (9), but it has not
yet been compared with an equally credible alternative
psychological treatment involving the same amount of
therapist contact.
Participants
Individuals (N=121) were recruited between 2003 and 2008
from consecutive referrals to a National Health Service outpa-
tient clinic for anxiety disorders in South London, U.K. (N=81) or
a research clinic at the University of Oxford, U.K. (N=40). Patients
were invited to participate if they met the following inclusion

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COGNITIVE THERAPY FOR PTSD AND EMOTION-FOCUSED SUPPORTIVE THERAPY

TABLE 1. Sample, Trauma, and Treatment Characteristics by Treatment Condition in a Study of Cognitive and Supportive
Therapies for PTSD
Intensive Cognitive Standard Weekly Cognitive Supportive Therapy Waiting List
Characteristics Therapy (N=30) Therapy (N=31) (N=30) (N=30)
Mean SD Mean SD Mean SD Mean SD
Age (years) 39.7 12.4 41.5 11.7 37.8 9.9 36.8 10.5
N % N % N % N %
Sex
Female 18 60.0 18 58.1 17 56.7 18 60.0
Male 12 40.0 13 43.9 13 43.4 12 40.0
Ethnic group
Caucasian 22 73.3 20 64.5 22 73.3 21 70.0
Ethnic minority 8 26.7 11 35.5 8 26.7 9 30.0
Marital status
Never married 9 30.0 10 32.3 12 40.0 10 33.3
Divorced/separated/widowed 3 10.0 4 12.9 4 13.4 5 16.7
Married/cohabitating 18 60.0 17 54.8 14 46.7 15 50.0
Education
College/university 6 20.0 8 25.8 8 26.7 10 33.3
High school examination (age 18) 1 3.3 6 19.4 6 20.0 6 20.0
Standard school examination (age 16) 18 60.0 12 38.7 12 40.0 13 43.3
None 5 16.7 5 16.1 4 13.3 1 3.3
Current employment
Unemployed 7 23.3 7 22.6 9 30.0 5 16.7
On disability/retired 2 6.7 3 9.7 3 10.0 3 10.0
Sick leave 7 23.3 3 9.7 5 16.7 4 13.3
Working full- or part-time 14 46.7 18 58.1 13 43.3 18 60.0
Profession
Professional 5 17.2 4 12.9 6 20.0 6 20.7
White collar 8 27.6 17 54.8 7 23.3 12 41.4
Blue collar 10 34.5 6 19.4 10 33.3 6 20.7
Homemaker/student/not working 6 20.6 4 12.9 7 23.3 5 17.2
Traumas
Type of main traumatic event
Interpersonal violence 12 40.0 12 38.7 11 36.7 10 33.3
Accidents/disaster 11 36.7 11 35.5 14 46.7 10 33.3
Death/harm to others 2 6.7 1 3.2 2 6.7 4 13.3
Other 5 16.7 7 22.6 3 10.0 6 20.0
Time since main traumatic event
3 months – 1 year 10 33.3 14 45.2 8 27.8 14 46.7
1–2 years 10 33.3 5 16.1 7 24.1 6 20.0
2–4 years 7 23.3 11 35.5 8 27.6 3 10.0
.4 years 3 10.0 1 3.2 6 20.7 7 23.3
History of other trauma
Yes 22 63.3 21 67.7 23 76.7 20 66.7
No 8 26.7 10 32.3 7 23.3 10 33.3
Reported history of childhood abuse
Yes 5 16.7 2 6.5 4 13.3 3 10.0
No 25 83.3 29 93.5 26 86.7 27 90.0
Comorbidity
Anxiety disorder
Yes 10 33.3 7 22.6 10 33.3 10 33.3
No 20 66.7 24 77.4 20 66.7 20 66.7
Depressive disorder
Yes 12 40.0 7 22.6 11 36.7 14 46.7
No 18 60.0 24 77.4 19 63.3 16 53.3
Substance abuse
Yes 6 20.0 6 19.4 6 20.0 2 6.7
No 24 80.0 25 80.6 24 80.0 28 93.3

continued

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 EHLERS, HACKMANN, GREY, ET AL.

TABLE 1. Sample, Trauma, and Treatment Characteristics by Treatment Condition in a Study of Cognitive and Supportive
Therapies for PTSD (continued)
Intensive Cognitive Standard Weekly Cognitive Supportive Therapy Waiting List
Characteristics Therapy (N=30) Therapy (N=31) (N=30) (N=30)

History of substance dependence

Yes 2 6.7 4 12.9 2 6.7 1 3.3
No 28 93.3 27 87.1 28 93.3 29 96.7
Axis II disorder
Yes 7 23.3 5 16.1 4 13.3 8 26.7
No 23 76.7 26 83.9 26 86.7 22 73.3
Treatment history
Previous treatment for PTSD
Yes 10 33.3 11 35.5 12 40.0 11 36.7
No 20 66.7 20 64.5 18 60.0 19 63.3
Psychotropic medication pretreatment
Yes 5 16.7 11 35.5 12 40.0 8 26.7
No 25 83.3 20 64.5 18 60.0 22 73.3
Changes in medication
Discontinued before 14 weeks 1 20.0 5 45.5 3 25.0 2 25
in follow-up 1 20.0 1 9.1 3 25.0 – –
Stayed on medication 3 60.0 5 45.5 6 50.0 6 75
Started medication during study 0 0 0 0 0 0 0 0
Other psychological treatment during study
Trauma-related 0 0 0 0 1 3.3 0 0
For other problems 0 0 1 3.2 0 0 0 0
Treatment received in trial Mean SD Mean SD Mean SD
Number of sessions
Before 14 weeks 10.13 2.18 10.10 3.26 10.27 3.21
Booster 1.90 0.80 2.07 1.46 2.20 1.32
Treatment credibility 23.63 4.40 24.29 4.60 22.00 5.12
Therapeutic alliance
Patient rating 5.94 0.56 5.70 0.68 5.53 0.51
Therapist rating 5.69 0.47 5.74 0.40 5.67 0.48

criteria: they were between 18 and 65 years old, met diagnostic
criteria for chronic PTSD as determined by the Structured
Clinical Interview for DSM-IV (14), their intrusive memories
were linked to one or two discrete traumatic events in adulthood,
and PTSD was the main problem. Exclusion criteria were history
of psychosis, current substance dependence, borderline person-
ality disorder, acute serious suicide risk, or if treatment could not
be conducted without the aid of an interpreter. Figure 1 depicts
the patient flow chart and Table 1 summarizes the details on
trauma and the clinical, demographic, and treatment character-
istics. No group differences were observed in any of the variables.
Seventy-one patients (58.7%) were women, and 36 (29.8%) were
from ethnic minorities. The most common index traumas were
interpersonal violence (physical or sexual assault, 37.2%), ac-
cidents or disaster (38.0%), or traumatic death of others (7.4%).
Most patients (71.9%) had a history of other traumas besides
their index traumas. The majority (63.6%) had other comorbid
axis I disorders (mainly mood and anxiety disorders or substance
abuse), and 19.8% had axis II disorders (mainly obsessive-
compulsive, depressive, paranoid, or avoidant disorders). Around
one-third (36.7%) had had previous treatment for PTSD. Patients
taking psychotropic medication (29.8%) were required to be on a
stable dosage for 2 months before random assignment.
Random Allocation and Masking
If the patients were suitable for the trial and willing to par-
ticipate, they signed the informed consent form. The participants
were then randomly allocated to one of the four trial conditions
by an independent researcher who was not involved in assessing
patients using the minimization procedure (15) to stratify for sex
and severity of PTSD symptoms. The assessors determining the
suitability of a patient for inclusion were not informed about the
stratification variables and algorithm. The assessments of treat-
ment outcome were conducted by independent evaluators with-
out knowledge of the patient’s treatment condition. Patients were
asked not to reveal their group assignment to the evaluators.
Participants were not blind to the nature of the treatment, but care
was taken to create similarly positive expectations in each treat-
ment group by informing them that several psychological treat-
ments were effective in PTSD and it was unknown which worked
best, and by giving a detailed rationale for the treatment condition
to which the patient was allocated. Patient ratings of treatment
credibility (16) and therapeutic alliance scores (17) were high in all
treatment conditions and did not differ (Table 1).
Treatment Conditions
Patients in all treatment conditions received up to 20 hours of
treatment by the 14-week assessment (posttreatment/wait). The
sessions were spread evenly over 3 months for standard cognitive
therapy and supportive therapy, whereas the main part of treat-
ment occurred within the first 7–10 days for intensive cognitive
therapy. The number of treatment or booster sessions received
did not differ between the treatment groups (Table 1).
Standard cognitive therapy for PTSD. This treatment was
delivered as in previous trials (9, 10) in up to 12 weekly individual

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COGNITIVE THERAPY FOR PTSD AND EMOTION-FOCUSED SUPPORTIVE THERAPY
sessions over the course of 3 months, with three optional
monthly booster sessions over the following 3 months. The
treatment follows Ehlers and Clark’s model of PTSD (18) and
aims to reduce the patient’s sense of current threat by 1)
identifying and modifying excessively negative appraisals of the
trauma and/or its sequelae, 2) elaborating the trauma memory
and discriminating triggers of intrusive reexperiencing, and 3)
reducing the use of cognitive strategies and behaviors (such as
thought suppression, rumination, and safety-seeking behaviors)
that maintain the problem. Therapists followed a treatment manual
(19). A description of treatment procedures is found at http://
oxcadat.psy.ox.ac.uk/downloads/CT-PTSD%20Treatment%
20Procedures.pdf/view. Patients were given homework assign-
ments to complete between sessions.
Seven-day intensive cognitive therapy for PTSD. This treat-
ment followed the same protocol as standard cognitive therapy,
but the main part of the treatment was delivered over a much
shorter period of time. In the intensive treatment phase, patients
received up to 18 hours of therapy over a period of 5–7 working
days. Treatment days usually comprised a morning and an after-
noon session lasting 90 minutes to 2 hours, with a break for
lunch. Up to two further sessions were conducted 1 week and 1
month after the intensive period to discuss progress and home-
work assignments, and up to three optional monthly booster
sessions were available. Patients receiving intensive cognitive
therapy completed homework assignments parallel to those in
standard cognitive therapy. However, during the intensive phase
homework was more limited because of time constraints.
Emotion-focused supportive therapy. This nondirective treat-
ment focused on patients’ emotional reactions rather than their
cognitions. It was designed to provide a credible therapeutic
alternative to control for nonspecific therapeutic factors so that
observed effects of cognitive therapy could be attributed to its
specific effects beyond the benefits of good therapy. Like
standard cognitive therapy, it comprised up to 12 weekly indi-
vidual sessions (up to 20 hours in total) over 3 months with three
optional monthly booster sessions. Therapists followed a manual
that specified procedures, building on similar treatment pro-
grams (20, 21). After normalizing PTSD symptoms, the therapist
gave the rationale that the trauma had left the patient with
unprocessed emotions and that therapy would provide them
with support and a safe context to address their unresolved
emotions. Patients could freely choose what problems to discuss
in the session, including any aspect of the trauma. Therapists
helped patients clarify their emotions and solve problems.
They did not restructure the patient’s appraisals, attempt to
elaborate their trauma memories or discriminate triggers, or
direct them in how to change their behavior. As homework,
patients kept a daily diary of their emotional responses to
the events of the week that was discussed in the following
session (20).
Waiting list. Patients allocated to the waiting list condition
waited for 14 weeks before receiving treatment.
Outcome Measures
Data were collected from all participants, including dropouts.
The primary assessment points were at baseline (pretreatment or
assignment to waiting list), 6 weeks (self-reports only), and 14
weeks (posttreatment/wait). Follow-ups for treated patients were
at 27 and 40 weeks after random treatment assignment. Figure 1
depicts the number of patients who provided data at each as-
sessment point. In addition, patients receiving therapy also
completed self-reports of PTSD symptoms, anxiety, and de-
pression at 3 weeks.
298 ajp.psychiatryonline.org
Primary Outcome Measures
Clinician-rated PTSD symptoms. Independent assessors
(trained psychologists) interviewed patients with the Clinician-
Administered PTSD Scale (CAPS) (22). The CAPS assesses the
frequency and severity of each of the PTSD symptoms specified
in DSM-IV. Interrater reliability for a PTSD diagnosis was
kappa=0.95, and r=0.98 for the total severity score (37 interviews,
14 interviewers, and 14 raters).
Severity of PTSD symptoms. Patients completed the Post-
traumatic Diagnostic Scale (23), a self-report questionnaire
measuring the overall severity of PTSD symptoms (score range,
0–51) that has shown good reliability and concurrent validity
with other PTSD measures.
Secondary Outcome Measures
Disability. Patients completed the Sheehan Disability Scale (24)
and rated the interference caused by their symptoms in their
work, social life and leisure activities, and family life and home.
The disability score was the sum of the ratings (score range,
0–30).
General anxiety and depression. Symptoms of anxiety and
depression were assessed with the Beck Anxiety Inventory (25) and
the Beck Depression Inventory (BDI) (26), standard 21-item self-
report measures with high reliability and validity (score range, 0–63).
Quality of life. Perceived quality of life was assessed with the
Quality of Life Enjoyment and Satisfaction Questionnaire (27).
This scale assesses the patient’s satisfaction in 14 life domains
and has been shown to be reliable and valid in clinical and
community samples (28).
Therapist Training and Treatment Fidelity
The therapists were qualified clinicians who had completed
a clinical psychology (AH, NG, JW, IA) or nurse therapist (SL, AD)
degree and had received further training in all treatments used in
this study. They had treated at least two individuals with each of
the therapy protocols under supervision before treating trial pa-
tients. They received weekly supervision from a senior clinician
(AE, AH, NG) trained in all treatment modalities for weekly cases,
and daily supervision for intensive cases to ensure compliance
with the treatment protocols.
To further evaluate treatment integrity, a randomly selected
recording from each patient was reviewed by a trained assessor
for compliance with the treatment protocol, using a detailed
checklist of procedures used. Only one minor deviation was
discovered: one of the supportive therapy patients worked on
spotting memory triggers for a few minutes. Another randomly
selected session from each patient was rated for therapist
competency. Cognitive therapy sessions were rated by a psychol-
ogist experienced in cognitive therapy using an adapted version
of the Cognitive Therapy Scale (29), on a scale from 0 to 6. A score
of 3 is considered satisfactory, and scores $4 indicate good-to-
excellent competency. The mean score was 4.7 (SD=0.41) for
standard cognitive therapy and 4.8 (SD=0.35) for intensive
cognitive therapy (p.0.18). Supportive therapy sessions were
evaluated for therapist competency by a counseling psychologist
experienced in supportive therapy (on a scale from 0 to 6 with
anchors as above, informed by ratings of dimensions of good
nondirective therapy such an empathic understanding) (30). The
mean rating was 4.7 (SD=0.49).
Data Analysis
All analyses were intention-to-treat using all 121 randomly
assigned participants. Dichotomous outcomes were compared
with chi-square tests. Continuous outcomes were analyzed with
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 EHLERS, HACKMANN, GREY, ET AL.

TABLE 2. Dichotomous Measures of Response to Treatment in a Study of Cognitive and Supportive Therapies for PTSD
1: Intensive 2: Standard
Cognitive Therapy Cognitive Therapy 3: Supportive 4: Waiting
(N=30) (N=31) Therapy (N=30) List (N=30) Analysis
Significant
Variablea N % N % N % N % x2 df Contrasts
Dropouts 1 3.3 1 3.2 3 10 0 0 0.26 3, 121
Symptom deterioration
Self-reports (PDS) 0 0 0 0.0 1 3.3 0 0.0 3.06 3, 121
Assessor-rated (CAPS) 0 0 1 3.2 3 10.0 6 20.0 9.31* 3, 121 1, 2,4
Loss of diagnosis (CAPS)
Posttreatment/wait (14 weeks) 22 73.3 24 77.4 13 43.3 2 6.7 38.92*** 3, 121 1, 2.3 . 4
Follow-up 1 (27 weeks) 22 73.3 23 74.2 11 36.7 N/A 11.70** 2, 91 1, 2.3
Follow-up 2 (40 weeks) 20 66.7 23 74.2 12 40.0 N/A 8.18* 2, 91 1, 2.3
Total remission (assessor-rated, CAPS)
Posttreatment or wait (14 weeks) 14 46.7 16 51.6 6 20.0 1 3.3 22.19*** 3, 121 1, 2.3.4
Follow-up 1 (27 weeks) 12 40.0 21 67.7 5 16.7 N/A 16.41*** 2, 91 1, 2.3
Follow-up 2 (40 weeks) 16 53.3 23 74.2 8 26.7 N/A 13.84** 2, 91 1, 2.3
Total remission (self-report, PDS)
Posttreatment or wait (14 weeks) 17 56.7 20 64.5 9 30.0 1 3.3 29.53*** 3, 121 1, 2.3.4
Follow-up 1 (27 weeks) 15 50.0 22 71.0 7 23.3 N/A 13.90** 2, 91 1, 2.3
Follow-up 2 (40 weeks) 17 56.7 18 58.1 9 30.0 N/A 6.05* 2, 91 1, 2.3
a
CAPS=Clinician-Administered PTSD Scale; PDS=Posttraumatic Diagnostic Scale.
* p,0.05. **p,0.01. ***p,0.001.

hierarchical linear modeling (31). This analysis models random
slopes and intercepts for participants and tests the fixed effects of
treatment condition and repeated assessments over time, using
data from all participants. Differential treatment efficacy shows
in significant interactions between treatment condition and
time. Significant overall effects were followed up with contrasts
between conditions. All variables were centered for the analysis
(32). Significance levels were set at p,0.05 (two-tailed). To test
whether the three treatment conditions led to better outcomes
than the waiting list, linear trends for symptom change over
assessments points from baseline to 6 weeks and 14 weeks were
compared between the four trial conditions. To compare the
efficacy of the three treatment conditions, hierarchical linear
modeling compared symptom scores from baseline to the 40-
week follow-up, fitting linear and quadratic trends for symptom
change over the five assessments (baseline and 6, 14, 27, and 40
weeks). Interactions of site, sex, medication status, and trauma
type with condition and time were explored in additional
analyses, but as effects were far from significant, these were
omitted from the final models.
For comparison with meta-analyses, we report Cohen’s d effect
sizes (33) for adjusted between-group differences (controlling for
pretreatment scores) and confidence intervals at posttreatment.
Effect sizes $0.5 are considered medium effects and $0.8 are
considered large effects. To compare the speed of recovery
between the treated groups, a further analysis compared symptom
scores on the Posttraumatic Diagnostic Scale, the Beck Anxiety
Inventory, and the BDI at 3 weeks for the treatment groups,
controlling for initial symptom severity. Effect sizes for within-
group changes in symptom scores between the pretreatment and
posttreatment/wait assessments were calculated as Cohen’s d
statistic (33), using the pooled standard deviation as reference,
which is more conservative in estimating improvement than using
pretreatment standard deviations.
Recovery from PTSD diagnosis according to the CAPS was
coded if the patient no longer met the minimum number of
symptoms in each symptom cluster required by DSM-IV, with
a score of at least 1 for both frequency and intensity and a global
severity score of at least 2 (9–11). Recovery was determined for all
randomly assigned participants. The status of a few participants
with missing CAPS observations was based on the Posttraumatic
Diagnostic Scale (if available for this time point) or the last
available value on the CAPS. In addition, for comparisons with
other research (21), we calculated the percentages of patients who
were totally remitted according to assessor ratings and self-report,
using cutoffs recommended in the respective manual: a CAPS score
of below 20 (“asymptomatic”) and a Posttraumatic Diagnostic Scale
score below 11. PTSD symptom deterioration was defined using
established cutoffs for statistically reliable change, i.e., symptom
increases greater than 6.15 on the Posttraumatic Diagnostic
Scale (34) and greater than 10 on the CAPS (21).
Sample size was determined by power analysis on the basis of
effect sizes for cognitive therapy observed in previous trials. A group
size of N=30 per condition yields 85% power for an effect size of 0.8.
Results
Adverse Effects, Dropouts, and Symptom
Deterioration
No adverse effects (i.e., negative reactions to treatment
procedures such as significant increases in dissociation,
suicidal intent, or hyperarousal) were reported in any of the
groups. Dropouts were defined as attending fewer than
eight sessions (35), unless earlier completion was agreed
with the therapist. Dropout rates were low and did not differ
between conditions (Table 2). Only one patient in the
supportive therapy group reported symptom deterioration
on the Posttraumatic Diagnostic Scale (Table 2). On the
CAPS, fewer patients treated with intensive and cognitive
therapy were rated as having symptom deterioration than
those in the waiting list condition. The supportive therapy
group did not statistically differ from the other groups.

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COGNITIVE THERAPY FOR PTSD AND EMOTION-FOCUSED SUPPORTIVE THERAPY

TABLE 3. Intent-to-Treat Results for Continuous Primary and Secondary Outcome Measures
Intensive Cognitive Therapy Standard Cognitive Therapy Supportive Therapy
Measurea (N=30) (N=31) (N=30) Waiting List (N=30)
Primary outcomes Mean SD Mean SD Mean SD Mean SD
Independent assessor (CAPS)
Baseline 78.72 19.80 70.60 13.45 74.60 15.39 69.95 14.17
14 weeks (posttreatment) 32.22 27.20 26.97 28.68 47.88 31.77 65.28 20.64
27 weeks (follow-up 1) 35.56 26.26 20.86 25.23 49.32 32.46
40 weeks (follow-up 2) 35.33 35.11 20.96 27.71 49.04 38.01
Self-report (PDS)
Baseline 33.21 7.66 32.44 6.94 34.26 7.40 32.46 7.60
6 weeks 14.85 8.92 16.33 11.58 23.30 12.90 31.92 6.84
14 weeks (posttreatment) 11.98 9.60 9.39 10.88 19.98 13.67 29.24 9.36
27 weeks (follow-up 1) 13.91 11.63 10.15 11.86 18.93 12.98
40 weeks (follow-up 2) 13.03 13.99 9.63 11.26 20.94 15.40
Secondary outcomes
Disability (SDS)
Baseline 20.48 5.55 21.39 5.11 19.65 6.97 17.28 7.74
6 weeks 10.72 7.51 14.02 9.35 16.60 7.90 17.22 6.67
14 weeks (posttreatment) 9.30 8.20 10.02 9.76 14.28 9.09 17.20 6.38
27 weeks (follow-up 1) 10.61 8.80 8.68 9.50 13.67 9.86
40 weeks (follow-up 2) 9.72 9.22 9.37 10.07 14.47 11.35
Anxiety (BAI)
Baseline 26.23 13.12 28.42 14.17 25.12 11.31 23.57 9.12
6 weeks 13.55 12.16 13.88 14.01 17.01 13.30 23.26 10.88
14 weeks (posttreatment) 11.57 11.94 9.24 12.09 16.35 14.56 22.13 10.59
27 weeks (follow-up 1) 10.37 11.59 9.63 13.71 15.50 13.74
40 weeks (follow-up 2) 11.85 13.35 9.00 12.61 15.99 16.15
Depression (BDI)
Baseline 23.93 9.86 21.90 10.77 26.18 10.68 23.47 8.96
6 weeks 14.34 9.30 13.39 10.70 19.79 12.42 21.26 8.06
14 weeks (posttreatment) 12.10 9.97 11.07 11.80 17.00 12.82 20.85 10.02
27 weeks (follow-up 1) 12.03 11.25 10.54 12.70 16.29 12.10
40 weeks (follow-up 2) 12.84 12.54 9.44 12.18 18.60 14.05
Quality of life
Baseline 36.93 12.84 39.36 21.87 38.78 18.40 45.68 20.98
6 weeks 49.54 17.23 57.49 20.82 44.86 25.25 41.74 15.13
14 weeks (posttreatment) 52.67 20.21 62.93 21.70 49.22 24.97 46.75 19.00
27 weeks (follow-up 1) 58.10 22.78 60.43 23.31 49.61 25.67
40 weeks (follow-up 2) 54.57 20.74 65.11 22.46 50.38 25.53
a
CAPS=Clinician-Administered PTSD Scale; PDS=Posttraumatic Diagnostic Scale; SDS=Sheehan Disability Scale; BDI=Beck Depression
Inventory; BAI=Beck Anxiety Inventory.

Comparison of Treatment Conditions With Waiting
List Condition
Table 2 summarizes the recovery rates for the treatment
and waiting list conditions. All treatment conditions were
more likely to lead to recovery from PTSD diagnosis than
the waiting list. Intensive and standard cognitive therapy
had excellent number-needed-to-treat statistics of 1.50
(95% confidence interval [CI]=1.18–2.06) and 1.41 (95%
CI=1.14–1.87), respectively. For supportive therapy, the
number needed to treat was 2.73 (95% CI=1.77–5.95).
Similar results were obtained for assessor-rated and self-
reported total remission.
Table 3 summarizes the results for the continuous
outcome measures. We observed significant condition-by-
time interactions (p,0.002 in all cases) for all primary and
secondary outcome measures: PTSD symptoms as mea-
sured by CAPS (F=21.50, df=3, 135.35) and the Post-
traumatic Diagnostic Scale (F=21.16, df=3, 106.56) (see
also Figure 2); disability (F=14.01, df=3, 109.86); anxiety
(F=13.57, df=3, 106.85); depression (F=5.16, df=3, 122.20);
and quality of life (F=6.96, df=3, 106.85). All contrasts
between treatment conditions and the waiting list were
significant (except for quality of life between supportive
therapy and waiting list), indicating greater improvement
for intensive and standard cognitive therapy and support-
ive therapy compared with waiting list. As summarized in
Table 4, pre-post effect sizes (Cohen’s d) for both intensive
and standard cognitive therapy revealed a very large im-
provement in PTSD symptoms and disability and large
improvements in anxiety, depression, and quality of life.

300 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 EHLERS, HACKMANN, GREY, ET AL.

TABLE 4. Within- and Between-Group Cohen’s d Effect Sizes at the 14-Week Assessment (Posttreatment/Wait) and Adjusted
Intent-to-Treat Group Differences
Comparison and Intensive Cognitive Standard Weekly Supportive Waiting
Measurea Therapy Cognitive Therapy Therapy List
Within-group
pre-post
effect sizes d d d d
PTSD 1.95 1.95 1.07 0.26
symptoms
(CAPS)
PTSD 2.45 2.53 1.30 0.38
symptoms
(PDS)
Disability 1.60 1.50 0.66 0.01
Anxiety 1.17 1.46 0.67 0.15
Depression 1.19 0.96 0.78 0.28
Quality of life 0.93 1.08 0.48 0.05
Between-group Adjusted Adjusted Adjusted
effect sizes Difference 95% CI d Difference 95% CI d Difference 95% CI d d
Waiting list and
PTSD 39.55*** 26.60–52.51 1.57 38.80*** 26.19–51.40 1.55 20.84** 8.06–33.61 0.84
symptoms
(CAPS)
PTSD 17.72*** 12.54–22.90 1.75 19.84*** 14.71–24.97 1.96 10.35*** 5.15–15.54 1.02
symptoms
(PDS)
Disability 9.96*** 6.10–13.81 1.33 9.82*** 5.95–13.68 1.30 4.45* 0.62–8.28 0.59
Anxiety 11.98*** 6.54–17.43 1.13 15.48*** 10.04–20.91 1.45 6.61* 1.18–12.05 0.62
Depression 9.04*** 4.26–13.81 0.97 8.81*** 4.06–13.55 0.95 5.54* 0.75–10.34 0.59
Quality of life –12.43** –21.28 to –3.58 0.73 –20.67*** –29.39 to –11.95 1.21 –7.98 –16.79 to 0.83 0.47
Supportive
therapy
and
PTSD 18.72** 5.96–31.45 0.75 17.96** 5.31–30.62 0.72
symptoms
(CAPS)
PTSD 7.37** 2.19–12.55 0.73 9.49*** 4.34–14.64 0.94
symptoms
(PDS)
Disability 5.51** 1.71–9.31 0.74 5.37** 1.59–9.15 0.72
Anxiety 5.37* 0.06–10.80 0.51 8.86** 3.46–14.27 0.83
Depression 3.49 –1.30 to 8.28 0.37 3.26 –1.50 to 8.05 0.35
Quality of life –4.45 –13.17 to 4.28 0.26 –12.69** –21.33 to –4.04 0.74
Standard weekly
cognitive
therapy and
PTSD 0.76 –12.06 to 13.57 0.03
symptoms
(CAPS)
PTSD –2.12 –7.26 to 3.02 0.21
symptoms
(PDS)
Disability 0.14 –3.63 to 3.91 0.02
Anxiety –3.49 –8.89 to 1.90 0.33
Depression 0.23 –4.52 to 4.98 0.02
Quality of life 8.24 –0.42 to 16.90 0.48
a
CAPS=Clinician-Administered PTSD Scale; PDS=Posttraumatic Diagnostic Scale.
* p,0.05. **p,0.01. ***p,0.001.

Comparison of Treatment Conditions
At the posttreatment and follow-up assessments, more
patients receiving intensive and standard cognitive ther-
apy had recovered from a PTSD diagnosis than patients
receiving supportive therapy (Table 2). Similar results were
obtained for assessor-rated and self-reported total re-
mission. For all primary and secondary continuous out-
comes except depression (Table 3), hierarchical linear
modeling revealed significant interactions between con-
dition and linear time effects: PTSD symptoms as measured

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 301

 COGNITIVE THERAPY FOR PTSD AND EMOTION-FOCUSED SUPPORTIVE THERAPY
FIGURE 2. Changes in PTSD Symptoms in a Randomized
Controlled Trial of Cognitive and Supportive Therapies for
PTSDa
40
35
Posttraumatic Diagnostic Scale score
30
25
20
15
10
5 indicating comparable outcomes. Baseline-adjusted differ-
0
Baseline 3 6 14 27
Posttreatment FU1
Weeks
a 1.63), d=0.24; depression, 0.27 (95% CI=23.59 to 4.13), d=0.03;
Scores were measured with the Posttraumatic Diagnostic Scale for 7-
day intensive cognitive therapy (iCT, all patients), standard weekly
cognitive therapy (sCT, all patients), weekly emotion-focused
supportive therapy (EST), and waiting list. All patients completed the
scale at baseline, 6 weeks, and 14 weeks (posttreatment/wait).
Patients receiving therapy also completed the scale at 3 weeks,
27 weeks (follow-up 1, FU1), and 40 weeks (follow-up 2, FU2).
by CAPS (F=7.83, df=2, 154.13, p=0.001) and the Post-
traumatic Diagnostic Scale (F=4.42, df=2, 215.14, p=0.01);
disability (F=7.45, df=2, 220.14, p=0.001); anxiety (F=5.40,
df=2, 176.80, p=0.005); depression (F=0.79, df=2, 213.98,
p.0.23); and quality of life (F=3.27, df=2, 231.98, p=0.04).
Contrasts revealed that both intensive and standard cog-
nitive therapy led to greater improvement than support-
ive therapy on the primary outcome measures (CAPS and
Posttraumatic Diagnostic Scale scores), disability, and anx-
iety. For quality of life, standard cognitive therapy was
superior to supportive therapy, and we observed a trend
for intensive cognitive therapy to be superior (p,0.10).
Baseline-adjusted mean group differences at posttreatment
and effect sizes are listed in Table 4.
Speed of Recovery
Comparison of the treatment groups at 3 weeks,
controlling for initial severity, revealed significant differ-
ences on Posttraumatic Diagnostic Scale scores (F=10.35,
df=2, 87, p,0.001) and measures of anxiety (F=4.23, df=2,
87, p=0.018) and depression (F=5.27, df=2, 87, p=0.007).
The intensive cognitive therapy group scored lower on
PTSD symptoms than the standard cognitive therapy and
supportive therapy groups (baseline-adjusted means,
16.65 [95% CI=13.19–20.12], 24.05 [95% CI=20.64–27.46],
and 27.65 [95% CI=24.18–31.12], respectively). The
302 ajp.psychiatryonline.org
intensive therapy group also had lower depression scores
at 3 weeks than both other treatment groups and lower
anxiety scores than patients receiving supportive therapy.
iCT Additional Comparison of Intensive and Standard
Weekly Cognitive Therapy Including Waiting List
sCT
EST Patients
Wait To further test the comparability of outcomes between
the intensive and standard cognitive therapy groups, waiting
list patients who still had PTSD at the post-waiting period
assessment and still wished treatment were randomly
assigned to either standard (N=13) or intensive (N=11)
cognitive therapy. The comparison of all patients treated
with intensive (N=41) and standard cognitive therapy (N=44)
had 80% power in detecting a difference of 4.4 points on the
Posttraumatic Diagnostic Scale. We found no interactions
between treatment condition and time on any measure,
ences at 14 weeks between all standard weekly and intensive
cognitive therapy patients were as follows: CAPS, 22.19 (95%
40 CI=212.97 to 8.60), d=0.08; Posttraumatic Diagnostic Scale,
FU2
21.48 (95% CI=25.35 to 2.39), d=0.15; disability, 0.51 (95%
CI 22.74 to 3.75), d=0.06; anxiety, 22.59 (95% CI=26.79 to
and quality of life, 4.8 (95% CI=23.18 to 12.72), d=0.23.
Discussion
The main findings were 1) that a novel 7-day intensive
version of cognitive therapy for PTSD was well tolerated,
achieved faster symptom reduction, and led to comparable
overall outcomes as the standard once-weekly cognitive
therapy delivered over 3 months, and 2) that both intensive
and standard cognitive therapy had specific effects and
were more efficacious in treating PTSD than emotion-
focused supportive therapy. The intent-to-treat pre-post
effect sizes for improvement in PTSD symptoms with both
intensive and standard cognitive therapy were very large,
and patients’ mean scores after treatment were in the
nonclinical range. We observed no site effects, suggesting
that the treatment worked as well in patients recruited from
a routine clinical setting as in those referred to a research
clinic. The study replicated the excellent outcomes ob-
served for cognitive therapy for PTSD in previous trials (9,
10) and is the first study to demonstrate that this treatment
not only leads to a large reductions in PTSD symptoms,
disability, anxiety, and depression, but also to large increases
in quality of life.
Some authors (6, 7) have expressed concerns about
a risk of symptom exacerbation with trauma-focused
psychological treatments, and it is therefore noteworthy
that both standard and intensive cognitive therapy were
well tolerated, in line with initial case reports of intensive
trauma-focused treatments (8, 36). Delivering cognitive
therapy in an intensive format did not increase dropout
rates or symptom deterioration. Both the standard and
Am J Psychiatry 171:3, March 2014

Patient Perspective
“Ms. D,” 29 years old, developed posttraumatic stress
disorder (PTSD) after a life-threatening medical emergency.
The trauma happened 3 years before she participated in
the trial.
“I sought treatment because I knew I wasn’t dealing
well with the after-effects of my trauma. I didn’t feel like
I was living; only existing. You see, during my trauma,
I had physical injuries and my legs had to be amputa-
ted below the knees. Afterward, I felt like my life was
over.
“I found all of the therapy helpful. Especially going
over my memories and making sense of them logically,
with the benefit of hindsight and realism. I also found the
intensive cognitive therapy groups were less likely to be rated
on the CAPS as having deteriorated than those waiting for
treatment. The present study thus underlines the safety of
this treatment approach. The feasibility of intensive cognitive
therapy is of interest for therapeutic settings where treat-
ment needs to be conducted over a short period of time, such
as in residential therapy units or occupational groups
exposed to trauma, or where patients have to get better
quickly to avoid secondary complications such as job loss or
marital problems. The feasibility of intensive treatment is
also of interest for patient choice, as some patients may find
a shorter condensed treatment preferable.
The novel intensive version of cognitive therapy for
PTSD may offer some advantages over weekly treatment.
Problems with concentration and memory are common in
PTSD, and the intensive format may help keep the
therapeutic material fresh in patients’ minds until the
next session. A possible disadvantage for some patients is
that the intensive treatment phase offers less opportunity
for the therapist to guide them to reclaim their lives
through homework assignments.
Emotion-focused supportive therapy led to greater
improvement than waiting for treatment, and a substantial
minority of 43% of patients no longer met criteria for
PTSD after therapy. Supportive therapy was included as
a credible therapeutic alternative so that observed effects
of cognitive therapy could be attributed to its specific
effects beyond the benefits of good therapy. Emotion-
focused supportive therapy is a plausible treatment for
PTSD, as the disorder is characterized by high levels of
emotional distress, and poor social support has been
shown to be a predictor of PTSD (37). Patients’ ratings of
credibility and therapeutic alliance were the same as for
cognitive therapy. Supportive therapy led to similar im-
provements as cognitive therapy in depression, but led to
substantially less improvement in PTSD symptoms,
disability, anxiety, and quality of life, indicating specific
treatment effects of cognitive therapy. Mean scores on the
Am J Psychiatry 171:3, March 2014
EHLERS, HACKMANN, GREY, ET AL.
homework essential to my recovery. I looked forward to
the ‘me’ time completing it.
“At the end of the treatment, I felt so much better! My
whole attitude to life had transformed and I looked forward
to every new day. Also, my symptoms had dramatically
reduced. I still thought of some of the memories (not in
a ‘flashback’ sense), but they no longer caused me to cry.
“Now, 3 years later, my life is very different. I feel totally
reconciled to the person I was pre-trauma. I don’t find
those memories from the past as painful anymore. I can
safely say that I am indeed living, not just existing anymore.
My experience of cognitive therapy was life changing and
I’m very grateful for it.”
primary outcome measures were still within the clinical
range after supportive therapy, whereas patients treated
with standard or intensive cognitive therapy had mean
scores in the nonclinical range. Thus, supportive therapy
was not as effective as cognitive therapy in treating PTSD,
but benefits some patients. The pattern of results is consistent
with studies that compared other forms of trauma-focused
psychological treatments with active nondirective treatments
(20, 21, 38, 39).
This study had some limitations. First, although the
observed differences between intensive and standard
cognitive therapy were small and nonsignificant, it is
conceivable that statistically significant differences could
be discovered in larger trials. However, it is debatable
whether such small differences would be clinically mean-
ingful. Second, the study focused on traumatic events in
adulthood, and it will need to be investigated whether the
results generalize for the treatment of childhood trauma.
Received April 25, 2013; revisions received July 16 and Aug. 27,
2013; accepted Sept. 6, 2013 (doi: 10.1176/appi.ajp.2013.13040552).
From the Department of Experimental Psychology, University of
Oxford, U.K., and National Institute for Health (NIHR) Research Oxford
Cognitive Health Clinical Research Facility; the NIHR Biomedical
Research Centre for Mental Health, South London and Maudsley NHS
Foundation Trust, King’s College London; and the Department of
Psychiatry, University of Oxford, U.K. Address correspondence to Dr.
Ehlers (anke.ehlers@psy.ox.ac.uk).
The authors report no financial relationships with commercial
interests.
Supported by Wellcome Trust (grant 069777 to Anke Ehlers and
David Clark).
The authors thank Kelly Archer, Anna Bevan, Francesca Brady,
Ruth Collins, Linda Horrell, Judith Kalthoff, and Catherine Seaman for
their help with trial administration, data collection, entry, and
analysis; Margaret Dakin, Sue Helen, and Julie Twomey for admin-
istrative support; Dirk Hillebrandt for statistical consultation; Sue
Clohessy, Martina Mueller, Antje Horsch, Hannah Murray, Anna
Sandall, Sandra Ewing, and Olivia Bolt for assessments; Louise
Waddington and Ruth Collins for ratings of treatment sessions; and
Michelle Moulds for therapist training.
The trial was registered as ISRCTN 48524925.
ajp.psychiatryonline.org 303
COGNITIVE THERAPY FOR PTSD AND EMOTION-FOCUSED SUPPORTIVE THERAPY
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Am J Psychiatry 171:3, March 2014
 Article

Results of a Multicenter Randomized Controlled Trial

of the Clinical Effectiveness of Schema Therapy
for Personality Disorders
Lotte L.M. Bamelis, Ph.D.
Silvia M.A.A. Evers, Ph.D.
Philip Spinhoven, Ph.D.
Arnoud Arntz, Ph.D.
Objective: The authors compared the ef-
fectiveness of 50 sessions of schema therapy
with clarification-oriented psychotherapy
and with treatment as usual among pa-
tients with cluster C, paranoid, histrionic,
or narcissistic personality disorder.
Method: A multicenter randomized con-
trolled trial, with a single-blind parallel de-
sign, was conducted between 2006 and
2011 in 12 Dutch mental health institutes.
A total of 323 patients with personality
disorders were randomly assigned (schema
therapy, N=147; treatment as usual, N=135;
clarification-oriented psychotherapy, N=41).
There were two cohorts of schema therapy
therapists, with the first trained primarily
with lectures and the second primarily
with exercises. The primary outcome was
recovery from personality disorder 3 years
after treatment started (assessed by blinded
interviewers). Secondary outcomes were
dropout rates and measures of personality
disorder traits, depressive and anxiety dis-
orders, general psychological complaints,
general and social functioning, self-ideal
discrepancy, and quality of life.
Results: A significantly greater propor-
tion of patients recovered in schema
therapy compared with treatment as usual
and clarification-oriented psychotherapy.
Second-cohort schema therapists had bet-
ter results than first-cohort therapists.
Clarification-oriented psychotherapy and
treatment as usual did not differ. Findings
did not vary with specific personality dis-
order diagnosis. Dropout was lower in the
schema therapy and clarification-oriented
psychotherapy conditions. All treatments
showed improvements on secondary out-
comes. Schema therapy patients had less
depressive disorder and higher general
and social functioning at follow-up. While
interview-based measures demonstrated
significant differences between treatments,
differences were not found with self-report
measures.
Conclusions: Schema therapy was supe-
rior to treatment as usual on recovery,
other interview-based outcomes, and
dropout. Exercise-based schema ther-
apy training was superior to lecture-
based training.

(Am J Psychiatry 2014; 171:305–322)

P ersonality disorders are complex mental health prob-

lems associated with chronic dysfunction in several life
domains (social, work, self-care) (1, 2), reduced quality of
life (3), high societal costs (4), and a high prevalence rate
(3%–15% in the general population) (5). Although psycho-
logical treatment is considered to be the treatment of
choice for personality disorders (6, 7), research into its
effectiveness is still in its infancy, troubled with method-
ological issues and strongly focused on borderline per-
sonality disorder. Studying the effectiveness of treatment
for understudied personality disorders is a highly priori-
tized recommendation in several reviews (8–10).
Schema therapy is a form of psychotherapy that has
proven to be efficacious for borderline personality disorder.
A randomized controlled trial comparing schema therapy
with transference-focused psychotherapy found domi-
nance of schema therapy over transference-focused psy-
chotherapy on all outcome measures and a significantly
lower dropout rate in schema therapy (11). Schema therapy
also proved to be a more cost-effective treatment (12). A
subsequent study found that schema therapy can be
successfully implemented in regular mental health care
(13). Another study reported superiority of schema therapy
over treatment as usual for borderline personality disorder
(14). However, the effectiveness of schema therapy for
personality disorders other than borderline personality
disorder remains to be evaluated.
The main objective of the present randomized con-
trolled trial was to examine the clinical effectiveness of
schema therapy for a group of six personality disorders:
cluster C (avoidant, dependent, and obsessive-compulsive),
histrionic, narcissistic, and paranoid personality disorders.
Other personality disorders were excluded because they
were deemed to require highly specialized and lengthier
treatment protocols. A treatment protocol of 50 schema
therapy sessions was compared with treatment as usual,

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CLINICAL EFFECTIVENESS OF SCHEMA THERAPY FOR PERSONALITY DISORDERS
FIGURE 1. Descriptions of Schema Therapy and Clarification-
Oriented Psychotherapy
Schema therapy and clarification-oriented psychotherapy are both
based on schema-conceptualizations and the idea that rigid
pathological characteristics of personality disorders are the result
of a negative childhood environment in which core fundamental
needs were not met. Although they share similar underlying
theoretical constructs, there are important differences.
Core Aspects of Schema Therapy:
• Integrative psychotherapy; combines cognitive, experiential,
behavioral, and interpersonal techniques
• Mode model (cf. “ego-states”: modes refer to particular sets of
schemas and coping styles that are active at a given time and can
be either adaptive or maladaptive) and specific therapy
techniques for each mode
• Emphasis on the therapeutic relationship as a limited way of
fulfilling needs and more directive and personal than most other
approaches
• Extensive processing of negative childhood experiences
(including trauma) with specific techniques (e.g., imagery
rescripting)
• Experiential work to evoke emotions and facilitate emotional
change, in addition to cognitive-behavioral therapy and
relational techniques
Core Aspects of Clarification-Oriented Psychotherapy:
• Originates in client-centered psychotherapy
• A conceptual model stressing dysfunctional interaction behavior
as a strategy to get unfulfilled needs met
• Primary channel of change is through insight
• Therapists help patients to discover dysfunctional patterns and
functional ways to get needs adequately met, in a nondirective
way
• An important technique is to respond to dysfunctional behavior
in noncomplementary ways and then to invite the patient to
express his or her needs in a functional way
which is primarily psychological treatment in the Nether-
lands, varying from supportive low-frequency contacts to
advanced psychotherapy. Because any novel specialized
psychotherapy might be more effective than treatment as
usual, we also wanted to compare treatment as usual with
a specialized psychotherapy other than schema therapy.
Therefore, we added clarification-oriented psychotherapy,
a form of client-centered therapy developed for person-
ality disorders (15). We hypothesized that schema therapy
would be superior to treatment as usual in preventing
treatment dropout and on primary and secondary outcome
measures. We explored whether similar effects would be
found for clarification-oriented psychotherapy. If both
experimental conditions could be superior to treatment
as usual, follow-up tests could compare schema therapy
and clarification-oriented psychotherapy. Schema therapy
therapists were trained in two cohorts with different edu-
cational formats, one mainly based on lectures and the
other on structured experiential training of techniques.
Training therapists in two cohorts at different time points
was necessitated by the need for additional therapists
during trial execution (since one center withdrew partici-
pation before the start of the study). Investigating the effects
of therapist training on treatment outcome is an important,
306 ajp.psychiatryonline.org
though neglected, topic (16, 17). Therefore, although ini-
tially not a research question, we tested schema therapy co-
hort differences and controlled condition effects for cohort.
Method
In this multicenter, pragmatic randomized controlled trial
(parallel-group design), patients from 12 Dutch mental health
institutes were enrolled (18), and three of the 12 centers had
enough client-centered-therapists available to add clarification-
oriented psychotherapy as a third arm (hence, comparisons
involving clarification-oriented psychotherapy had a smaller
sample size). Participants had at least one of the personality
disorder diagnoses discussed above, based on the Structured
Clinical Interview for DSM-IV Axis II Personality Disorders (SCID
II [19]), as the principal diagnosis (diagnosis for which the patient
seeks help). Additional inclusion criteria were availability to
participate in the study and age 18 to 65. Exclusion criteria were
the presence (also subthreshold) of antisocial, schizotypal,
schizoid, or borderline personality disorder; lifetime prevalence
of psychosis or bipolar disorder; IQ ,80; and immediate suicide
risk or substance abuse needing clinical detoxification. With 125
participants per arm, the study was powered at 90% to detect
a schema therapy versus treatment as usual recovery difference
of an odds ratio of 2.70 at an alpha of 0.05 (80% power to detect
for clarification-oriented psychotherapy [N=50] versus treatment
as usual) (18). An independent statistician generated computer-
based lists using adaptive biased urn randomization for small
strata (20). After checking the inclusion and exclusion criteria, an
independent research assistant randomly assigned patients to two
groups (schema therapy compared with treatment as usual with
equal prior rates) per center in nine participating centers and to
three groups (schema therapy compared with treatment as usual
compared with clarification-oriented psychotherapy with equal
prior rates) per center in three participating centers. Matching of
patient to therapist was done through local schema therapy and
clarification-oriented psychotherapy peer-supervision groups or
by local staff in treatment as usual. A test battery including assessor-
based and self-report instruments was administered at 6, 12, 18, 24,
and 36 months. At 36 months (the 3-year follow-up), diagnostic
interviews were repeated. Assessments were conducted by inde-
pendent research assistants at local sites, except for 3-year follow-
up diagnostic interviews that were conducted by central blinded
interviewers. All patients provided written informed consent before
participating in the study, and the study was approved by the
medical ethical committee of Maastricht University.
The primary outcome measure was recovery from all per-
sonality disorders (defined as not meeting criteria for any
personality disorder), as measured with SCID II by blinded
independent interviewers at the 3-year follow-up. Data from 42
double-rated audiotaped interviews demonstrated good inter-
rater reliability, with the mean intraclass correlation coefficient
between interviewers being 0.84 (from 0.50 to 0.97 over sub-
scales). Missing SCID II assessments were replaced by person-
ality disorder diagnoses obtained from the most recent scores
on the Assessment of DSM-IV Personality Disorders Question-
naire (21), using the categorical scoring algorithms (22). Assessor-
based secondary measures were axis I mood and anxiety disorders
(assessed with SCID I [23] by SCID II interviewers) and Global
Assessment of Functioning Scale (24) and Social and Occupational
Functioning Assessment Scale (24) scores, assessed by research
assistants at regular assessments, who also monitored medication
use. Self-report secondary measures included the Assessment of
DSM-IV Personality Disorders Questionnaire dimensional sub-
scales, the Symptom Checklist-90 (25) for general symptoms, the
Am J Psychiatry 171:3, March 2014

TABLE 1. Comparison of Schema Therapy and Clarification-Oriented Psychotherapy
Schema Therapy
Therapeutic relationship
Directive (with regard to both content and process).
Limited re-parenting: The therapist partly meets unmet
childhood needs within healthy therapy boundaries
(e.g., offers safe attachment, praises the patient,
stimulates playfulness, and sets limits).
The therapist is open about personal responses evoked by the
patient, with frequent self-disclosure if deemed helpful.
Psychoeducation: The therapist teaches the patient
about core needs, as well as functional and
dysfunctional behaviors, and links present problems to
childhood experiences.
Conceptual model of the personality disorder
The patient’s problems are framed through schema
modes: different “sides” of themselves that become
activated by triggers related to childhood experiences.
These modes govern the patient’s emotions,
cognitions, and behaviors.
Importance of determining childhood origins of
schemas/schema modes
Central to model and treatment. Dysfunctional parenting
and traumas in childhood are viewed as origins of
dysfunctional schemas/modes. The therapist
frequently links the present and the past. Extensive
processing of childhood experiences (including
traumas) and correcting internalized messages are
achieved.
Main mechanisms of change
Corrective emotional experiences, cognitive change, and
change in behaviors. The therapist is internalized as
the “healthy adult.”
Targets of interventions
Therapeutic relationship (limited re-parenting).
Memories of childhood are linked to present problems.
Present problems outside therapy.
Main techniques
Experiential, cognitive, and behavioral techniques are
geared to specific modes.
The therapist initially takes the lead (e.g., challenges
punitive parent mode on empty chair, intervenes in
imagery re-scripting, empathically confronts the
patient with dysfunctional behaviors, and proposes
and stimulates functional behaviors).
Gradually, patients apply techniques themselves.
Treatment phase
Year 1
Session 1–6: introduction into schema therapy,
bonding and case conceptualization in terms of
mode model.
Session 7–24: focus on reducing coping modes and on
historical and experiential work (e.g., imagery re-
scripting, empty chair technique).
Session 25–40: focus mostly on present (e.g.
behavioral pattern breaking).
Year 2
Session 41–50: monthly booster sessions to maintain
and deepen changes.
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BAMELIS, EVERS, SPINHOVEN, ET AL.
Clarification-Oriented Psychotherapy
Nondirective as to content, directive with regard to process (the therapist
proposes processes that foster clarification, confrontation with
interfering processes).
No focus on meeting the patient’s unmet childhood needs in the
therapeutic relationship but on helping the patient to become aware of
dysfunctional ways in which basic needs and motives are expressed.
When the patient displays dysfunctional, unauthentic behavior, the
therapist responds in ways not expected by patient (“noncomplementary
response”).
Rogerian therapy conditions (unconditional acceptance, empathy, and
genuineness) are necessary but not sufficient for change.
No psychoeducation.
The patient’s problems are framed as dysfunctional interpersonal
strategies to get basic motives/needs met. These nonauthentic and
manipulative interpersonal strategies are shaped by cognitive-affective
schemas about self, personal problems, and relationships with others
evolved during development.
Childhood origins are important to understand development of cognitive-
affective schemas but are not targets of specific change techniques.
Insight: Patients should become aware of their authentic motives/needs
and the dysfunctional cognitive-affective schemas interfering with
functional interpersonal behaviors.
Process: Promote clarification (e.g., by proposing to attend to a basic need/
motive) and challenge attempts to avoid clarification.
Schema change: Acquiring insight that dysfunctional schemas are incorrect.
The therapist responds to problem behavior during the session in
unexpected (noncomplementary) ways to create awareness.
The therapist responds to functional behavior in accepting
(“complementary”) ways to strengthen the behavior.
The therapist proposes constructive clarification processes and challenges
avoidance.
The therapist facilitates patients to acquire insight into the incorrectness of
cognitive-affective schemas (e.g., by one-person role-play).
Phase 1: Bonding, understanding the patient, and being complementary
to authentic expression of basic needs and not complementary to
unauthentic expression.
Phase 2: Bonding, confronting dysfunctional interpersonal strategies, and
defining treatment goals.
Phase 3: Bonding, clarification of schemas, and confronting avoidance
tendencies.
Phase 4: Facilitating patients in acquiring insight into incorrectness of
cognitive-affective schemas (e.g., with one-person role-play).
Phase 5: Transfer to behavior: facilitating patients to change their
behaviors.
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TABLE 2. Baseline Demographic and Clinical Characteristics of Patients With Personality Disorders by Treatment Received
Treatment
Schema Therapy Clarification-Oriented Treatment As Usual
Characteristic (N=145) Psychotherapy (N=41) (N=134) Analysis
Mean SD Mean SD Mean SD pa
Age (years) 37.57 9.69 39.20 9.37 38.06 9.63 0.63
N % N % N % pb
Male 66 45.5 18 43.9 55 41 0.75
Education
Primary school 6 4.1 3 7.3 3 2.2 0.85c
Lower vocational 6 4.1 4 9.8 15 11.2
Lower secondary 22 15.2 3 7.3 8 6
Higher secondary 11 7.6 2 4.9 15 11.2
Intermediate vocational 46 31.7 15 36.6 45 33.6
Preuniversity 11 7.6 2 4.9 10 7.5
Higher vocational 29 20 12 29.3 25 18.7
Academic 14 9.7 0 0 13 9.7
Employment status
Housewife 7 4.8 1 2.4 5 3.7 0.96
Student 7 4.8 3 7.3 6 4.5
Employed 66 45.5 16 39 63 47
Disability 47 32.4 17 41.5 46 34.3
Welfare 17 11.7 4 9.8 14 10.4
Retired 1 0.7 0 0 0 0
Primary personality
disorder diagnosis
Avoidant 74 51 19 46.3 70 52.2 0.86
Dependent 16 11 6 14.6 14 10.4
Obsessive-compulsive 41 28.3 11 26.8 37 27.6
Paranoid 8 5.5 1 2.4 5 3.7
Histrionic 0 0 1 2.4 1 0.7
Narcissistic 6 4.1 3 7.3 7 5.2
Secondary personality
disorder diagnosis
None 80 55.2 19 46.3 69 51.5 0.58
Avoidant 13 9 8 19.5 22 16.4 0.09
Dependent 9 6.2 3 7.3 2 1.5 1.00
Obsessive-compulsive 11 7.6 7 17.1 15 11.2 0.19
Paranoid 3 2.1 3 7.3 4 3 0.23
Histrionic 0 0 0 0 0 0
Narcissistic 0 0 0 0 1 0.7 0.50
Passive-aggressive 6 4.1 1 2.4 3 2.2 0.64
Depressive 41 28.3 13 31.7 39 29.1 0.91
Axis I comorbidity (current)
Anxiety disorders 82 56.6 25 61 80 59.7 0.82
Depressive disorder 61 42.1 23 56.1 59 44.0 0.28
Somatoform disorders 17 11.7 4 9.8 11 8.2 0.62
Substance abuse 7 4.8 5 12.2 1 0.7 ,0.01
Eating disorders 3 2.1 1 2.4 6 4.5 0.50
Other axis I disorders 11 7.6 7 17.1 19 14.2 0.11
Psychotropic medication at baseline 71 49 18 43.9 74 55.2 0.36
Mean SD Mean SD Mean SD p
Number of treatments before baseline 2.44 2.35 2.12 3.3 2.28 2.22 0.72a
Number of treatment modalities 1.51 1.23 1.27 1.30 1.36 1.18 0.41a
before baseline
Total duration of previous 29.73 42.70 31.98 78.51 35.75 63.73 0.68a
treatments (months)
Number of principal treatments 1.33 0.69 1.51 0.93 1.39 0.73 0.40c
over 3 years
Number of secondary treatments 0.68 1.04 0.85 1.04 0.92 1.32 0.14c
over 3 yearsd
continued

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TABLE 2. Baseline Demographic and Clinical Characteristics of Patients With Personality Disorders by Treatment Received
(continued)
Treatment
Schema Therapy Clarification-Oriented Treatment As Usual
Characteristic (N=145) Psychotherapy (N=41) (N=134) Analysis
25th–75th 25th–75th 25th–75th
Median Percentile Median Percentile Median Percentile pc
Total number of sessions of 50 31–50 51 28–74 22 11–47 ,0.01
indicated principal
treatments over 3 years
Total number of sessions of 0 0–11 5 0–18 3 0–18 0.04
additional treatments
over 3 years
Total number of days in principal 694 481–766 895 393–1038 522 243–863 ,0.01
treatments over 3 years
N % N % N % p
Distribution of indicated
principal treatments
Did not receive 2 1.4 0 0 7 5.2
indicated treatment
Schema therapy 143 98.6 0 0 0 0
Clarification-oriented 0 0 41 100.0 0 0
psychotherapy
Cognitive-behavioral therapy 0 0 0 0 26 19.4
Eye movement desensitization 0 0 0 0 2 1.5
and reprocessing
Insight-oriented psychotherapy 0 0 0 0 56 41.8
Supportive therapy 0 0 0 0 43 32.1
% 95% CI % 95% CI % 95% CI pf
Medication use during 3 years 40.4e 34–47.1 50.0 40.1–59.8 58.2 51.2–64.9 ,0.001
N % N % N % pb
Number of patients still in 19 13.1 15 36.6 35 26.1 ,0.01
treatment at follow-up
Results of treatment
integrity tests Mean SD Mean SD Mean SD pa
Schema therapy techniques 1.65g 0.40 1.19 0.15 1.21 0.16 ,0.001
Clarification-oriented 1.60 0.41 1.79h 0.46 1.51i 0.38 ,0.001
psychotherapy techniques
Facilitative conditions 3.80g 0.63 3.52 0.67 3.45 0.69 ,0.001
Explicit directiveness 3.47g 0.50 3.15 0.48 3.24 0.60 ,0.001
a
Value is based on analysis of variance F test.
b
Value is based on the Pearson’s chi-square test unless otherwise indicated.
c
Value is based on the Kruskal-Wallis test.
d
Secondary treatments are therapies given to patients alongside principal treatments.
e
Schema therapy differs significantly from treatment as usual and clarification-oriented psychotherapy (p,0.05).
f
Value is based on an F test from mixed logistic regression.
g
Schema therapy differs significantly from treatment as usual and clarification-oriented psychotherapy (p,0.01).
h
Clarification-oriented psychotherapy differs significantly from schema therapy and treatment as usual (p,0.01).
i
Treatment as usual differs significantly from schema therapy (p,0.05) and from clarification-oriented psychotherapy (p,0.01).

Work and Social Adjustment Scale (26) for social functioning, the
Miskimins Self-Goal-Other Discrepancy Scale (27) for actual-ideal
self-discrepancy, and the modified World Health Organization
Quality of Life Assessment [28]).
Treatment, Therapists, and Treatment Integrity Check
Descriptions and comparisons of schema therapy and
clarification-oriented psychotherapy are presented in Figure 1 and
Table 1; our design for specific characteristics of treatment
conditions has been described elsewhere (18). Schema therapy
and clarification-oriented psychotherapy were both individual
outpatient psychotherapies (initially) delivered weekly and included
a standardized treatment protocol (15, 29). Schema therapy con-
sisted of 40 sessions in the first year and 10 booster sessions in
the second year, while clarification-oriented psychotherapy was
open-ended. Therapists in both conditions received a 4-day
training session at the start of the study, yearly national super-
vision, and weekly local peer supervision. Clarification-oriented
psychotherapists were required to be accredited client-centered
therapists or trainees, while any theoretical orientation was al-
lowed for schema therapists. Therapists eventually included in
the schema therapy arm were recruited through self-expressed
interest to learn schema therapy. All other therapists could be
treatment as usual therapists. In treatment as usual, local intake
staff chose a specific treatment method and modality for a par-
ticular patient, depending on the patient’s capacity, needs, and
circumstances. In this way, treatment as usual was optimized
and mimicked usual practice. Treatment as usual did not include

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CLINICAL EFFECTIVENESS OF SCHEMA THERAPY FOR PERSONALITY DISORDERS
FIGURE 2. Study CONSORT Diagram
Allocated to schema therapy (N=147)
• 143 received allocated intervention
• 4 did not start allocated intervention
2 not available for study (moved away), 1
continued current treatment unexpect-
edly, 1 protocol deviation: site allocated
patient to treatment as usual
Lost to follow-up (N=28)
• 5 between 0 and 6 months
• 10 between 6 and 12 months
• 3 between 12 and 18 months
• 6 between 18 and 24 months
• 4 between 24 and 36 months
• reasons: 12 refused, 12 not motivated, 3
life events, 1 protocol deviation (site
allocated patient to treatment as usual)
Discontinued indicated intervention
(N=38)
• 7 refused, 2 required immediate crisis
care, 1 life event, 3 protocol deviation (1
site allocated patient to treatment as
usual, 1 site did not cover continuation of
treatment when therapist fell ill, 1 patient
was not available because prior treatment
was unexpectedly continued), 8 not
motivated, 10 dissatisfied with treatment,
4 had no more complaints, 2 found
treatment too expensive, 1 no longer
wanted to participate in trial
Analyzed (N=145)
• excluded from analyses
2 moved away during randomization
period
310 ajp.psychiatryonline.org
Excluded (N=285)
Assessed for eligibility (N=624)
• not meeting inclusion criteria (N=140)
• met exclusion criteria (N=108)
• declined to participate (N=37)
Dropout before completion of
baseline assessment (N=16)
• declined to participate (N=11)
• no show (N=3)
• moved away (N=1)
• too vulnerable for the extensive
Randomly assigned (N=323)
assessments according to staff (N=1)
Allocation
Allocated to treatment as usual (N=135) Allocated to clarification-oriented
• 127 received allocated intervention psychotherapy (N=41)
• 8 did not start allocated intervention • 41 received allocated intervention
2 sought treatment outside the site, 2 had • 0 did not start allocated intervention
no treatment as usual therapist available,
1 was referred to autism screening, 1
found treatment too confronting, 1 did not
show, 1 refused treatment as usual (only
wanted schema therapy)
Follow-Up
Lost to follow-up (N=44) Lost to follow-up (N=7)
• 19 between 0 and 6 months • 3 between 0 and 6 months
• 11 between 6 and 12 months • 1 between 6 and 12 months
• 6 between 12 and 18 months • 1 between 12 and 18 months
• 3 between 18 and 24 months • 0 between 18 and 24 months
• 5 between 24 and 36 months • 2 between 24 and 36 months
• reasons: 21 refused, 16 not motivated, 3 life • reasons: 3 refused, 3 not motivated, 1
events, 2 required immediate crisis care, 2 required immediate crisis care
protocol deviation (site removed 1 patient from
study because of autism suspicion and 1 patient Discontinued indicated interven-
because no treatment as usual therapist was tion (N=9)
available) • 3 refused, 3 required immediate crisis
care
Discontinued indicated intervention • 2 not motivated, 1 dissatisfied with
(N=51) treatment
• 16 refused, 2 required immediate crisis care, 2
life events, 2 protocol deviation (site removed 1
patient from study because of autism suspicion
and 1 patient because no treatment as usual
therapist was available), 11 not motivated, 12
dissatisfied with treatment, 4 had no more
complaints, 1 found treatment too expensive,
1 no longer wanted to participate in trial
Analysis
Analyzed (N=134) Analyzed (N=41)
• excluded from analyses • excluded from analyses (N=0)
1 withdrew consent
Am J Psychiatry 171:3, March 2014

a standardized study protocol or training/supervision of thera-
pists. Treatment as usual therapists had standard, local peer su-
pervision. Therapists in this condition were expected to follow
the clinical guidelines for personality disorders in the Nether-
lands. All primary treatment as usual was psychological treatment
(insight-oriented psychotherapy, 42%; supportive therapy, 32%;
cognitive-behavioral therapy, 19%; eye movement desensitization
Proportion of Patients in Therapy
and reprocessing, 1.5%). For all three conditions, if the patients
discontinued treatment or were referred again for treatment after
treatment termination, another treatment was offered with a
different therapist, if deemed necessary or helpful. Because of the
naturalistic treatment flow of this trial, it was possible that patients
could still receive treatment at the 3-year follow-up. Baseline de-
mographic and clinical characteristics of patients and the treat-
ments they received are presented in Table 2.
Sixty-four therapists treated one patient (schema therapy,
N=13; treatment as usual, N=50; clarification-oriented psycho-
therapy, N=1), 55 treated two (schema therapy, N=32; treatment
as usual, N=15; clarification-oriented psychotherapy, N=8), 32
treated three (schema therapy, N=17; treatment as usual, N=11;
clarification-oriented psychotherapy, N=4), nine treated four
(schema therapy, N=4; treatment as usual, N=2; clarification-
oriented psychotherapy, N=3), and one treated five (treatment as
usual). Training of schema therapy therapists occurred in two
waves (referred to as cohorts) (18). Cohort 1 received mainly
lectures and video demonstrations, while cohort 2 was trained by
another trainer, actively participated in compulsory role-play,
and received individual feedback (see the data supplement that
accompanies the online version of this article). Cohort effects
were incorporated in the analyses. All therapists had previous
experience in psychological treatment (mean years: schema
therapy, 16.05 years [SD=7.72]; treatment as usual, 16.10 years
[SD=9.82]; clarification-oriented psychotherapy, 20.38 years
[SD=8.58]), with no between-group differences. Therapists were
asked to rate their experience with delivered treatment on
a scale from 0 (none) to 5 (professional). As expected, treatment
as usual therapists (4.12 [SD=1.43]) were more experienced than
schema therapy (2.20 [SD=1.81]) and clarification-oriented
psychotherapy (1.82 [SD=2.24]), p,0.001) therapists with regard
to treatments delivered to study patients.
Treatment integrity (adherence to protocol) was monitored by
means of supervision (see reference 18). Independent blinded
raters scored randomly selected audiotapes on a series of 7-point
Likert scales, indicating the amount of time specific therapeutic
interventions were heard. In addition to specific schema therapy
and clarification-oriented psychotherapy techniques, we assessed
two general therapeutic styles, taken from the Collaborative Study
Psychotherapy Rating Scale, version 6 (30): facilitative conditions
(e.g., supportive encouragement, involvement) and explicit direc-
tiveness (e.g., level of verbal activity, explicit guidance). While 16.87%
of audiotapes were missing or lost because of poor sound quality, the
remaining audiotapes were rated by nine independent raters who
were blind to allocation. The mean intraclass correlation coefficient
across subscales of 78 double-rated audiotapes was 0.52, ranging
from 0.33 (explicit directiveness) to 0.85 (schema therapy items).
Results of 631 audiotapes are presented in Table 2. Condition-
specific techniques were highest in schema therapy and clarification-
oriented psychotherapy (p,0.001), respectively, although schema
therapy also differed significantly from treatment as usual on
clarification-oriented psychotherapy techniques. Therapists in the
second-cohort schema therapy group scored significantly higher on
schema therapy-specific techniques (p,0.05). The two general
therapeutic styles were most prominent in schema therapy.
Statistical Analyses
A detailed description of statistical procedures is presented in
the online data supplement. Results were analyzed according to
Am J Psychiatry 171:3, March 2014
BAMELIS, EVERS, SPINHOVEN, ET AL.
FIGURE 3. Proportion of Patients in Indicated Principal
Treatment (Schema Therapy, Treatment as Usual, or
Clarification-Oriented Psychotherapy)a
1.0
0.8
0.6
0.4
Schema therapy
Clarification-oriented
0.2
psychotherapy
Treatment as usual
0.0
0 200 400 600 800 1000
Days of Indicated Therapy
a
Successful termination of indicated therapy was not coded as
dropout.
the intent-to-treat principle using SPSS, version 19.0 (SPSS, Inc.,
Chicago), for logistic and linear mixed regression, with center as
random effect. For repeated measures, unstructured covariance
was used. Cohort and baseline severity were used as covariates
(the latter in analyses of diagnostic outcomes unless indicated).
Baseline severity index was a composite measure based on
standardized baseline values of the number of axis I and II
disorders, Assessment of DSM-IV Personality Disorders Ques-
tionnaire trait and distress scores, Symptom Checklist-90 score,
Global Assessment of Functioning Scale score, Social and
Occupational Functioning Assessment Scale score, and disability
(internal consistency, 0.77). For the primary outcome, a series of
sensitivity analyses was conducted. Dropout was analyzed with
survival analysis controlling for severity and cohort, as well as
with mixed logistic regression, using the same model used in the
primary outcome analysis. Because estimation failed in mixed
analyses of depressive and anxiety disorder presence at the 3-
year follow-up (as a result of missing data), multiple imputation
followed by logistic regression was used. For diagnostic out-
comes, we report effects of all condition comparisons, schema
therapy-by-cohort, and severity and sensitivity covariates when
applicable. For repeated measures, we report effects of time, all
condition comparisons of time effects, and (schema therapy
compared with treatment as usual)-by-cohort-by-time as rele-
vant to the research questions.
Results
Patient Accrual
The study was conducted between May 2006 and
January 2011. The CONSORT diagram for the study is
presented in Figure 2. A total of 624 patients were initially
referred to the study, 285 of whom were excluded during
the screening procedure. A total of 140 individuals did
not meet diagnostic criteria; 108 met exclusion criteria (89
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TABLE 3. Mixed Logistic Regression Analyses of Recovery and Dropout Among Patients With Personality Disorders Randomly
Assigned to Schema Therapy (ST), Clarification-Oriented Psychotherapy (COP), or Treatment as Usual (TAU)a
Analysis Outcome
Estimated
Analysis and Contrast B t df p Exp(B)b 95% CI Proportion 95% CI
Primary analysis
Recovery controlled for
baseline severityc, d
ST versus TAU 1.404 3.326 314 0.001 4.073 1.774–9.350
COP versus TAU 0.334 0.725 314 0.47 1.397 0.564–3.459
ST versus COP 1.070 2.047 314 0.041 2.916 1.043–8.157
Cohort-by-schema therapy 2.120 2.520 314 0.012 8.334 1.592–43.631
Severity –1.178 –5.252 314 ,0.001 0.308 0.198–0.479
Follow-up at 3 years
Schema therapy 0.814 0.674–0.902
Clarification-oriented psychotherapy 0.600 0.406–0.767
Treatment as usual 0.518 0.383–0.650
Sensitivity analysis
Recovery not controlled
for baseline severity
ST versus TAU 1.224 3.134 315 0.002 3.402 1.577–7.338
COP versus TAU 0.026 0.062 315 0.95 1.027 0.45–2.372
ST versus COP 1.198 2.471 315 0.014 3.313 1.276–8.601
Cohort-by-schema therapy 1.869 2.391 315 0.017 6.479 1.393–30.138
Follow-up at 3 years
Schema therapy 0.796 0.663–0.885
Clarification-oriented psychotherapy 0.541 0.364–0.708
Treatment as usual 0.534 0.409–0.654
Recovery controlled for
assessment timee
ST versus TAU 1.073 2.399 313 0.017 2.925 1.213–7.052
COP versus TAU –0.003 –0.006 313 .0.99 0.997 0.386–2.574
ST versus COP 1.076 1.999 313 0.046 2.933 1.017–8.458
Cohort-by-schema therapy 2.112 2.367 313 0.019 8.261 1.428–47.810
Severity –1.335 –5.330 313 ,0.001 0.263 0.161–0.431
Assessment time 0.489 6.743 313 ,0.001 1.631 1.414–1.881
Follow-up at 3 years
Schema therapy 0.869 0.755–0.935
Clarification-oriented psychotherapy 0.694 0.503–0.835
Treatment as usual 0.694 0.558–0.804
Recovery controlled for
assessment typef
ST versus TAU 1.049 2.405 313 0.017 2.856 1.210–6.738
COP versus TAU 0.016 0.034 313 0.97 1.016 0.400–2.584
ST versus COP 1.033 1.952 313 0.05 2.810 0.992–7.958
Cohort-by-schema therapy 1.835 2.119 313 0.035 6.264 1.140–34.427
Severity –1.185 –5.048 313 ,0.001 0.306 0.193–0.485
Assessment type 1.740 6.121 313 ,0.001 5.696 3.256–9.963
Follow-up at 3 years
Schema therapy 0.746 0.582–0.861
Clarification-oriented psychotherapy 0.511 0.320–0.699
Treatment as usual 0.507 0.373–0.639
Recovery in subsample that
started indicated treatment
ST versus TAU 1.298 3.071 304 0.002 3.664 1.594–8.418
COP versus TAU 0.226 0.496 304 0.62 1.254 0.511–3.075
ST versus COP 1.072 2.071 304 0.039 2.922 1.055–8.094
Cohort-by-schema therapy 2.289 2.712 304 0.007 9.864 1.873–51.932
Severity –1.185 –5.201 304 ,0.001 0.306 0.195–0.479
continued

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TABLE 3. Mixed Logistic Regression Analyses of Recovery and Dropout Among Patients With Personality Disorders Randomly
Assigned to Schema Therapy (ST), Clarification-Oriented Psychotherapy (COP), or Treatment as Usual (TAU)a (continued)
Analysis Outcome
Estimated
Analysis and Contrast B t df p Exp(B)b 95% CI Proportion 95% CI
Follow-up at 3 years
Schema therapy 0.819 0.684–0.904
Clarification-oriented psychotherapy 0.607 0.417–0.770
Treatment as usual 0.552 0.419–0.679
Recovery defined by absence of
subthreshold personality
disorder (stringent criterion)g
ST versus TAU 1.410 3.436 314 0.001 4.096 1.827–9.185
COP versus TAU 0.454 1.012 314 0.31 1.574 0.652–3.800
ST versus COP 0.957 1.886 314 0.06 2.603 0.959–7.061
Cohort-by-schema therapy 2.219 2.713 314 0.007 9.202 1.840–46.018
Severity –0.979 –4.612 314 ,0.001 0.376 0.248–0.571
Follow-up at 3 years
Schema therapy 0.789 0.645–0.885
Clarification-oriented psychotherapy 0.589 0.402–0.754
Treatment as usual 0.477 0.350–0.607
Recovery controlled for
personality disorder categoryh
ST versus TAU 1.428 3.374 311 0.001 4.172 1.814–9.597
COP versus TAU 0.342 0.741 311 0.46 1.408 0.568–3.490
ST versus COP 1.087 2.075 311 0.039 2.964 1.058–8.304
Cohort-by-schema therapy 2.164 2.567 311 0.011 8.709 1.658–45.753
Severity –1.215 –5.335 311 ,0.001 0.297 0.190–0.465
Dependent personality disorder –0.075 –0.174 311 0.86 0.928 0.399–2.160
Obsessive-compulsive personality disorder –0.410 –1.354 311 0.18 0.664 0.366–1.204
Paranoid, narcissistic, or histrionic –0.102 –0.236 311 0.81 0.903 0.386–2.112
personality disorder
Follow-up at 3 years
Schema therapy 0.813 0.666–0.904
Clarification-oriented psychotherapy 0.594 0.395–0.766
Treatment as usual 0.510 0.367–0.651
Recovery controlled for
medication use at
treatment start
ST versus TAU 1.420 3.352 313 0.001 4.136 0.180–0.458
COP versus TAU 0.355 0.771 313 0.44 1.427 0.576–3.533
ST versus COP 1.064 2.036 313 0.043 2.899 1.036–8.110
Cohort-by-schema therapy 2.072 2.456 313 0.015 7.937 1.511–41.667
Severity –1.248 –5.256 313 ,0.001 0.287 0.180–0.458
Medication use at treatment start 0.264 0.969 313 0.33 1.302 0.762–2.223
Follow-up at 3 years
Schema therapy 0.817 0.678–0.904
Clarification-oriented psychotherapy 0.606 0.412–0.772
Treatment as usual 0.519 0.384–0.651
Recovery controlled for
medication use during 3 yearsi
ST versus TAU 1.416 3.343 313 0.001 4.120 1.791–9.478
COP versus TAU 0.342 0.741 313 0.459 1.408 0.568–3.492
ST versus COP 1.074 2.052 313 0.041 2.926 1.045–8.192
Cohort-by-schema therapy 2.114 2.511 313 0.013 8.280 1.580–43.383
Severity –1.200 –5.146 313 ,0.001 0.301 0.190–0.477
Medication use during trial 0.107 0.344 313 0.731 1.113 0.602–2.057
Follow-up at 3 years
Schema therapy 0.815 0.675–0.903
Clarification-oriented psychotherapy 0.600 0.406–0.767
Treatment as usual 0.516 0.381–0.649
continued

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TABLE 3. Mixed Logistic Regression Analyses of Recovery and Dropout Among Patients With Personality Disorders Randomly
Assigned to Schema Therapy (ST), Clarification-Oriented Psychotherapy (COP), or Treatment as Usual (TAU)a (continued)
Analysis Outcome
Estimated
Analysis and Contrast B t df p Exp(B)b 95% CI Proportion 95% CI
Dropout analysis
Dropout controlled for
baseline severity
ST versus TAU –1.321 –3.003 314 0.003 0.267 0.112–0.634
COP versus TAU –0.951 –2.003 314 0.046 0.386 0.152–0.983
ST versus COP –0.370 –0.654 314 0.51 0.691 0.227–2.103
Cohort-by-schema therapy –2.149 –2.443 314 0.015 0.117 0.021–0.658
Severity 0.287 1.383 314 0.167 1.333 0.886–2.005
Follow-up at 3 years
Schema therapy 0.154 0.076–0.285
Clarification-oriented psychotherapy 0.208 0.103–0.376
Treatment as usual 0.405 0.294–0.527
Dropout not controlled for
baseline severity
ST versus TAU –1.309 –2.984 315 0.003 0.270 0.114–0.640
COP versus TAU –0.878 –1.901 315 0.06 0.416 0.168–1.031
ST versus COP –0.431 –0.775 315 0.44 0.650 0.218–1.941
Cohort-by-schema therapy –2.137 –2.435 315 0.015 0.118 0.021–0.663
Follow-up at 3 years
Schema therapy 0.154 0.077–0.283
Clarification-oriented psychotherapy 0.219 0.112–0.384
Treatment as usual 0.402 0.296–0.519
a
All analyses included baseline severity as a covariate, except when indicated; higher-order interactions involving baseline severity were not
significant; bold indicates significant values; cohort was coded as –0.5 for cohort 1 (schema therapy, treatment as usual), 0.5 for cohort 2
(schema therapy, treatment as usual), and 0 for clarification-oriented psychotherapy.
b
Data represent the effect size odds ratio expressing the effect as estimated in the mixed-regression analysis; treatment as usual is the
reference condition; an odds ratio .1 denotes superior effects in schema therapy respectively, clarification-oriented psychotherapy compared
with treatment as usual; for the cohort-by-schema therapy interaction, an odds ratio .1 denotes superior effects of schema therapy
compared with treatment as usual in the group with second-cohort therapists, compared with first-cohort therapists; for dropout, smaller
odds ratios denote superior effects.
c
The raw estimates for schema therapy, clarification-oriented psychotherapy, and treatment as usual are 0.710, 0.561, and 0.582, respectively.
d
Higher-order interactions involving severity were not significant.
e
Time of last assessment was added as a covariate; higher-order interactions involving time were not significant.
f
Type of assessment (Structured Clinical Interview for DSM-IV Axis II Personality Disorders [SCID II] or Assessment of DSM-IV Personality Disorders
Questionnaire in case the patient declined to take the SCID II) was added as a covariate; higher-order interactions involving this covariate were not
significant.
g
The stringent recovery criterion was defined as not meeting any personality disorder or subthreshold personality disorder diagnosis, with
subthreshold defined as the number of criteria required for a personality disorder diagnosis minus 1.
h
The primary personality disorder diagnosis is grouped into four categories: avoidant (reference condition); dependent; obsessive-compulsive;
and paranoid, histrionic, and narcissistic personality disorders combined; the main effect of primary personality disorder diagnosis and
higher-order interactions involving primary personality disorder were not significant.
i
Medication use during the trial is the mean number of years with medication use during the 3-year study period.

had a diagnosis or subthreshold diagnosis of borderline,
antisocial, schizotypal, or schizoid personality disorder; 11
had lifetime psychotic disorder; four had lifetime bipolar
disorder; two had an IQ ,80; and two suffered from
substance abuse needing detoxification); and 37 declined
further participation (21 did not agree with the study
procedure; seven did not show; six did not want to focus
on personality; one had a life-threatening disease; one
had insufficient availability; and one felt too miserable
to participate). Another 16 patients dropped out before
baseline assessment, and thus 323 patients were ran-
domly assigned (schema therapy, N=147; treatment as
usual, N=135; clarification-oriented psychotherapy, N=41).
Despite extending the inclusion period originally allowed
by the grant, inclusion at sites offering clarification-oriented
psychotherapy progressed too slowly to achieve the in-
tended 50, while in schema therapy and treatment as
usual more than the planned minimal 125 were randomly
assigned. Four patients in schema therapy and eight in
treatment as usual did not start treatment (no single
session).
The percentage of missing data ranged from 8.4% (at 6
months) to 24.6% (at 3 years; schema therapy, N=28;
treatment as usual, N=44; clarification-oriented psycho-
therapy, N=7 [Figure 2]). The SCID assessments at follow-
up took place apart from other assessments, with 35.9%

314 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


missing data (schema therapy, N=43; treatment as usual,
N=61; clarification-oriented psychotherapy, N=11). Three
randomly assigned patients were excluded from analyses:
one withdrew consent (treatment as usual), and two
withdrew participation during the randomization pro-
cedure because of their decision to move (schema
therapy). The trial ended when the scheduled closure date
was reached (3 years after patients who were included last
started treatment).
Thirty-eight patients in schema therapy (25.8%), 51 in
treatment as usual (37.8%), and nine in clarification-
oriented psychotherapy (22%) dropped out of indicated
treatment (Figure 2, Figure 3). Survival analysis showed
that patients in schema therapy had a significantly lower
dropout risk than those in treatment as usual (Cox
regression: b=21.22, p=0.002; relative risk=0.30, 95%
confidence interval [CI]=0.14–0.65), while a significant
interaction between therapist cohort and condition
revealed higher treatment retention in schema therapy
compared with treatment as usual with the second-
therapist cohort relative to the first (b=21.72, p=0.03;
relative risk=0.18, 95% CI=0.04–0.85). Comparing clarification-
oriented psychotherapy and treatment as usual revealed
a significant difference in favor of clarification-oriented
psychotherapy with regard to dropout risk (b=20.81,
p=0.03; relative risk=0.45, 95% CI=0.21–0.93). Schema
therapy and clarification-oriented psychotherapy did not
significantly differ. Covariate severity was not significant.
Mixed logistic regression revealed similar effects when
controlling for baseline severity (Table 3). When not
controlling for baseline severity, clarification-oriented
psychotherapy lost its dominance in treatment reten-
tion over treatment as usual.
There was one serious adverse event reported: one pa-
tient in treatment as usual died, and postmortem analysis
revealed that the patient may have committed suicide.
Treatment Outcomes
Primary outcome. Results of primary outcome analyses are
summarized in Table 3. Schema therapy was dominant
over treatment as usual, with a significantly greater
proportion of recovered patients in this group than in
the treatment as usual group (Figure 4), while the
significant condition-by-cohort interaction showed that
recovery was relatively higher among those receiving
schema therapy from second-cohort therapists. The
comparison of treatment as usual with clarification-oriented
psychotherapy revealed greater recovery in treatment as
usual but did not reach statistical significance. The severity
effect reflects less recovery among patients with worse
baseline severity. Effects were replicated in all sensitivity
analyses and also when recovery was controlled for as-
sessment type (diagnoses based on SCID II compared with
Assessment of DSM-IV Personality Disorders). Schema ther-
apy outperformed clarification-oriented psychotherapy in
the primary analysis and in all but two sensitivity analyses
Am J Psychiatry 171:3, March 2014
BAMELIS, EVERS, SPINHOVEN, ET AL.
FIGURE 4. Recovery Rate Per Treatment Conditiona
100
90
80
70
60
Percent
50
40
30
20
10
0
Schema Clarification-Oriented Treatment
Therapy Psychotherapy as Usual
a
Estimated proportions are based on primary analysis; error bars
represent 95% confidence intervals.
(recovery controlled for assessment type and recovery de-
fined by absence of subthreshold personality disorder).
Estimated recovery proportions and 95% confidence inter-
vals by condition are presented in Table 3.
Secondary outcomes. Results of mixed-regression analyses
with estimated group differences and their effect sizes on
secondary outcome measures are summarized in Table 4.
On all outcome measures, the main time effect was sig-
nificant, pointing at improvement during therapy (p,0.001).
Global Assessment of Functioning Scale scores improved
significantly more among patients in schema therapy than
among those in treatment as usual (p,0.05), while no
difference between schema therapy and clarification-
oriented-psychotherapy was found. The time-by-condition-
by-cohort interaction was significant, indicating a superior
effect in the cohort with therapists who followed exercised-
based training for schema therapy. Changes in Social and
Occupational Functioning Assessment Scale scores re-
vealed dominance of schema therapy over treatment as
usual and clarification-oriented psychotherapy (p,0.03),
while clarification-oriented psychotherapy and treatment
as usual did not differ, and the three-way interaction was
not significant. No significant effect involving condition
or cohort was found on the Symptom Checklist-90, the
Assessment of DSM-IV Personality Disorders Question-
naire, the Work and Social Adjustment Scale, the Miskimins
Self-Goal-Other Discrepancy Scale, or the World Health
Organization Quality of Life Assessment. The only excep-
tion was a significant time-by-condition-by-cohort effect
on the Miskimins Self-Goal-Other Discrepancy Scale, in-
dicating that patients receiving schema therapy from
the second-cohort therapists achieved better results in
reducing self-ideal discrepancy compared with patients in
treatment as usual, whereas patients receiving schema
therapy from first-cohort therapists did not (p=0.035). All
within-condition effect sizes were large, ranging from
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CLINICAL EFFECTIVENESS OF SCHEMA THERAPY FOR PERSONALITY DISORDERS

TABLE 4. Secondary Outcome Measure Analyses Among Patients With Personality Disorders Randomly Assigned to Schema
Therapy (ST), Clarification-Oriented Psychotherapy (COP), or Treatment as Usual (TAU)a
Analysis and Measure Analysis Effect Size
Mixed-regression repeated- Within
measures analyses B 95% CI (B) t df p rb dc Conditiond
Global Assessment of
Functioning Scale score
Timee 2.10 1.28 to 2.91 5.22 29.64 ,0.001 0.69 1.27
Time-by-condition
ST versus TAU 0.83 0.03 to 1.62 2.05 224.87 0.042 0.14 0.50
COP versus TAU –0.27 –1.43 to 0.90 –0.46 135.56 0.65 0.04 –0.16
ST versus COP 1.09 –0.04 to 2.22 1.92 126.62 0.057 0.17 0.66
Time-by-cohort-by-schema therapy 1.77 0.18 to 3.35 2.20 224.49 0.029 0.15 0.53
Change over 3 years
Schema therapy 1.76
Clarification-oriented psychotherapy 1.11
Treatment as usual 1.27
Social and Occupational Functioning
Assessment score
Timee 1.97 1.13 to 2.81 4.82 25.89 ,0.001 0.69 1.05
Time-by-condition
ST versus TAU 1.12 0.35 to 1.89 2.87 217.61 ,0.005 0.19 0.60
COP versus TAU –0.17 –1.34 to 0.99 –0.29 138.32 0.77 0.02 –0.09
ST versus COP 1.29 0.15 to 2.42 2.26 128.91 0.025 0.20 0.69
Time-by-cohort-by schema therapy 1.44 –0.10 to 2.99 1.85 217.21 0.066 0.12 0.39
Change over 3 years
Schema therapy 1.65
Clarification-oriented psychotherapy 0.96
Treatment as usual 1.05
Symptom Checklist-90 scoref
Timee –0.143 –0.186 to –0.101 –6.77 50.05 ,0.001 0.69 0.95
Time-by-condition
ST versus TAU 0.004 –0.047 to 0.055 0.14 265.16 0.89 0.01 –0.02
COP versus TAU –0.027 –0.097 to 0.043 –0.77 105.34 0.45 0.07 0.18
ST versus COP 0.031 –0.037 to 0.098 0.90 100.87 0.37 0.09 –0.20
Time-by-cohort-by-schema therapy –0.059 –0.160 to 0.043 –1.14 264.72 0.26 0.07 0.19
Change over 3 years
Schema therapy 0.93
Clarification-oriented psychotherapy 1.13
Treatment as usual 0.95
Assessment of DSM-IV Personality Disorders
Questionnaire trait scoref
Timee –0.157 –0.200 to –0.114 –7.39 35.90 ,0.001 0.78 1.14
Time-by-condition
ST versus TAU 0.039 –0.012 to 0.091 1.50 261.34 0.14 0.09 –0.28
COP versus TAU –0.001 –0.152 to 0.054 –0.04 80.57 0.97 0.00 0.01
ST versus COP 0.04 –0.028 to 0.109 1.18 77.01 0.24 0.13 –0.29
Time-by-cohort-by-schema therapy –0.049 –0.152 to 0.054 –0.93 260.58 0.35 0.06 0.18
Change over 3 years
Schema therapy 0.86
Clarification-oriented psychotherapy 1.13
Treatment as usual 1.14
Work and Social Adjustment Scale score
Timee –1.19 –1.75 to –0.63 –4.34 29.49 ,0.001 0.62 0.77
Time-by-condition
ST versus TAU –0.16 –0.72 to 0.40 –0.56 249.18 0.57 0.04 0.10
COP versus TAU –0.31 –1.14 to 0.51 –0.75 133.65 0.45 0.06 0.20
ST versus COP 0.15 –0.64 to 0.95 0.38 124.29 0.71 0.03 –0.10
Time-by-cohort-by-schema therapy –0.52 –1.64 to 0.60 –0.91 248.74 0.36 0.06 0.17
Change over 3 years
Schema therapy 0.87
Clarification-oriented psychotherapy 0.97
Treatment as usual 0.77
continued

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 BAMELIS, EVERS, SPINHOVEN, ET AL.

TABLE 4. Secondary Outcome Measure Analyses Among Patients With Personality Disorders Randomly Assigned to Schema
Therapy (ST), Clarification-Oriented Psychotherapy (COP), or Treatment as Usual (TAU)a (continued)
Analysis and Measure Analysis Effect Size
Mixed-regression repeated- Within
measures analyses B 95% CI (B) t df p rb dc Conditiond
Miskimins Self-Goal-Other Discrepancy
Scale scoref
Timee –0.171 –0.211 to –0.131 –8.64 39.99 ,0.001 0.81 1.32
Time-by-condition
ST versus TAU 0.006 –0.041 to 0.053 0.25 256.34 0.80 0.02 –0.05
COP versus TAU –0.024 –0.089 to 0.041 –0.73 107.40 0.47 0.07 0.18
ST versus COP 0.030 –0.033 to 0.093 0.95 100.52 0.35 0.09 –0.23
Time-by-cohort-by-schema therapy –0.101 –0.195 to –0.007 –2.12 255.65 0.035 0.13 0.78
Change over 3 years
Schema therapy 1.27
Clarification-oriented 1.55
psychotherapy
Treatment as usual 1.32
World Health Organization Quality of
Life Assessment scoreg
Timee 10.14 7.14 to 13.14 6.83 40.44 ,0.001 0.73 1.04
Time-by-condition
ST versus TAU –0.60 –4.03 to 2.82 –0.35 255.43 0.73 0.02 –0.06
COP versus TAU 1.44 –3.36 to 6.24 0.60 115.86 0.55 0.06 0.15
ST versus COP –2.04 –6.70 to 2.61 –0.87 110.08 0.39 0.08 –0.21
Time-by-cohort-by-schema therapy 3.12 –3.73 to 9.96 0.90 254.98 0.37 0.06 0.16
Change over 3 years
Schema therapy 0.98
Clarification-oriented psychotherapy 1.19
Treatment as usual 1.04
Multiple imputation logistic Estimated
regression analysesh B SE(B) p Odds Ratio 95% CI Proportion
Depressive disorders (at 3 years)
Baseline depressive disorder 1.94 2.41 0.46 6.95 0.01–3868.76
Severity 1.08 0.82 0.24 2.94 0.40–21.69
ST versus TAU –1.45 0.68 0.033 0.23 0.06–0.89
COP versus TAU –1.83 1.43 0.23 0.16 0.01–3.70
ST versus COP 0.37 1.30 0.78 1.45 0.10–21.93
Cohort-by-schema therapy –2.00 1.32 0.13 0.14 0.01–1.81
Presence at follow-up by conditioni
Schema therapy 0.135
Clarification-oriented psychotherapy 0.122
Treatment as usual 0.252
Anxiety disorders (any at 3 years)
Number of baseline anxiety disorders 0.32 0.69 0.67 1.37 0.224–8.40
Severity 0.83 0.42 0.066 2.30 0.94–5.65
ST versus TAU 0.09 0.64 0.89 1.10 0.27–4.44
COP versus TAU 0.03 0.72 0.97 1.03 0.25–4.22
ST versus COP 0.07 0.78 0.93 1.07 0.23–5.09
Cohort-by-schema therapy –0.87 1.31 0.52 0.42 0.02–7.41
Presence at follow-up by conditioni
Schema therapy 0.275
Clarification-oriented psychotherapy 0.351
Treatment as usual 0.274
a
Data represent all models with random intercept and time effects (at center level); bold indicates significance; cohort was coded as –0.5 for cohort
1 (schema therapy, treatment as usual), 0.5 for cohort 2 (schema therapy, treatment as usual), and 0 for clarification-oriented psychotherapy.
b
Data represent the effect size (r) expressing the change effect as estimated in the mixed-regression analysis; absolute values are given.
c
Data represent the effect size (Cohen’s d) expressing the change effect at the 3-year follow-up as related to baseline standard deviation
(“dRAW,” see Feingold [reference 32]), with baseline standard deviation from the mixed-regression residual baseline variance; positive values
indicate more improvement and negative values less improvement.
d
Data represent the effect sizes of change over 3 years with Cohen’s d per condition.
e
The time effect is that of the primary reference category, the treatment as usual condition.
f
Both dependent variable scores and time were log-transformed to reduce skewness and to model a linear time-response relationship.
g
Time was log-transformed to model a linear time-response relationship.
h
Multiple imputation based logistic regression (with center as factor) as mixed-regression estimations failed.
i
Data represent the 3-year depressive and anxiety disorder proportion estimates per condition from logistic regression, controlled for center effects.

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CLINICAL EFFECTIVENESS OF SCHEMA THERAPY FOR PERSONALITY DISORDERS
0.86 to 1.76 (Table 4). For depressive and anxiety disorders
(measured assessor-based only at baseline and follow-up),
multiple imputation-based logistic regression revealed
a significant main effect of schema therapy on depressive
disorder diagnoses, with an odds ratio of 0.23, reflecting
lower risk of depressive disorder at follow-up in schema
therapy. No condition differences regarding anxiety dis-
orders were found.
Discussion
We compared the effectiveness of schema therapy and
clarification-oriented psychotherapy with treatment as
usual for cluster C, paranoid, histrionic, and narcissistic
personality disorders. The primary analysis and all sen-
sitivity analyses revealed consistently that schema therapy
was superior to treatment as usual on primary outcome
(greater recovery from personality disorder), as well as
when recovery was defined more stringently, and when we
controlled for assessment instrument. Patients receiving
schema therapy showed greater improvement in scores on
the Global Assessment of Functioning Scale and the Social
and Occupational Functioning Assessment Scale and had
lower depressive disorder rates at follow-up compared
with patients in treatment as usual. The lower dropout rate
in schema therapy suggests higher acceptability by pa-
tients. Patients receiving schema therapy showed greater
improvement in recovery from personality disorders and
in scores on the Social and Occupational Assessment Scale
than patients receiving clarification-oriented psychother-
apy, but schema therapy patients did not show a signifi-
cant difference in dropout rate or in scores on the Global
Assessment of Functioning Scale. Clarification-oriented
psychotherapy did not outperform treatment as usual on
any measure, countering the argument that any experi-
mental treatment achieves better results than treatment
as usual. On other secondary measures assessing anxiety
disorders, general pathology, personality disorder traits,
social functioning, quality of life, and self-ideal discrep-
ancy, improvement over time occurred in all conditions,
with large effect sizes. However, no between-condition
differences emerged. The number of patients still in
treatment after 3 years was lowest in the schema therapy
group (13% compared with 26% in treatment as usual and
36.6% in clarification-oriented psychotherapy), pointing to
the ability of schema therapy to achieve at least compara-
ble results in less time. The type of schema therapy train-
ing among therapists influenced dropout, recovery, global
functioning, and self-ideal discrepancy, with exercise-based
training attaining superior effects. In trying to detect specific
elements that may account for schema therapy superiority,
several aspects can be mentioned. First, an adjacent quali-
tative study assessing patient and therapist perspectives on
schema therapy (N. De Klerk et al., unpublished 2013 data)
revealed that working with the mode model was highly
appreciated by patients and therapists, since it guided
318 ajp.psychiatryonline.org
therapists in choosing adequate techniques and helped
patients to better understand their own behaviors and
feelings. Schema therapy may also be highly effective because
multiple channels are addressed to achieve structural
personality change by using experiential, behavioral, cogni-
tive, and interpersonal techniques. Experiential techniques
have been experienced as very helpful by patients and
therapists (M.C. Ten Napel-Schutz et al., unpublished 2013
data). Unlike most other treatments for personality disorders,
schema therapy involves extensive processing of traumatic
and other aversive childhood experiences, core factors in the
development of personality disorders, which may be another
reason for its effectiveness.
Since the present study was aimed to be an effectiveness
trial, rather than an efficacy trial, many aspects resembled
clinical reality (e.g., no preselection of therapists, no optimal
training, no detailed treatment manual, no supervised pilot
treatment before starting the study, and no intensive central
supervision during the trial). Staying close to daily prac-
tice, our approach enhances the generalizability of our
findings and yields a valid indication for effects of schema
therapy implementation. Other strengths include a large
sample size, multicenter design, long-term duration of the
study, broad range of outcomes, intention-to-treat anal-
yses, and an extensive integrity check with good results.
Schema therapy and clarification-oriented psychotherapy
share some conceptual overlap, but the techniques differ
substantially, which was confirmed by our integrity check.
Major differences include 1) the higher directiveness of
schema therapy, which includes content (e.g., psycho-
education); 2) the therapeutic relationship, in which
schema therapists attempt to meet the unmet childhood
needs of patients; 3) extensive processing of childhood
trauma; and 4) behavioral pattern breaking. Some limi-
tations of this study also should be mentioned. Comparing
experimental treatments with treatment as usual inher-
ently means impossibility to control for factors such as
session frequency and treatment dosage. Because treat-
ment as usual therapists received no central training and
supervision, there may have been between-group differ-
ences in treatment/study commitment. On the other
hand, therapists in the schema therapy and clarification-
oriented psychotherapy groups were less experienced
in their methods and reported uncertainty. Strong con-
clusions about the three noncluster C personality disorders
cannot be made because of the limited numbers of patients
with these disorders. Conditions differed in the proportions
of patients with substance abuse disorders, but given the
low numbers of these patients, we could not control for this
statistically. Another limitation is with regard to the fact that
some intraclass correlation coefficients of scales assessing
treatment integrity were only modest. Additionally, the fact
that patients in the treatment as usual condition received
a much lower number of sessions on average but completed
treatment less often complicated simple interpretation of
the results. Lastly, the clarification-oriented psychotherapy
Am J Psychiatry 171:3, March 2014

Patient Perspectives
Schema Therapy
“Ms. A” is a 30-year-old married woman who was
referred by her general practitioner for treatment of
anxiety and depression. After partially successful treatment
of axis I disorders, the patient reveals that she continues to
struggle with uncertainties and perfectionism and fears
experiencing a new burnout if she were to resume
employment. She does not dare have children, although
she clearly wants to have them. Scores on the Structured
Clinical Interview for DSM-IV Axis II Personality Disorders
(SCID-II) revealed dependent and obsessive-compulsive
personality disorders and avoidant traits. The patient
grew up on a small farm where the children had to work
hard and had little autonomy. Her mother was over-
concerned, cold, controlling, rigid (about work, morals,
and religion), and suffered from depressive episodes.
When angry at her daughter, the mother sometimes
refused to speak and remained in bed for days, which
induced a feeling of “being bad” in the patient. The father
was submissive to the mother and avoided conflicts. The
patient’s anxiety and depression increased when she was
put under pressure on her job, where she could not set
limits and felt overwhelmed by responsibilities. She quit
her job. Her request for help is to get rid of her anxieties
and worries.
Therapy for this patient is divided into four phases,
following each other but without strict boundaries.
1) Starting phase (sessions 1–6)
The request for help, current problems, and life history
are explored. The patient imagines being a child alone with
her mother and alone with her father, and affect, unmet
needs, cognitions, and behavioral patterns are explored.
Based on this information, a schema mode model, depict-
ing central emotional cognitive-behavioral states, is formu-
lated. For this patient, the following modes are formulated:
punitive-demanding parent (guilt feelings and high stand-
ards internalized from the mother’s behavior); vulnerable-
dependent child (feeling vulnerable and overwhelmed as
a little child given too much responsibility); perfectionistic
overcompensator (perfectionism and overdedication to
work to cope with uncertainties); compliant surrender
(being compliant with others’ requests, even when she
disagrees). Healthy adult and happy child modes are
underdeveloped.
2) Addressing historical roots of dysfunctional modes
(sessions 7–25)
Using exploration, psychoeducation, and experiential
work, childhood memories of experiences associated with
the dysfunctional modes are addressed. Central with this
patient are confronting the punitive-demanding parent
mode, both on an empty chair (with the therapist firmly
disagreeing with the voice of the mode and standing up for
the patient) and in imagery re-scripting (with the therapist
entering in fantasy the image of childhood memories and
standing up for the rights and needs of the child, e.g., by
Am J Psychiatry 171:3, March 2014
BAMELIS, EVERS, SPINHOVEN, ET AL.
stopping the mother’s abuse and confronting the father’s
avoidance). The therapist chooses to first address the mode
that is activated during the session or that played a role in
recent problems. With perfectionistic-overcompensator
and surrender modes, the function is discussed, and the
triggering events are explored, after which the therapist
helps the patient to access the punitive-demanding parent
and/or the vulnerable-dependent child mode, which are
then addressed. Gradually, the patient experiences anger
toward the parents and sadness about what she missed in
childhood. She reports becoming more assertive and starts
to do more pleasurable things. She starts to take the lead in
the experiential exercises.
3) Addressing current problems and behavioral
change (sessions 26–40)
The focus is now more on current problems, and the
therapist pushes toward actual behavioral change. For
example, the patient practices with becoming more assertive
instead of submissive and expresses her needs more. She has
a difficult discussion with her parents about what she has
missed in her childhood and how she often felt guilty by her
mother’s responses. This helps her to emancipate from her
parents’ values and to lead her own life.
4) Booster sessions (sessions 41–50)
In the second year, once every month, a booster
session is planned. The patient reports how she looked
for a job and found one, and the therapist supports her in
preventing to return to perfectionism and overworking.
Assertiveness is practiced when needed (related to work
and family issues). Halfway through the second year, the
patient reveals that she is pregnant and is happy about
the pregnancy. The future responsibilities of becoming
a mother are also a topic.
Clarification-Oriented Psychotherapy
“Mr. B” is a 35-year old married father of two, who is
referred by a crisis service and diagnosed with major
depression and dependent personality traits (which
turned out to be a dependent personality disorder based
on SCID II criteria). He has suicidal ideations but no
concrete plans. He experienced mood complaints since
his youth. He was born as the youngest of three, with two
older sisters, a dominant father, and a mother who
hardly set any boundaries. The family never quarreled,
since they strived for perfect harmony. The patient never
learned to deal with problems because every problem
was taken out of his hands. Achievement was an
important issue for the outside world.
Since his oldest child was born, 6 years ago, the patient
has felt that his problems have increased. He feels
pressured by his current responsibilities. During his referral,
he said that he wanted to learn to get in contact with his
feelings and to set boundaries.
Therapy for this patient is divided into five phases,
following each other but without strict boundaries.
continued
ajp.psychiatryonline.org 319
CLINICAL EFFECTIVENESS OF SCHEMA THERAPY FOR PERSONALITY DISORDERS
1) Building of relationship
In order to establish a safe and workable therapeutic
relationship, the therapist is complementary with the
patient’s basic unfulfilled needs (in this case, solidarity
and reliability) and noncomplementary with manipulative
behavior (dysfunctional interpersonal behavior; in the
present case, attempts to hand over responsibility by
behaving as a child or acting helpless).
2) Developing treatment goals and confronting ma-
nipulative behavior
Patients with very rigid interaction patterns do not have
genuine therapy goals but merely aim at stabilizing their
system (both their inner and outer worlds). To formulate
true goals, it is necessary that the patient is confronted with
his or her manipulative behaviors and what these cost.
When the therapeutic relationship is growing, the patient is
bound to test whether the therapeutic relation is authentic
or not. In the above case, the patient tests whether the
solidarity and reliability of the therapist is real. Gradually,
he learns to formulate true treatment goals: he wants to
feel less vulnerable and small.
3) Clarifying schemas
For the patient, it was not clear on what experiences his
self- and relation schemas were based. By making this
explicit, it becomes clear that it concerned a subtle but
sample size limited power to detect clarification-oriented
psychotherapy-treatment as usual differences, although no
indications of superiority of clarification-oriented psycho-
therapy over treatment as usual were found, except perhaps
with regard to dropout and depressive disorder.
Comparing results with previous studies, our findings
resemble those of previous randomized controlled trials
that demonstrated more recovery and less dropout with
schema therapy among individuals with borderline per-
sonality disorder (11, 13, 14), while our effect sizes are in
the same range as those found in previous research on
schema therapy techniques for personality disorders (31).
What is different is the fact that our study does not dem-
onstrate overall supremacy of schema therapy (i.e.,
schema therapy did not excel on self-reported measures).
The discrepancy in results obtained with self-reports com-
pared with assessor-based instruments is remarkable but
not without precedent. Other studies have found such
differences (e.g., personality disorders [33] and mood
disorders [34]). There are indications that interviews more
validly assess objectifiable symptom manifestations and
self-reports better capture symptom experience (35), while
the discrepancy between these kinds of measures is
related to personality characteristics, such as neuroti-
cism (34). Especially in personality disorders, in which
symptoms are ego-syntonic, other measures may better
and more rapidly detect objective changes than the pa-
tients themselves, since it might take more time to change
one’s self-representation than to change primary cognitions,
320 ajp.psychiatryonline.org
intrusive interaction pattern between him and his parents.
Throughout his childhood and youth, he learned that he
could not rely on his parents for support, and he felt alone
all the time. Based on his biography, his relation schema is
“you will be left alone in relationships, there is no support,”
and his self-schema is “I am small.”
4) Schema work
When manipulative behavior is decreased and the
patient is truly experiencing his or her feelings, the
actual content of the schema is further explored (e.g., by
using focusing techniques) and affectively and cogni-
tively restructured. Restructuring is mostly done by
a one-person role-play. In this role-play, the patient,
coached by the therapist, plays a therapist who chal-
lenges the dysfunctional schemas symbolically seated
on an empty chair. The aim is that patients not only
understand but also experience that their schemas are
not true. The patient in the present case would then feel
that he is not small and that he is not abandoned in
relationships per se.
5) Translation to behavior
This patient tries out new behavior and starts to take
up his responsibilities. He feels less anxious inside and
dares to accept challenges, such as starting his own
company.
feelings, behaviors, and impulse regulation. For example,
the self-definition and thus self-report as a mature person
may lag behind the new mature behavior that is observ-
able by others. It may therefore be concluded that schema
therapy is especially effective in the objectifiable domain
of psychopathology manifestations, at least in the time
scale of our study.
The finding that positive schema therapy effects on
assessor-based instruments emerged with different in-
terviewers for the SCID assessments, the Global As-
sessment of Functioning Scale, and the Social and
Occupational Functioning Assessment Scale enlarges
the validity of the study results. In addition, the schema
therapy compared with treatment as usual contrast may
have been limited by individual optimization of treatment
as usual. Instead of low-intensive maintenance care these
patients usually receive (36), psychotherapy was dominant
in treatment as usual and was akin to what is also labeled as
community treatment by experts (37).
Despite large effect sizes, we believe that there is room
for improvement of schema therapy. First, further elabo-
ration of the schema therapy protocol with techniques
fine-tuned for specific personality disorders and the pos-
sibility to increase treatment duration when necessary
might increase effects. Second, therapists reported the
reluctance to undergo personality changing treatment
among some patients as related to rigidity and motivational
problems. Future studies should assess this formally. We
advise assessing “readiness” for change and presence of
Am J Psychiatry 171:3, March 2014

autism-related disorders (since these often co-occur with
personality disorder [38] and may indicate inability to
change). A motivational module may prepare patients
better. Third, as indicated in previous research, effective-
ness might increase when therapists become more experi-
enced (31). Fourth, training method influences outcome.
Our adjacent qualitative study revealed that therapists
who followed the exercise-based training felt better
equipped to integrate all methods and techniques and
to apply them in practice than those who followed the
lecture-based training. Thus, exercise-based training us-
ing experiential learning (e.g., role-playing to exercise
specific techniques with immediate feedback) may in-
crease effects.
In conclusion, this trial found large improvements in
time in all treatment conditions, with superior recovery
from personality disorder and depressive disorder, better
general and social functioning, and less dropout in schema
therapy. Thus, with our study, we enlarge evidence-based
support for schema therapy as a valuable treatment for
personality disorders. We also found that how therapists
are trained in a new method influences clinical effective-
ness. The results point toward the possibility of schema
therapy being not only clinically effective but also cost
effective. Because the latter is an important additional
aspect in evaluating new treatments, this is the topic of
a separate article on the economic evaluation of the
present trial.
Previously presented in part at the 40th Annual Congress of the
Dutch Society for Psychiatry, April 3–5, 2012, Maastricht, the Nether-
lands; the 20th Annual European Congress of Psychiatry, March 3–6,
2012, Prague; the 41st Annual Congress of the European Association
for Behavioural and Cognitive Therapies, Aug. 31–Sept. 3, 2011,
Reykjavik, Iceland; the 6th Annual World Congress of Behavioral and
Cognitive Therapies, June 2–5, 2010, Boston; the Annual Congress of
the Dutch Society for Behavioral and Cognitive Therapy, Nov. 12–13,
2009, Veldhoven, the Netherlands; and the Annual Congress of the
Dutch Society for Behavioral and Cognitive Therapy, Nov. 13–14,
2008, Veldhoven, the Netherlands. Received April 19, 2012; revisions
received Aug. 17, 2012, and Feb. 28 and July 31, 2013; accepted
Sept. 12, 2013 (doi: 10.1176/appi.ajp.2013.12040518). From the
Department of Clinical Psychological Science, Maastricht University,
Maastricht, the Netherlands. Address correspondence to Dr. Bamelis
(l.bamelis@maastrichtuniversity.nl).
The authors report no financial relationships with commercial
interests.
Supported by grant 945-06-406 from the Netherlands Organization
for Health Research and Development (ZonMw) (to Dr. Arntz) and by
the Research Institute Experimental Psychopathology, Maastricht
University, the Netherlands.
Netherlands Trial Register 566 (www.trialregister.nl).
The authors thank the participating patients, therapists, coordina-
tors, trainers, research assistants, students, and statistical advisors.
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 Article

Fluoxetine Administered to Juvenile Monkeys: Effects on

the Serotonin Transporter and Behavior
Stal Saurav Shrestha, B.A. Victor W. Pike, Ph.D.
Eric E. Nelson, Ph.D. James T. Winslow, Ph.D.
Jeih-San Liow, Ph.D. Ellen Leibenluft, M.D.
Robert Gladding, B.S. Daniel S. Pine, M.D.
Chul Hyoung Lyoo, M.D., Ph.D. Robert B. Innis, M.D., Ph.D.
Objective: This study examined the long-
Pam L. Noble, M.S.
term effects of fluoxetine administered to
juvenile rhesus monkeys who, as young
Cheryl Morse, M.S. adults, were imaged with positron emission
tomography for two serotonergic markers:
Ioline D. Henter, M.A. serotonin transporter (SERT) and serotonin
1A (5-HT1A) receptor. An equal number of
Jeremy Kruger, B.S.
monkeys separated from their mothers at
birth—an animal model of human child-
Bo Zhang, Ph.D. hood stress—were also studied.
Method: At birth, 32 male rhesus mon-
Stephen J. Suomi, Ph.D. keys were randomly assigned to either
maternal separation or normal rearing
Per Svenningsson, M.D., Ph.D. conditions. At age 2, half (N=8) of each
group was randomly assigned to fluoxetine
(3 mg/kg) or placebo for 1 year. To eliminate
the confounding effects of residual drug in
the brain, monkeys were scanned at least
1.5 years after drug discontinuation. Social
interactions were assessed both during and
after drug administration.
Results: Fluoxetine persistently upregu-
lated SERT, but not 5-HT1A receptors, in
both the neocortex and the hippocampus.
Whole-brain voxel-wise analysis revealed
that fluoxetine had a significant effect in
the lateral temporal and cingulate cortices.
In contrast, neither maternal separation by
itself nor the rearing-by-drug interaction
was significant for either marker. Fluoxe-
tine had no significant effect on the behav-
ioral measures.
Conclusions: Fluoxetine administered to
juvenile monkeys upregulates SERT into
young adulthood. Implications regarding
the efficacy or potential adverse effects of
SSRIs in patients cannot be directly drawn
from this study. Its purpose was to in-
vestigate effects of SSRIs on brain develop-
ment in nonhuman primates using an
experimental approach that randomly as-
signed long-term SSRI treatment or placebo.

(Am J Psychiatry 2014; 171:323–331)

I n 2004, the Food and Drug Administration issued

a black box warning regarding the use of antidepressants
in the pediatric population (1). However, overwhelming
evidence supports the efficacy of selective serotonin
reuptake inhibitors (SSRIs) in treating mood and anxiety
disorders in this population (2). Nevertheless, studies on
the use of SSRIs suggest transient, age-delimited effects on
suicidal ideation (3, 4) as well as long-lasting effects on the
developing brain in rodents (5, 6). These issues are
particularly salient in humans as a result of the protracted
development of the human brain (7, 8). Furthermore, in
rodents, specific alterations in the serotonin transporter
(SERT) or serotonin 1A (5-HT1A) receptor have been shown
to affect neuronal development (9), and short-term SSRI
exposure during a time-sensitive developmental window
appears to induce long-lasting effects on serotonergic
functioning and anxious behavior into adulthood (5, 10,
11). It should be noted that both emotional experiences
and environmental conditions may also affect brain
development and that such changes could occur in-
dependently or synergistically with any effect of SSRIs on
development (12). Therefore, it is notable that no pro-
spective study has examined the long-term effects of SSRIs
on the developing primate brain.
Monkeys arguably provide the best model of human
brain function related to psychiatric disorders because
of similarities in brain structure, social organization, and
protracted development (13). Maternal separation of in-
fant monkeys is a well-established animal model of early-
life stress, which in humans predisposes to the development
of mood and anxiety disorders later in life (14, 15). Simi-
larly, monkeys with a history of maternal separation dis-
play both behavioral and serotonergic abnormalities similar
to those seen in anxious and depressed humans (16–18).
Although SSRIs rapidly increase 5-HT concentrations in
the synapse by inhibiting SERT, their therapeutic effects

This article is featured in this month’s AJP Audio, is the subject of a CME course (p. 377), and is discussed in an
Editorial by Drs. Brent, Cameron, and Lewis (p. 252)

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 323

FLUOXETINE ADMINISTERED TO JUVENILE MONKEYS
are typically delayed by about 8 weeks. Animal studies
suggest that one potential explanation for this delay is the
time required for 5-HT1A autoreceptors in the raphe to
desensitize, thereby leading to increased release of 5-HT in
terminal areas (19). Thus, SERT and the 5-HT1A receptor
are two important serotonergic markers, both direct and
indirect, in assessing the effects of long-term SSRI
treatment.
The present study sought to answer one primary and
two secondary questions regarding the effects of SSRIs
on the developing primate brain. First, does long-term,
prepubertal fluoxetine treatment have effects on the
serotonergic system that are discernible in adulthood?
Second, do these effects vary based on rearing conditions,
i.e., whether the monkeys were maternally separated or
normally reared? Third, does fluoxetine induce any long-
lasting behavioral changes into adulthood? To answer
these three questions, 32 differentially reared monkeys
received either fluoxetine or placebo from age 2 to 3 years,
which corresponds to the prepubertal period. Monkeys
were scanned at ∼4.7 years with two serotonergic positron
emission tomographic (PET) radioligands: [11C]DASB for
SERT and [11C](R)-RWAY for 5-HT1A receptors.
Method
Study Design
At birth, 32 male rhesus monkeys (Macaca mulatta) from four
annual birth cohorts were randomly assigned to maternally
separated or normally reared conditions (i.e., eight newborns
from each of 4 years were equally divided between the two
rearing conditions). Maternal separation consisted of the stan-
dard protocol as previously described (20) (see supplemental
methods in the data supplement that accompanies the online
edition of this article).
At 2 years of age, half of each rearing group was randomly
assigned to receive either fluoxetine or placebo. Although the
allometric scaling of doses between species is controversial, most
pharmacologists agree that the best index of whether one has
corrected for differences in absorption and disposition of a med-
ication is the similarity of the resulting plasma concentrations
across species. Thus, we selected doses of fluoxetine for this
study that produced concentrations of fluoxetine and norfluox-
etine (a pharmacokinetic measure) and 5-hydroxyindoleacetic
acid (5-HIAA; a pharmacodynamic measure) that were similar to
those concentrations seen in human patients (21, 22). Fluoxetine
(3 mg/kg/day) or placebo was administered orally in mashed
bananas for 1 year. This dosage results in steady state fluoxetine
concentrations of ∼70 ng/mL and norfluoxetine concentrations
of ∼220 ng/mL, both of which are in the clinical range for children
(23) (see methods and Figure S1 in the online data supplement).
A number of pharmacological agents were used as part of routine
veterinary care for the monkeys. For example, all monkeys re-
ceived intramuscular injections of ketamine (7 mg/kg) and
xylazine (6 mg/kg) four times for MRI scans. In addition, mon-
keys received telazol (2–6 mg/kg) a total of 8–10 times over the
course of the study; this agent was administered prior to blood
draws and CSF taps. All monkeys received twice daily feedings
and access to water ad libitum. The study was approved by the
Animal Care and Use Committee of the National Institute of Men-
tal Health.
324 ajp.psychiatryonline.org
Positron Emission Tomography (PET) Scans
All monkeys (mean age=4.7 years, SD=0.6; mean weight=7.4 kg,
SD=1.5) underwent 120-minute dynamic scans on a Focus 220
(Siemens Medical Solutions, Knoxville, Tenn.) using two PET
radioligands: [11C]DASB to label SERT and [11C](R)-RWAY to
label 5-HT1A receptors (24, 25). The injected activity, specific
activity, and injected mass dose of both radioligands were similar
for monkeys that were administered either placebo or fluoxetine
(see Table S1 in the online data supplement).
Calculation of Binding Potential (BPND) Using
a Reference Tissue Model
Binding potential (BPND), which is the ratio at equilibrium of
specific binding to nondisplaceable uptake in the brain, was used
to measure receptor density (26). Binding potential was cal-
culated with a reference tissue model, using cerebellar white
matter as the reference region for both radioligands. With regard
to the location of the SERT and 5-HT1A receptors, we a priori
selected only three regions: the raphe, the hippocampus, and the
neocortex. The raphe contains serotonergic neurons with high
densities of SERT and somatodendritic 5-HT1A autoreceptors.
Both the hippocampus and the neocortex primarily have 5-HT1A
receptors postsynaptically.
Binding potential was calculated in three steps 1): coregister-
ing PET and MR images in template space, 2) generating time-
activity curves, and 3) performing kinetic analysis. Dynamic PET
images were coregistered to averaged MRI templates from six
monkeys in standardized space. Time-activity curves were
generated using predefined regions of interest for both the
neocortex and the hippocampus (27) and manually for the raphe
(28). For the neocortex, five different cortical regions were com-
bined and weighted for volume: the frontal, cingulate, temporal,
parietal, and occipital cortices. The raphe (volume=110 mm3) was
drawn using a circular region of interest directly on three slices
(one midsagittal and two adjacent) of the summed PET images.
Radioactivity concentrations were expressed as standardized up-
take value, which normalizes for weight and injected activity.
Kinetic analyses were performed using the multilinear reference
tissue model with two parameters, which requires a priori es-
timation of k2 of the cerebellum (k2:), the clearance rate constant
from cerebellum relative to a region of specific binding. Using
the multilinear reference tissue model, k2: values were obtained
from the cerebellum relative to the thalamus for [11C]DASB and
from the cerebellum relative to the neocortex for [11C](R)-RWAY.
[11C]DASB binding had a good fit with a one-tissue compartment
model. [11C](R)-RWAY binding had a good fit with a two-tissue
compartment model (27, 29). As such, the start times (t*) were set
to 0.25 minutes for [11C]DASB and 50 minutes for [11C](R)-RWAY.
Parametric images were generated using PMOD 3.0 (PMOD Tech-
nologies, Zurich, Switzerland).
Voxel-Wise Analysis
An exploratory voxel-wise analysis of the whole brain was
performed using parametric images and statistical parametric
mapping (SPM8, Wellcome Trust Centre for Neuroimaging, U.K.).
Parametric images were generated using the multilinear reference
tissue model with two parameters, smoothed to full width at half
maximum of 4 mm and analyzed using a factorial design in SPM.
Statistical parametric maps were initially thresholded at un-
corrected p,0.05, and an exploratory stringent Gaussian random
field theory cluster level (i.e., family-wise error) correction for
multiple comparisons was applied.
Social Behavior
Peer social behavior was evaluated in a series of round robin
tests that took place between 4 and 8 months after the initiation
Am J Psychiatry 171:3, March 2014

of drug administration and then again 2–6 months after drug
cessation (see supplemental methods in the online data sup-
plement for further details of the ethogram). Behaviors from the
ethogram were consolidated into nine composite measurements:
locomotion, stereotypy, passivity, affiliation (physical proximity
or grooming), dominance, submissiveness, coo vocalizations, bark
vocalizations, and social (attack or bite) or nonsocial (cage shake)
aggression. However, only eight of these were analyzed as a result
of insufficient variability for one of the nine measures (aggression).
Intra- and interrater reliability were greater than 0.85 on all scored
behaviors.
Statistics
We used rearing-by-drug analyses of variance (ANOVA) to
examine both interaction and main effects in the PET studies and
a rearing-by-treatment-by-period ANOVA for each of the eight
behavioral composite measurements for the behavioral studies.
For both PET and behavioral studies, we report the uncorrected
p value, the correction factor, and the corrected p value. We used
IBM SPSS 19.0.0.1 (http://www-01.ibm.com/software/analytics/
spss/) for statistical analysis.
Results
Selecting Dosage of Fluoxetine
To select a dosage of fluoxetine to mimic that used
therapeutically in humans, we conducted a pilot study in
a separate group of 12 monkeys that received three doses
of fluoxetine (0.5, 2, or 3 mg/kg) in an attempt to ap-
proximate the levels of drug exposure in humans (see
Figure S1 in the online data supplement) (14, 15). Spe-
cifically, we measured the plasma concentrations of drug
and the expected decrease of 5-HIAA concentrations in
CSF (22). These 12 monkeys received oral fluoxetine for
3–4 weeks. Blood and CSF were sampled 24 hours after the
last drug administration. The lowest dosage (0.5 mg/kg)
resulted in undetectable plasma concentrations of fluox-
etine and norfluoxetine and no changes in 5-HIAA con-
centrations in CSF. Compared with levels in humans
treated chronically with 20 mg/day, the intermediate
dosage (2 mg/kg) generated lower plasma concentrations
of fluoxetine and norfluoxetine. Again, compared with
levels in humans treated chronically with 20 mg/day, the
3 mg/kg dosage generated lower plasma concentrations
of fluoxetine but comparable plasma concentrations of
norfluoxetine (see Figure S1 in the online data supple-
ment). At both 2 and 3 mg/kg of fluoxetine, 5-HIAA con-
centrations in CSF were reduced in monkeys relative to
placebo, although not to the extent reported in humans
(see Figure S2 in the online data supplement). Based on
these pilot data, as well as previously published studies, we
selected the 3 mg/kg dosage because it provided similar
pharmacokinetic measures as humans taking 20 mg/day,
albeit slightly lower pharmacodynamic measures.
To confirm that these pharmacokinetic measures were
achieved during the study, we measured plasma concen-
trations of drug and its active metabolite in the first cohort
of eight monkeys. The concentrations were measured during
and after the treatment period. During drug administration,
Am J Psychiatry 171:3, March 2014
SHRESTHA, NELSON, LIOW, ET AL.
FIGURE 1. Distribution of [11C]DASB Binding to Serotonin
Transporters (SERT) and [11C](R)-RWAY Binding to Serotonin
1A (5-HT1A) Receptors in the Representative Brain of
a Normally Reared Monkey That Received Placeboa
SUV
Caudate
6
SERT
0
Thalamus Raphe
MRI
Cingulate SUV
3
5-HT1A
0
Hippocampus
a
The top row summed images from 30 to 60 minutes show high
SERT density in the thalamus, raphe, and caudate. The middle row
MRI images show the anatomical structures for the coregistered
PET images. The bottom row summed images from 30 to 60
minutes show high 5-HT1A receptor density in hippocampus and
cingulate. SUV=standardized uptake value.
the concentrations were 41 ng/mL (SD=25.2) for fluoxetine
and 159 ng/mL (SD=78.4) for norfluoxetine. In the placebo
group, concentrations were undetectable. Eight weeks
after drug administration, concentrations of both fluoxe-
tine and norfluoxetine were also undetectable in either the
drug- or placebo-administered groups.
PET Imaging
For both [11C]DASB and [11C](R)-RWAY, the distribution
and time course of brain uptake were similar to those
observed in previous studies (18, 27). [11C]DASB uptake in
the monkey brain reflected the known distribution of
SERT, with high binding in the raphe, thalamus, and
caudate (Figure 1, top row). [11C](R)-RWAY uptake in the
monkey brain reflected the known distribution of 5-HT1A
receptors, with high binding in the cingulate cortex and
hippocampus (Figure 1, bottom row). With regard to time
course of uptake for both radioligands, higher density
regions had later times of peak uptake, reflecting the
greater amount of radioligand that had to be delivered to
achieve equilibrium binding. For both radioligands, uptake
in cerebellar white matter (the reference region) peaked
early and was similar between groups of animals, the latter
fulfilling a requirement to use reference tissue modeling.
Serotonin Transporter
Fluoxetine upregulated SERT binding in the neocortex
(+19%, F=12.8, df=1, 31; p,0.00132=0.002; Figure 2) and
the hippocampus (+17%, F=6.6, df=1, 31; p,0.01632=0.032;
ajp.psychiatryonline.org 325
FLUOXETINE ADMINISTERED TO JUVENILE MONKEYS
FIGURE 2. Effects of Fluoxetine and Maternal Separation on Serotonin Transporter (SERT) in the Neocortexa
A B
0.7
0.6
SERT BPND
0.5
0.4
0.3
Placebo Fluoxetine
a
Panel A shows fluoxetine upregulated SERT by 19%. Panel B shows that maternal separation had no statistically significant effect on SERT.
BPND=binding potential; bars represent mean6SD.
* p,0.00132=0.002.
see Figure S3 in the online data supplement). Whole-brain
voxel-wise analysis revealed that fluoxetine’s effects on
cortical binding were localized to the lateral temporal,
cingulate, and orbitofrontal cortices (Figure 3). However,
only the lateral temporal and posterior cingulate survived
multiple comparisons at the voxel level after family-wise
error correction (see Table S2 in the online data supple-
ment). Maternal separation had no significant effect on
SERT binding. Two-way ANOVA analysis also revealed no
statistically significant rearing-by-treatment interaction in
either the hippocampus or neocortex.
Kinetic modeling essentially calculates the area under
the time activity curves from time zero to infinity. Without
a clear identification of the time of peak uptake and rate
of washout (slope) prior to the end of the scan, the ex-
trapolated area to infinity is vulnerable to error. Our scan
period of 120 minutes was sufficient to calculate binding
potential for both the neocortex and hippocampus, be-
cause both of these regions had early peak uptake and
fast washout (see Figure S4, panel A, in the online data
supplement). However, we could not reliably quantify
binding potential in the raphe because of its late time of
peak uptake (consistent with its high SERT density), its slow
washout from the brain, and its relatively high noise at later
scan times. In fact, in some animals, radioactivity continued
to rise in the raphe for the entire 120-minute scan (see
Figure S4, panel A, in the online data supplement); that is,
we could not clearly identify the time of peak uptake. Such
rising time-activity curves seemed randomly distributed in
all four groups of monkeys. For these reasons, we excluded
the raphe from our analysis of [11C]DASB binding.
326 ajp.psychiatryonline.org
0.7
0.6
SERT BPND
0.5
0.4
0.3
Normal Separated
5-HT1A Receptor
In contrast to [11C]DASB, [11C](R)-RWAY showed a time-
activity curve in the raphe with a clearly defined time of peak
uptake and rate of washout (see Figure S4, panel B, in the
online data supplement). Thus, all three regions (hippocam-
pus, neocortex, and raphe) were analyzed for [11C](R)-RWAY.
Neither fluoxetine nor maternal separation had a statis-
tically significant effect on 5-HT1A receptor binding
(Figure 4). Although 5-HT1A receptor binding in the raphe
was increased by 23% in maternally separated monkeys,
this finding did not survive the statistical correction for the
three regions examined (F=5.1, df=1, 29; p,0.0333=0.09).
Furthermore, no statistically significant effect was ob-
served for each individual variable or any of the inter-
actions using voxel-wise whole-brain analysis.
Social Behavior
Eight behaviors expressed in a social context (see Table
S3 in the online data supplement) were examined for
effects of drug (i.e., fluoxetine compared with placebo),
rearing, and period (i.e., whether animals were observed
“during treatment” or “after treatment” with either flu-
oxetine or placebo). None of the behavioral effects of drug
or rearing were statistically significant after correcting for
multiple comparisons. However, overly liberal, uncorrected
thresholds generated results that could be pursued in
future studies. Namely, fluoxetine reduced dominance
displays both during and after the treatment period in
both rearing groups (F=4.75, df=1, 28; p,0.03838=0.30). In
addition, a drug-by-period interaction was observed for
submissive displays (F=4.22, df=1, 28; p,0.04938=0.39),
Am J Psychiatry 171:3, March 2014
 SHRESTHA, NELSON, LIOW, ET AL.

FIGURE 3. Fluoxetine Increased Serotonin Transporter (SERT) Binding in the Lateral Temporal, Cingulate, and Orbitofrontal
Cortices as Shown by Whole-Brain Voxel-Wise Analysisa

p value (uncorrected) <0.01 <0.001 <0.0001 <0.00001

a
The four different colors represent uncorrected p values. The coregistered MRI template is shown in grayscale and is merged with each PET
image.

FIGURE 4. Main Effects of Fluoxetine and Maternal Separation on Serotonin 1A (5-HT1A) Receptor Density in the Raphea
A B
3.0 3.0

2.5 2.5
5-HT1A BPND

5-HT1A BPND

2.0 2.0

1.5 1.5

1.0 1.0
Placebo Fluoxetine Normal Separated
a
Panel A shows that fluoxetine had no statistically significant effect on 5-HT1A receptor density. Panel B shows that maternal separation
increased 5-HT1A receptor density by 23%, which did not reach significance after correction for multiple comparisons across the three regions
(p,0.0333=0.09). BPND=binding potential; bars represent mean6SD.

reflecting between-group differences after, but not during,
fluoxetine treatment (Figure 5). Finally, we observed main
effects of both period and rearing (independent of flu-
oxetine treatment) on other behaviors. Period effects were
observed for locomotion (F=5.95, df=1, 28; p,0.0238=0.16),
passivity (F=18.01, df=1, 28; p,0.000238=0.002), and affili-
ative behaviors (F=22.35, df=1, 28; p,0.0000638=0.0005).
Only the period-related increase in passivity and decrease
in affiliative behavior survived the statistical correction for
multiple comparisons. The causes of these period-related
effects are unknown but could reflect developmental
changes, as the animals were almost 1 year older after
treatment than during treatment.
Rearing effects were observed for locomotion (F=4.26,
df=1, 28; p,0.04838=0.38), stereotypy (F=7.01, df=1, 28;
p,0.01338=0.10), and bark frequency (F=5.04, df=1, 28;
p,0.0338=0.24). These rearing effects were unaffected by
fluoxetine and persisted across both testing periods.
However, as with the effects of treatment, none of the
effects of rearing survived corrected statistical thresholds.
Discussion
This study examined the effects of long-term prepuber-
tal fluoxetine administration on serotonergic neurotrans-
mission in young adult monkeys (4.7 years old) that were
either maternally separated or normally reared from birth.
Fluoxetine persistently upregulated [11C]DASB binding
in the neocortex and hippocampus, regardless of rearing
and more than 1.5 years after drug cessation. Whole-brain

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 327

FLUOXETINE ADMINISTERED TO JUVENILE MONKEYS

FIGURE 5. Main Effects of Fluoxetine on Social Behaviors in Monkeysa

A B
8 7
7 Placebo Placebo
6
Fluoxetine Fluoxetine
Dominance Displays

Submissive Displays
6
5
5
4
4
3
3

2 2

1 1

0 0
During Treatment After Treatment During Treatment After Treatment
a
Panel A shows that fluoxetine reduced dominance displays both in the “during treatment” period (between 4 and 8 months after treatment
began) and in the “after treatment” period (2–6 months after treatment ceased) but this effect did not survive after statistical correction for
eight behavioral measurements (p,0.03838=0.30). Panel B shows that fluoxetine increased submissive displays only in the after treatment
period, which also did not survive correction for multiple comparisons (p,0.04938=0.39). Bars represent mean6SD.

voxel-wise analysis revealed that fluoxetine had a statistically
significant effect in the lateral temporal, cingulate, and
orbitofrontal cortices. Interestingly, maternal separation
at birth, which had previously been shown to induce
lasting behavioral abnormalities in monkeys (17), had no
significant effect by itself on SERT binding in either the
neocortex or hippocampus in this cohort of monkeys; this
negative finding is tempered by the small number of
placebo-exposed monkeys in each of the two rearing
conditions.
With regard to the 5-HT1A receptor, fluoxetine had no
significant effect in the neocortex, hippocampus, or raphe.
While maternal separation increased 5-HT1A receptor
binding in the raphe by 23% compared with normal
rearing, this finding did not reach significance after
correcting for multiple comparisons across the three
regions (p=0.0333=0.09). No rearing-by-treatment inter-
action was observed in any region for either SERT or
5-HT1A receptor. Taken together, our results demonstrate
that long-term prepubertal fluoxetine treatment altered
a key serotoninergic marker (SERT) into young adulthood,
regardless of rearing.
Behavioral Effects of Adverse Rearing and Fluoxetine
Treatment
A number of behavioral and neuroendocrine abnormal-
ities have been demonstrated in maternally separated
monkeys (17, 30). Furthermore, previous studies with the
current cohort, conducted prior to fluoxetine exposure,
found that the adversely reared monkeys displayed several
abnormal behaviors or responses, including increased
fear-potentiated startle, increased consummatory behav-
ior, increased cortisol secretion, altered locomotor activ-
ity, and altered circadian patterns (31, 32). However, these
rearing-related differences diminished as the animals
aged. In the present study, no statistically robust rearing
effects were found in either social behavior or other
behaviors not reported here, including potentiated startle
and cortisol. It is unclear whether the failure to find effects
of rearing in adult monkeys was the result of habituation to
repeated testing, repeated exposure to ketamine for routine
handling, low statistical power (only eight monkeys in the
two placebo cells), or normalization as a result of aging.
Just as differential rearing for the first 6 months after
birth had no consistent effects on behavior, fluoxetine
administered from age 2 to 3 years had no statistically
significant effect on behavior. However, this negative
finding must be tempered by the small sample size and
relative high variability in the behavioral measures. For
example, displays of dominance and submissiveness
showed the greatest response to fluoxetine, with an effect
size of 0.8, an effect considered to be medium-to-large in
most behavioral studies. Nevertheless, using appropriate
statistical criteria (two-tailed alpha=0.05 and power=0.8),
an adequately powered study testing for an effect size of
this magnitude requires 104 monkeys divided among four
groups. Our study had only 32. Nevertheless, our cohort
was unique and valuable, thereby justifying exploratory
analyses to identify potential findings to be pursued either
in a more focused way or in a much larger study.
Effects of SSRIs on 5-HT Neurotransmission in
Rodents
Although the effects of long-term SSRI administration in
early life have not been investigated previously in mon-
keys, rodent studies found that SSRIs had long-term effects
on both neurochemistry and behavior that persisted into
adulthood (33, 34). Of direct relevance to the findings
presented here, two previous rat studies (5, 6) found that
fluoxetine upregulated SERT in cortical regions by ∼20%
when administered during the juvenile period, but not
during adulthood. Furthermore, fluoxetine exposure dur-
ing early life—but not adulthood—produced delayed, per-
sistent perturbations of emotional behaviors similar to

328 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


those seen in mice lacking SERT (35, 36). A rat study (34)
found that fluoxetine increased some depressive-like
behaviors but decreased others, with varying effects in
immature and mature rodents. Biochemical studies of the
effects of SSRIs on SERT and 5-HT1A receptors in rats
achieved varied and inconsistent results; various studies
(37–40) have noted increases, decreases, or no changes
in these markers, possibly a result of differences in
strain, age, sex, and genetic polymorphisms.
Effects of Maternal Separation in Monkeys
Previous PET studies of monkeys with a history of
maternal separation reported disparate effects on SERT
and 5-HT1A receptors (18, 41). The present study found
that maternal separation did not affect SERT density in the
neocortex or hippocampus, but excluded the raphe for
technical reasons. Two previous PET studies that used
[11C]DASB found that maternal separation either de-
creased SERT binding (18) or had no effect (42). Like the
present study, the previous negative report scanned older
monkeys (age 6.5 years in the study by Jedema et al. [42]
and age 4.7 years in the present study) than the one
positive study (age 3 years). Thus, it is possible that any
putative effects of maternal separation on SERT binding
may normalize by 5–6 years of age. Notably, the timing of
previous studies—between ages 3 and 6 years—bridges
the pubertal transition in rhesus monkeys, which typically
occurs at approximately 4 years of age.
Regarding 5-HT1A receptors, the only previous study
(41) found that maternal separation increased binding in
the dorso-medial prefrontal cortex of female, but not male,
rhesus monkeys. However, this finding was likely not
statistically significant after correcting for multiple com-
parisons, i.e., the study included multiple regions and
three different measures of receptor binding (binding
potential, density, and dissociation constant). The values
of 5-HT1A receptor binding potential in the present study
differed from those in our previous publication (27)
because our new camera has higher resolution than the
old one. The resolution of the camera used in the present
study (Siemens microPET Focus 220) is ∼1.6 mm full width
at half maximum, whereas that of the old camera (GE
Advance) was ∼7 mm full width at half maximum. The
higher resolution explains why binding potential values for
a small region like the raphe are higher in the present study
than in the previous publication (27). In contrast, and as
expected, resolution had little effect on large regions like
the neocortex.
Advantages and Limitations
This prospective study in monkeys had the major
advantage of examining the long-term prepubertal effects
of fluoxetine in a well-controlled experimentally deter-
mined environmental setting. However, given the small
sample size of only eight monkeys per group, the study has
limited statistical power, making it vulnerable to both false
Am J Psychiatry 171:3, March 2014
SHRESTHA, NELSON, LIOW, ET AL.
positive and false negative results. To minimize false
positives, we used stringent statistical analyses with both
the Bonferroni correction for multiple measures as well as
correction for multiple regions in our PET data. Neverthe-
less, our study was vulnerable to false negatives, which
may have occurred, for example, with regard to the effect
of maternal separation on 5-HT1A receptors in the raphe or
of either separation or fluoxetine on behavior.
A second limitation was that our PET study looked at
only one time point after fluoxetine administration. How-
ever, two previous studies in rats showed that fluoxetine
has age-dependent effects and persistently upregulated
SERT by ∼20%, primarily in cortical regions, when ad-
ministered during the juvenile period but not in adulthood
(5, 6). A third limitation was that our PET study used
ketamine to initially immobilize the monkeys; ketamine
has widespread effects on glutamatergic transmission and
induces rapid antidepressant effects in humans (43). To
minimize the effects of ketamine, we did not inject the
radioligands until at least 120 minutes after the ketamine
injection. Furthermore, while ketamine was used in all
monkeys, including those receiving placebo, SERT upreg-
ulation was observed only in the fluoxetine group, not in
the placebo group. A fourth limitation was that this and
all previous PET studies used antagonist radioligands for
the 5-HT1A receptor. Antagonists do not discriminate be-
tween the active and inactive states of G-protein coupled
receptors, including the 5-HT1A receptor. In neuropsychi-
atric disorders, the active (i.e., agonist-preferring) state of
the receptor might be more affected; thus, it would be
useful to investigate this issue using agonist radioligands
in the future.
Implications
Readers should note that many findings from behavioral
and biochemical studies in monkeys and other animals are
not replicated in humans. Accordingly, this study cannot
directly address the safety or efficacy of SSRIs in children
and adolescents with psychiatric disorders. Nevertheless,
we provide guidance below on which of our findings may
or may not parallel those in humans.
Most notably, this study was not designed to establish
whether SSRIs are effective in treating children or adoles-
cents with psychiatric disorders. First, the sample size was
too small to assess the efficacy of fluoxetine on the behav-
ioral effects of maternal separation in monkeys. Second, this
animal model of maternal separation has never been vali-
dated as a measure of drug efficacy in humans.
In terms of potentially harmful effects associated with
SSRIs, we have no evidence that the persistent upregula-
tion of SERT observed here was either harmful or
beneficial to the monkeys. In light of the known plasticity
of the serotonergic system, we suspect that upregulation
of SERT may have been part of several compensatory
mechanisms to normalize 5-HT transmission in the brain.
Because the human brain is thought to have similar
ajp.psychiatryonline.org 329
FLUOXETINE ADMINISTERED TO JUVENILE MONKEYS
homeostatic mechanisms, chronic SSRI use during de-
velopment may persistently upregulate SERT in humans.
In fact, we designed this study in monkeys to mimic fluoxetine
treatment in a pediatric population. For example, the plasma
concentrations of fluoxetine and norfluoxetine in mon-
keys were similar to those in children (see Figure S1 in the
online data supplement); the duration of administration (1
year in monkeys, equivalent to approximately 4 years in
humans) occurs in clinical practice; and the drug had
a similar, albeit diminished, pharmacodynamic effect on
5-HT turnover in monkeys as in humans, indirectly assessed
as the concentration of a 5-HT metabolite in CSF (see Figure
S2 in the online data supplement). In addition, the washout
period of more than 1 year resulted in no direct drug effect
in the brain. In fact, any residual drug, if present, would
have had the opposite effect—i.e., an apparent down-
regulation of SERT by competing with binding of the
radioligand.
The only way to know definitively whether SSRIs persis-
tently upregulate SERT in humans would be to study our
species. Based on our results, it appears that such PET
research studies, which are commonly performed in
adults, may well be justified. To our knowledge, no PET
study has examined the long-term effects of antidepres-
sants on the serotonergic system in the adult human brain.
It should be noted, however, that our results apply to the
administration of SSRIs only during the prepubertal period,
a time when the brain may have special developmental
sensitivities. Furthermore, ethical concerns about radia-
tion exposure to children, especially for an age-matched
healthy comparison group, would likely preclude such a
PET study. Nevertheless, given the robust, persistent ef-
fect of SERT upregulation observed in monkeys, it is pos-
sible that such changes would similarly be observed in
children exposed to SSRIs. However, we do not know whether
such changes are restricted to a particular developmental
period; for instance, such persistent changes may or may
not occur when SSRIs are administered in adulthood.
Conclusions
This study was to our knowledge the first in nonhuman
primates to demonstrate that an antidepressant adminis-
tered during development has long-lasting effects in the
primate brain. The persistent SERT upregulation identi-
fied by the present study was a substantial, robust effect—
particularly for a PET study conducted with such a limited
sample size—and survived stringent statistical analyses
both at the regional and voxel levels. Specifically, 2-year-
old monkeys receiving fluoxetine, regardless of rearing,
had persistently upregulated SERT binding 1.5 years after
drug discontinuation. Implications regarding the efficacy
or potential adverse effects of SSRIs in patients cannot
be directly drawn from this study. Its purpose was to in-
vestigate the effect of SSRIs on brain development in
nonhuman primates using an experimental approach that
330 ajp.psychiatryonline.org
permitted the random assignment of long-term SSRI treat-
ment or placebo. In contrast, human studies are neces-
sarily confounded by the administration of SSRIs only to
children with mental disorders, which themselves could
affect brain development.
Received Feb. 9, 2013; revisions received April 30, June 18, and July
19, 2013; accepted Aug. 29, 2013 (doi: 10.1176/appi.ajp.2013.
13020183). From the NIMH Intramural Research Program, Bethesda,
Md., and the Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden. Address correspondence to Mr. Shrestha (saurav.
shrestha@nih.gov).
Mr. Shrestha and Dr. Nelson contributed equally as first authors;
Dr. Pine and Dr. Innis contributed equally as last authors.
The authors report no financial relationships with commercial
interests.
The authors dedicate this paper to the memory of our colleague,
Dr. James Winslow, who was one of the leaders of this study before
his untimely death in November 2010.
The authors acknowledge the support of the Intramural Research
Program of the NIMH and thank Masanori Ichise, Masahiro Fujita,
Sami S. Zoghbi, Paul Cumming, Allison Nugent, Kimberly J. Jenko,
David A. Luckenbaugh, George M. Anderson, Alex Cummins, and the
joint National Institutes of Health-Karolinska Institutet Doctoral
Program in Neuroscience.
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ajp.psychiatryonline.org 331
 Article

Association of Violence With Emergence of Persecutory

Delusions in Untreated Schizophrenia
Robert Keers, Ph.D. Objective: Psychosis is considered an
important risk factor for violence, but
studies show inconsistent results. The
Simone Ullrich, Ph.D.
mechanism through which psychotic dis-
orders influence violence also remains
Bianca L. DeStavola, Ph.D. uncertain. The authors investigated whether
psychosis increased the risk of violent be-
Jeremy W. Coid, M.D. havior among released prisoners and
whether treatment reduced this risk. They
also explored whether active symptoms of
psychosis at the time of violent behavior
explained associations between untreated
psychosis and violence.
Method: The U.K. Prisoner Cohort Study
is a prospective longitudinal study of
prisoners followed up in the community
after release. Adult male and female
offenders serving sentences of 2 or more
years for a sexual or violent offense were
classified into four groups: no psychosis
(N=742), schizophrenia (N=94), delusional
disorder (N=29), and drug-induced psycho-
sis (N=102). Symptoms of psychosis, in-
cluding hallucinations, thought insertion,
strange experiences, and delusions of
persecution, were measured before and
after release. Information on violence
between release and follow-up was col-
lected through self-report and police
records.
Results: Schizophrenia was associated
with violence but only in the absence
of treatment (odds ratio=3.76, 95%
CI=1.39–10.19). Untreated schizophrenia
was associated with the emergence of
persecutory delusions at follow-up (odds
ratio=3.52, 95% CI=1.18–10.52), which
were associated with violence (odds ra-
tio=3.68, 95% CI=2.44–5.55). The mediat-
ing effects of persecutory delusions were
confirmed in mediation analyses (b=0.02,
95% CI=0.01–0.04).
Conclusions: The results indicate that
the emergence of persecutory delusions
in untreated schizophrenia explains vio-
lent behavior. Maintaining psychiatric
treatment after release can substantially
reduce violent recidivism among prisoners
with schizophrenia. Better screening and
treatment of prisoners is therefore essen-
tial to prevent violence.

(Am J Psychiatry 2014; 171:332–339)

F indings on associations between major mental illness

and violent behavior are controversial. Earlier studies
suggested that violence can be driven by symptoms of
psychosis, including delusions (1), threat/control-override
(2, 3), and command hallucinations (4, 5). However, cross-
sectional and case-register studies have found little or no
association between psychotic illness and violence (6, 7)
and suggest that risk factors for violence are the same
among individuals with and without psychosis (8). Never-
theless, there is evidence that violence by patients with
psychosis is more common during acute episodes (9–11).
Consistent with these findings, more recent studies, which
take into account temporal ordering and proximity of
symptoms to outcome, have demonstrated an independent
association between severe mental illness and violence (10,
12), emphasizing the relevance of persecutory/threat delu-
sions as causal risk factors (11). Patients with psychosis who
do not adhere to treatment are both more likely to experience
a re-emergence of active symptoms (13, 14) and are at greater
risk of violent behavior than their adherent counterparts
(15–19). Moreover, first-episode studies suggest that the risk
of violence is higher at first presentation than following
treatment (9, 20). Despite the high prevalence of mental
disorders among prisoners (21, 22), treatment opportunities
are less often available in correctional settings than in the
community (23). Untreated psychosis may therefore be an
important risk factor for violent recidivism in released
prisoners and an important target for intervention. The
United Kingdom Prisoner Cohort Study is a large, observa-
tional longitudinal investigation of risk factors for future
violence among released prisoners previously convicted of
violent and sexual offenses. Taking into account temporal
ordering and proximity, in the present study we aimed to
answer the following questions: 1) whether violent offending
is more common among prisoners with psychosis after
release, 2) which specific symptoms have an effect on their
violent behavior, and 3) whether treatment is an important
factor in the pathway between symptoms and violence.

This article is featured in this month’s AJP Audio, is an article that provides Clinical Guidance (p. 339),
and is discussed in an Editorial by Dr. Large (p. 256)

332 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


Method
Study Sample
The Prisoner Cohort Study was designed to identify predictors
of re-offending among prisoners released into the community
from prisons in England and Wales. Study design and sample
characteristics have been described previously (24). In brief, the
Prison Service Inmate System identified adult male and female
offenders serving sentences of $2 years for a sexual or violent
principle offense and who were expected to be released within 12
months of the study start date (June 2001). The study included
two phases of data collection: baseline and follow-up. All 1,717
prisoners who entered the study received a baseline assessment,
and 967 (56.3%) were successfully followed up (mean follow-up
time=39.2 weeks [SD=33.0]; median=29.6 weeks). The majority, 816
(84.4%), were in the community at follow-up, while 151 (15.6%) had
returned to prison. The mean age of the sample was 30.9 (SD=11.6
years) and included 787 (81.4%) men and 180 (18.6%) women.
Measure
A semistructured interview was administered at baseline to
collect data on demography and self-reported information on
psychiatric treatments received during the current sentence.
These included receiving medication for a mental health
problem, seeing a psychiatrist or psychologist, or being trans-
ferred to a psychiatric hospital.
A lifetime diagnosis of schizophrenia, delusional disorder, or
drug-induced psychosis was established at baseline using
a module from the Schedule for Affective Disorders and
Schizophrenia—Lifetime version (25). Personality disorders were
assessed using the Structured Clinical Interview for DSM-IV Axis
II Personality Disorders (26), and psychopathy was assessed using
the Hare Psychopathy Checklist—Revised (27). All interviews were
carried out by research assistants trained in the use of the in-
struments and after achieving satisfactory interrater reliability (24).
All participants completed the Psychosis Screening Questionnaire
(28) at baseline by self-report, which measured the occurrence of
four symptoms: auditory and visual hallucinations, thought in-
terference, strange experiences, and persecutory delusions.
At follow-up, participants completed a questionnaire admin-
istered by lay interviewers using a laptop computer and designed
to capture the occurrence of risk factors for violence occurring
between release and the interview. Participants were asked again
whether they received any psychiatric treatments. Participants
also completed the Psychosis Screening Questionnaire to in-
dicate symptoms of psychosis they experienced in the past
3 months. This allowed us to identify symptoms that emerged
between baseline and follow-up.
Data on violent behavior occurring in the time between
release and follow-up were collected from two sources: 1) self-
report and 2) information on convictions obtained from the
Police National Computer. For the self-report, participants were
asked whether they had been in a physical fight or assaulted
or deliberately hit anyone since they were released from prison.
The Police National Computer data included offenses committed
during the same time span, classified according to the United
Kingdom Home Office standard list for “Violence Against the
Person.” Using both sources of information, 218 (22.9%) partic-
ipants were identified as violent between release and follow-up.
Statistical Analyses
The demographic and clinical characteristics of prisoners with
schizophrenia, delusional disorder, or drug-induced psychosis
were compared with those with no psychotic disorder using
logistic regressions (29). We also tested for differences in psy-
chopathy scores between those with schizophrenia, delusional
Am J Psychiatry 171:3, March 2014
KEERS, ULLRICH, DESTAVOLA, ET AL.
disorder, or drug-induced psychosis and those with no psychosis
using t tests.
We examined the relationship between baseline psychosis and
violent recidivism during the follow-up period, defined as a
binary outcome denoted “violence,” by fitting logistic regression
models. These allowed for comparison of the risk of violence
among prisoners with schizophrenia, delusional disorder, or drug-
induced psychosis with those with no psychosis. Time at risk was
calculated as time (days) between release and follow-up inter-
view minus any time spent in prison. Time at risk and location of
follow-up interview (prison or community), as well as potentially
confounding clinical and demographic variables, were included
as covariates in all adjusted models.
To investigate whether treated or untreated psychotic disor-
ders were associated with increased risk of violent re-offending,
we compared the occurrence of violence at follow-up among
prisoners with psychosis who did not receive treatment at either
time point, who received discontinuous treatment (treatment
only during prison), or who received continuous treatment
(treatment during prison and after release) with prisoners with
no psychosis, using logistic regression models. The observational
nature of the study and lack of randomization meant that
associations between treated or untreated psychosis and vio-
lence may be confounded by differences between treatment
groups. To detect potential confounders, we modeled the odds of
receiving no treatment, discontinuous treatment, and continu-
ous treatment on numerous demographic, historical, and clinical
variables using multinomial logistic regression models (30) (see
Table S1 in the online data supplement that accompanies this
article). Potential confounders for the effects of treatment (var-
iables that differed significantly between treatment groups) were
then added to adjusted models.
Finally, we tested whether increased risk of violence among
persons with untreated psychotic disorders was a result of the
emergence of active symptoms. Using logistic regression models,
we investigated whether emergence of symptoms was related to
violence and whether individuals with untreated psychosis were
more likely to experience these symptoms at follow-up. To test
whether emergence of symptoms significantly mediated the
association between untreated psychoses and violent outcome,
we standardized regression coefficients as recommended for
binary mediators and outcomes (31) and produced bootstrapped
standard errors and confidence intervals (using 1,000 repetitions)
for the estimated indirect effects to provide statistical evidence of
the significance of the mediation by the emergence of symptoms.
All analyses were conducted in STATA, version 12 (StataCorp,
College Station, Tex.).
Results
Sample Characteristics and Psychopathology
In total, 94 (9.9%) prisoners with follow-up data met the
diagnostic criteria for schizophrenia, 29 (3.0%) for de-
lusional disorder, and 102 (10.7%) for drug-induced
psychosis. Initially, the demographic and clinical charac-
teristics of individuals in each of the three diagnostic
groups were compared with those with no psychosis
(N=742). Persons with delusional disorder did not differ
from those with no psychosis on any of the tested
demographic characteristics. However, those with
drug-induced psychosis were significantly younger
(odds ratio per year of age=0.96, 95% confidence
interval [CI]=0.94–0.98, p,0.001), and individuals with
ajp.psychiatryonline.org 333
ASSOCIATION OF VIOLENCE WITH PERSECUTORY DELUSIONS IN UNTREATED SCHIZOPHRENIA
schizophrenia were more likely to be women (odds
ratio=2.65, 95% CI=1.75–4.02, p,0.001) and to be
unemployed before imprisonment (odds ratio=2.41, 95%
CI=1.59–3.64, p,0.001).
Rates of comorbid axis I and axis II disorders varied
markedly between each psychotic disorder group and the
no psychosis group. Individuals with schizophrenia were
significantly more likely to have comorbid major de-
pression (odds ratio=3.08, 95% CI=1.78–5.31, p,0.001),
alcohol (odds ratio=1.93, 95% CI=1.14–3.28, p=0.02)
and drug (odds ratio=1.81, 95% CI=1.07–3.09, p=0.03)
dependence, and schizotypal (odds ratio=12.03, 95%
CI=4.42–32.78, p,0.001) and borderline (odds ratio=2.46,
95% CI=1.39–4.37, p=0.002) personality disorders. Those
with delusional disorder were more likely to have a
diagnosis of major depression (odds ratio=6.35, 95%
CI=2.49–16.20, p,0.001) and obsessive-compulsive dis-
order (odds ratio=3.38, 95% CI=1.12–10.17, p=0.03). Per-
sons with drug-induced psychosis were more likely to
be dependent on alcohol (odds ratio=3.02, 95%
CI=1.84–4.97, p,0.001) and drugs (odds ratio=5.49, 95%
CI=3.26–9.24, p,0.001) but no more likely to have
personality disorders or major depression than those with
no psychosis.
Individuals with schizophrenia or drug-induced psy-
chosis also had higher psychopathy scores when com-
pared with persons without psychosis (schizophrenia:
t=3.53, df=834, p,0.001; drug-induced psychosis: t=2.78,
df=842, p,0.006). However, on adjustment for age and
gender in a linear regression model, these findings only
remained significant for schizophrenia and not drug-
induced psychosis (estimated score difference b=0.43, 95%
CI=0.22–0.64, p,0.001 and b=0.16, 95% CI=20.04 to 0.37,
not significant, respectively). Delusional disorder was not
associated with psychopathy either before or after adjust-
ment for age and gender.
Psychotic Disorders and Violent Re-Offending
We investigated the effects of schizophrenia, delusional
disorder, or drug-induced psychosis on the risk of violent
re-offending by comparing the occurrence of violence
among persons in each of these three groups with persons
in the no psychosis group, using a logistic regression
model (Table 1). Schizophrenia and delusional disorder
were not significantly associated with increased risk of
violent re-offending either before or after adjustment for
confounders. While drug-induced psychosis was associ-
ated with increased violence in univariable analyses, these
findings did not remain significant on adjustment for drug
and alcohol dependence.
Treated and Untreated Psychotic Disorders and
Violence
To explore whether treated or untreated psychotic
disorders were associated with increased risk of violence,
we compared violence in persons with schizophrenia,
334 ajp.psychiatryonline.org
delusional disorder, or drug-induced psychosis stratified
by treatment type (no treatment, discontinuous treat-
ment, or continuous treatment) with those with no
psychosis, using logistic regression models (Table 2). After
adjustment, treated and untreated individuals with drug-
induced psychosis or delusional disorder were no more
likely to be violent at follow-up than those with no
psychosis.
Persons with schizophrenia who reported receiving
treatment either during prison only or both during prison
and after release were also no more likely to violently
re-offend than their counterparts with no psychosis.
However, when compared with no psychosis, untreated
schizophrenia was associated with a significant increased
risk of violence (Table 2). We further investigated the
effects of treatment on violence among those with
schizophrenia by comparing violent re-offending in un-
treated individuals with those receiving either continuous
or discontinuous treatment. In these analyses, individuals
with untreated schizophrenia were significantly more
likely to be violent at follow-up than their treated
counterparts (odds ratio=3.33, 95% CI=1.03–10.75,
p=0.04).
Analyses to identify potential confounders on treatment
revealed only two significant differences between the three
treatment types (see Table S1 in the online data supple-
ment). Those who reported continuous treatment were
significantly more likely to be women (odds ratio=7.25,
95% CI=1.51–34.85, p=0.01) and to have comorbid
borderline personality disorder (odds ratio=6.22, 95%
CI=1.59–24.31, p=0.009) than untreated individuals with
schizophrenia. On inclusion of these potential confound-
ers, individuals with untreated schizophrenia remained
significantly more likely to be violent at follow-up
than those with no psychosis (odds ratio=3.84, 95%
CI=1.22–12.08, p=0.02) or those with schizophrenia re-
ceiving treatment (odds ratio=3.64, 95% CI=1.06–12.41,
p=0.04).
Finally, we examined whether the effects of treatment
were specific to psychiatric treatment or whether they
extended to treatment for substance abuse. We therefore
compared violence among persons with schizophrenia,
delusional disorder, or drug-induced psychosis stratified
by substance abuse treatment type (no treatment, discon-
tinuous treatment, or continuous treatment) with those
with no psychosis, using logistic regression models. These
analyses suggested that the risk of violence among in-
dividuals with schizophrenia, drug-induced psychosis, or
delusional disorder did not differ according to whether they
received any treatment for substance abuse disorders.
Symptoms at Follow-Up and Violence
To identify symptoms that may explain the association
between untreated schizophrenia and violence, we first
investigated whether emergence of specific symptoms of
psychosis at follow-up was associated with violence. As
Am J Psychiatry 171:3, March 2014
 KEERS, ULLRICH, DESTAVOLA, ET AL.

TABLE 1. Comparison of the Occurrence of Violent Re-Offenses Among Prisoners With No Psychosis and Those With Lifetime
Schizophrenia, Delusional Disorder, or Drug-Induced Psychosis
Violent Incident After Release Logistic Regression
No Yes Unadjusted Adjusteda
Group N % N % Odds Ratio 95% CI p Odds Ratio 95% CI p
No psychosis (reference) 586 79.4 156 21.6 1.00 1.00
Schizophrenia 67 71.2 27 28.8 1.52 0.94–2.45 0.089 1.65 0.94–2.90 0.082
Delusional disorder 23 79.3 6 20.7 0.94 0.38–2.34 0.895 0.83 0.31–2.25 0.718
Drug-induced psychosis 69 67.6 33 32.4 1.80 1.15–2.82 0.011 1.29 0.78–2.11 0.320
All groups 745 77.0 222 23.0
a
Estimates were obtained by fitting logistic regression models with adjustment for gender, age (years), major depression, drug dependence,
alcohol dependence, psychopathy, and time at risk (which accounted for prison sentences occurring between release and violent re-offense).

TABLE 2. Violent Re-Offending Among Prisoners With a Lifetime Diagnosis of Psychotic Disorders Receiving No Treatment,
Treatment During Prison, or Continued Treatment Compared With Those With No Psychosis
Violent Incident After Release Logistic Regression
No Yes Unadjusted Adjusteda
Diagnosis N % N % Odds Ratio 95% CI p Odds Ratio 95% CI p
No psychosis (reference) 586 79.4 156 21.6 1.00 — — 1.00 — —
Schizophrenia
No treatment 8 50.0 8 50.0 3.76 1.39–10.19 0.009 3.43 1.10–10.72 0.034
Treatment during prison only 16 72.7 6 27.3 1.41 0.54–3.67 0.480 1.39 0.49–3.96 0.532
Continued treatment 40 75.5 13 24.5 1.22 0.64–2.34 0.544 1.40 0.66–2.97 0.380
Delusional disorder
No treatment 3 75.0 1 25.0 1.19 0.12–11.50 0.881 0.71 0.07–7.38 0.778
Treatment during prison only 10 77.0 3 23.0 1.07 0.29–3.93 0.919 0.96 0.24–3.89 0.958
Continued treatment 13 92.9 1 7.1 0.27 0.04–2.11 0.214 0.23 0.03–1.81 0.161
Drug-induced psychosis
No treatment 38 71.7 15 28.3 1.49 0.80–2.77 0.213 1.10 0.57–2.12 0.787
Treatment during prison only 8 53.3 7 46.7 3.29 1.18–9.22 0.023 2.59 0.88–7.61 0.083
Continued treatment 19 79.2 5 20.8 0.99 0.36–2.69 0.985 0.88 0.31–2.56 0.821
a
Estimates were obtained by fitting logistic regression models with adjustment for gender, age (years), major depression, drug dependence,
alcohol dependence, psychopathy, and time at risk (which accounted for prison sentences occurring between release and violent re-offense).

shown in Table 3, the emergence of hallucinations,
thought insertion, or strange experiences at follow-up
was not significantly associated with increased risk of
violence, either before or after adjustment for confound-
ers. However, individuals who developed persecutory
delusions at follow-up were significantly more likely to be
violent (before and after adjustment).
Given the association between persecutory delusions
and violence, we explored whether emergence of these
symptoms explained the association between untreated
schizophrenia and violence. Individuals with untreated
schizophrenia were significantly more likely to experi-
ence persecutory delusions at follow-up than those who
received either continuous (odds ratio=1.57, 95%
CI=1.15–2.98, p=0.03) or discontinuous (odds ratio=2.39,
95% CI=1.12–4.67, p=0.04) treatment or those with no
psychosis (odds ratio=1.28, 95% CI=1.18–2.38, p=0.02).
Mediation analyses confirmed that the emergence of
persecutory delusions significantly mediated the as-
sociation between untreated schizophrenia and vio-
lence (b=0.02, 95% CI=0.01–0.04, p=0.03), accounting
for approximately 26% of the total effect of untreated
schizophrenia.
Discussion
This study demonstrated that prisoners with schizo-
phrenia who remained untreated during and after impris-
onment were more likely to be violent following release
than those who received treatment or those without
psychosis. The association between untreated schizophre-
nia was explained, in part, by the emergence of persecu-
tory delusions in these individuals.
Before taking into account whether treatment had been
received, there were no differences between prisoners with
either schizophrenia or delusional disorder with respect to
violence compared with prisoners with no psychotic
disorder. These negative findings are in line with previous
studies of psychosis and violent recidivism that did not
account for the effects of treatment (32). Persons with
schizophrenia who did not receive treatment were more
than three times as likely to be violent than their treated

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 335

ASSOCIATION OF VIOLENCE WITH PERSECUTORY DELUSIONS IN UNTREATED SCHIZOPHRENIA
TABLE 3. Effects of the Emergence of Symptoms of Psychosis on Violence During the Follow-Up Period
Unadjusted
Emergent Symptom Odds Ratio 95% CI
Hallucinations (N=11) 1.97 0.57–6.79
Thought insertion (N=51) 1.42 0.76–2.64
Strange experiences (N=76) 0.73 0.40–1.34
Persecutory delusions (N=110) 3.68 2.44–5.55
a
Estimates were obtained by fitting logistic regression models with adjustment for gender, age (years), major depression, drug dependence,
alcohol dependence, psychopathy, and time at risk (which accounted for prison sentences occurring between release and violent re-offense).
counterparts. It was of interest that this effect was not ob-
served for untreated persons with delusional disorder. How-
ever, it is possible that persons with this diagnosis responded
less well to treatment than those with schizophrenia.
In unadjusted analyses, drug-induced psychosis was
associated with a nearly twofold risk for violence following
release, which became nonsignificant following adjust-
ments for substance dependence. These effects may
therefore be the result of substance-related comorbidity.
Indeed, findings did not differ according to treatment,
which suggests that subsequent violence had little or no
relationship with psychotic symptoms and instead may
reflect re-engagement in the drug economy and criminal
networks.
We are not aware of any previous study of violent
recidivism that has compared risk among treated and
untreated prisoners with psychosis. The results of the
present study are therefore novel and require replication
in independent samples. Nevertheless, our findings are
consistent with those in studies of treatment compliance
in psychosis that report that nonadherence to medication
is associated with increased risk of violence (15–19). They
are also in line with findings from studies of first-episode
patients that suggest that the risk of violence is higher at
first presentation than following treatment (9, 20). Our
results confirm the opinion of most clinicians that
treatment reduces the risk of violence among persons
with schizophrenia and that the risk of future violence is
greatly increased among prisoners with schizophrenia if
they are not treated. They also indicate that the incon-
sistent findings reported thus far in studies of psychosis
and recidivism may, in part, be explained by the moderating
effects of treatment. In line with this hypothesis, a recent
meta-analysis (32) suggested that in prison samples, for
which the likelihood of treatment is lower than in the com-
munity, psychosis is a significant risk factor (33). However,
in community or secure hospital samples, with a high like-
lihood of receiving treatment, studies report no effects or
even protective effects on subsequent violence (34).
Untreated Schizophrenia, Emergence of Persecutory
Delusions, and Violence
The emergence of persecutory delusions at follow-up
significantly mediated the association between untreated
336 ajp.psychiatryonline.org
Logistic Regression
Adjusteda
p Odds Ratio 95% CI p
0.284 3.14 0.81–12.16 0.097
0.270 1.79 0.91–3.52 0.089
0.314 0.78 0.42–1.46 0.441
,0.001 3.42 2.19–5.33 ,0.001
schizophrenia and violence. This is in accordance with
previous findings that associations between nonadher-
ence to treatment and violence are explained by a lack of
overall improvement in symptoms (18). However, our
study is the first, to our knowledge, to demonstrate the
specificity of these effects for persecutory delusions. We
did not find associations with hallucinations, thought
insertion, or strange experiences.
There has been considerable debate over the causal
pathways between schizophrenia and violence. Some
investigators have argued that the association is driven
entirely by comorbid conditions, such as drug and alcohol
dependence (6). However, others have suggested that
active symptoms, in particular delusions (35, 36), play
a significant causal role in violent behavior. Our results
support this latter hypothesis, suggesting that, if left
untreated, schizophrenia is associated with the emergence
of persecutory delusions, which in turn increase the
likelihood of violence.
Limitations
The prevalence of psychosis in this study (23%) was
considerably higher than that reported in a recent meta-
analysis (37). This is largely because our study considered
lifetime rather than current diagnoses of psychotic disor-
ders. Rates were lower when considering past-year preva-
lence (11.8% in men and 22.0% in women) but still higher
than those found in the largest and most comprehensive
survey conducted in the United Kingdom, which reported
1-year prevalences of 8% in men and 14% in women (38). It
is probable that the high rates of psychosis in the present
study were affected by overselection of serious violent and
sexual offenders who received closer attention from prison
health care services. Despite the high prevalence of psy-
chosis, sample sizes for individual disorders were small,
particularly when stratified by treatment, increasing the
likelihood of both type I and type II error. Our findings
therefore require replication in larger, more representative
samples of the general prison population.
Psychiatric treatment was self-reported, broadly de-
fined, and did not include detailed information on compli-
ance and treatment efficacy. Future investigations should
assess the effects of specific treatments and treatment
efficacy on violent recidivism.
Am J Psychiatry 171:3, March 2014

Patient Perspectives
Case 1
A 21-year-old man with alcohol dependence and
a history of cocaine and amphetamine abuse served
a sentence of 2 years for attacking a stranger with
a 3.5-kg weight during an argument. The victim, a 25-
year-old man, required hospital treatment for his
injuries. The participant had been diagnosed with
schizophrenia, first experiencing symptoms at age 17.
He did not receive any treatment for a mental
disorder while in prison and remained untreated
after release. During his prison stay, the researcher
found residual psychotic symptoms, including expe-
riences of bodily influence and delusions of external
control. At the follow-up, the participant reported
that he was initially supported by his parents after
release and that they found employment for him.
However, he returned to his former criminal network
and confirmed that his friends had encouraged drug
misuse. He generally denied using drugs after release
but was not willing to confirm or deny questions
about cocaine use. He confirmed that a group or
organization was plotting to cause him serious harm
or injury, indicating the presence of persecutory
delusions. He reported that he had become involved
in fights with strangers and acquaintances encoun-
tered in bars. Police records revealed that he was
subsequently convicted of assaulting a police officer
who had been called to a bar where he was acting in
a strange and threatening manner.
Case 2
A 21-year-old man with antisocial personality
disorder served a 4-year prison sentence for the
armed robbery of a liquor store in which he
threatened staff with a knife and imitation firearm.
He initially required alcohol detoxification in prison.
He reported physical abuse from age 3 by his father
and a family history of alcoholism. He experienced
psychotic symptoms for 12 months at age 17 and had
been admitted to the hospital and diagnosed with
The Prisoner Cohort Study was a naturalistic study.
Measured and unmeasured differences between treated
and untreated prisoners may therefore have confounded
relationships between treatment and violent outcomes. In
our study, individuals with untreated schizophrenia did
not differ from their treated counterparts in terms of
several demographic, historical, clinical, and criminolog-
ical variables. Borderline personality disorder and female
gender were associated with increased odds of treat-
ment. However, these factors were unlikely to confound
the relationship between untreated schizophrenia and
Am J Psychiatry 171:3, March 2014
KEERS, ULLRICH, DESTAVOLA, ET AL.
schizophrenia. He did not receive any treatment
during or after his imprisonment. At follow-up, he
reported that he had returned to his previous criminal
network and had been involved in burglaries and
thefts. He confirmed that a group or organization was
plotting to cause him serious harm or injury, in-
dicating persecutory delusions. These were accom-
panied by auditory hallucinations, a feeling that
strange things were going on around him, severe
symptoms of anxiety, and ruminations of different
ways of harming other persons on a daily basis. He
attended appointments with his parole officer regu-
larly, who was unaware that he had violently
assaulted friends on several occasions, one requiring
hospital treatment. Because these incidents had not
been reported, he had not been charged with a
criminal offense.
Case 3
A 52-year-old woman served a 2-year sentence for
the robbery of a liquor store to obtain money for her
heroin addiction. She had been neglected as a child
following her mother’s death, and there was a family
history of alcohol dependence. She was estranged
from her children who were taken into foster care.
She first reported psychotic symptoms in childhood
and was later diagnosed with schizophrenia. Al-
though previously admitted to a psychiatric hospital,
she did not receive assessment or treatment, either
during prison or following release. At follow-up, she
reported that she had returned to live with her
boyfriend. There were repeated moves of accom-
modation and eviction because of nonpayment of
rent and debts. She admitted to heavy misuse of
cannabis but denied using other drugs. She reported
that a group or an organization was plotting to cause
her serious harm or injury, indicating persecutory
delusions. She had violently assaulted her boyfriend
on one occasion and a female acquaintance in a bar
on another, resulting in her arrest and conviction for
common assault.
violence because they were included as covariates in
adjusted analyses. Nevertheless, replication of our findings
in a randomized design is necessary to safely exclude the
effects of any bias.
A recent study (11) demonstrated that angry affect is an
important intermediate factor in the pathway between
delusions implying threat (including persecutory delu-
sions) and serious violence. Affect as a result of delusions
was not measured in the Prisoner Cohort Study. It is
therefore possible that the effects of emerging persecutory
delusions on violent re-offending in untreated prisoners
ajp.psychiatryonline.org 337
ASSOCIATION OF VIOLENCE WITH PERSECUTORY DELUSIONS IN UNTREATED SCHIZOPHRENIA
were further influenced by anger as a result of delusional
beliefs. Future studies are required to investigate this
pathway.
Implications
The findings from this study have important implica-
tions for the development of risk assessment instruments
and risk management to prevent violence. Risk assessment
instruments are currently divided according to whether
psychosis is a risk (39) or protective factor for violent
recidivism (34). Our results suggest that measuring the
presence or absence of treatment may reconcile these
differences. Failure to treat, or refusal to be treated, should
be included as a risk factor.
Our findings emphasize the need for improved screen-
ing, ensuring treatment of psychosis among persons in
correctional settings and treatment adherence following
release if the aim is to manage their risk of violence. A
recent study found that only one-quarter of prisoners with
severe mental illnesses were successfully identified by
mental health in-reach teams and just 13% accepted onto
their caseloads (40). Rates of treatment were relatively high
among those with psychosis in our study, probably re-
sulting from more careful assessment of our participants
because of the seriousness of their offending. Neverthe-
less, 22% of those with schizophrenia did not report
receiving any treatment either during prison or following
release. Furthermore, it is estimated that in the United
Kingdom, less than one-quarter of prisoners who screen
positive for psychosis in the correctional population will
subsequently receive an appointment with a mental
health professional after release (23). Growing evidence
suggests a complex association between delusions and
violence (11), and our findings demonstrate that failure to
treat schizophrenia results in the emergence of persecu-
tory delusions and violence among released prisoners.
Received Jan. 30, 2013; revision received July 1, 2013; accepted
Sept. 9, 2013 (doi: 10.1176/appi.ajp.2013.13010134). From the
Forensic Psychiatry Research Unit, Wolfson Institute of Preventive
Medicine, Barts and The London School of Medicine and Dentistry,
Queen Mary University of London; and the Centre for Statistical
Methodology, London School of Hygiene and Tropical Medicine.
Address correspondence to Dr. Keers (r.keers@qmul.ac.uk).
The authors report no financial relationships with commercial
interests.
This article presents independent research commissioned by the
U.K. National Institute for Health Research under its Program Grants
for Applied Research funding scheme (RP-PG-0407-10500).
The views expressed in this article are those of the authors and not
necessarily those of the U.K. National Health System, the U.K.
National Institute for Health Research, or the U.K. Department of
Health.
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Clinical Guidance: Violence and Persecutory Delusions

Individuals with schizophrenia who have been imprisoned for violent crimes but
not treated are more likely to commit violent acts after release from prison than
are those without psychosis or those with schizophrenia who are treated in prison
or after release. Keers et al. followed 967 released prisoners in the United
Kingdom for a mean of 39 weeks. In the United Kingdom Prisoner Cohort, 22% of
those with schizophrenia reported that they had not received any treatment in
prison or after release. The higher risk for violence is related to persecutory
delusions but not to hallucinations or other psychotic experiences. In an editorial,
Large (p. 256) underscores the value of antipsychotic treatment for violent
prisoners with schizophrenia to prevent further violent crimes.

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 339

 Article

Multicenter Voxel-Based Morphometry Mega-Analysis of

Structural Brain Scans in Obsessive-Compulsive Disorder
Stella J. de Wit, M.D. Kenji Fukui, M.D., Ph.D. on 1.5-T structural T1-weighted MRI scans
derived from the International OCD Brain
Imaging Consortium. Regional gray and
Pino Alonso, M.D., Ph.D. Wi Hoon Jung, Ph.D.
white matter brain volumes were com-
pared between 412 adult OCD patients
Lizanne Schweren, M.Sc. Sung Nyun Kim, M.D. and 368 healthy subjects.

David Mataix-Cols, Ph.D.
Christine Lochner, Ph.D.
José M. Menchón, M.D., Ph.D.
Dan J. Stein, M.D., Ph.D.
Jean-Paul Fouche, M.Sc.
Carles Soriano-Mas, Ph.D.
Joao R. Sato, Ph.D.
Marcelo Q. Hoexter, M.D., Ph.D.
Damiaan Denys, M.D., Ph.D.
Takashi Nakamae, M.D., Ph.D.
Seiji Nishida, M.D., Ph.D.
Jun Soo Kwon, M.D., Ph.D.
Joon Hwan Jang, M.D., Ph.D.
Geraldo F. Busatto, M.D., Ph.D.
Narcís Cardoner, M.D., Ph.D.
Danielle C. Cath, M.D., Ph.D.
Euripides C. Miguel, M.D., Ph.D.
Jin Narumoto, M.D., Ph.D.
Mary L. Phillips, M.D., Ph.D.
Jesus Pujol, M.D., Ph.D.
Peter L. Remijnse, M.D., Ph.D.
Yuki Sakai, M.D., Ph.D.
Na Young Shin, M.A.
Kei Yamada, M.D., Ph.D.
Dick J. Veltman, M.D., Ph.D.
Odile A. van den Heuvel, M.D.,
Ph.D.
Objective: Results from structural neuro-
imaging studies of obsessive-compulsive
disorder (OCD) have been only partially
consistent. The authors sought to assess
regional gray and white matter volume
differences between large samples of OCD
patients and healthy comparison subjects
and their relation with demographic and
clinical variables.
Method: A multicenter voxel-based mor-
phometry mega-analysis was performed
Results: Relative to healthy comparison
subjects, OCD patients had significantly
smaller volumes of frontal gray and white
matter bilaterally, including the dorsome-
dial prefrontal cortex, the anterior cingu-
late cortex, and the inferior frontal gyrus
extending to the anterior insula. Patients
also showed greater cerebellar gray matter
volume bilaterally compared with healthy
subjects. Group differences in frontal gray
and white matter volume were significant
after correction for multiple comparisons.
Additionally, group-by-age interactions
were observed in the putamen, insula,
and orbitofrontal cortex (indicating rel-
ative preservation of volume in patients
compared with healthy subjects with
increasing age) and in the temporal
cortex bilaterally (indicating a relative
loss of volume in patients compared
with healthy subjects with increasing
age).
Conclusions: These findings partially sup-
port the prevailing fronto-striatal models of
OCD and offer additional insights into the
neuroanatomy of the disorder that were
not apparent from previous smaller stud-
ies. The group-by-age interaction effects
in orbitofrontal-striatal and (para)limbic
brain regions may be the result of altered
neuroplasticity associated with chronic
compulsive behaviors, anxiety, or com-
pensatory processes related to cognitive
dysfunction.

(Am J Psychiatry 2014; 171:340–349)

S tructural and functional brain changes in the frontal-

basal ganglia-thalamic loops and the limbic circuit have
been associated with obsessive-compulsive disorder (OCD)
symptoms and associated neurocognitive dysfunctions, but
probably also extend to other brain circuits (1). With voxel-
based morphometry, it is possible to assess alterations in
regional gray and white matter volume across the whole
brain in an automated unbiased fashion.
Recent meta-analyses (2–5) that included 10–14 partially
overlapping adult and pediatric voxel-based morphome-
try studies consistently showed smaller frontal gray matter
volume in OCD, mainly of the dorsomedial prefrontal and
anterior cingulate cortex (2–5), regions associated with
cognitive control and performance monitoring (6). Find-
ings in other brain regions, such as the orbitofrontal and
inferior frontal cortex, which are implicated in behavioral

340 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


inhibition and flexibility (1, 7), have been less consistent,
with reports of normal (2, 3), greater (4), or smaller (4, 5)
gray matter volumes. Greater striatal volume is often found
in OCD patients compared with healthy subjects (2–5),
whereas reports on gray matter volume alterations outside
the frontal-striatal circuit in OCD are less consistent (2–5).
The involvement of white matter volume alterations in OCD
remains unclear as well, with either nonsignificant findings
(e.g., reference 8), smaller dorsal frontal (9, 10) and temporal
white matter volume (11), or greater ventral frontal white
matter volume (10). Although white matter volume infor-
mation is automatically available in voxel-based morphom-
etry, many studies do not report such findings, suggesting a
reporting bias. Inconsistent findings can probably be at-
tributed to differences between individual studies in the
analysis methods used, heterogeneity of study samples (e.g.,
varying age groups), and lack of power because of limited
sample sizes.
It has been suggested that regional brain volume ab-
normalities in OCD may result from altered neurodevel-
opment (endophenotype model), with additional effects of
abnormal aging trajectories (8). Development- and aging-
dependent effects on brain structure in OCD would ex-
plain the differential effects that inclusion of pediatric
samples had on previous meta-analytical results (2–4). As-
sessing the effects of aging on brain structure in OCD is
important, since age-by-disorder interactions may provide
leads as to whether changes in brain structure are related to
developing the disorder (present in young patients) or are
the result of persistent OCD symptoms, compensatory
processes, or treatment effects (present in older patients).
Additionally, heterogeneity in clinical characteristics
such as OCD illness severity (2), illness onset time or
duration, medication exposure (12), comorbidity (13, 14),
and symptom dimensions (8, 9) may affect regional brain
volume. In meta-analyses, only group-level demographic
and clinical information is available, so accounting for effects
of participant-level variability is problematic. An image-
based mega-analysis, in which a large sample of raw images
from multiple sources is pooled and processed in a uni-
form preprocessing and analysis pipeline, improves statis-
tical power compared with meta-analyses because of noise
reduction and information preservation (15). Moreover,
compared with previously published well-powered inde-
pendent studies (e.g., reference 8), an image-based mega-
analysis may have greater sensitivity in revealing significant
but small effects and additionally allows generalization of
findings across ethnic groups. Multicenter data pooling for
voxel-based morphometry mega-analysis in other neuro-
psychiatric disorders has been proven successful (e.g.,
reference 16).
In this study, we aimed to overcome the limitations of
previous structural brain imaging research in OCD by
pooling data from six academic OCD centers, across three
continents (Asia, Europe, and South America), participat-
ing in the international OCD Brain Imaging Consortium.
Am J Psychiatry 171:3, March 2014
DE WIT, ALONSO, SCHWEREN, ET AL.
With high-quality data from 412 adult OCD patients and
368 healthy comparison subjects, this is, to our knowledge,
the largest structural neuroimaging study in OCD conducted
so far. This approach provides greater power to study subtle
alterations in regional gray and white matter volume and to
examine the effects of demographic and clinical factors,
including medication use, comorbidity, and OCD symptom
dimensions. We hypothesized that OCD patients would
exhibit abnormalities in frontal-striatal-thalamic and (para)
limbic gray matter and interconnecting white matter.
Additionally, we hypothesized age-by-disorder interac-
tion effects in relevant structures previously implicated
in the disorder.
Method
Participants
Six research centers contributed data to the OCD Brain
Imaging Consortium (VU University Medical Center, Amsterdam;
Hospital de Bellvitge, Barcelona, Spain; Institute of Psychiatry,
King’s College London, London; University of São Paulo Medical
School, São Paulo, Brazil; Kyoto Prefectural University of Medicine
Hospital, Kyoto, Japan; and Seoul National University College of
Medicine, Seoul, Republic of Korea). Each study was approved by
the local ethical review board, and all participants provided
written informed consent to participate in the different studies
performed at each center. All centers obtained permission to
participate in the consortium from their local ethical review board,
and permission for multicenter data analysis was obtained from
the ethical review board of the VU University Medical Center.
The study included 436 OCD patients and 382 healthy com-
parison subjects who underwent 1.5-T structural T1-weighted
MRI scanning (see Tables 1 and 2). All participants were screened
for DSM-IV axis I disorders with a standardized structured
interview (see the Supplemental Methods section in the data
supplement that accompanies the online edition of this article).
Patients were recruited through local outpatient or specialist
OCD clinics, and healthy subjects through local advertisements.
Exclusion criteria were age under 18 or over 65 years, a current
psychotic disorder, a recent history of a substance use disorder,
mental retardation, and severe organic or neurological pathology,
except tic disorder. In patients, psychiatric comorbidity (including
tic disorders) was not an exclusion criterion provided that OCD
was the primary diagnosis. Healthy comparison subjects had no
current axis I psychiatric disorders.
Detailed sociodemographic and clinical data were collected at
each center. Age at onset, OCD illness severity ratings, symptom
dimension scores, and current medication use were available
from most patients (see the online data supplement).
Data Acquisition and Quality Control
The parameters of the structural scans are listed in Table S1 in
the online data supplement. After extensive quality checking (see
the data supplement and Table 2), 780 participants (412 patients
and 368 healthy subjects; Table 1) were included in the analysis.
Data on 530 of these 780 participants have not been published
before or been included in previous meta-analyses (see Table
S1 in the data supplement).
Statistical Analysis
Group differences in sample characteristics were assessed with
SPSS, version 20 (IBM, Armonk, N.Y.). The significance threshold
was set at 0.05, two-tailed.
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MEGA-ANALYSIS OF STRUCTURAL BRAIN SCANS IN OBSESSIVE-COMPULSIVE DISORDER

TABLE 1. Demographic and Clinical Characteristics of OCD Patients and Healthy Comparison Subjects
Characteristica OCD Patients (N=412) Healthy Subjects (N=368) Statistical Analysis
Mean SD Mean SD t df p
Age (years) 32.1 9.6 30.2 9.3 2.9 778 0.004
Education level (years) 13.7 2.8 14.6 3.1 –4.0 760 ,0.001
OCD illness severity scoreb 24.9 6.2
Age at onset of clinical symptoms (years)c 20.1 8.7
Total gray matter volume (mL) 700.6 63.3 705.1 66.2 –0.9 778 0.33
Total white matter volume (mL) 513.6 49.2 511.7 52.6 0.5 778 0.60
N % N % x2 p
Male 202 49.0 195 53.0 1.2 1 0.28
Right-handed 354 85.9 330 89.7 1.0 2 0.65
Ethnicity 2.7 2 0.26
Caucasian 195 47.3 192 52.2
Asian 171 41.5 146 39.7
Other 6 1.5 11 3.0
Medication use at time of scan 176 42.7 0 0.0 210.1 1 ,0.001
Current comorbidity 149 36.2 0 0.0 174.0 1 ,0.001
Lifetime comorbidity 213 51.7 7 1.9 253.7 1 ,0.001
Prepubertal OCD onset 51 13.0
OCD symptom dimensionsc
Aggressive/checking 236 57.2
Contamination/cleaning 202 49.0
Symmetry/ordering 168 40.8
Sexual/religious 130 31.6
Hoarding 87 21.1
a
Missing data for characteristics ranged from N=0 to N=40.
b
As measured with the Yale-Brown Obsessive Compulsive Scale (YBOCS) total score. Mean score on the obsessions subscale, 12.6 (SD=3.4);
mean score on the compulsions subscale, 12.3 (SD=3.8).
c
As measured with the YBOCS symptom checklist.

TABLE 2. Number of Scans Provided and Included for OCD Patients and Healthy Comparison Subjects at Each Center

Initial Number of Scans Included After Quality Check Exclusions

Site OCD Patients Healthy Subjects Total OCD Patients Healthy Subjects Total Pathology Poor Qualitya Total
Amsterdam 55 50 105 53 49 102 1 2 3
Barcelona 88 103 191 86 102 188 1 2 3
Kyoto 89 48 137 84 48 132 1 4 5
London 55 37 92 44 33 77 3 12 15
São Paulo 60 46 106 58 39 97 0 9 9
Seoul 89 98 187 87 97 184 1 2 3
Total 436 382 818 412 368 780 7 31 38
a
Poor quality is an umbrella term referring to scans being either nonsegmentable or having artifacts related to motion, poor contrast, or
imaging.

Imaging data processing and analysis were done using opti-
mized voxel-based morphometry (17) in the SPM8 program
(www.fil.ion.ucl.ac.uk/spm/software/spm8). After manual reor-
ientation, images were segmented into gray and white matter
with the “New Segment” tool (default settings) and resampled
to a resolution of 1.531.531.5 mm. Using the diffeomorphic
anatomical registration through exponential Lie algebra algo-
rithm (DARTEL [17], default settings), an analysis-specific group
template was created (i.e., with N=780 for the main group analysis
and N=412 for within-patient analyses). The gray and white matter
images were first warped to the group-specific template using the
flow fields (specifying the deformations between each participant’s
individual scan and the group-specific template) and subsequently
to Montreal Neurological Institute (MNI) standard space using the
warping parameters of the group template to the tissue prior map
in standard space. To preserve regional volumetric information,
images were modulated during the warping. To increase the
signal-to-noise ratio, images were smoothed with a 10-mm
isotropic Gaussian kernel.
Group effects and age-by-group interactions on regional gray
and white matter volume were investigated by feeding the pre-
processed gray and white matter images of OCD patients (N=412)
and healthy subjects (N=368) into general linear models that always
included total gray or white matter, scan sequence, age, gender,
and education level as covariates. Aging in healthy individuals is
associated with both bilinear (an even rate of change over time)
and nonlinear (quadratic; acceleration/deceleration of the rate of
change over time) patterns of regional brain volume loss or pre-
servation as compared with global brain volume loss (see reference
18, for example). We therefore assessed the effect of age and age-

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 DE WIT, ALONSO, SCHWEREN, ET AL.

FIGURE 1. Regional Gray and White Matter Volume Differences Between OCD Patients (N=412) and Healthy Comparison
Subjects (N=368)a

a
Compared with healthy subjects, OCD patients exhibit smaller (blue/green) regional medial and inferior frontal gray (panel A) and white
(panel B) matter volume and greater (red/yellow) regional cerebellar gray matter volume (panel C). Brain slices in panels A–C are in coronal
(left), sagittal (middle), and axial (right) direction; left side of brain is on the left. MNI coordinates (x, y, z) of panel A, –1, 18, 0; of panel B, –11,
23, 12; of panel C, 6, –55, –40. All presented imaging results are T-statistic images overlain over the SPM8 single-subject T1 standard brain
with MRIcron (www.mccauslandcenter.sc.edu/mricro/mricron) and thresholded at p,0.001 uncorrected with a minimum cluster extent of
100 voxels. T values are displayed from red/blue (T=3.1) to yellow/green (T$4.0).

by-group interactions using both age (bilinear) and age squared
(nonlinear) as covariates (18). Multiple linear regression models
were used to investigate the effects of age at onset, illness duration,
severity of OCD, comorbid major depressive disorder, comorbid
anxiety disorders, OCD symptom dimensions, and medication use
within patients. To maximize statistical sensitivity by including
only relevant within-brain voxels, absolute masking was applied at
an estimated optimal threshold of 0.2 (19). For maximal com-
parability with previous results in the field (e.g., references 9, 20,
21; see also references 2–5), resulting T-maps were thresholded at
p,0.001 uncorrected at the voxel level and a minimum cluster
extent of 100. Additionally, whole-brain family-wise error, multiple
comparison, and nonstationarity corrected cluster-level statistics
are reported at a family-wise error corrected p threshold of 0.05 (22).
Results
Group Comparisons
The OCD group (N=412) and the healthy comparison
group (N=368) did not differ in gender, handedness,
ethnicity, and total gray matter and white matter volume,
but on average the OCD group was significantly older, had
a lower education level, and scored higher on all clinical
measures (Table 1). As shown in Figure 1, compared with
healthy subjects, patients had smaller regional gray matter
volume in the left and right dorsomedial frontal cortex
(Brodmann’s area [BA] 6/8/9) extending to the anterior
cingulate cortex (BA 24/32) and inferior frontal cortex/
anterior insula (BA 13/47); greater cerebellar gray matter
volume bilaterally; and smaller frontal white matter volume
bilaterally (Table 3). Post hoc analyses (see the Supplemen-
tal Results section in the online data supplement) showed
that scan sequence/site and current medication use did not
affect group interaction results.
To ensure that the observed group differences were not
confounded by age or education level, we performed
a post hoc analysis (N=645) in patient (N=329) and healthy
(N=316) samples that were matched on all demographic

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MEGA-ANALYSIS OF STRUCTURAL BRAIN SCANS IN OBSESSIVE-COMPULSIVE DISORDER

TABLE 3. Regional Brain Volume Differences Between OCD Patients (N=412) and Healthy Comparison Subjects (N=368)a
MNI Coordinates
Region and Contrast Side BA ke x y z Z pb
Gray matter
Healthy subjects . OCD patients
Inferior frontal cortex/anterior insula L 47/13/45 1,295 –44 17 –3 4.97 0.05
Dorsomedial prefrontal cortex/anterior R/L 32/9/8/6/24 2,008 0 9 45 4.11 0.01
cingulate cortex –3 38 36 3.95
2 41 51 3.91
Inferior frontal cortex/anterior insula R 47/13 165 47 17 –5 3.77 0.33
OCD patients . healthy subjects
Cerebellum (extending through R/L 581 9 –48 –48 3.96 0.74
flocculonodular, anterior, and –5 –51 –44 3.48
posterior lobes) –5 –57 –36 3.24
L 223 –12 –56 –26 3.51 0.81
White matter
Healthy subjects . OCD patients
Frontal white matter
Medial L 945 –11 33 27 4.71 0.04
–12 39 18 4.70
Inferior/middle L 968 –30 29 6 3.91 0.07
–29 20 12 3.78
Medial L 104 –9 12 47 3.52 0.52
Inferior/middle R 592 29 20 12 3.82 0.23
24 27 23 3.30
35 27 6 3.12
Thalamic region R 216 15 –26 9 3.44 0.50
11 –20 14 3.29
OCD patients . healthy subjects: ns
a
Analysis of covariance thresholded at p,0.001 uncorrected and a minimum cluster extent (ke) of 100 voxels. Table shows local maxima more
than 8.0 mm apart. Results are corrected for age, gender, education level, total gray matter or white matter volume, and scan sequence.
BA=Brodmann’s area; MNI=Montreal Neurological Institute; L=left; R=right; ns=not significant.
b
Whole-brain cluster family-wise error corrected and nonstationarity corrected p value.

variables (see the data supplement). Results of this post
hoc analysis were similar to those in the larger sample (see
Table S2 in the data supplement).
Group-by-Age Interactions
The linear group-by-age interaction analyses (Table 4,
Figure 2) showed a relative preservation of right putamen/
insular gray matter volume with aging in OCD patients
compared with healthy subjects and greater loss of tem-
poral gray matter volume bilaterally. The nonlinear analysis
showed a greater loss of fusiform and parahippocampal
gray matter and preservation of frontal white matter
volume with aging in OCD patients compared with healthy
subjects (see the data supplement for within-group effects).
Post hoc matched samples analysis (see Table S3 in the
data supplement) confirmed these group-by-age inter-
action effects, with the putamen/insula cluster reaching
family-wise error corrected significance and the nucleus
accumbens and inferior and orbitofrontal gray matter
reaching the statistical threshold.
Effect of Clinical Variables on Brain Structure
in Patients
Illness severity, illness duration, and age at onset were
not significantly related to regional brain volume. Patients
on medication at the time of the scan (N=176; mean age,
33.2 years; median time on medication, 24 weeks; missing,
N=46) showed significantly greater operculum/posterior
insula gray matter volumes and smaller middle frontal
gray matter and posterior frontal white matter volumes
compared with patients who were not on medication
(N=222; mean age, 30.9 years; see Table S4 in the data
supplement). Since medicated and unmedicated patients
differed in several characteristics, we used stepwise multiple
linear regression (see the data supplement) to assess whether
the results truly could be attributed to medication. After
controlling for demographic and clinical variability, medica-
tion effects remained significant only in middle frontal gray
matter volume (p=0.014).
OCD patients with one or more comorbid anxiety dis-
orders (N=83) had greater left cerebellar gray matter volume
and smaller volumes of the right temporo-occipital gray
matter, left superior frontal gyrus, midcingulum, and insula
compared with those without comorbid anxiety (N=190;
missing data, N=139; for a detailed description of analyses, see
the Supplemental Results section and Table S5 in the data
supplement). Patients with a lifetime diagnosis of depression
(N=101) had a smaller right supplementary motor area gray
matter volume compared with patients without (N=287;

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 DE WIT, ALONSO, SCHWEREN, ET AL.

TABLE 4. Group-by-Age Interactions on Regional Brain Volume in OCD Patients (N=412) and Healthy Comparison Subjects
(N=368)a
MNI Coordinates
Region and Interaction Side BA ke x y z Z pb
Gray matter
Relative preservation with aging in OCD patients
compared with healthy subjects
Linear
Putamen extending to insula R 13/NA 585 42 6 –6 3.67 0.27
33 5 –9 3.60
Nonlinear: ns
Relative loss with aging in OCD patients compared
with healthy subjects
Linear
Middle temporal gyrus R 21 147 56 –35 –8 3.94 0.37
Inferior temporal gyrus L 20 245 –60 –39 –23 3.91 0.55
Nonlinear
Fusiform gyrus L 37/19 546 –47 –62 –21 4.39 0.16
–38 –54 –12 3.25
Parahippocampal gyrus extending to thalamus L 35/27 244 –20 –33 4 3.76 0.45
–20 –30 –20 3.21
White matter
Relative preservation with aging in OCD patients
compared with healthy subjects
Linear: ns
Nonlinear
Frontal white matter
Middle L 447 –18 48 4 4.35 0.17
Inferior L 135 –33 30 0 3.80 0.51
Medial R 189 20 38 0 3.28 0.56
Relative loss with aging in OCD patients compared
with healthy subjects
Linear, nonlinear: ns
a
Linear (age) and nonlinear (age squared) group-by-age interaction analysis thresholded at p,0.001 uncorrected and a minimum cluster
extent (ke) of 100 voxels. Table shows local maxima more than 8.0 mm apart. Results are corrected for gender, education level, total gray
matter or white matter volume, and scan sequence. BA=Brodmann’s area; MNI=Montreal Neurological Institute; L=left; R=right; ns=not
significant.
b
Whole-brain cluster family-wise error corrected and nonstationarity corrected p value.

missing data, N=24). Patients with current comorbid major
depressive disorder (N=46) had smaller left frontal gray and
white matter volumes compared with those without (N=287).
OCD symptom dimension analyses in patients (N=331;
missing data, N=81) showed an association of the presence
of aggression/checking symptoms with greater lingual gyrus
volume and smaller superior parietal gray and white matter
volumes, of hoarding with a smaller right cerebellar gray
matter volume, of sexual/religious obsessions with greater
middle temporal volume, and of symmetry/ordering with
a smaller fusiform gray matter volume (see the Supplemental
Results section and Table S4 in the data supplement).
Discussion
To our knowledge, this is the largest neuroimaging study
in OCD conducted to date. The large sample size allowed
sufficient statistical power to detect possible subtle
abnormalities in OCD and to examine potential effects
of age and clinical characteristics on brain volumes.
Frontal and Cerebellar Volume Changes in OCD
In agreement with prevailing frontal-striatal models of
OCD pathophysiology, we found smaller volumes of the
left and right medial and inferior frontal gray matter and
adjacent white matter in OCD patients compared with
healthy subjects. Smaller medial frontal gray matter volume
in OCD is in accordance with previous voxel-based mor-
phometry studies (2–5) and with studies showing reduced
levels of N-acetylaspartate, a measure of neuronal density,
in this region in OCD (23). Smaller volumes of the left and
right inferior frontal gyrus extending to the anterior insula
were reported once before in OCD (21) but are in contrast
with other studies showing greater (e.g., reference 4) or nor-
mal (5, 8) inferior frontal cortex/anterior insula volume. Our
finding of smaller medial and inferior frontal white matter
volumes bilaterally in OCD is notable considering inconsis-
tent previous reports (e.g., references 8–10) and converges
with studies showing altered frontal-striatal white matter
microstructure in OCD (5). Frontal volume changes may be
related to impairments in cognitive functions that have been

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FIGURE 2. Group-by-Age Interactions in the Putamen and Orbitofrontal Cortex in OCD Patients (N=412) and Healthy
Comparison Subjects (N=368)a

beta value per time bin (aU)

Y=4 X=–20 OCD patients

(x=42, y=6, z=–6), mean

Right putamen/insula
Healthy subjects

L 0.1

0
20 30 40 50 60
Z=–7

beta value per time bin (aU)

(x=–20, y=57, z=–6), mean
Left orbitofrontal cortex
L T≥4.0

0.1

OCD patients
Healthy subjects
T=3.1 0
20 30 40 50 60
Age (Years)
a
The left-hand panel shows relative preservation of putamen/insular (circle in upper image) and orbitofrontal (circle in lower image) gray
matter volume with increasing age in OCD patients compared with healthy subjects. T-statistic images are from linear and nonlinear age-by-
group analyses and are thresholded at p,0.001 uncorrected with a minimum cluster extent of 98 voxels for illustration purposes. In the right-
hand panel, the line plots show mean peak voxel values of the right putamen/insula cluster (upper plot; linear age scale) and left
orbitofrontal frontal cortex (lower plot; quadratic age scale) in patients and healthy subjects. Displayed values are the mean parameter
estimate (which relates to relative gray matter volume) per time bin (1 year) per group in arbitrary units (aU). L=left.

consistently demonstrated in OCD patients, such as cogni-
tive control and emotion regulation (6), and are associated
with altered activity in the dorsomedial prefrontal cortex and
inferior frontal cortex/anterior insula (1, 7). Smaller medial
frontal gray matter volume has been reported in anxiety and
depression (3, 24), and in our sample it was more pro-
nounced in patients with additional comorbid anxiety and/
or depression, which may thus be indicative of a common
pathophysiological mechanism across affective disorders
related to a shared deficit in emotion regulation (3, 24). On
the other hand, smaller inferior frontal cortex/anterior insula
volumes may be a neuroanatomical characteristic more
specific to OCD and related disorders (14, 24, 25), although
this speculation awaits empirical confirmation.
We found greater cerebellar gray matter volume in OCD
patients relative to healthy subjects. The cerebellum is
structurally and functionally connected to the parallel
cortico-striatal-thalamic-cortical circuits and is thought to
integrate cortico-striatal information flow (26). There is
accumulating evidence that the cerebellum, besides its
role in motor control, is also involved in cognitive and
emotional regulatory processes (13, 26, 27). Smaller
cerebellar volume has been found in disorders often com-
orbid with OCD, such as Tourette’s disorder (13), tri-
chotillomania (28), depression, and anxiety (29). Previous
studies in adult OCD populations showed smaller (20), nor-
mal (2), or greater (4, 5, 8) cerebellar gray matter volume. The
cerebellar volume alterations we observed are more extensive
than those reported in previous studies (4, 5, 8). Aberrant
cerebellar activity has been shown in OCD patients during
rest and task performance (1). Cerebellar volume changes
may thus be directly related to cognitive dysfunction and
OCD symptomatology (26, 27). In the context of the existing
literature, our data suggest a greater role for the cerebellum
in OCD illness models than is currently recognized.
Altered Brain Volume Changes in OCD During Aging
It has been suggested that abnormal regional brain
volume in OCD might result from a combination of abnor-
mal neurodevelopmental processes and additional altered
aging-related trajectories due to several factors operating on
multiple levels—for example, genetic variations influencing
neuronal pruning and aging processes, activity-dependent
neuronal plasticity associated with chronic symptoms or
compensatory processes, and neurochemical effects of
pharmacological treatment or stress (30, 31). Patients
showed relative preservation of the putamen, nucleus
accumbens, and inferior and orbitofrontal cortex during
aging, which was in contrast to the loss associated with
healthy aging (18). Evidence from electrophysiology and
neuroimaging (1) studies has long indicated the in-
volvement of the basal ganglia in OCD. Greater putamen
and caudate volume is often (2–5) but not consistently
found, and findings may be dependent on the age of the

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recruited samples, treatment history, or treatment status
(12). We did not find striatal volume alterations in the
overall OCD patient group, but in line with a previous
report (8), we observed a relatively preserved volume of
the putamen and nucleus accumbens during aging in
patients. Given the involvement of the putamen in motor
behavior, aging-related putamen volume preservation in
OCD may be related to activation-induced neuroplastic-
ity as a result of chronic compulsive behaviors (30). Age-
by-group interactions in the orbitofrontal cortex and
striatum, core nodes of the neural reward circuit (32),
may also be the result of compensatory processes. Neuro-
imaging studies have shown dysfunction in this circuit in
OCD during rest (33) and task performance (1), associated
with impaired feedback learning, behavioral inflexibility,
and a motivational bias toward negative stimuli. Addition-
ally, parts of the inferior frontal lobe adjacent to the inferior
frontal cortex/anterior insula regions showing smaller
volume overall showed a relative preservation with aging
in OCD patients. Besides having a role in cognitive control
(6), the inferior frontal cortex/anterior insula is implicated
in attention (34), interoceptive awareness (35), and dis-
gust perception (36). Given that these functions are
thought to be abnormal in OCD (1, 37), it may be that the
observed aging effect in the inferior frontal cortex/anterior
insula is related to (compensatory) activation-induced
neuroplasticity.
In line with most previous reports (e.g., reference 5), we
did not observe volume differences in the amygdala-
hippocampal complex in OCD. Our data do indicate, how-
ever, that (para)limbic parts of the medial and lateral
temporal cortex, regions that are relatively preserved in
healthy aging (38), show greater aging-related volume loss in
OCD. The fusiform, parahippocampal, and inferior temporal
cortices are involved in higher-level visual processing, visual
emotional perception (39), and emotional memory forma-
tion (40). Greater volume loss in these regions may thus be
related to chronic stress and the exaggerated emotional res-
ponsiveness seen in OCD (1, 31).
Association With Clinical Characteristics
In patients, illness severity, age at onset, and illness
duration were not significantly related to regional brain
volume, which is in accordance with some (e.g., references 8,
10), but not other (e.g., reference 21) previous studies. It must
be noted that age at onset was ascertained retrospectively,
and therefore the negative findings must be interpreted in
light of this limitation. Although topologically not converging
with previous findings (e.g., references 8, 9), the results of the
symptom dimension analyses broadly agree with the notion
that the various subphenotypes of OCD have overlapping
but also unique neural correlates (41), which may in turn
reflect genetic and especially environmental influences on
each of these phenotypes (42).
Consistent with previous meta-analyses (2, 3), the
results from the main group comparisons were robust in
Am J Psychiatry 171:3, March 2014
DE WIT, ALONSO, SCHWEREN, ET AL.
controlling for current medication use. The within-patient
medication analyses showed opposing effects of medica-
tion on dorsal and ventral frontal gray matter. Moreover,
only the middle frontal gray matter finding (a region not
overlapping with the main group effects) remained sig-
nificant after we controlled for the differing sample
characteristics of the medicated versus unmedicated
patients in a multiple regression analysis. Therefore, it is
possible that gray matter alterations in the middle frontal
cortex may be partially attributable to current medication
use, a finding that deserves further investigation, ideally
using longitudinal designs (12).
Limitations and Future Directions
With our study design, we gained statistical power and
the ability to assess and control for the effect of participant-
level variability by performing an image-based mega-
analysis on pooled data. This experimental gain was
potentially offset by the introduction of possible confound-
ing effects, such as ethnicity, MRI scanner hardware/
sequence, and medication use—confounders that individ-
ual well-powered studies may not have. However, we think
it is unlikely that these possible confounders affected our
results. First, we corrected for site/scanning sequence in all
the analyses. Second, group-by-site interaction effects did
not explain the group results, and current medication use
did not affect the main results. Furthermore, since we in-
cluded age and education level as covariates in all
analyses, and since our results were robust against appro-
priate age and education level matching with a correspond-
ing sample size reduction, we think it safe to conclude that
the reported brain volume alterations in OCD are not
explained by demographic variability. A limitation of ana-
lyzing age-by-disorder interactions with a cross-sectional
instead of a longitudinal study design is that aging-related
intrasubject changes cannot be disentangled from possible
intersubject differences (18). Assessing group and group-by-
age interactions in a large cohort increases statistical
sensitivity, but it also introduces intersubject variation that
may have caused real effects to be underestimated. Analysis
of this data set with a toolbox with putative superior sub-
cortical image segmentation (e.g., FreeSurfer) is a logical
future step, since this additionally would ascertain whether
the observed regional volume differences are related to
differences in cortical thickness or surface area. Additionally,
whether our findings also hold true for youths with OCD
remains to be ascertained. Of further note is that data for 530
of the 780 participants included in this study have not been
published before; divergent findings here may represent
methodological differences, the substantial increase in power
in the present study, or the inclusion of additional subjects.
Conclusions
The results of this study support involvement of the
frontal-striatal and (para)limbic circuits and the cerebel-
lum in OCD. Our data indicate that whereas involvement
ajp.psychiatryonline.org 347
MEGA-ANALYSIS OF STRUCTURAL BRAIN SCANS IN OBSESSIVE-COMPULSIVE DISORDER
of the dorsomedial prefrontal cortex/anterior cingulate
cortex/inferior frontal cortex/anterior insula and the
cerebellum may be directly related to the pathophysiology
of OCD, orbitofrontal-striatal and temporal volume alter-
ations may be secondary to activation-dependent neuro-
plasticity due to persistent symptoms or compensatory
processes related to cognitive dysfunction. This suggests
that age is an important contributor to the variability in
previous reports on brain structure alterations in OCD.
Further insight into the development of structural brain
changes in OCD across the lifespan should come from
longitudinal studies as well as studies involving pediatric
OCD patients.
Received April 29, 2013; revision received Aug. 28, 2013; accepted
Sept. 12, 2013 (doi: 10.1176/appi.ajp.2013.13040574). From the
Departments of Psychiatry and of Anatomy and Neurosciences, VU
University Medical Center, Amsterdam; Department of Psychiatry,
Bellvitge University Hospital-Bellvitge Institute for Biomedical Re-
search (IDIBELL), University of Barcelona, Barcelona, Spain; Carlos III
Health Institute, Center for Biomedical Research Network on Mental
Health (CIBERSAM), Barcelona; Institute of Psychiatry, King’s College
London, London; MRC Unit on Anxiety and Stress Disorders, De-
partment of Psychiatry, University of Stellenbosch, Stellenbosch,
South Africa; Departments of Human Biology and of Psychiatry and
Mental Health, University of Cape Town, Cape Town, South Africa;
Center of Mathematics, Computation, and Cognition, Federal Univer-
sity of ABC, Santo André, Brazil; Department and Institute of
Psychiatry, University of São Paulo Medical School, São Paulo, Brazil;
Department of Psychiatry, Academic Medical Center, Amsterdam;
Departments of Psychiatry and Radiology, Graduate School of
Medical Science, Kyoto Prefectural University of Medicine, Kyoto,
Japan; Department of Psychiatry, Seoul National University College of
Medicine, Seoul, Republic of Korea; Department of Psychiatry,
Western Psychiatric Institute and Clinic, University of Pittsburgh
School of Medicine, Pittsburgh; and CRC-Hospital del Mar, Barcelona.
Address correspondence to Dr. van den Heuvel (oa.vandenheuvel@
vumc.nl).
The authors report no financial relationships with commercial
interests.
Supported by the Dutch Organization for Scientific Research (NWO)
(grants 912-02-050, 907-00-012, 940-37-018, and 916.86.038); the
Carlos III Health Institute (PI09/01331, PI10/01753, PI10/01003,
CP10/00604, and CIBER-CB06/03/0034); the Agency for Administra-
tion of University and Research (AGAUR, Barcelona; 2009SGR1554);
a “Miguel Servet” contract from the Carlos III Health Institute (CP10/
00604) to Dr. Soriano-Mas; Ministry of Education, Culture, Sports,
Science, and Technology (Japan) Grants-in-Aid for Young Scientists to
Dr. Narumoto (23591724) and to Dr. Nakamae (24791223); Well-
come Trust project grant 064846; a grant from the Foundation for
the Support of Research in the State of São Paulo (FAPESP) to Dr.
Miguel (2005/55628-8); a FAPESP scholarship to Dr. Hoexter (2005/
04206-6); and a National Research Foundation of Korea grant funded
by the Korean government (Ministry of Education, Science, and
Technology, 2012-0005150).
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ajp.psychiatryonline.org 349
 Article

Revisiting Schizophrenia Linkage Data in the NIMH

Repository: Reanalysis of Regularized Data Across
Multiple Studies
Veronica J. Vieland, Ph.D. Objective: The Combined Analysis of Psy-
chiatric Studies (CAPS) project conducted
extensive review and regularization across
Kimberly A. Walters, Ph.D.
studies of all schizophrenia linkage data
available as of 2011 from the National
Thomas Lehner, Ph.D. Institute of Mental Health-funded Center
for Collaborative Genomic Studies on Men-
Marco Azaro, Ph.D. tal Disorders, also known as the Human
Genetics Initiative (HGI). The authors rean-
Kathleen Tobin, Ph.D. alyzed the data using statistical methods
tailored to accumulation of evidence
Yungui Huang, Ph.D. across multiple, potentially highly hetero-
geneous, sets of data.
Linda M. Brzustowicz, M.D. Method: Data were subdivided based on
contributing study, major population
group, and presence or absence within
families of schizophrenia with a substantial
affective component. The posterior prob-
ability of linkage (PPL) statistical frame-
work was used to sequentially update
linkage evidence across these data subsets
(omnibus results).
Results: While some loci previously im-
plicated using the HGI data were also
identified in the present omnibus analysis
(2q36.1, 15q23), others were not. Several
loci were found that had not previously
been reported in the HGI samples but are
supported by independent linkage or as-
sociation studies (3q28, 12q23.1, 11p11.2,
Xq26.1). Not surprisingly, differences were
seen across population groups. Of parti-
cular interest are signals on 11p15.3,
11p11.2, and Xq26.1, for which data from
families with a substantial affective com-
ponent support linkage while data from
the remaining families provide evidence
against linkage. All three of these loci
overlap with loci reported in independent
studies of bipolar disorder or mixed
bipolar-schizophrenia samples.
Conclusions: Public data repositories
provide the opportunity to leverage large
multisite data sets for studying complex
disorders. Analysis with a statistical method
specifically designed for such data enables
us to extract new information from an
existing data resource.

(Am J Psychiatry 2014; 171:350–359)

F or the past two decades, investigators funded by the

National Institute of Mental Health (NIMH) conducting
genetic research have been strongly encouraged to contribute
biospecimens, along with whatever corresponding genotypic
and phenotypic information they have assembled, to a
centralized repository housed at the Center for Collaborative
Genomic Studies on Mental Disorders. The repository grows
immortalized cell lines, supplies DNA to researchers, and
provides downloadable copies of clinical and genotypic data
files through the Human Genetics Initiative (HGI) (see www.
nimhgenetics.org). We report the first wave of results from
the HGI’s Combined Analysis of Psychiatric Studies (CAPS)
project, which is undertaking extensive review and analysis
of data in the repository. Our focus here is the reanalysis of
the seven separate schizophrenia family studies that had
deposited genotypic and phenotypic data with the repository
as of April 2011.
The CAPS project is specifically funded to reanalyze
HGI data using the posterior probability of linkage (PPL)
framework as implemented in the software package
KELVIN (1). There are three principal advantages to using
the PPL for linkage analysis of the HGI data (see the
Method section for details). First, it is essentially model
free, while retaining the advantages of likelihood-based
analyses, making full use of all available data, including
from unaffected individuals. Second, it is specifically
tailored to handle multiple, potentially highly heteroge-
neous data sets or subsets, using Bayesian sequential
updating to accumulate linkage evidence across subsets
while allowing explicitly for genetic differences between
subsets. And third, in stark contrast to p values or maximum
LOD scores, based on either “mega-analysis” or traditional
meta-analysis, the PPL can accumulate evidence both for
and against linkage at each genomic position. This in-
creases resolution of a genome scan by excluding stretches
of the genome in an essentially model-free manner, while
also distinguishing common as opposed to distinct genetic
features across different populations or clinical subgroups.
The PPL is thus uniquely well suited to the analysis of
multisite, potentially highly heterogeneous, genetic data.
Here we consider omnibus linkage results, based on all of
the HGI schizophrenia family data in aggregate. We also

350 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


consider population-specific findings and the possibility
of specific loci underlying a clinical schizophrenia subtype
involving affective components.
Method
Data Classification and Subdivision
Data for all multiplex pedigrees with available genome-wide
genotyping available as of April 2011 were downloaded from the
HGI. Families in the download came from seven different studies
(2–9), referred to here as studies 1–7. An extensive data regulari-
zation protocol was applied to both genotypic and phenotypic
information as downloaded from the HGI. This included applying
strict criteria to the DSM diagnostic codes provided to the HGI by
the individual studies to define a narrow schizophrenia phenotype
and a schizophrenia/affective phenotype, which included schizo-
affective disorder or any schizophrenia disorder and a significant
affective disorder. (See online data supplements SA1 and SA2 for
details of genotype and phenotype processing, respectively.)
Families were included in these analyses if they contained at
least one case of schizophrenia, at least one additional case of
either schizophrenia or schizophrenia/affective diagnoses, and at
least two affected genotyped individuals. This left 970 multiplex
families for analysis, containing 4,023 phenotyped individuals (av-
erage, 4.1 per pedigree) and 4,208 genotyped individuals (average,
4.3 per pedigree). (See online data supplement ST1 for an an-
notated list of families included and excluded from these anal-
yses.) We elected to use stringent diagnostic and inclusion criteria
in order to minimize clinical heterogeneity within data subsets, and
especially in order to minimize the effects of clinical differences
across studies. Such differences may tend to be more pronounced
for broad-spectrum conditions than for the core diagnoses.
We grouped families into subsets by study and population
(African American, European American, Han Chinese, and
Hispanic). Each of the original studies either contained a single
group or, in the cases of study 1 (2, 3) and study 2 (4), divided their
own analyses into European American and African American
families in published analyses. Thus, these subgroupings match
previous treatments of the data sets.
Additionally, because schizophrenia with a significant affective
component is now considered to be a potentially genetically distinct
form of schizophrenia, we further subdivided the data based on the
presence or absence of any individuals with schizophrenia/affective
diagnoses within the pedigree. (When referring to families, “schizo-
phrenia” refers to families whose affected members are all clas-
sified as having schizophrenia; and “schizophrenia/affective”
refers to families in which at least one affected individual is
classified as having a schizophrenia/affective diagnosis.) While
it is impossible to distinguish a family that would never have
produced a case meeting schizophrenia/affective criteria from
a family that, by chance, failed to manifest this affective phenotype
among the small number of affected individuals present, even an
imperfect classifier can be helpful in detecting linkage in one but
not the other group (10).
Several of the studies had multiple data collection sites, and
“site” itself might demarcate more homogeneous subsets of the
data. However, further subdivision by site results in sample sizes
that are too small for meaningful analysis (,10 small families/
data set), so we did not subdivide by site. (See online data
supplement ST2 for sample sizes by subset.)
Statistical Analysis
All analyses were conducted using the software package
KELVIN (1), which implements the PPL class of models for
measuring the strength of genetic evidence. The specific statistic
Am J Psychiatry 171:3, March 2014
VIELAND, WALTERS, LEHNER, ET AL.
employed here was the PPL itself (posterior probability of linkage).
The PPL is essentially a straightforward application of Bayes’s
theorem. Letting L represent “linkage” to a given genomic po-
sition and D be the data, the PPL is calculated as
PðDjLÞPðLÞ
PPL ¼ PðLjDÞ ¼ :
PðDjLÞPðLÞ þ PðDjno LÞPðno LÞ
The two likelihoods appearing in this equation, P(D|L) and
P(D|no L), are the numerator and denominator, respectively, of
the exponentiated ordinary LOD score. They are functions of the
parameters of the unknown trait model, and what distinguishes
the PPL as computed by KELVIN is the way in which these
parameters are handled within and across data subsets, as de-
scribed below.
The PPL as applied here represents the probability of a
schizophrenia gene at each location, given the available data. For
the microsatellite data, four-point (three-marker) multipoint
calculations were run; for the single-nucleotide polymorphism
data, full multipoint analysis using all markers was used. (Tech-
nical details and all primary references to the supporting theoretical
literature may be found in reference 1; examples of previous ap-
plications may be found in references 11–13.)
The PPL is based on an approximating single-locus likelihood
allowing for within-sample heterogeneity using Smith’s admix-
ture parameter a (14). All parameters of the trait model, in-
cluding a, are integrated out of the PPL using (independent)
uniform priors on each parameter (see reference 1 for details),
implicitly allowing for dominant, recessive, or intermediate models.
This provides a robust approximation for mapping complex traits
in terms of the marginal model at each locus, and because the
parameters are integrated out, no specific assumptions regarding
their values are required.
The PPL framework accumulates evidence across data subsets
by integrating the trait parameters out of the likelihood sep-
arately for each subset (allowing their values to differ across
subsets), then using Bayesian sequential updating to carry the
posterior linkage evidence from previously analyzed data forward
as prior evidence as new data subsets are analyzed at each
genomic position in turn. This allows for differences in allele
frequencies, penetrances (due to background genetic or envi-
ronmental differences across subsets), and chance fluctuations
in the proportion of “linked” pedigrees at a given locus. The
order in which data sets are analyzed does not affect the final
result. In the presence of appreciable heterogeneity, sequential
updating is far more robust in retaining true signals originating
from individual subsamples than analyses that simply combine
subsets for a single analysis (10, 15, 16). It is also substantially
more sensitive in detecting true genetic effects across heteroge-
neous disorders than standard meta-analyses (17, 18). Moreover,
the PPL accumulates evidence against linkage as well as in favor
of linkage. Thus, inspection of subset-specific contributions to the
omnibus signal can distinguish among subsets that are (perhaps
only weakly) supporting linkage and subsets that are actually
contributing evidence against linkage, as we illustrate below. Here
we sequentially updated across data subsets defined by study
(studies 1–7), major population group (African American, European
American, Han Chinese, Hispanic), and clinical type (presence or
absence of any individual meeting schizophrenia/affective criteria
within the family).
The PPL is on the probability scale, and its interpretation is
therefore straightforward: e.g., a PPL of 40% means that there is
an estimated 40% probability of a trait gene at the given location
based on these data. Based on Elston and Lange’s analysis (19),
the prior probability at each location is set to 2%, so that PPLs
.2% indicate (some degree of) evidence in favor of a trait gene at
the locus, while PPLs ,2% represent evidence against the lo-
cation. This prior probability is based on empirical data (19), and
ajp.psychiatryonline.org 351
REVISITING SCHIZOPHRENIA LINKAGE DATA IN THE NIMH REPOSITORY
FIGURE 1. Omnibus Linkage Results, Including All Popula-
tion Groups and Families With Either Schizophrenia or
Schizophrenia With a Substantial Affective Componenta
1.0
0.8
0.6
PPL
0.4
0.2
0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920 22 X
Chromosome
a
Data from the Human Genetics Initiative. The posterior probability
of linkage (PPL) is on the probability scale (0 to 1.0); values ,2%
(horizontal line) indicate evidence against linkage, while values
.2% indicate (some degree of) evidence in favor of linkage.
because it is calculated as the probability of linkage between
a random marker location and a single disease gene, it is con-
servative for multilocus disorders. The PPL is a measure of
statistical evidence, not a decision-making procedure; therefore,
there are no “significance levels” associated with it, and it is not
interpreted in terms of associated error probabilities (20, 21).
By the same token, no multiple testing corrections are applied
to the PPL, just as one would not “correct” a measure of the
temperature made in one location for readings taken at different
locations (22). Nevertheless, it may assist readers to have some
sense of scale relative to more familiar frequentist test statistics.
In simulations of 10,000 replicates of sets of 1,000 affected sib
pairs (the predominant data structure in these analyses) under
the null hypothesis (no linkage), “significance” cutoffs of PPLs of
5%, 10%, 15%, and 25% were associated with type I error pro-
babilities (the rate at which the PPL crossed the given threshold
under the null) of 0.0070, 0.0011, 0.0004, and 0.0001, respectively.
In the Results section, we highlight loci with PPL $25%; complete
results are presented in online data supplement ST3.
Results
We first present omnibus linkage results, considering all
of the data in aggregate. We then consider common and
distinct loci, by major population group and by clinical
subgroup (families with narrow schizophrenia only versus
families containing at least one case of a schizophrenia/
affective diagnosis). We then compare our results with
results from the original publications for studies 1–7, as
well as with results based on independent sets of data and
meta-analyses.
Omnibus Results
Figure 1 presents omnibus linkage results, sequentially
updated across all data subsets. Overall, 76% of the genome
showed evidence against linkage (PPL,0.02), while only
10% showed PPL.0.05 and 4% showed PPL.0.1. There
352 ajp.psychiatryonline.org
were twenty distinct loci with PPL.0.1, 13 with PPL.0.15,
and four with PPL.0.25. These last occurred at 2q36.1
(PPL=0.41), 3q28 (PPL=0.27), 12q23.1 (PPL=0.26), and 15q23
(PPL=0.27) (Table 1).
Population-Specific Results
Figure 2 presents population-specific results. There are
four population-specific loci with PPL.0.25 (Table 1). Two
of these come from Han Chinese (10q22.3, PPL=0.36;
10q26.12, PPL=0.34), and at both these loci all three of the
other population groups show evidence against linkage.
Similarly, European American data support 1p32.3 (PPL=0.27),
with data from all other population groups providing
evidence against linkage at this locus. By contrast, the
Hispanic-specific peak at 5p14.1 (PPL=0.26) receives
modest support from African American data (PPL=0.04)
but evidence against linkage in the other two sets. The four
omnibus peaks (see above) are each supported by at least
three population groups, in each case with the remaining
group being neutral, that is, showing evidence neither for
nor against linkage (Table 1).
Clinical Subset-Specific Results
Figure 3 presents results by clinical subgroup. There are
five loci with PPL.0.25 in either of the two clinical sub-
groups (Table 1), and in every case the other subgroup
provides evidence against linkage (in each case, PPL,0.01).
Notably, three of these peaks (11p15.3, 11p11.2, 23q26.1)
are supported by the far smaller schizophrenia/affective
subset, suggesting that this really does constitute a more
homogeneous classification of the families. However, there
is possible confounding by population group here, since
each clinical subset includes all four population groups, but
in differing proportions (see the Discussion section).
Comparison With Original Study Results
Figure 4 illustrates salient differences between the
omnibus results and results extracted from the original
published linkage analyses of the individual studies. The
10% PPL threshold was chosen based on qualitative visual
separation of salient signals from background noise in
Figure 1 and is intended to mimic the criterion of “sug-
gestive” evidence as shown in the figure based on the
original publications. There is no rigorous way to precisely
compare the magnitude of results across data-analytic
methods or to derive and apply exactly comparable
interval estimates. Thus, the figure is intended to convey
in broad strokes differences in the overall genomic
landscape between the individual original reports and
our omnibus analyses rather than to present precise
quantitative differences.
Of the 20 intervals with PPL.0.10, 12 line up in or near an
originally reported interval. This could be coincidental,
however, since all but three chromosomes are implicated
(generally at the level of “suggestive” linkage) by at least one
of the original publications, with little overlap in reported
loci across the original studies. Figure 4 also shows the large
Am J Psychiatry 171:3, March 2014
 VIELAND, WALTERS, LEHNER, ET AL.

TABLE 1. Primary Linkage Findings Across Data Subsets (Omnibus) and for Population Groups and Clinical Subgroupsa
Genetic Position Omnibus African European Han Schizophrenia/Affective Schizophrenia
Locus (cM)b Results American American Chinese Hispanic Families Families
1p32.3 80 0.06 0.015 0.27 0.010 0.014 0.02 0.06
2q36.1 230 0.41 0.05 0.02 0.02 0.18 0.16 0.07
3q28 210 0.27 0.03 0.15 0.02 0.03 0.18 0.03
5p14.1 48 0.20 0.04 0.019 0.010 0.26 0.09 0.04
6q14.1–q15 94 0.10 0.017 0.11c 0.018 0.03 0.000 0.46
10q22.3 98 0.04 0.015 0.009 0.36 0.009 0.009 0.11
10q26.12 144 0.04 0.010 0.008 0.34 0.015 0.010 0.09
11p15.3 22 0.12 0.10 0.02 0.015 0.04 0.30 0.009
11p11.2 68 0.14 0.06 0.09 0.014 0.016 0.36 0.008
12q23.1–q23.2 112 0.26 0.08c 0.03 0.02 0.04 0.017 0.30c
15q23 72 0.27 0.02 0.03 0.02 0.18 0.10 0.06
Xq26.1 146 0.011 0.04 0.012 0.010 0.02 0.27 0.000
a
Data from the Human Genetics Initiative. Shown here are posterior probabilities of linkage (PPLs) for all loci with PPL.0.25 in at least one
subsample. The highest PPL per row is in boldface. By convention, PPLs $2% are reported to two decimal places and those ,2% to three.
b
Genetic positions (in centimorgans) refer to hg19 Build 37. When the PPL exceeds 0.25 in multiple subgroups, the position shown is from the
omnibus scan if the omnibus PPL .0.25 or for the subgroup with the largest PPL otherwise.
c
Instances in which a subgroup peak is close to but not directly over the omnibus peak: on chromosome 6, the European American peak is
PPL=0.256 at 104 cM; on chromosome 12, African American and schizophrenia peaks at 116 cM are PPL=0.254 and PPL=0.356, respectively.

FIGURE 2. Linkage Results by Population Groupsa

A B
1.0 1.0

African American European American

0.8 0.8

0.6 0.6
PPL

PPL

0.4 0.4

0.2 0.2

0.0 0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19202122 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19202122 X
Chromosome Chromosome
C D
1.0 1.0

Han Chinese Hispanic

0.8 0.8

0.6 0.6
PPL

PPL

0.4 0.4

0.2 0.2

0.0 0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920 22 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920 22 X
Chromosome Chromosome
a
Data from the Human Genetics Initiative. PPL=posterior probability of linkage.

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REVISITING SCHIZOPHRENIA LINKAGE DATA IN THE NIMH REPOSITORY

FIGURE 3. Linkage Results by Clinical Subgroupsa a negative symptom factor score (29). While the 12q
1.0 candidate gene DAO is located beyond the boundaries of
Schizophrenia
this peak, in an area where the omnibus analysis produced
evidence against linkage, the gene PAH is located near the
0.8
edge of the omnibus peak, in a region with PPL scores
slightly above 2%. PAH, the gene for phenylalanine hy-
0.6
droxylase, while traditionally associated with phenylke-
tonuria, has been suggested as a schizophrenia candidate
PPL

gene in multiple studies (29–33). Of further interest is the

0.4 12q linkage peak observed in the African American subset;
this peak has a maximum PPL score of 25.4% located 4
centimorgans (cM) telomeric to the omnibus peak, very
0.2
near PAH. The omnibus peak on chromosome 15q23
overlays a suggestive linkage peak that was originally re-
0.0 ported in the Hispanic samples included in this analysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920 22 X
Chromosome (8).
1.0 Four additional peaks over 25% were observed in spe-
cific population groups. The 10q22.3 and 10q26.12 peaks
Schizophrenia/affective
in the Han Chinese sample overlap the linked regions
0.8 from the original report on these families (5). Similarly, the
Hispanic-specific peak at 5p14.1 overlaps a suggestive
linkage peak that was previously reported in these families
0.6
(8). By contrast, the 1p32.3 locus seen in the European
PPL

American subset was not suggested by the individual

0.4
0.2
0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 22 X
Chromosome
a
Data from the Human Genetics Initiative. PPL=posterior probabil-
ity of linkage.
portions of the genome showing evidence against linkage
using the PPL. The PPL’s ability to accumulate evidence
against linkage has no correlate in either the original non-
parametric linkage or meta-analyses.
Comparison With Results From Independent Studies
Of the four omnibus loci with PPL over 25%, all are in
regions of previous schizophrenia linkage reports. Chro-
mosome 2q36.1 is in a region that has been implicated in
several previous linkage reports, including a significant
finding in a Finnish sample (23), and has received sug-
gestive support from other reports (5, 24, 25) that include
families found in study 2 and study 3. SCG2, the gene
encoding secretogranin II, is located under the center of
this peak and has been reported to have increased
expression in the dorsolateral prefrontal cortex in individ-
uals with schizophrenia (26). Chromosome 3q28 is sup-
ported by suggestive linkage results in studies in Finnish
(23), Palauan (27), and Dagestani (28) samples that are not
part of the NIMH-HGI collection. Chromosome 12q23.1
has been implicated by a suggestive linkage report with
studies contributing to this subset (4, 34, 35). Having data
from one population group provide evidence for linkage
and data from the other groups provide combined evi-
dence against is consistent with either separate sets of
genes operating in the different population groups or,
more likely, dependence of the salience of genetic effects
on the background (ancestral) genome or environment. It
is also consistent, however, with the subset-specific PPLs
being overestimates of the actual probability of linkage,
which is given by the omnibus PPL. Differences in sample
sizes across groups (139 African American, 187 European
American, 483 Han Chinese, and 161 Hispanic) also
complicate interpretation.
Dividing the data by clinical subgroup (families con-
taining individuals with schizophrenia/affective diagnoses
versus families with only narrow schizophrenia) yielded
four additional loci with PPL.25%, and in every case the
locus was supported by data from one group while data
from the other group provided evidence against linkage.
This strongly suggests that the genetics of schizophrenia
in families characterized by the presence of schizoaffec-
tive disorder or schizophrenia with a comorbid affective
disorder may be distinct from the genetics of schizophre-
nia in individuals without a significant mood disorder. On
the other hand, there is considerable confounding by
population, since the preponderance of families with
individuals with a schizophrenia/affective diagnosis varies
by group as well. The proportions of groups (African
American, European American, Han Chinese, Hispanic)
within schizophrenia-only families and families that
include schizophrenia/affective diagnoses are 0.11, 0.15,
0.59, 0.15 and 0.28, 0.41, 0.04, 0.26, respectively.

354 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 VIELAND, WALTERS, LEHNER, ET AL.

FIGURE 4. Linkage Findings for the Combined Analysis of Psychiatric Studies (CAPS) Project and Compared With Original
Reportsa
0 50 150 250 0 50 150 250 0 50 150 250
chr 1 chr 2 chr 3 chr 4 chr 5 chr 6

CAPS For
CAPS Against

7
6
5
4
3
2
1
chr 7 chr 8 chr 9 chr 10 chr 11 chr 12
CAPS For
CAPS Against

7
6
5
4
3
2
1
Study

chr 13 chr 14 chr 15 chr 16 chr 17 chr 18

CAPS For
CAPS Against

7
6
5
4
3
2
1
chr 19 chr 20 chr 21 chr 22 chr X
CAPS For
CAPS Against

7
6
5
4
3
2
1
0 50 150 250 0 50 150 250 0 50 150 250
Genetic Position (cM)
a
Thresholds and intervals for inclusion of original signals were taken directly from published reports and generally correspond to “suggestive”
linkage. Where intervals were not reported, the average reported interval of 16 cM was imposed. Omnibus posterior probability of linkage
(PPL) results are shown above the dotted line. “CAPS For” includes all regions with PPL.10%. This threshold was selected to similarly reflect
what might correspond to a “suggestive” level of support. “CAPS Against” includes all regions with PPL,2% (evidence against linkage). Note
also that because of the low resolution of genetic scale in this figure, no attempt was made to harmonize the genetic maps across the original
reports; different studies reported their results on Rutgers, Marshfield, Genethon, and genetic location database maps.

Interestingly, however, all three locations identified with bipolar disorder or mixed samples with schizophre-
in the families with schizophrenia/affective diagnoses nia and bipolar disorder (36–40). The 11p15.3 region was
(11p15.3, 11p11.2, and Xq26.1) have been previously also reported as a main finding in the original publication
implicated in linkage or association studies using samples for study 7 (9), and indeed, the African American-specific

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REVISITING SCHIZOPHRENIA LINKAGE DATA IN THE NIMH REPOSITORY
PPL reaches 15% at 28 cM. Of particular note is that study 7
reported (9) a marked strengthening of the linkage signal
at 11p15.3 when using a phenotype that included
schizophrenia and schizoaffective disorder rather than
schizophrenia only. Finally, the schizophrenia subset
produced a peak of 46% at 6q14.1 that overlaps a peak of
26% in the European American subgroup but was not re-
ported by any of the original European American studies.
In aggregate, these results have significant implications for
the inclusion of individuals with schizoaffective disorder in
linkage or association studies of schizophrenia. (See also
online data supplement SA3 for a comparison with results
in the National Human Genome Research Institute genome-
wide association study database.)
Insofar as population is a major source of heterogeneity
in these analyses, it is noteworthy that, with the exception
of the Han Chinese sample, the remaining sample sizes for
the different groups remain quite small. It is not surprising,
therefore, that even the largest PPLs remain moderate in
size. Similarly, dividing the data based on the presence of
affective illness results in a far smaller subset for the group
containing schizophrenia/affective diagnoses. Strikingly,
however, this group also produces some of the highest
PPLs. Our results suggest that both population and clinical
subgroup are key classifiers for the purposes of gene map-
ping. Ideally, we would like to use subsets simultaneously
on both criteria. However, the extremely small subsets that
would result preclude this approach.
It is also of interest to compare our results with the
meta-analyses of Nato et al. (41) and Ng et al. (42), both of
which included studies from the HGI collection as well as
other studies. Nato et al. identified 22 regions of interest,
while Ng et al. reported eight regions with aggregate
genome-wide evidence for linkage, all of which overlap
with regions identified by Nato et al. While the majority of
the Nato et al. (13 of 22) and Ng et al. (five of eight) regions
produced some level of evidence in favor of linkage under
the omnibus analysis, only two of our four omnibus peaks
.25% (2q36.1 and 3q28) overlapped a region of interest
from either study, with our largest peak of 41% overlapping
regions of interest from both studies. Of our eight peaks
.25% that were specific to an ethnic or clinical subset,
only two (5p14.1 and 10q26.12) overlapped a region of
interest from either study, again with the larger peak of
34% overlapping regions of interest from both studies. (See
online data supplement ST4 for detailed comparisons.)
Discussion
Our reanalyses of HGI data present a picture of the
schizophrenia genome with some overlap with previous
reports but also some novel loci, with differences both in
terms of the specific loci implicated and in the rank
ordering of these loci by relative strength of evidence.
While a number of loci previously implicated using the
samples from the HGI were also identified in the present
356 ajp.psychiatryonline.org
analyses, such as 2q36.1 and 15q23, others were not. At the
same time, several loci not previously reported in the HGI
samples but supported by other reports in the literature
have now been identified in the HGI collection, such as
3q28 and 12q23.1. Loci without any previous linkage re-
ports in schizophrenia but with positional support from
association studies were also identified, such as 11p11.2
and Xq26.1. Differences in the genetics of schizophrenia
across population groups and in families with differing
amounts of affective illness were also highlighted, in par-
ticular with 11p15.3, 11p11.2, and Xq26.1, which are prom-
inent in the schizophrenia/affective group, overlapping
with loci reported from independent studies of bipolar
disorder or mixed bipolar-schizophrenia samples.
One caveat is that we employed a highly conservative
approach both in deciding whom to categorize as “affected”
(e.g., narrow schizophrenia with multiple exclusion crite-
ria) and in our inclusion criteria for families (at least one
case of schizophrenia plus one additional schizophrenia or
schizophrenia/affective diagnosis), which led us to drop
a large number of families from these analyses. While we
believe that this approach is justified, particularly when
attempting to make “apples to apples” comparisons across
multiple different studies, we are aware that other inves-
tigators might make quite different judgments regarding
these decisions. All data on the full set of families, including
those we did not analyze here, are available on the HGI web
site (www.nimhgenetics.org), as are all protocols used in
preparing the data files (www.nimhgenetics.org/projects/
CAPS). We hope that other investigators will find this
a useful resource for carrying out their own analyses.
A second potential caveat is that we relied on linkage
analysis. Given the relative paucity of validated linkage
findings in psychiatric genetics, it is not unreasonable to be
skeptical regarding this approach. There is a certain irony
here, because past failures may be attributable in part to the
fact that psychiatry was an early and enthusiastic endorser
of the technique. Some of the schizophrenia data consid-
ered here date back to the 1990s, and the original studies
taken individually were almost certainly underpowered, for
a variety of reasons. By revisiting the HGI data and applying
modern data processing and newer data-analytic methods
to the existing multisite data as a whole, we believe that we
have succeeded in extracting new information from older
data sets of families. Of course, we have also lost something
in working with the repository data, insofar as the original
investigators had access to additional clinical information.
Historically there have been few gene discoveries under
psychiatric linkage peaks. In this regard, too, having been
a leader in methodological development put the field of
psychiatric genetics ahead of its time: earlier molecular
techniques were cumbersome and expensive, and com-
bined with the width of linkage peaks in the older studies,
this made gene identification under the peaks impractical.
But the increasing practicality of high-throughput DNA
sequencing should support gene discovery at linked loci in
Am J Psychiatry 171:3, March 2014

a manner unavailable until very recently. Indeed, human
genetics is returning to a focus on “co-segregation” (i.e.,
linkage analysis) as a critical adjuvant to whole genome
sequencing, because narrowing the search down to only
those portions of the genome showing evidence of linkage
dramatically reduces the amount of sequence needing
to be interrogated. One could even argue that linkage anal-
ysis as a technique for gene discovery has yet to be pro-
perly applied in much of psychiatric genetics.
Even so, it might be argued that genome-wide associ-
ation studies and case-control-based whole genome
sequencing are a better investment than multiplex family
studies. But linkage analysis and association analysis
(whether to common single-nucleotide polymorphisms
or rare variants) have the power to detect very different
types of genetic effects: genome-wide association studies
are well adapted to finding common variants conferring
low relative risks in a manner that is consistent across
populations (43) (requiring independent replication en-
sures that effects specific to one data set are discounted
[44]). While linkage analysis is adapted to finding loci
containing genes of large effect (in general, with rarer allele
frequencies and much higher genotypic relative risks), and
particularly when conducted using statistical methods
specifically tuned for such conditions, it can find such
genes even when they are causally relevant only in a subset
of families (10). One reason to continue to search for such
genes is precisely because a gene discovered by linkage
analysis almost certainly is a gene of large effect, albeit
perhaps only in some families. Such genes may yield
different insights into gene pathways and networks than
genes discovered through alternative study designs.
Linkage analysis is also robust to allelic heterogeneity,
which can eliminate allelic associations altogether (45).
The genetic architecture for complex disorders likely
involves many different types of effects simultaneously:
major gene effects in subsets of families; common back-
ground genes conferring small risks; copy number variants,
perhaps particularly important in causing sporadic forms of
disease; extensive locus heterogeneity, which might or
might not be alleviated by refined clinical subtyping; and
more complex features, including gene-by-gene and gene-
by-environment interactions, epigenetics, and probably
other things we have not even thought of yet. Under such
circumstances, no one study design can solve all problems.
The psychiatric genetics community has an enormous
resource on hand: extensive collections of multiplex families
with considerable clinical information. These collections
were labor intensive and expensive to amass; by contrast,
the cost of genotyping or even sequencing is becoming
relatively small. Returning to these collections with the
benefits of hindsight seems a promising and cost-effective
way to contribute to the growing understanding of genetic
architecture emerging from a multitude of studies and
study designs all being considered simultaneously. We
have tried here to illustrate the potential of such use of
Am J Psychiatry 171:3, March 2014
VIELAND, WALTERS, LEHNER, ET AL.
retrospective data to alter and augment our understanding
of the genetic underpinnings of psychiatric disorders. Of
course, interpretation of the results is still hampered by
the limited information content afforded by the available
genotype data.
Finally, we note an important methodological issue high-
lighted by these results, namely, that conventional inter-
pretations of statistical significance in terms of independent
replication can lead us to overlook important loci that may
have salient effects only in subsets of the data. As is well
known, failure to replicate true loci is to be expected for even
moderately complex disorders (46). What is perhaps less
widely appreciated is that traditional meta-analysis will
tend to fail in precisely those same circumstances where
independent replication cannot be relied upon for confir-
mation of results (17, 18). At the same time, we are ap-
propriately skeptical of weak findings that fail to replicate.
Indeed, as reports of weak signals obtained by individually
underpowered studies accumulate in the literature, and
particularly in view of the failure of standard statistical
methods to appropriately indicate evidence against linkage,
the overall picture of the schizophrenia genome becomes
murkier, not clearer, as time goes on.
By design, repositories such as the HGI offer a solution
by permitting analysis of far larger quantities of data than
can be collected by any one study. However, under exactly
these same conditions of underlying genetic complexity,
the so-called mega-analyses, which simply pool all data
into a single file for analysis, can also end up washing out
important subset-specific loci by failing to appropriately
allow for heterogeneity between data sets. For these rea-
sons, we view the PPL—which does not require agreement
across all data subsets, but rather accumulates the ag-
gregate evidence both for and against linkage in a math-
ematically rigorous manner while allowing for differences
between data sets—as particularly well suited to the task of
accurately and efficiently extracting genetic information
from repository collections. With the advent of affordable
sequence data, we predict that revisiting family data
already amassed in the HGI will provide a cost-effective
mechanism not just for discovering linkage peaks, but for
fine-mapping these peaks down to the level of the
individual gene or variant.
Received Dec. 6, 2011; revisions received Jan. 14, June 2, and Aug.
5, 2013; accepted Aug. 12, 2013 (doi: 10.1176/appi.ajp.2013.
11121766). From the Battelle Center for Mathematical Medicine,
Research Institute at Nationwide Children’s Hospital, Columbus, Ohio;
the Department of Genetics, Rutgers University, Piscataway, N.J.; and
NIMH, Bethesda, Md. Address correspondence to Dr. Vieland (veronica.
vieland@nationwidechildrens.org).
Dr. Brzustowicz serves as a consultant for the Janssen Pharmaceu-
tical Companies of Johnson & Johnson. The other authors report no
financial relationships with commercial interests.
Supported by NIH grants R01 MH086117 and U24 MH068457.
The authors are grateful to their Clinical Advisory Board for valu-
able contributions: Anne Bassett, Prudence Fisher, Ellen Leibenluft,
Deborah Levy, Michel Maziade, Kathleen Merikangas, Joe Piven, and
Peter Szatmari. John Burian and William Valentine-Cooper contributed
ajp.psychiatryonline.org 357
REVISITING SCHIZOPHRENIA LINKAGE DATA IN THE NIMH REPOSITORY
extensive and essential programming support. The authors also thank
the investigators who contributed these data sets to the Human
Genetics Initiative (HGI) and the families who participated in these
studies, as well as HGI staff at Washington University for their
assistance throughout the data review process.
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ajp.psychiatryonline.org 359
 Article

Randomized Trial of an Electronic Personal Health

Record for Patients With Serious Mental Illnesses
Benjamin G. Druss, M.D., M.P.H. Objective: The authors evaluated the
effect of an electronic personal health
record on the quality of medical care in
Xu Ji, M.S.P.H.
a community mental health setting.
Gretl Glick, B.A. Method: A total of 170 individuals with a
serious mental disorder and a comorbid
medical condition treated in a community
Silke A. von Esenwein, Ph.D.
mental health center were randomly as-
signed to either a personal health record or
usual care. One-year outcomes assessed
quality of medical care, patient activation,
service use, and health-related quality of
life.
Results: Patients used the personal health
record a mean of 42.1 times during the 1-year
intervention period. In the personal health
record group, the total proportion of eligible
preventive services received increased from
24% at baseline to 40% at the 12-month
follow-up, whereas it declined in the usual
care group, from 25% to 18%. In the subset
of patients with one or more cardiometa-
bolic conditions (N=118), the total propor-
tion of eligible services received improved
by 2 percentage points in the personal health
record group and declined by 11 percentage
points in the usual care group, resulting in
a significant difference in change between
the two groups. There was an increase in
the number of outpatient medical visits,
which appeared to explain many of the sig-
nificant differences in the quality of medical
care.
Conclusions: Having a personal health
record resulted in significantly improved
quality of medical care and increased use
of medical services among patients.
Personal health records could provide
a relatively low-cost scalable strategy for
improving medical care for patients with
comorbid medical and serious mental
illnesses.

(Am J Psychiatry 2014; 171:360–368)

P atients with serious mental illnesses are at risk for

elevated rates of medical comorbidity and adverse health
outcomes, including premature mortality (1). One of the most
important factors contributing to these poor health outcomes
is deficits in the quality of medical care (2, 3). At the patient
level, symptoms of psychiatric illness, such as amotivation (4),
cognitive limitations (5), and low health literacy (6, 7), make it
challenging for people with serious mental illness to effectively
manage their illnesses and obtain needed care. At the provider
and system levels, patients with comorbid mental and general
medical conditions typically receive care across multiple lo-
cations, leading to challenges in coordination of care be-
tween mental health and general medical providers (8).
Personal health records hold the potential to improve
quality and outcomes of care by providing patients and
providers timely access to key health information. Whereas
electronic medical records are most commonly developed
by individual provider organizations, electronic personal
health records shift the ownership and locus of health
information from being scattered across multiple pro-
viders to the patient (9, 10).
For patients with serious mental disorders, personal
health records may be able to provide particular benefits for
improving care (11). Personal health records may help
patients to better engage in care, facilitate communication
across multiple providers, and provide a single record that
follows patients across multiple settings. However, the same
challenges that patients with mental disorders face in
obtaining health services could also adversely affect their
ability to use personal health records. To date, there has
been almost no research testing the potential feasibility and
benefits of personal health records to improve care for
persons with mental disorders (12).
We report the results of a randomized trial testing the
effects of a mental health personal health record in a
sample of patients with serious mental illnesses and comor-
bid medical conditions. The results can help inform the
use of this emerging technology in the care of people with
mental disorders, as well as in other vulnerable populations.
Method
Overview
The project adapted an existing community-based personal
health record to patients with serious mental illnesses. A 12-
month randomized trial tested the effect of the record on the

This article is featured in this month’s AJP Audio, is the subject of a CME course (p. 377),
and is discussed in an Editorial by Drs. Fortney and Owen (p. 259)

360 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


FIGURE 1. My Health Record Screenshot
quality of medical care received in an urban community mental
health center.
Intervention
My Health Record is an adaptation of the Shared Care Plan,
a community-based personal health record developed by pro-
viders and by patients with chronic medical conditions to self-
manage their illnesses and interact with the health system (13).
The core features consist of personal details; diagnoses; goals and
action steps; health indicators, including fields for blood pressure
and cholesterol and glucose levels; medications and allergies;
hospital visits; immunizations; and health and family health
history. Prompts remind patients about routine preventive
services.
To adapt the health record to the needs of patients with
serious mental disorders, a series of focus groups consisting of
mental health consumers (two groups), mental health providers
(one group), and primary care providers (one group) presented
the personal health record and identified potential modifica-
tions that were needed for this population. Based on the find-
ings, the following changes were made: 1) rewriting all elements
of the personal health record to a sixth-grade reading level to
address limited health literacy in the population (7); 2) adding
a section establishing mental health and health goals to help
patients overcome amotivation and improve patient en-
gagement with self-management and medical care; 3) adding
Am J Psychiatry 171:3, March 2014
DRUSS, JI, GLICK, ET AL.
a mental health advanced directive section addressing patient
preferences for mental health care in cases in which the patient is
unable to make mental health decisions (14); and 4) providing
contact information about resources, including grocery stores,
YMCAs, and safety net health providers in the patients’ neigh-
borhoods. A screenshot of the My Health Record web interface is
presented in Figure 1.
Because of low levels of digital literacy, a 4-hour computer
literacy training curriculum was provided to all patients in the
personal health record arm to enable them to effectively use the
computer and the personal health record.
Data from the personal health record were stored on an
encrypted server, and passwords were required to log in. Clients
were able to access the personal health record data with pro-
tected passwords from any computer with an Internet connec-
tion. Additionally, they were allowed to designate health partners
(including physicians, other providers, and friends and/or family),
who could obtain access to the personal health record, and to
identify the fields that health partners could access. For those
without access to a computer, a workstation was provided at
the mental health clinic.
A study staff member was available to patients to help orient
them to the use of the personal health record and to enter and
retrieve data during the first 6 months of the intervention. An
initial 1-hour visit orienting patients to the personal health
record was followed by 30-minute follow-up visits as needed.
ajp.psychiatryonline.org 361
ELECTRONIC PERSONAL HEALTH RECORD FOR PATIENTS WITH SERIOUS MENTAL ILLNESSES
FIGURE 2. Study CONSORT Diagram
Assessed for eligibility (N=644)
Randomly assigned (N=170)
Allocated to
intervention arm (N=85)
Total interviewed (N=64)
Lost to follow-up (N=13)
Withdrew (N=8)
Total with chart review (N=85)
On average, patients had 14.8 support visits (SD=5.53), for a
total of approximately 8 hours of support time during the study
period.
After entering the initial data, clients were encouraged to
access the personal health record at least every other week.
Each patient printed out a wallet-sized card that provided an
overview of his or her medical history, laboratory workup, and
medications. Before each medical appointment, patients also
printed out a detailed, full-size printout for their providers.
Recruitment and Randomization
Patients with schizophrenia, schizoaffective disorder, bi-
polar disorder, major depression, or posttraumatic stress dis-
order and one or more chronic medical condition confirmed
through chart review were eligible to participate. Patients were
also required to have a primary care provider and to have a
minimum of a sixth-grade reading level to ensure full par-
ticipation in the project. Individuals were recruited through
clinician referral or community mental health center waiting
room screening or self-referred through recruitment flyers or
word-of-mouth. Participants assigned to the usual care group
continued to receive medical and mental health care as usual
in the community and returned for follow-up interviews but
were not provided a personal health record. After complete
description of the study to the participants, written informed
consent was obtained.
Outcome Assessment
Interviews and reviews of all medical and mental health charts
were conducted at baseline and the 12-month follow-up. Quality
362 ajp.psychiatryonline.org
Excluded (N=474)
Not meeting inclusion criteria (N=443)
No regular primary care provider (N=208)
No regular mental health provider (N=102)
<6th-grade reading level (N=58)
No chronic illness (N=75)
Declined to participate (N=31)
Allocated to
usual care arm (N=85)
Total interviewed (N=77)
Lost to follow-up (N=7)
Withdrew (N=1)
Total with chart review (N=85)
and service use indicators were assessed through review of
all medical and mental health charts; patient activation and
health-related quality of life were assessed through patient
interviews.
The primary study outcome was quality of medical care,
which included 1) quality of preventive services and 2) quality
of cardiometabolic care in the subset of individuals with car-
diometabolic conditions. Quality of preventive services measures
were obtained from the U.S. Preventive Services Task Force
guidelines (15). These include four measures of physical ex-
amination, eight screening measures, seven vaccination mea-
sures, eight education measures, two measures of preventive
services for men, and five preventive services measures for
women. A score for each domain was calculated as the total
number of preventive services for which an individual was eli-
gible that were received by the individual. An aggregate score
was developed as the total number of services across all do-
mains for which an individual was eligible that were received by
the individual.
Quality indicators for cardiometabolic risk factors were
used as a second outcome measure because of the relatively
high prevalence, clinical burden, and availability of indicators
for this group of conditions. For the subset of individuals with
these conditions (N=118), indicators were developed using
the RAND Community Quality Index (16–18). Cardiometa-
bolic measures included 11 indicators for hypertension, seven
measures for diabetes, and six measures for hyperlipidemia.
As with preventive services, a score for each group of cardio-
metabolic indicators was calculated as the total number of ser-
vices for which an individual was eligible that were received by
Am J Psychiatry 171:3, March 2014
 DRUSS, JI, GLICK, ET AL.

TABLE 1. Demographic and Clinical Characteristics of the Study Samplea

Study Arm
Characteristic Personal Health Record (N=85) Usual Care (N=85) Analysis
Mean SD Mean SD p
Age (years) 49.3 7.1 49.3 8.1 0.98
Income (monthly [U.S. dollars]) 554.8 379.4 607.9 448.6 0.41
Number of medical comorbidities 2.3 1.5 2.3 1.3 0.74
N % N % p
Male 43 50.6 41 48.2 0.76
Race/ethnicity
White 13 15.3 8 9.4 0.24
Black 68 80 74 87.1 0.21
Hispanic 0 0 2 2.4 0.15
Single 45 54.2 38 44.7 0.21
Stable housing 66 79.5 71 83.5 0.50
Stable employment 41 49.4 52 61.2 0.12
Disability 23 27.1 26 30.6 0.61
Medical diagnosis
Asthma 19 22.4 21 24.7 0.72
Osteoarthritis 29 34.1 17 20 0.03
Chronic obstructive pulmonary disease 8 9.4 10 11.8 0.61
Coronary artery disease 10 11.8 8 9.4 0.61
HIV 2 2.4 7 8.2 0.08
Hepatitis 15 17.7 19 22.4 0.44
Active tuberculosis 3 3.5 2 2.4 0.65
Cardiometabolic conditions 58 68.2 60 70.6 0.74
Diabetes 20 23.5 22 25.9 0.72
Hyperlipidemia 36 42.4 28 32.9 0.21
Hypertension 55 64.7 57 67.1 0.75
Mental diagnosis
Schizophrenia 21 24.7 26 30.6 0.39
Bipolar disorder 14 16.5 6 7.1 0.06
Depression 40 47.1 41 48.2 0.89
Substance use disorder 2 2.4 7 8.2 0.09
Other mental illness 4 4.7 1 1.2 0.17
a
For continuous variables, a t test was used, and a chi-square test was used for dichotomous variables.

the individual. An aggregate cardiometabolic quality score was Results

developed as the total number of services across all domains
for which an individual was eligible that were received by the
individual.
Secondary outcomes included 1) health services use, including
mental and medical inpatient, outpatient, and emergency de-
partment use; 2) patient activation, as measured by the Patient
Activation Measure (19), a 22-item measure of patient skills and
confidence in self-management behaviors; and 3) health-related
quality of life, using the physical and mental component sum-
mary measures of the Medical Outcomes Study 36-Item Short-
Form Health Survey (20).
Data Analysis
All analyses were conducted as intent-to-treat. General
linear analyses were conducted using the SAS PROC GLM (SAS
Institute, Cary, N.C.) procedure to model change in each
outcome as a function of being in the personal health record
group compared with the usual care group. For dichotomous
outcomes, the baseline value was included as a covariate in
the regression predicting the measure at the follow-up in-
terview. For continuous outcomes, changes in scores between
baseline and follow-up were specified as dependent variables.
Two-tailed tests of significance were used for all analyses.
Study Flow, Participant Characteristics, and Use of
the Personal Health Record
Of a total of 644 individuals screened, 170 were eligible
and randomly assigned; the most common reasons that
patients were screened but not enrolled were 1) lack of
a regular primary care (N=208) or mental health (N=102)
provider and 2) lack of a comorbid chronic medical illness
(N=75) (Figure 2). All individuals in the personal health
record and usual care groups had complete baseline and
12-month chart data available for the primary quality
outcomes; a total of 141 (82.9%) had 12-month interviews.
All demographic and clinical parameters were balanced
between the intervention and usual care groups (Table 1).
The mean age of participants was 49.3 years (SD=7.62).
One-half (49.4%) of the participants in the sample were
men, and a majority (83.5%) were African American. Most
participants were poor, with a mean annual income in the
sample of $6,966 (SD=$4,985.13). On average, participants

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 363

ELECTRONIC PERSONAL HEALTH RECORD FOR PATIENTS WITH SERIOUS MENTAL ILLNESSES

TABLE 2. Quality of Preventive and Cardiometabolic Care

Study Arm
Personal Health Record Usual Care Analysis
Variable Mean SD Mean SD F df pa
Quality of preventive services
Physical examination 12.78 169 0.0005
Baseline 0.53 0.18 0.55 0.14
12-Month interview 0.55 0.13 0.46 0.21
Screening 5.76 169 0.02
Baseline 0.29 0.13 0.33 0.16
12-Month interview 0.21 0.16 0.18 0.15
Vaccination 20.13 169 ,0.0001
Baseline 0.08 0.12 0.08 0.13
12-Month interview 0.19 0.2 0.06 0.09
Education 153.82 168 ,0.0001
Baseline 0.17 0.16 0.17 0.16
12-Month interview 0.73 0.34 0.15 0.16
Preventive care for women 0.19 85 0.66
Baseline 0.32 0.37 0.27 0.33
12-Month interview 0.27 0.31 0.27 0.3
Preventive care for men 0.4 83 0.53
Baseline 0.16 0.28 0.15 0.23
12-Month interview 0.14 0.27 0.09 0.19
Total percentage of eligible services receivedb 99.35 169 ,0.0001
Baseline 0.24 0.1 0.25 0.1
12-Month interview 0.4 0.14 0.18 0.11
Quality of cardiometabolic services
Hypertension 9.98 169 0.002
Baseline 0.73 0.24 0.78 0.2
12-Month interview 0.78 0.19 0.7 0.3
Hyperlipidemia 0.04 34 0.85
Baseline 0.87 0.34 0.92 0.28
12-Month interview 0.71 0.46 0.86 0.35
Diabetes 3.02 36 0.09
Baseline 0.42 0.25 0.58 0.25
12-Month interview 0.54 0.22 0.51 0.27
Total percentage of eligible services receivedb 9.39 169 0.003
Baseline 0.73 0.24 0.78 0.2
12-Month interview 0.75 0.2 0.67 0.31
a
The data represent the values for group type (personal health record compared with usual care), the key independent variable of interest,
without adjusting for the number of outpatient medical visits.
b
The data indicate the proportion of services for which a participant was eligible and obtained.

had a mean of 2.3 comorbid medical conditions; the most
common mental health conditions were major depression
(47.6%) and schizophrenia (27.6%). A total of 118 patients
(65.6% of the sample) had one or more cardiometabolic
conditions.
Based on data from the personal health record web
server, participants used the personal health record a mean
of 42.1 (SD=55.0) times during the 1-year intervention
period.
Effects on Quality of Medical Care
The total proportion of eligible preventive services
received increased in the personal health record group
(from 24% at baseline to 40% at the 12-month follow-up,
compared with a decline in the usual care group from 25%
to 18%), resulting in a significant difference in change
between the personal health record and usual care groups
(p,0.001) (Table 2). Compared with the usual care group,
the personal health record group had significantly greater
improvements in rates of physical examination (p,0.001),
screening (p=0.02), vaccination (p,0.001), and education
(p,0.001). The overall rate of preventive service use in the
personal health record and usual care groups is presented
in Figure 3.
In the sample of patients with cardiometabolic con-
ditions (N=118), the total proportion of eligible cardio-
metabolic services received improved by 2 percentage
points in the personal health record group but declined

364 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


by 11 percentage points in the usual care group, result-
ing in a significant difference in change between the two
groups (p=0.003) (Table 2). In the personal health record
arm, there was a significantly greater improvement in
Total Percentage of Eligible Services Received
care for hypertension (p=0.002) but not for diabetes or
hyperlipidemia.
Effects on Secondary Outcomes
Participants in the personal health record group had
a significant increase in the number of outpatient medical
visits compared with those in the usual care group (mean
increase: 14.9 [SD=10.71] compared with 0.5 [SD=11.15],
p,0.001) (Table 3). There were no significant changes in
other measures of inpatient, outpatient, or emergency
department services.
Both groups exhibited small improvements in patient
activation, physical health-related quality of life, and men-
tal health-related quality of life; however, none of these
changes differed significantly between the two groups
(Table 3).
Mediation Analysis
To explore whether the number of visits might explain
a portion of the effect on quality measures, an exploratory
mediation analysis was conducted examining whether
controlling for the number of outpatient medical visits
attenuated the association between the intervention and
the quality scores. After adjusting for outpatient use of
services, only education and total number of preventive
services remained significant (p,0.001). The magnitudes
of differences in preventive services changes and cardio-
metabolic care changes between the personal health re-
cord and usual care groups all decreased substantially,
except for preventive services for women, preventive
services for men, and quality of hyperlipidemia treatment
(Table 4).
Discussion
In a sample of patients with serious mental illnesses and
comorbid medical conditions, having a personal health
record was associated with improved quality of preventive
care and cardiometabolic care, as well as increased use of
general medical services. There were no evident benefits
regarding patient activation, quality of life, or other mea-
sures of service use.
An increasing number of studies have found that per-
sonal health records can improve rates of routine pre-
ventive services in general medical populations (21, 22).
Our study demonstrated that a poor and complex popu-
lation of people with serious mental illnesses can derive
similar benefits from these new technologies. In contrast
to most personal health records, which are developed as
extensions of electronic health records, the community-
based personal health record in this study made it possible
for patients to include information from multiple providers,
Am J Psychiatry 171:3, March 2014
DRUSS, JI, GLICK, ET AL.
FIGURE 3. Personal Health Record and Rate of Receipt of
Indicated Preventive Care Services
0.5
Personal Health Record Group
Usual Care Group
0.4
0.3
0.2
0.1
Baseline 1-Year Follow-Up
a high priority for populations whose care may be scattered
across multiple organizations.
While the study showed that implementing such pro-
grams is feasible, particularly for this population, they
need to be implemented with adequate support. In this
study, computer training helped address deficits in com-
puter literacy, and technical assistance was important in
helping patients enter data and access their personal health
record. As with other health technology interventions, im-
plementation studies are needed to identify which training
and technical assistance approaches can most efficiently
allow patients to reap the benefits (23).
What allowed patients with a personal health record to
obtain higher quality of medical care? Analyses suggested
that greater rates of medical utilization in the personal
health record group appeared to be an important driver of
higher quality of preventive and cardiometabolic services.
Underuse of medical services commonly underlies quality
deficits in this population (2); increasing patients’ use of
services, in turn, may help foster improved quality of care.
Several limitations to this study should be noted. The
study was conducted in a single, urban community mental
health center. Further work is needed to establish genera-
lizability to other mental health settings. Second, the study
was only conducted among the subset of patients with a
regular mental health and medical provider. For popula-
tions without a regular source of care, addressing access
barriers may be needed before implementing interven-
tions such as personal health records, in which the goal is
to improve quality and engagement in treatment. Finally,
reflecting the state of technology at the time the study was
conducted, the web-based personal health record relied on
participants to enter all data and access the record through
ajp.psychiatryonline.org 365
ELECTRONIC PERSONAL HEALTH RECORD FOR PATIENTS WITH SERIOUS MENTAL ILLNESSES

TABLE 3. Service Use, Patient Activation, and Health-Related Quality of Life

Study Arm
Variable Personal Health Record Usual Care Analysis
N % N % F df pa
Services use (dichotomous)
Inpatient mental health hospitalization 1.03 168 0.16
Baseline 1 1.2 1 1.2
12-Month interview 0 0 2 2.4
Emergency department mental health visit 3.68 168 0.68
Baseline 23 27.1 14 16.5
12-Month interview 10 11.8 7 8.3
Inpatient medical hospitalization 3.01 168 0.68
Baseline 3 3.5 4 4.7
12-Month interview 10 11.8 12 14.3
Emergency department medical visit 3.6 168 0.85
Baseline 50 58.8 41 48.2
12-Month interview 39 45.9 38 45.2
Mean SD Mean SD F df pa
Services use (continuous)
Number of outpatient mental health visits 2.65 168 0.11
Baseline 12.1 8.1 11.4 8.1
12-Month interview 21.5 23.8 15.4 21.9
Number of outpatient medical visits 73.36 168 ,0.0001
Baseline 12.2 9.8 13.1 14.3
12-Month interview 27.1 11.5 13.7 12.2
Patient activation measure (100 possible score) 0.02 138 0.90
Baseline 56.1 14.3 55.6 14.4
12-Month interview 58.9 12.5 59.2 15.7
Medical Outcomes Study 36-Item Short-Form Health Survey composite
indices
Physical component measure 0.85 139 0.36
Baseline 33.4 11.2 32.7 9.2
12-Month interview 33.4 9.7 33.6 8.9
Mental component measure 0.64 139 0.42
Baseline 33.4 10.9 33.8 11.1
12-Month interview 34.6 10.9 36.2 11.3
a
The data represent the values for group type (personal health record compared with usual care), the key independent variable of interest.

TABLE 4. Quality of Preventive and Cardiometabolic Care (Mediation Analysis)

Prediction of Service Change Between Baseline and Follow-Up Interview
Without Adjustment for the Number With Adjustment for the Number of
of Outpatient Medical Visits Outpatient Medical Visits
Quality of Care Coefficienta pb Coefficienta pb
Preventive services
Physical examination 0.118 0.0005 0.021 0.58
Screening 0.071 0.02 0.037 0.30
Vaccination 0.128 ,0.0001 0.038 0.24
Education 0.587 ,0.0001 0.441 ,0.0001
Preventive care for women 0.043 0.66 –0.065 0.58
Preventive care for men 0.038 0.53 0.060 0.42
Total percentage of eligible services receivedc 0.228 ,0.0001 0.140 ,0.0001
Cardiometabolic services
Hypertension 0.129 0.002 0.074 0.12
Hyperlipidemia –0.033 0.85 –0.194 0.28
Diabetes 0.152 0.09 0.119 0.29
Total percentage of eligible services receivedc 0.127 0.003 0.082 0.09
a
The data represent the coefficient of group type (personal health record compared with usual care).
b
The values for group type are presented.
c
The data indicate the proportion of services for which a participant was eligible and obtained.

366 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014


Patient Perspective
“Ms. J” is a 58-year-old African American woman with
a history of schizophrenia, diabetes, and hypertension who
participated in the personal health record arm of the study.
She received her mental health care from a community
mental health center and her medical care from a federally
qualified health center in the neighborhood. She often left
her appointments feeling overwhelmed and uncertain as
to how to manage her health. She did not own a computer
but had some experience in using e-mail and the web and
was able to access a computer from the public library.
During the study, she accessed the personal health record
on average once per week, using it to update her medi-
cations and health goals. She brought a printout of her
personal health record to each of her medical and mental
desktop computers. Exchange of health information across
providers (24), along with patient portals (25), will increasingly
make it possible to directly synchronize with clinical and
laboratory data, reducing patient burden and increasing
utility of personal health records as tools for coordinating
care. The increasing ubiquity of smartphones may further
increase the ability of patients to access health records and
communicate with providers whenever and wherever the
need arises (26, 27). Further research is needed to examine
the benefits of these new technologies in improving care.
This study demonstrated that personal health records
hold potential to improve the quality of care among in-
dividuals with serious mental illnesses treated in public
mental health settings. More generally, personal health re-
cords point to the promise of new health technologies for
improving care in vulnerable populations who have tradi-
tionally not been included in developing the interventions
or in evaluating their effectiveness. As these technologies
are developed and disseminated in the coming years, it will
be essential to ensure that they are available to, as well as
tested in, patients with serious mental illnesses and other
disadvantaged populations.
Received July 12, 2013; revision received Sept. 25, 2013; accepted
Oct. 25, 2013 (doi: 10.1176/appi.ajp.2013.13070913). From the
Rollins School of Public Health and the Department of Health Policy
and Management, Emory University, Atlanta. Address correspon-
dence to Dr. Druss (bdruss@emory.edu).
The authors report no financial relationships with commercial
interests.
Funded by a grant (R18HS017829) from the Agency for Healthcare
Research and Quality.
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health appointments and began attending her primary care
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experience with the record as follows: “My Health Record
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Am J Psychiatry 171:3, March 2014
 Letters to the Editor
Developmental Lag and Course of Cognitive
Deficits From the Premorbid to Postonset
Period in Schizophrenia
To the Editor: In their article published online September
13, 2013, Meier et al. (1) update earlier findings of their well-
conducted population-based longitudinal study (2). Previ-
ously, the authors reported cognitive changes between ages 7
and 13 years and found that children who later developed
schizophrenia had stable cognitive deficits that were already
evident at age 7. The earlier report also provided evidence of
change in other cognitive domains, as some children had
more severe working memory and processing speed deficits at
follow-up. In the present article, Meier et al. (1) extend their
findings to age 38. This report has a number of strengths. It
revealed that antipsychotic and illicit drug use could not
explain the reported cognitive changes. It also provided some
evidence of specificity to schizophrenia as no similar cogni-
tive changes were found in clinical and healthy comparison
groups.
However, there is a significant concern regarding this most
recent report. The article presents the message that schizo-
phrenia patients are losing acquired cognitive skills from the
premorbid to the postonset period. The authors also suggest
that decline is observed in fluid abilities but not crystallized
abilities and imply that different pathophysiological mecha-
nisms underlie these deficits. Such interpretations could be
considered by many as strong support for neurodegenerative
models of schizophrenia.
However, these findings should not be considered real
evidence of cognitive decline in schizophrenia because of two
important limitations. First, in most cognitive tests that were
included, a more challenging version of the task was used at
the follow-up assessment. Second, reported IQ results were
based on the corrected norms. Previous studies also had the
same limitations, and some studies used completely different
tests at the follow-up assessment. Studies reporting follow-up
data of raw scores of the same cognitive measures adminis-
tered to patients with ultra-high risk to psychosis and patients
with first-episode schizophrenia have not supported the idea
of cognitive decline (3).
In reality, the evidence suggests that schizophrenia patients
simply lag behind healthy individuals in cognitive develop-
ment, and such cognitive changes are quite naturally more
apparent for fluid skills than crystallized skills in adolescence
and adulthood, as the development of advanced cognitive
skills continues after age 13. There is no need for a different
pathophysiological mechanism. In fact, the authors shyly ac-
knowledge this in their discussion of the symbol coding
findings; however, their main emphasis is cognitive decline. Cog-
nitive deficits observed in schizophrenia can be best explained
by problems in acquisition during neurodevelopment from birth
to adulthood rather than by the loss of acquired abilities.
References
1. Meier MH, Caspi A, Reichenberg A, Keefe RS, Fisher HL, Harrington
H, Houts R, Poulton R, Moffitt TE: Neuropsychological decline in
schizophrenia from the premorbid to the postonset period: evi-
dence from a population-representative longitudinal study. Am
J Psychiatry 2014; 171:91–101
Am J Psychiatry 171:3, March 2014
2. Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RS, Murray
RM, Poulton R, Moffitt TE: Static and dynamic cognitive deficits in
childhood preceding adult schizophrenia: a 30-year study. Am J
Psychiatry 2010; 167:160–169
3. Bora E, Murray RM: Meta-analysis of cognitive deficits in
ultra-high risk to psychosis and first-episode psychosis:
do the cognitive deficits progress over, or after, the onset
of psychosis? Schizophr Bull (Epub ahead of print, Jun 14,
2013)
EMRE BORA, M.D.
From the Department of Psychiatry, Melbourne Neuropsychi-
atry Centre, University of Melbourne and Melbourne Health,
Carlton South, Victoria, Australia.
Dr. Bora reports no financial relationships with commercial
interests.
This letter (doi: 10.1176/appi.ajp.2013.13091283) was accepted
for publication in November 2013.
Response to Bora
To the Editor: Schizophrenia researchers wonder if schizo-
phrenia is a neurodevelopmental or neurodegenerative con-
dition. Data from our life-course study suggest it may be both.
We previously reported that children who later develop
schizophrenia show slowed growth in fluid cognitive abilities
across ages 7 to 13 years (1), consistent with a neurodevel-
opmental model of schizophrenia. With new data at mid-
life (2), we think we have documented that these same
individuals show some cognitive degeneration (i.e., loss of
acquired cognitive abilities) from before to after the onset of
schizophrenia.
Usually, the mental abilities of an individual are inter-
preted against a standard of performance that is normative,
where normative is defined as age typical. Childhood and
adult tests tap the same abilities, but they often use age-
appropriate test materials. However, the clearest evidence
that neuropsychological decline in schizophrenia represents
a loss of acquired cognitive abilities would be seen if the test
given at follow-up precisely matched the initially adminis-
tered test, as Bora (3) notes. In the Dunedin Multidisciplinary
Health and Development Study, two tests given in adulthood
(age 38) were identical to those given in childhood (age 13):
the Grooved Pegboard Test and the Rey Auditory Verbal
Learning Test. Regarding the Grooved Pegboard Test, the
schizophrenia group took 4 seconds longer in adulthood
than in childhood to complete the same test; thus, the
schizophrenia group lost some of the motor ability they once
had in childhood. (In contrast, the healthy and persistent
depression groups completed the test about 2.5 seconds more
quickly in adulthood than in childhood, thus showing that
motor abilities normatively improve slightly from childhood to
adulthood.) Regarding the Rey Auditory Verbal Learning Test,
the schizophrenia group recalled seven fewer words over the
four trials (Rey total recall) as adults than they had as children
on the same test; thus, the schizophrenia group lost some of
their ability to learn. (In contrast, the healthy and persistent
depression groups recalled three fewer words as adults than they
had as children, thus showing that ability to learn normatively
ajp.psychiatryonline.org 369
LETTERS TO THE EDITOR
declines from childhood to adulthood. Individuals with
schizophrenia showed accelerated decline in ability to learn.)
In summary, we previously demonstrated that in child-
hood, when the normative trajectory of cognitive ability is one
of growth, children who later develop schizophrenia exhibit
slowed growth in fluid cognitive abilities (1). Here, we dem-
onstrate that in adulthood, when fluid cognitive abilities start
to normatively decline (4), individuals with schizophrenia in
our cohort exhibited early degeneration and accelerated de-
cline. Granted, these latter findings are based on only two
tests, but to us, they blur the distinction between develop-
ment and degeneration. Moreover, unlike fluid abilities, de-
ficits in crystallized abilities were apparent as early as age 7
and remained stable to age 38 years (1, 2). Fluid abilities
are thought to support the acquisition of crystallized skills,
with the developmental trajectory of crystallized abilities
lagging behind that for fluid abilities (5). Therefore, it is
somewhat surprising that deficits in crystallized abilities
emerged before deficits in fluid abilities and did not worsen
over time. Whether different pathophysiological mech-
anisms underlie cognitive deficits in fluid and crystal-
lized abilities in schizophrenia is a key question for future
research.
References
1. Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RS, Murray
RM, Poulton R, Moffitt TE: Static and dynamic cognitive deficits in
childhood preceding adult schizophrenia: a 30-year study. Am J
Psychiatry 2010; 167:160–169
2. Meier MH, Caspi A, Reichenberg A, Keefe RS, Fisher HL, Harrington
H, Houts R, Poulton R, Moffitt TE: Neuropsychological decline in
schizophrenia from the premorbid to the postonset period: evi-
dence from a population-representative longitudinal study. Am
J Psychiatry 2014; 171:91–101
3. Bora E: Developmental lag and course of cognitive deficits from
the premorbid to postonset period in schizophrenia. Am J Psy-
chiatry 2014; 171:369
4. Salthouse T: Consequences of age-related cognitive declines.
Annu Rev Psychol 2012; 63:201–226
5. Li SC, Lindenberger U, Hommel B, Aschersleben G, Prinz W, Baltes
PB: Transformations in the couplings among intellectual abilities
and constituent cognitive processes across the life span. Psychol
Sci 2004; 15:155–163
MADELINE H. MEIER, PH.D.
TERRIE E. MOFFITT, PH.D.
AVSHALOM CASPI, PH.D.
RICHIE POULTON, PH.D.
From the Department of Psychology, Arizona State University,
Tempe, Ariz.; the Department of Psychology and Neuroscience,
Duke University, Durham, N.C.; the Institute for Genome
Sciences and Policy, Duke University, Durham; the Depart-
ment of Psychiatry and Behavioral Sciences, Duke University
Medical Center, Durham; the Social, Genetic, and Devel-
opmental Psychiatry Centre, Institute of Psychiatry, King’s
College London; and the Dunedin Multidisciplinary Health
and Development Research Unit, Department of Preventive and
Social Medicine, School of Medicine, University of Otago,
Dunedin, New Zealand.
The authors’ disclosures accompany the original article.
This reply (doi: 10.1176/appi.ajp.2013.13091283r) was ac-
cepted for publication in October 2013.
370 ajp.psychiatryonline.org
Management Issues During Pregnancy in
Women With Bipolar Disorder
To the Editor: We read with interest the article by Clark
et al. (1) on lamotrigine dosing in pregnant patients with
bipolar I disorder. The authors report on the use of lamotrigine
in eight patients with bipolar disorder, six of whom received
concomitant psychotropic drugs including four women who
were taking antidepressant drugs. Dosage adjustments of
lamotrigine were made in response to hypomanic, manic, or
depressive symptoms. It is not clear whether the dosages of
concomitant psychotropic drugs remained the same during
pregnancy. Of the three women requiring a dosage increase to
manage symptoms, two were also taking antidepressants that
can increase the recurrence of bipolar mood episodes both
during and after pregnancy (2). There are no data suggesting
that monitoring serum levels with corresponding adjustments
to lamotrigine dosing will protect against antidepressant-led
mood instability. Interestingly, the authors did not report a
correlation between lamotrigine concentration and scores on
rating scales for depression and mania. Thus, the conclusion
that women with bipolar disorder who are treated with
lamotrigine experience an increase in symptoms as a result of
declining concentrations of this drug is not justified.
While lamotrigine has a role in the management of bipo-
lar disorder during pregnancy, no data on its effectiveness
in the prevention of postpartum mood episodes are currently
available. Moreover, lamotrigine is generally not recommended
for the acute treatment of mania (3).
Finally, the statement that pregnancy is a vulnerable period
for recurrence of mood episodes is true for women treated at
tertiary care centers with complex and often comorbid dis-
orders and women who discontinue mood-stabilizing drugs.
However, evidence from studies using nonclinical samples,
retrospective studies, and studies on psychiatric hospitaliza-
tion rates is suggestive of a positive effect of pregnancy on
bipolar disorder (4).
References
1. Clark CT, Klein AM, Perel JM, Helsel J, Wisner KL: Lamotrigine
dosing for pregnant patients with bipolar disorder. Am J Psychi-
atry 2013; 170:1240–1247
2. Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z,
Reminick A, Zurick A, Cohen LS: Risk of recurrence in women with
bipolar disorder during pregnancy: prospective study of mood
stabilizer discontinuation. Am J Psychiatry 2007; 164:1817–1824
3. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda
M, O’Donovan C, Macqueen G, McIntyre RS, Sharma V, Ravindran
A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B,
Birmaher B, Ha K, Nolen WA, Berk M: Canadian Network for
Mood and Anxiety Treatments (CANMAT) and International Society
for Bipolar Disorders (ISBD) collaborative update of CANMAT
guidelines for the management of patients with bipolar disor-
der: update 2013. Bipolar Disord 2013; 15:1–44
4. Sharma V, Pope CJ: Pregnancy and bipolar disorder: a systematic
review. J Clin Psychiatry 2012; 73:1447–1455
VERINDER SHARMA, M.B.B.S.
CHRISTINA SOMMERDYK, M.SC.
From the Departments of Psychiatry and Obstetrics & Gynecol-
ogy, University of Western Ontario, London, Ontario, Canada;
the Perinatal Clinic, London Health Sciences Centre, London,
Ontario; and Regional Mental Health Care, London, Ontario.
Am J Psychiatry 171:3, March 2014

Professor Sharma has received grant support from, partici-
pated on scientific advisory boards for, or served on the
speakers’ bureaus of AstraZeneca, Bristol-Myers Squibb,
Cephalon, Eli Lilly, Janssen, Lundbeck, the Ontario Mental
Health Foundation, Pfizer, Servier, and the Stanley Foundation.
Ms. Sommerdyk reports no financial relationships with com-
mercial interests.
This letter (doi: 10.1176/appi.ajp.2014.13111493) was accepted
for publication in January 2014.
Response to Sharma and Sommerdyk
To the Editor: As Prof. Sharma and Ms. Sommerdyk
highlight, optimizing medication management in pregnant
women with bipolar disorder is an area with an urgent need
for data to drive decision making. The objectives of the
Treatment in Psychiatry article (1) were to combine a review
of the data on the pharmacokinetic changes of lamotrigine in
pregnant women with epilepsy with observations from our
case series and to generate recommendations for lamotrigine
dosing in pregnant women with bipolar disorder. Sharma and
Sommerdyk raise an important point about whether women
treated with lamotrigine in pregnancy experience an increase
in mood symptoms as a result of declining lamotrigine con-
centrations. Serum level reductions of psychotropic med-
ications as a result of dosage decreases or drug nonadherence
are associated with episode recurrence and symptom wors-
ening. Data on lamotrigine use in pregnant women with
bipolar disorder are sparse; however, the literature on
managing lamotrigine in women with epilepsy is relevant for
guidance about pharmacokinetic changes during gestation.
Women with epilepsy experience increased seizure frequency
associated with declining lamotrigine levels during preg-
nancy. Similarly, if the bioavailability of lamotrigine for
maintenance treatment of bipolar disorder is not sustained
in the pregnant woman, she is at risk for symptom worsening.
As Sharma and Sommerdyk recommend, careful symptom
monitoring is essential in the gravid woman taking lamotrigine,
since pregnancy may increase clearance and lower levels
(2). Establishing a baseline serum level at the patient’s
therapeutic dose of lamotrigine and adjusting the dosage to
maintain the baseline level increases the likelihood of pre-
ventive efficacy.
As we discussed (1), an association between lamotrigine
serum levels and mania and depression scores was not found.
In our naturalistic study from which the case series was
derived, the individuals’ lamotrigine dosages were managed
by their community-based physicians. Serum levels were
checked during scheduled study protocol visits rather than at
the time their physician observed a change in symptoms and
changed the dosage. A study designed to address these
pharmacokinetic and pharmacodynamic questions for opti-
mal management of lamotrigine dosing and prevention of
relapse is underway in our center.
Am J Psychiatry 171:3, March 2014
LETTERS TO THE EDITOR
Whether lamotrigine prevents postpartum episodes remains
to be investigated; however, continuing effective maintenance
therapy prior to and during pregnancy is good clinical practice,
and every woman with bipolar disorder requires close obser-
vation after birth regardless of medication status (3).
The predictors of episode recurrence during pregnancy
may be related to the bipolar disorder variant rather than
sample characteristics (tertiary care or community psychiatric
setting). In a large-scale screening study for postpartum de-
pression in an obstetrical population, 22.6% of women with
positive screens were diagnosed with bipolar disorder (4). The
majority of these women were symptomatic during preg-
nancy, with episode onset either before pregnancy (38%) or
during pregnancy (33%) and continuing through 4–6 weeks
postpartum (unpublished 2013 data from K. L. Wisner).
Bergink et al. (5) reported that women with chronic bipolar
disorder (such as the individuals in our case series) benefitted
from continued lithium prophylaxis during pregnancy, while
those with a history limited to postpartum episodes remained
well during gestation without medication but relapsed post-
partum. In sum, pregnancy is a vulnerable time for episode
recurrence in many women with bipolar disorder.
References
1. Clark CT, Klein AM, Perel JM, Helsel J, Wisner KL: Lamotrigine
dosing for pregnant patients with bipolar disorder. Am J Psychi-
atry 2013; 170:1240–1247
2. Sharma V, Pope CJ: Pregnancy and bipolar disorder: a systematic
review. J Clin Psychiatry 2012; 73:1447–1455
3. Yonkers KA, Wisner KL, Stowe Z, Leibenluft E, Cohen L, Miller L,
Manber R, Viguera A, Suppes T, Altshuler L: Management of bi-
polar disorder during pregnancy and the postpartum period. Am
J Psychiatry 2004; 161:608–620
4. Wisner KL, Sit DK, McShea MC, Rizzo DM, Zoretich RA, Hughes CL,
Eng HF, Luther JF, Wisniewski SR, Costantino ML, Confer AL, Moses-
Kolko EL, Famy CS, Hanusa BH: Onset timing, thoughts of self-
harm, and diagnoses in postpartum women with screen-positive
depression findings. JAMA Psychiatry 2013; 70:490–498
5. Bergink V, Bouvy PF, Vervoort JS, Koorengevel KM, Steegers EAP,
Kushner SA: Prevention of postpartum psychosis and mania in
women at high risk. Am J Psychiatry 2012; 169:609–615
CRYSTAL T. CLARK, M.D., M.SC.
KATHERINE L. WISNER, M.D., M.S.
From the Asher Center for the Study and Treatment of
Depressive Disorders, Departments of Psychiatry and Behav-
ioral Sciences and Obstetrics and Gynecology, Northwestern
University, Chicago.
The authors’ disclosures accompany the original article.
Dr. Clark is supported in part by grant K12 HD055884 from
the Eunice Kennedy Shriver National Institute of Child Health
and Human Development received in September 2013.
This reply (doi: 10.1176/appi.ajp.2014.13111493r) was ac-
cepted for publication in December 2013.
ajp.psychiatryonline.org 371
 Book Forum
Working With Families in Medical Settings: A Multidis-
ciplinary Guide for Psychiatrists and Other Health
Professionals, edited by Alison M. Heru. New York, Routledge,
2013, 254 pp., $54.95 (paper).
Family therapy is at the top of any list of things psychiatrists
know are important and yet avoid. There are many reasons for
this. Psychiatry residency requirements mention the need to
expose residents to family therapy, but they are vague as to
what or how much this exposure should be. Thus, with limited
training in family interventions, the average practicing psy-
chiatrist is often reluctant to venture beyond the doctor-patient
dyad, citing theoretic stances or confidentiality concerns. This
tendency to ignore family members belies common sense,
given the degree that most of us depend on our loved ones for
both practical and emotional support when we are ill.
This is all the more true for psychosomatic medicine. When
consulting in the medical setting, it is not unusual for the
psychiatrist to enter a patient’s room and find it filled with
family members. And what does the consultant do? Ask them
to leave, of course. Which may be reasonable for a first con-
tact, but how often does the psychiatrist take the time to
subsequently include the family in the interview process for
more than a perfunctory history check?
This book aims to address this practice gap—the gap be-
tween what we know we should do and what we actually
do—head on.
It is organized in three sections. The first summarizes fam-
ily theory and research as it pertains to the medical setting.
Putting together this section must have been a challenge,
given the many studies from various fields that bear on the
issue of how a family can influence an individual’s health.
The discussion of protective and risk factors is interesting, but
most relevant is the review of evidence-based interventions. It
can be hard to generalize, as the studies range from the acute
(e.g., recovery from coronary artery bypass surgery) to the
chronic (e.g., chronic lower back pain), but it seems that
regardless of the illness, family interventions help on many
levels. Not only do they help coping, but they also improve
medical outcomes. The idea that families should be involved
in any illness is reinforced by several meta-analyses that show
improved mortality rates for patients with diseases such as
cardiac illness, stroke, diabetes, or HIV.
The second section looks at various models for involv-
ing families in the health care system. One example of an
innovative approach is family-centered care, which can be
372 ajp.psychiatryonline.org
seen as an extension of patient-centered care. This approach
includes families in activities such as ward rounds and in-
tensive care treatment planning meetings. It has been adopted
by a number of medical centers with various degrees of success,
and there is thoughtful consideration of the reasons for suc-
cess or failure. Other chapters consider specialized inter-
ventions for specific situations, for example, helping medical
teams deal constructively with disruptive families.
The final section focuses on systems theory, particularly the
McMaster approach. In these chapters, the authors describe
methods for family systems assessment and then present a
stepwise approach to interventions, from simple inclusion to
psychoeducation and family systems therapy.
The book does a good job considering both the theoretical
and the practical, and it is clearly designed to give the reader
useful concepts and skills that can be easily adopted. It is well
organized, and each chapter generally begins with a list of the
points it will cover and ends with a detailed summary (thus
following Carnegie’s advice to tell us what they are going to say,
say it, and then tell us what they said). In between, there are
many tables and bulleted lists to highlight the major points.
These points are further illustrated with excellent case examples.
This book should be required reading for any psychiatrist
pursuing a career in psychosomatic medicine. Beyond that, it
should be of interest to any mental health care professional
treating patients in the medical setting. Given that the future
psychiatrist will likely be expected to be a practitioner of col-
laborative and integrative care, the audience for this book
might just include all of us.
ROBERT J. BOLAND, M.D.
Dr. Boland is a Professor in the Department of Psychiatry and
Human Behavior, Brown University, Providence, R.I.
The author reports no financial relationships with commer-
cial interests.
Book review accepted for publication October 2013 (doi: 10.
1176/appi.ajp.2013.13101363).
Clinical Guide to Depression and Bipolar Disorder:
Findings From the Collaborative Depression Study, edited
by Martin B. Keller, M.D., William H. Coryell, M.D., Jean Endicott,
Ph.D., Jack D. Maser, Ph.D., and Pamela J. Schettler, Ph.D.
Washington, DC, American Psychiatric Publishing, 2013, 234
pp., $58.00.
Am J Psychiatry 171:3, March 2014

This book presents a summary of some of the clinical findings
of the Collaborative Depression Study, a 31-year longitudinal
follow-up of patients with mood disorders treated in various
settings. At the time this book went to press, the study had
generated 285 research reports. The authors, who have par-
ticipated in the study, do an excellent job of summarizing the
mountain of data that has emerged from it. Each chapter ends
with a brief summary of clinical implications of the findings.
An important finding of the Collaborative Depression Study
that patients and astute clinicians have always known (but not
always paid attention to) is that the standard definitions of
response (50% improvement) and remission (depression or
mania rating scale scores that are about two-thirds better but
not zero), which are the primary outcome measures of the
clinical trials on which we all base treatment choices, are not
satisfactory outcomes. Most of us would not be satisfied with
feeling better but not well, and any residual symptoms greatly
increase the risk of major relapse and recurrence. Even mild,
subsyndromal symptoms are associated with significant levels
of impairment, which is an independent predictor of relapse.
Indeed, the observation that “many individuals have residual
subsyndromal symptoms and disabling psychosocial impair-
ment when recovered from major episodes of depression for
at least 2 months” (p. 169) indicates that the true meaning of
“recovery” does not apply to many patients. The investigators
point out that residual depressive symptoms deserve as much
aggressive attention as the less common residual manic and
hypomanic symptoms in bipolar disorder, and they suggest that
antidepressants may not worsen the course of all cases of bipo-
lar disorder. However, they are not yet able to reassure us about
which bipolar disorder patients can and which cannot tolerate
ongoing treatment with antidepressants. Despite the widely
acknowledged need to treat mood disorders early and aggres-
sively, to combine pharmacologic and psychological therapies,
and to reduce the risk of relapse by continuing whatever treat-
ment is effective acutely, mood disorders remain undertreated.
It will come as no surprise that past suicide attempts,
especially those with high intent, increase the risk of suicide in
the future, as do anxiety and substance abuse. The Food and
Drug Administration and some professional groups should
review data indicating that antidepressants not only do not
increase the risk of suicide, but they reduce it. It may be less
apparent that around one-quarter of patients with a diagnosis
of major depressive disorder will go on to develop bipolar
disorder. Risk factors for such conversion include psychotic
symptoms, family history of bipolar disorder, early onset of
depression, and subsyndromal hypomanic symptoms. Re-
sults of the Collaborative Depression Study suggest that it may
be possible to treat alcoholism at the same time as mood dis-
orders, but each active disorder makes the other more re-
sistant to treatment.
Anyone who has passed the American Board of Psychiatry
and Neurology oral examination knows not to diagnose a
personality disorder in a patient with an active mood disorder,
and the Collaborative Depression Study supports the belief
that assessment of personality by the patient and others is
state dependent. It may be less well known that the secular
trend toward increased incidence of depression in more
recent generations can skew estimates of the heritability of
depression because parents tend to have a lower prevalence
of depression than their children.
Am J Psychiatry 171:3, March 2014
BOOK FORUM
The Collaborative Depression Study has been at the fore-
front of psychiatric diagnosis throughout its course, and its
findings include features of unipolar and bipolar disorders
that alter course, such as anxiety, psychosis, and substance
abuse. However, it relies heavily on the categorical diagnoses
that have largely continued from DSM-IV to DSM-5. An enor-
mous amount has been learned, but it is still not possible to
determine whether patients with early-onset depression and
a history of trauma, for example, have a different course and
require different treatment approaches than other patients,
or whether depressed patients who experience dissociation have
a course similar to those with psychosis. And since most studies
are of monotherapy or of combinations of a single medication
with a single psychotherapy, we have no empirical guide to the
combinations of therapies that are necessary for patients with
more complex mood disorders. Yet the Clinical Guide to De-
pression and Bipolar Disorder offers the most current infor-
mation that is available in a single place—and certainly the most
readable source for investigators and clinicians. It is a clear
springboard for the next generation of studies of mood disorders.
STEVEN L. DUBOVSKY, M.D.
Dr. Dubovsky is affiliated with the Department of Psychiatry,
University at Buffalo, Buffalo, N.Y.
Dr. Dubovsky has received research support from Hoffman-La
Roche, Janssen, Lilly, Otsuka, Pfizer, Research for Health in
Erie County, Inc., Sumitomo, and the Tower Foundation.
Book review accepted for publication October 2013 (doi: 10.
1176/appi.ajp.2013.13101308).
Comprehensive Care for Complex Patients: The Medical-
Psychiatric Coordinating Physician Model, by Steven
A. Frankel, James A. Bourgeois, and Philip Erdberg. Cam-
bridge, United Kingdom, Cambridge University Press, 2012,
201 pp., $90.00.
In one sense, the title says it all. It introduces the reader to
what will be the foremost themes of the book. How can we
provide comprehensive care in our modern health care cli-
mate? And how should this help us to treat our more complex
patients? The answer to both, according to the authors, is in
the subtitle: by using the medical-psychiatric coordinating
physician model.
But what is meant by “comprehensive care”? In explaining
this, the authors consider the way health care was, how it is,
and what it could become. Historically, health care was a
dyad: the doctor-patient relationship. Although we may yearn
for this romantic image, it is clear that the days of the country
doctor who meets all of his or her patients’ needs are long
gone, and in the modern era, the health care system com-
prises a large team of various primary care and specialist
doctors, as well as an assortment of various other profes-
sionals. Although this heath care team is, ideally, all very
impressive, in reality it is a mess. There is usually little effective
communication between different providers, and the various
treatments prescribed occur independently of and, at times,
at odds with one another. With this in mind, the authors
sketch out a plan for the future, one of coordinated care in
which the providers can function like a true team.
ajp.psychiatryonline.org 373
BOOK FORUM
And what are “complex patients”? Initially, they are defined
as patients whose symptoms do not respond to our “normal”
medical approaches. This is often because their medical
illness is complicated by psychiatric factors. However, the
authors soon expand this definition to include the many
other types of complexities, including various psychological,
social, and systems issues that can affect the straightforward
delivery of care. As they broaden their definition, we begin to
wonder which patients are not complex. One is forced to
consider the possibility that the only patients who are
“straightforward” are the ones we haven’t thought about
enough and that “simple” patients represent a figment of our
failed imaginations.
Much of the book is devoted to describing the importance
of collaborative care, and there is already a good deal writ-
ten about this subject. So what makes this book different?
The answer is in the subtitle: the concept of the medical-
psychiatric coordinating physician model (or MPCP; beware,
as there are a good deal of unfamiliar acronyms of which the
reader will have to keep track). Every team needs a leader.
In many of the current collaborative care or medical home
models, psychiatrists are relegated to the sidelines. However,
the authors suggest that psychiatrists’ unique skill set makes
them the ideal persons to integrate the many data points our
system generates into a coherent narrative. If some of the
unconverted ever hear this sermon, this book might stir some
controversy. That said, the authors back up their contention
with example after example of how psychiatrists are best
suited to appreciate each level of complexity that may chal-
lenge a treatment team.
Along the way, the reader is introduced to important tech-
niques and concepts meant to guide the budding medical-
psychiatric coordinating physician model, including the
concept of “tuning,” which means using varied bits of ob-
jective and subjective information to hone in on the “truth” of
what is really going on with a patient, and SOPA (self-other
rapid assessment), a method for monitoring oneself and one’s
treatment, as well as various strategic approaches for dealing
with patient (and sometimes practitioner) resistance.
This method of operationalizing one’s approach to complex
patients is reason enough to read this book. However, the
book also serves a greater purpose. Here, the title does the
book an injustice, as it gives one the impression that this will
be a somewhat dry, technical manual. What a surprise then, to
encounter the book’s disarmingly engaging prose. The tone is
often conversational, even mischievous at times, often written
in the first person and addressing the reader directly—the
prose feels more like the transcript of an unusually erudite
soliloquy from a gifted colleague (although there are three
authors, it is largely written with a single voice). This is a book
meant to be enjoyed cover to cover.
Perhaps most compelling are the exquisitely rendered case
studies employed throughout the book. For those who be-
moan the loss of this art, rest assured, the authors here
present robust cases, full of nooks and crannies that are
unfailingly honest in their depiction of the foibles of both
patients and doctors. The cases are put to excellent use, and
the authors frequently return to them throughout the book to
illustrate increasingly deeper points.
Who should read this book? Most practically, it is aimed at
those interested in psychosomatic medicine and collaborative
374 ajp.psychiatryonline.org
care, as the book focuses on the complexities that lie on the
(imaginary yet practical) body-mind interface. However, this
book serves a greater purpose as it meditates on the doctor’s
role in modern medicine. My sense is that medical students,
residents, and many of my colleagues all hunger to see them-
selves as more than useful technicians in the machine that is
modern health care. This book helps us refocus on what it
means to be a true healer.
ROBERT J. BOLAND, M.D.
Dr. Boland is a Professor in the Department of Psychiatry and
Human Behavior, Brown University, Providence, R.I.
The author reports no financial relationships with commer-
cial interests.
Book review accepted for publication October 2013 (doi: 10.
1176/appi.ajp.2013.13101331).
Management of Treatment-Resistant Major Psychiatric
Disorders, edited by Charles B. Nemeroff, M.D., Ph.D. New
York, Oxford University Press, 2012, 384 pp., $89.99.
While the notion of treatment-resistant psychiatric disor-
ders may bring to mind narrowly defined subsets of severely ill
individuals not normally encountered by the average mental
health care provider, the definition employed in this volume
is considerably more encompassing, to include patients who
experience persistent psychiatric symptoms with impaired
functioning despite one or more adequate treatment trials.
The book chapters represent thoughtfully distilled tutorials on
how to manage everyday clinical challenges across the major
psychiatric disorders, including a range of mood and anxiety
disorders, schizophrenia, substance abuse, and insomnia, as
well as anorexia/bulimia nervosa, personality disorders, and
one chapter on childhood mood and anxiety disorders.
It is interesting to compare how treatment resistance is ap-
proached across the various disorders. For major depression,
formal treatment-resistant staging methods have been ar-
ticulated both in the United States and internationally.
Large-scale clinical trials, such as the Sequenced Treatment
Alternatives to Relieve Depression Study, have unequivocally
established the high prevalence of treatment resistance for
people with major depression, and evidence-based treat-
ment algorithms for treatment-resistant depression are begin-
ning to emerge. Despite the modest added efficacy of each
subsequent antidepressant, it is also encouraging to note that
the 10-year remission rate approaches 90%. Schizophrenia is
another diagnosis that has a formalized definition of treat-
ment resistance, which emerged from the need to determine
the appropriateness of patients who could be considered for
clozapine therapy. While clozapine was approved over 20
years ago in the United States, the schizophrenia chapter
makes it clear that there remains a dearth of proven options
beyond clozapine for treatment-resistant schizophrenia.
And although not emphasized in the text, it continues to be
the case that only a fraction of clozapine-eligible patients
ever receive a clozapine trial for reasons that appear to have
less to do with the risk of actual side effects but rather with
the burdens and hurdles associated with ongoing hemato-
logical monitoring.
Am J Psychiatry 171:3, March 2014
 BOOK FORUM

Most other disorders do not have formally defined treatment-
resistant subtypes, but the prevalence of persistent and de-
bilitating symptoms is a ubiquitous problem. For example, in
patients with anorexia nervosa, the authors emphasize that
almost every patient has very difficult-to-treat symptoms, that
full remission is rarely achieved, and that most patients have
at least some “treatment resistance.” Similarly, in the chapter
on personality disorders, Dr. Gabbard emphasizes that per-
sonality disorders have always been difficult to treat and that
the term “treatment resistant” could also be designated “more
difficult than usual.” This chapter offers a surprisingly hope-
ful assessment of the long-term outcome for patients with
treatment-resistant personality disorders. For example, a re-
cent 10-year prospective study of patients with borderline
personality disorder, funded by the National Institute of Men-
tal Health, found that over 90% of patients achieved remission
of symptoms that lasted at least 2 years, although somewhat
over 30% of remitted patients subsequently experienced
a relapse. Furthermore, at least seven distinct psychothera-
peutic approaches for borderline personality disorder have
demonstrated efficacy in randomized controlled trials. This
therapeutic armamentarium should help practitioners in-
dividualize treatment approaches for their patients.
Given that most psychiatric disorders are chronic and re-
lapsing, this book represents an unusually practical text that
combines standard treatment protocols with less conventional
but eminently usable treatment suggestions for recalcitrant
symptoms. All practicing psychiatrists and more advanced
trainees can benefit from having this book on their shelf.
L. FREDRIK JARSKOG, M.D.
Dr. Jarskog is affiliated with the Department of Psychiatry,
University of North Carolina at Chapel Hill, Chapel Hill, N.C.
Dr. Jarskog has served as a consultant for AstraZeneca and on
a data and safety monitoring board for Janssen, and he has
received research grant support from GlaxoSmithKline, Novartis,
Roche, and Sunovion.
Book review accepted for publication October 2013 (doi: 10.
1176/appi.ajp.2013.13101338).

Correction
In the article “A Double-Blind Randomized Controlled Trial of Augmentation and Switch Strategies for
Refractory Social Anxiety Disorder” by Mark H. Pollack, M.D., et al. (Am J Psychiatry 2014; 171:44–53), the
structured assessment used to make the initial diagnoses was the Mini-International Neuropsychiatric In-
terview, meaning reference 11 should have been the following:
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar
GC: The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a
structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(suppl
20):22–33

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 375


The following books are presented here
as a service to our readership to alert
them of new titles and as a courtesy to
those who have sent copies of these
books to the Journal office.
Sensory Processing Challenges: Effective
Clinical Work with Kids and Teens, by
Lindsey Biel. American Psychiatric Publish-
ing, 2014, 296 pp., $32.95.
Mindful Anger: A Pathway to Emotional
Freedom, by Andrea Brandt. W.W. Norton
and Company, 2014, 224 pp., $22.95.
Neurobiologically Informed Trauma Ther-
apy With Children and Adolescents: Un-
derstanding Mechanisms of Change, by
Linda Chapman. W.W. Norton and Com-
pany, 2014, 272 pp., $39.95.
Care of Military Service Members, Veterans,
and Their Families, edited by Stephen J.
Cozza, M.D., Matthew N. Goldenberg, M.D.,
and Robert J. Ursano, M.D. American Psychi-
atric Publishing, 2014, 339 pp., $48.00 (paper).
Disordered Thought and Development: Chaos
to Organization in the Moment, by Theodore
Fallon, with Susan P. Sherkow. Jason Aronson,
2014, 100 pp., $70.00.
Therapy Talk: Conversation Analysis in
Practice, by Pamela E. Fitzgerald. Palgrave
Macmillan, 2013, 208 pp., $28.00 (paper).
376 ajp.psychiatryonline.org
Books Received
Your Mind Is What Your Brain Does for
a Living: Learn How to Make It Work for
You, by Steven Jay Fogel. Greenleaf Book
Group Press, 2014, 272 pp., $15.95 (paper).
Positive Emotion: Integrating the Light Sides
and Dark Sides, edited by June Gruber, Ph.D.
and Judith Tedlie Moskowitz, Ph.D., M.P.H.
Oxford University Press, 2014, 576 pp.,
$125.00.
Handbook of Good Psychiatric Management
for Borderline Personality Disorder, by
John G. Gunderson, M.D., with Paul Links,
M.D., M.Sc., F.R.C.P.C. American Psychi-
atric Publishing, 2014, 180 pp., $55.00
(paper).
Promise Land: My Journey Through Amer-
ica’s Self-Help Culture, by Jessica Lamb-
Shapiro. Simon and Schuster, 2014, 224 pp.,
$25.00.
Parental Alienation: The Handbook for
Mental Health and Legal Professionals,
edited by Demosthenes Lorandos, William
Bernet, and S. Richard Sauber. Charles C.
Thomas, Publisher, Ltd., 2013, 550 pp.,
$89.95.
Romania’s Abandoned Children: Depriva-
tion, Brain Development, and the Struggle
for Recovery, by Charles A. Nelson, Nathan
A. Fox, and Charles H. Zeanah. Harvard
University Press, 2014, 416 pp., $29.95.
Recover: Stop Thinking Like an Addict and
Reclaim Your Life With the PERFECT Pro-
gram, by Stanton Peele, Ph.D. Da Capo
Press, 2014, 320 pp., $24.99.
Lives in the Balance: Asylum Adjudication by
the Department of Homeland Security, by
Andrew I. Schoenholtz, Philip G. Schrag, and
Jaya Ramji-Nogales. New York University
Press, 2014, 288 pp., $45.00.
Race, Memory, and the Apartheid Archive:
Towards a Transformative Psychosocial
Praxis, edited by Garth Stevens, Norman
Duncan, and Derek Hook. Palgrave Macmil-
lan, 2013, 392 pp., $100.00.
Mastering the Art of Quitting: Why It Matters
in Life, Love, and Work, by Peg Streep and
Alan Bernstein, L.C.S.W. Da Capo Lifelong,
2013, 272 pp., $24.99.
Psychological Well-Being in the Gulf States:
The New Arabia Felix, by Justin Thomas.
Palgrave Macmillan, 2013, 208 pp., $99.00.
The Proteus Paradox: How Online Games
and Virtual Worlds Change Us- And How
They Don’t, by Nick Yee. Yale University
Press, 2014, 264 pp., $28.00.
Terror Within and Without: Attachment and
Disintegration: Clinical Work on the Edge,
edited by Judy Yellin and Orit Badouk
Epstein. Karanac Books, 2013, 93 pp., $24.95
(paper).
Am J Psychiatry 171:3, March 2014
 Continuing Medical Education
You now have an opportunity to earn CME credits by reading articles in The American Journal of Psychiatry. Three articles in this issue each
comprise a short course for up to 1 AMA PRA Category 1 Credit™ each. The course consists of reading the article and answering three multiple-
choice questions with a single correct answer. CME credit is issued only online. Readers who want credit must subscribe to the AJP Continuing
Medical Education Course Program (psychiatryonline.org/cme.aspx), select The American Journal of Psychiatry at that site, take the course(s) of
their choosing, complete the evaluation form, and submit their answers for CME credit. A link from the question to the correct answer in
context will be highlighted in the associated article. A certificate for each course will be generated upon successful completion. This activity is
sponsored by the American Psychiatric Association.

Information to Participants Information on Courses

Objectives. After evaluating a specific journal
article, participants should be able to dem-
onstrate an increase in their knowledge of
clinical medicine. Participants should be able
to understand the contents of a selected
research or review article and to apply the
new findings to their clinical practice.
Participants. This program is designed for all
psychiatrists in clinical practice, residents in
Graduate Medical Education programs, med-
ical students interested in psychiatry, and
other physicians who wish to advance their
current knowledge of clinical medicine.
Explanation of How Physicians Can Partici-
pate and Earn Credit. In order to earn CME
credit, subscribers should read through the
material presented in the article. After read-
ing the article, complete the CME quiz online
at cme.psychiatryonline.org and submit your
evaluation and study hours (up to 1 AMA PRA
Category 1 Credit™).
Credits. The American Psychiatric Association
is accredited by the Accreditation Council for
Continuing Medical Education to provide con-
tinuing medical education for physicians.
The American Psychiatric Association des-
ignates this enduring material for a maximum
of 1 AMA PRA Category 1 Credit(s)™. Physicians
should only claim credit commensurate with
the extent of their participation in the activity.
Title: Behavioral and Psychiatric Symptoms in Prion Disease
Faculty: Andrew Thompson, B.Sc., M.R.C.P., Angus MacKay, Ph.D., F.R.C.Psych., Peter
Rudge, F.R.C.P., Ana Lukic, B.Sc., M.R.C.P., Marie-Claire Porter, B.Sc., M.R.C.P., Jessica
Lowe, B.Sc., John Collinge, F.R.C.P., F.R.S., Simon Mead, Ph.D., F.R.C.P.
Affiliations: From the National Health Service (NHS) National Prion Clinic, National
Hospital for Neurology and Neurosurgery, University College London Hospitals NHS
Foundation Trust, London (A.T., P.R., A.L., M-C.P., J.C., S.M.); the NHS Highland Mental
Health Services, Argyll and Bute Hospital, Blarbuie Road, Lochgilphead, Scotland (A.M.);
and the Medical Research Council (MRC) Prion Unit, Department of Neurodegenerative
Disease, University College London Institute of Neurology, London (P.R., J.C., S.M.).
Disclosures: Prof. Collinge is a director and shareholder of D-Gen Limited, an academic
spinout company working in the field of prion disease diagnosis, decontamination,
and therapeutics. The other authors report no financial relationships with
commercial interests.
Discussion of unapproved or investigational use of products*: No
Title: Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Trans-
porter and Behavior
Faculty: Stal Saurav Shrestha, B.A., Eric E. Nelson, Ph.D., Jeih-San Liow, Ph.D., Robert
Gladding, B.S., Chul Hyoung Lyoo, M.D., Ph.D., Pam L. Noble, M.S., Cheryl Morse, M.S.,
Ioline D. Henter, M.A., Jeremy Kruger, B.S., Bo Zhang, Ph.D., Stephen J. Suomi, Ph.D.,
Per Svenningsson, M.D., Ph.D., Victor W. Pike, Ph.D., James T. Winslow, Ph.D., Ellen
Leibenluft, M.D., Daniel S. Pine, M.D., Robert B. Innis, M.D., Ph.D.
Affiliations: From the NIMH Intramural Research Program, Bethesda, Md. (S.S.S., E.E.N.,
J-S.L., R.G., C.H.L., P.L.N., C.M., I.D.H., J.K., B.Z., S.J.S., V.W.P., J.T.W., E.L., D.S.P., R.B.I.),
and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm,
Sweden (S.S.S., P.S.).
Disclosures: The authors report no financial relationships with commercial interests.
Discussion of unapproved or investigational use of products*: Yes
Title: Randomized Trial of an Electronic Personal Health Record for Patients With
Serious Mental Illnesses
Faculty: Benjamin G. Druss, M.D., M.P.H., Xu Ji, M.S.P.H., Gretl Glick, B.A., Silke A. von
Esenwein, Ph.D.
Affiliations: From the Rollins School of Public Health and the Department of Health
Policy and Management, Emory University, Atlanta.
Disclosures: The authors report no financial relationships with commercial interests.
Discussion of unapproved or investigational use of products*: No

*APA policy requires disclosure by CME authors of unapproved or investigational use of products discussed in CME programs. Off-label use of
medications by individual physicians is permitted and common. Decisions about off-label use can be guided by scientific literature and clinical
experience.

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 377

 Continuing Medical Education

Exams are available online only at psychiatryonline.org/cme.aspx

INFORMATION TO PARTICIPANTS
OBJECTIVES. After evaluating a specific journal article, participants
should be able to demonstrate an increase in their knowledge of
clinical medicine. Participants should be able to understand the
contents of a selected research or review article and to apply the
new findings to their clinical practice.
PARTICIPANTS. This program is designed for all psychiatrists in
clinical practice, residents in Graduate Medical Education programs,
medical students interested in psychiatry, and other physicians who
wish to advance their current knowledge of clinical medicine.
EXPLANATION OF HOW PHYSICIANS CAN PARTICIPATE AND EARN
CREDIT. In order to earn CME credit, subscribers should read
through the material presented in the article. After reading the
article, complete the CME quiz online at psychiatryonline.org/cme.
aspx and submit your evaluation and study hours (up to 1 AMA PRA
Category 1 Credit™).
CREDITS. The American Psychiatric Association is accredited by the
Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
The American Psychiatric Association designates this enduring material
for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should
only claim credit commensurate with the extent of their participation in
the activity.
Estimated Time to Complete: 1 Hour
Begin date March 1, 2014 – End date February 29, 2016

EXAMINATION QUESTIONS
Select the single best answer for each question below.

Behavioral and Psychiatric Symptoms in Prion Disease

Andrew Thompson, B.Sc., M.R.C.P., et al.
Am J Psychiatry 2014; 171:265–274
Learning Objective. The learner will appreciate the psychiatric manifestations of prion disease and the suggested approach to their
treatment.

1. In patients with sporadic Creutzfeldt-
Jakob disease, which of the following
features was significantly associated
with behavioral or psychiatric
symptoms at the onset of the illness?
A. Heterozygosity at the codon 129
polymorphism of the prion protein
gene (PRNP)
B. Younger age at disease onset
C. Signal change in the cortex on brain
MRI
D. Female gender
2. What best describes the natural
history of depressive symptoms
observed in the study?
A. They were very rarely seen in mildly
affected patients in the early stages
of illness.
B. Their prevalence was highly
associated with the latest stage of
disease progression.
C. They very rarely improved once they
had developed.
D. They improved in around 40% of
patients.
3. Which of the following is true about the
treatment of psychotic symptoms with
antipsychotic medications in the study?
A. Most prescriptions for antipsychotics
were discontinued because of
adverse effects.
B. Antipsychotics produced apparent
clinical benefit in around 30% of
those treated.
C. Extrapyramidal side effects were the
most frequently recorded adverse
effects.
D. Antipsychotics produced apparent
clinical benefit in around 75% of
those treated.

EVALUATION QUESTIONS
This evaluation form is adapted from the MedBiquitous Journal-Based Continuing Education Guidelines 28 November 2005.
This evaluation will appear online at the end of each CME course. Participants must complete this evaluation in order to
receive credit. Select the response which best indicates your reaction to the following statements about this activity.

STATEMENT 1. The activity achieved its STATEMENT 3. I plan to change my current STATEMENT 5. The activity provided
stated objectives. practice based on what I learned in the sufficient scientific evidence to support the
1. Strongly agree activity. content presented.
2. Agree 1. Strongly agree 1. Strongly agree
3. Neutral 2. Agree 2. Agree
4. Disagree 3. Neutral 3. Neutral
5. Strongly disagree 4. Disagree 4. Disagree
5. Strongly disagree 5. Strongly disagree
STATEMENT 2. The activity was relevant to
my practice. STATEMENT 4. The activity validated my STATEMENT 6. The activity was free of
1. Strongly agree current practice. commercial bias toward a particular product
2. Agree 1. Strongly agree or company.
3. Neutral 2. Agree 1. Strongly agree
4. Disagree 3. Neutral 2. Agree
5. Strongly disagree 4. Disagree 3. Neutral
5. Strongly disagree 4. Disagree
5. Strongly disagree

378 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

 Continuing Medical Education

Exams are available online only at psychiatryonline.org/cme.aspx

INFORMATION TO PARTICIPANTS
OBJECTIVES. After evaluating a specific journal article, participants
should be able to demonstrate an increase in their knowledge of
clinical medicine. Participants should be able to understand the
contents of a selected research or review article and to apply the
new findings to their clinical practice.
PARTICIPANTS. This program is designed for all psychiatrists in
clinical practice, residents in Graduate Medical Education programs,
medical students interested in psychiatry, and other physicians who
wish to advance their current knowledge of clinical medicine.
EXPLANATION OF HOW PHYSICIANS CAN PARTICIPATE AND EARN
CREDIT. In order to earn CME credit, subscribers should read
through the material presented in the article. After reading the
article, complete the CME quiz online at psychiatryonline.org/cme.
aspx and submit your evaluation and study hours (up to 1 AMA PRA
Category 1 Credit™).
CREDITS. The American Psychiatric Association is accredited by the
Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
The American Psychiatric Association designates this enduring material
for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should
only claim credit commensurate with the extent of their participation in
the activity.
Estimated Time to Complete: 1 Hour
Begin date March 1, 2014 – End date February 29, 2016

EXAMINATION QUESTIONS
Select the single best answer for each question below.

Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior
Stal S. Shrestha, B.A., et al.
Am J Psychiatry 2014; 171:323–331
Learning Objective. The participant will learn about the long-term, neurochemical, and behavioral effects of fluoxetine on two serotonergic
markers (serotonin transporter [SERT] and serotonin 1A [5-HT1A ] receptor) when administered during the juvenile period in a nonhuman
primate brain.

1. What long-term effects on the
serotonergic system are seen with
fluoxetine administration during the
juvenile period?
A. 5-HT1A receptor binding is
downregulated while SERT binding
is upregulated in the hippocampus.
B. SERT and 5-HT1A receptor binding
are upregulated in the occipital
cortex.
C. SERT binding is upregulated in the
lateral temporal, cingulate, and
orbitofrontal cortices.
D. SERT binding is downregulated in
the hippocampus and the occipital
cortex.
2. While the study found no statistically
significant long-term effects of fluoxetine
treatment or maternal separation on
social behavior, what correlations of
interest were reported?
A. Displays of dominance and
submissiveness showed the greatest
response to maternal separation.
B. Fluoxetine treatment was associated
with reduced dominance displays.
C. Fluoxetine effects were observed for
locomotion and bark frequency.
D. Fluoxetine treatment was associated
with reduced submissiveness
displays.
3. What implications regarding SSRI use
in the pediatric population may be
inferred from this study of primates?
A. Chronic SSRI use may be harmful in
children.
B. The study demonstrated a lack of
plasticity of the serotonergic system
during development.
C. No implications may be inferred
because the plasma SSRI
concentrations in the primates were
not comparable to human use.
D. Chronic SSRI use during development
may persistently upregulate SERT in
humans.

EVALUATION QUESTIONS
This evaluation form is adapted from the MedBiquitous Journal-Based Continuing Education Guidelines 28 November 2005.
This evaluation will appear online at the end of each CME course. Participants must complete this evaluation in order to
receive credit. Select the response which best indicates your reaction to the following statements about this activity.

STATEMENT 1. The activity achieved its STATEMENT 3. I plan to change my current STATEMENT 5. The activity provided
stated objectives. practice based on what I learned in the sufficient scientific evidence to support the
1. Strongly agree activity. content presented.
2. Agree 1. Strongly agree 1. Strongly agree
3. Neutral 2. Agree 2. Agree
4. Disagree 3. Neutral 3. Neutral
5. Strongly disagree 4. Disagree 4. Disagree
5. Strongly disagree 5. Strongly disagree
STATEMENT 2. The activity was relevant to
my practice. STATEMENT 4. The activity validated my STATEMENT 6. The activity was free of
1. Strongly agree current practice. commercial bias toward a particular product
2. Agree 1. Strongly agree or company.
3. Neutral 2. Agree 1. Strongly agree
4. Disagree 3. Neutral 2. Agree
5. Strongly disagree 4. Disagree 3. Neutral
5. Strongly disagree 4. Disagree
5. Strongly disagree

Am J Psychiatry 171:3, March 2014 ajp.psychiatryonline.org 379

 Continuing Medical Education

Exams are available online only at psychiatryonline.org/cme.aspx

INFORMATION TO PARTICIPANTS
OBJECTIVES. After evaluating a specific journal article, participants
should be able to demonstrate an increase in their knowledge of
clinical medicine. Participants should be able to understand the
contents of a selected research or review article and to apply the
new findings to their clinical practice.
PARTICIPANTS. This program is designed for all psychiatrists in
clinical practice, residents in Graduate Medical Education programs,
medical students interested in psychiatry, and other physicians who
wish to advance their current knowledge of clinical medicine.
EXPLANATION OF HOW PHYSICIANS CAN PARTICIPATE AND EARN
CREDIT. In order to earn CME credit, subscribers should read
through the material presented in the article. After reading the
article, complete the CME quiz online at psychiatryonline.org/cme.
aspx and submit your evaluation and study hours (up to 1 AMA PRA
Category 1 Credit™).
CREDITS. The American Psychiatric Association is accredited by the
Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
The American Psychiatric Association designates this enduring material
for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should
only claim credit commensurate with the extent of their participation in
the activity.
Estimated Time to Complete: 1 Hour
Begin date March 1, 2014 – End date February 29, 2016

EXAMINATION QUESTIONS
Select the single best answer for each question below.

Randomized Trial of an Electronic Personal Health Record for Patients With Serious Mental Illnesses
Benjamin G. Druss, M.D., M.P.H., et al.
Am J Psychiatry 2014; 171:360–368
Learning Objective. The participant will recognize the impact of personal health records on the quality of care perceived by persons with
mental illness.

1. What factors contribute to poor
quality of medical care in patients with
serious mental disorders?
A. Cognitive limitations
B. Symptoms of psychiatric illness
C. Challenges in coordination of care
D. All of the above
2. How do personal health records help
people with serious mental illnesses?
A. They can replace electronic medical
records.
B. They shift the ownership and locus
of health information to a central
medical director.
C. They can facilitate communication
across multiple providers.
D. All of the above
3. Which of the following factors most
commonly prevented enrollment in this
study?
A. Lack of willingness to consent to
participate
B. Reading below a 6th-grade level
C. Lack of a regular primary care or
mental health provider
D. There were no significant barriers to
enrollment

EVALUATION QUESTIONS
This evaluation form is adapted from the MedBiquitous Journal-Based Continuing Education Guidelines 28 November 2005.
This evaluation will appear online at the end of each CME course. Participants must complete this evaluation in order to
receive credit. Select the response which best indicates your reaction to the following statements about this activity.

STATEMENT 1. The activity achieved its STATEMENT 3. I plan to change my current STATEMENT 5. The activity provided
stated objectives. practice based on what I learned in the sufficient scientific evidence to support the
1. Strongly agree activity. content presented.
2. Agree 1. Strongly agree 1. Strongly agree
3. Neutral 2. Agree 2. Agree
4. Disagree 3. Neutral 3. Neutral
5. Strongly disagree 4. Disagree 4. Disagree
5. Strongly disagree 5. Strongly disagree
STATEMENT 2. The activity was relevant to
my practice. STATEMENT 4. The activity validated my STATEMENT 6. The activity was free of
1. Strongly agree current practice. commercial bias toward a particular product
2. Agree 1. Strongly agree or company.
3. Neutral 2. Agree 1. Strongly agree
4. Disagree 3. Neutral 2. Agree
5. Strongly disagree 4. Disagree 3. Neutral
5. Strongly disagree 4. Disagree
5. Strongly disagree

380 ajp.psychiatryonline.org Am J Psychiatry 171:3, March 2014

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
BRINTELLIX (vortioxetine) tablets, for oral use
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behavior in
children, adolescents, and young adults in short-term studies. These
studies did not show an increase in the risk of suicidal thoughts and
behavior with antidepressant use in patients over age 24; there was a
trend toward reduced risk with antidepressant use in patients aged 65
and older [see Warnings and Precautions].
In patients of all ages who are started on antidepressant therapy,
monitor closely for worsening, and for emergence of suicidal thoughts
and behaviors. Advise families and caregivers of the need for close
observation and communication with the prescriber [see Warnings
and Precautions].
BRINTELLIX has not been evaluated for use in pediatric patients [see
Use in Specific Populations].
INDICATIONS AND USAGE
Major Depressive Disorder
BRINTELLIX is indicated for the treatment of major depressive disorder
(MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies
(including one study in the elderly) and one maintenance study in adults.
CONTRAINDICATIONS
• Hypersensitivity to vortioxetine or any components of the formulation.
Angioedema has been reported in patients treated with BRINTELLIX.
• The use of MAOIs intended to treat psychiatric disorders with
BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX
is contraindicated because of an increased risk of serotonin syndrome.
The use of BRINTELLIX within 14 days of stopping an MAOI intended
to treat psychiatric disorders is also contraindicated [see Warnings
and Precautions].
Starting BRINTELLIX in a patient who is being treated with MAOIs
such as linezolid or intravenous methylene blue is also contraindicated
because of an increased risk of serotonin syndrome [see Warnings
and Precautions].
WARNINGS AND PRECAUTIONS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality) or unusual changes in behavior, whether
or not they are taking antidepressant medications, and this risk may persist
until significant remission occurs. Suicide is a known risk of depression and
certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern,
however, that antidepressants may have a role in inducing worsening of
depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled studies
of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and
others) showed that these drugs increase the risk of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults (ages 18 to
24) with MDD and other psychiatric disorders. Short-term studies did not
show an increase in the risk of suicidality with antidepressants compared
to placebo in adults beyond age 24; there was a trend toward reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled studies in children and adolescents
with MDD, obsessive compulsive disorder (OCD), or other psychiatric
disorders included a total of 24 short-term studies of nine antidepressant
drugs in over 4,400 patients. The pooled analyses of placebo-controlled
studies in adults with MDD or other psychiatric disorders included a total of
295 short-term studies (median duration of two months) of 11 antidepressant
drugs in over 77,000 patients. There was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk
of suicidality across the different indications, with the highest incidence in
MDD. The risk differences (drug vs. placebo), however, were relatively stable
within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1000 patients treated)
are provided in Table 1.
The risk differences (drug-placebo difference in the number of cases
of suicidality per 1000 patients treated) are provided in Table 1 of the
BRINTELLIX Full Prescribing Information, which states: 14 additional cases
in patients under the age of 18, 5 additional cases in patients between 18 and
24 years of age. There was 1 fewer case in patients between 25 and 64 years
of age and 6 fewer cases in patients 65 years of age and over.
No suicides occurred in any of the pediatric studies. There were suicides in
the adult studies, but the number was not sufficient to reach any conclusion
about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e.,
beyond several months. However, there is substantial evidence from placebo-
controlled maintenance studies in adults with depression that the use of
antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should
be monitored appropriately and observed closely for clinical worsening,
suicidality, and unusual changes in behavior, especially during the initial
few months of a course of drug therapy, or at times of dose changes, either
increases or decreases.
The following symptoms anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, and mania have been reported in adult and pediatric patients
being treated with antidepressants for MDD as well as for other indications,
both psychiatric and nonpsychiatric. Although a causal link between the
emergence of such symptoms and either the worsening of depression and/or
the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is
persistently worse, or who are experiencing emergent suicidality or symptoms
that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s
presenting symptoms.
Families and caregivers of patients being treated with antidepressants
for MDD or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence
of agitation, irritability, unusual changes in behavior, and the other
symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to healthcare providers. Such
monitoring should include daily observation by families and caregivers.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled studies) that
treating such an episode with an antidepressant alone may increase the
likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent
such a conversion is unknown. However, prior to initiating treatment with
an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening
should include a detailed psychiatric history, including a family history of
suicide, bipolar disorder, and depression. It should be noted that BRINTELLIX
is not approved for use in treating bipolar depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has
been reported with serotonergic antidepressants including BRINTELLIX,
when used alone but more often when used concomitantly with other
serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with
drugs that impair metabolism of serotonin (in particular, MAOIs, both those
intended to treat psychiatric disorders and also others, such as linezolid and
intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes
(e.g., agitation, hallucinations, delirium, and coma), autonomic instability
(e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing,
hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea). Patients should be monitored for the
emergence of serotonin syndrome.
The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric
disorders is contraindicated. BRINTELLIX should also not be started in a
patient who is being treated with MAOIs such as linezolid or intravenous
methylene blue. All reports with methylene blue that provided information
on the route of administration involved intravenous administration in the
dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of
methylene blue by other routes (such as oral tablets or local tissue injection)
or at lower doses. There may be circumstances when it is necessary to initiate
treatment with a MAOI such as linezolid or intravenous methylene blue in
a patient taking BRINTELLIX. BRINTELLIX should be discontinued before
initiating treatment with the MAOI [see Contraindications].
If concomitant use of BRINTELLIX with other serotonergic drugs, including
triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone,
tryptophan, and St. John’s Wort is clinically warranted, patients should be
made aware of a potential increased risk for serotonin syndrome, particularly
during treatment initiation and dose increases.
Treatment with BRINTELLIX and any concomitant serotonergic agents
should be discontinued immediately if the above events occur and supportive
symptomatic treatment should be initiated.
Abnormal Bleeding
The use of drugs that interfere with serotonin reuptake inhibition, including
BRINTELLIX, may increase the risk of bleeding events. Concomitant use of
aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other
anticoagulants may add to this risk. Case reports and epidemiological studies
(case-control and cohort design) have demonstrated an association between
use of drugs that interfere with serotonin reuptake and the occurrence
of gastrointestinal bleeding. Bleeding events related to drugs that inhibit
serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and
petechiae to life-threatening hemorrhages.
Patients should be cautioned about the increased risk of bleeding when
BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that
affect coagulation or bleeding [see Drug Interactions].
Activation of Mania/Hypomania
Symptoms of mania/hypomania were reported in <0.1% of patients treated
with BRINTELLIX in pre-marketing clinical studies. Activation of mania/
hypomania has been reported in a small proportion of patients with major
affective disorder who were treated with other antidepressants. As with all
antidepressants, use BRINTELLIX cautiously in patients with a history or
family history of bipolar disorder, mania, or hypomania.
Hyponatremia
Hyponatremia has occurred as a result of treatment with serotonergic drugs.
In many cases, hyponatremia appears to be the result of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). One case with serum
sodium lower than 110 mmol/L was reported in a subject treated with
BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at
greater risk of developing hyponatremia with a serotonergic antidepressant.
Also, patients taking diuretics or who are otherwise volume depleted can be
at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic
hyponatremia and appropriate medical intervention should be instituted. Signs
and symptoms of hyponatremia include headache, difficulty concentrating,
memory impairment, confusion, weakness, and unsteadiness, which can
lead to falls. More severe and/or acute cases have included hallucination,
syncope, seizure, coma, respiratory arrest, and death.
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other
sections of the label.
• Hypersensitivity [see Contraindications]
• Clinical Worsening and Suicide Risk [see Warnings and Precautions]
• Serotonin Syndrome [see Warnings and Precautions]
• Abnormal Bleeding [see Warnings and Precautions]
• Activation of Mania/Hypomania [see Warnings and Precautions]
• Hyponatremia [see Warnings and Precautions]
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical studies of another drug and may not reflect
the rates observed in clinical practice.
Patient Exposure
BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of
age) diagnosed with MDD who participated in pre-marketing clinical studies;
2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebo-
controlled studies at doses ranging from 5 mg to 20 mg once daily and
204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebo-
controlled maintenance study at doses of 5 mg to 10 mg once daily. Patients
from the 6 to 8 week studies continued into 12-month open-label studies. A
total of 2586 patients were exposed to at least one dose of BRINTELLIX in
open-label studies, 1727 were exposed to BRINTELLIX for six months and
885 were exposed for at least one year.
Adverse Reactions Reported as Reasons for Discontinuation of Treatment
In pooled 6 to 8 week placebo-controlled studies the incidence of patients who
received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and
discontinued treatment because of an adverse reaction was 5%, 6%, 8% and
8%, respectively, compared to 4% of placebo-treated patients. Nausea was
the most common adverse reaction reported as a reason for discontinuation.
Common Adverse Reactions in Placebo-Controlled MDD Studies
The most commonly observed adverse reactions in MDD patients treated with
BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and
at least twice the rate of placebo) were nausea, constipation and vomiting.
Table 2 shows the incidence of common adverse reactions that occurred in
≥2% of MDD patients treated with any BRINTELLIX dose and at least 2%
more frequently than in placebo-treated patients in the 6 to 8 week placebo-
controlled studies.
Table 2 of the BRINTELLIX Full Prescribing Information shows the incidence
of common adverse reactions that occurred in ≥2% of MDD patients treated
with any BRINTELLIX dose and at least 2% more frequently than in placebo-
treated patients in the 6- to 8-week placebo-controlled studies. The following
values from Table 2 show the percentage of patients exhibiting the adverse
reaction while receiving BRINTELLIX 5 mg (N=1013), 10 mg (N=699), 15 mg
(N=449), 20 mg (N=455), and placebo (N=1621) respectively. Gastrointestinal
Disorders: Nausea (21%, 26%, 32%, 32%, vs. 9%); Diarrhea (7%, 7%, 10%,
7%, vs. 6%); Dry Mouth (7%, 7%, 6%, 8%, vs. 6%); Constipation (3%, 5%,
6%, 6%, vs. 3%); Vomiting (3%, 5%, 6%, 6%, vs. 1%); Flatulence (1%, 3%,
2%, 1%, vs. 1%); Nervous System Disorders: Dizziness (6%, 6%, 8%, 9%,
vs. 6%); Psychiatric Disorders: Abnormal Dreams (<1%, <1%, 2%, 3%, vs.
1%); Skin and Subcutaneous Tissue Disorders: Pruritus (including pruritus
generalized) (1%, 2%, 3%, 3%, vs. 1%).
Nausea
Nausea was the most common adverse reaction and its frequency was dose-
related (Table 2). It was usually considered mild or moderate in intensity and
the median duration was 2 weeks. Nausea was more common in females than
males. Nausea most commonly occurred in the first week of BRINTELLIX
treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of
treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to
20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.
Sexual Dysfunction
Difficulties in sexual desire, sexual performance and sexual satisfaction
often occur as manifestations of psychiatric disorders, but they may also be
consequences of pharmacologic treatment.
In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported
adverse reactions related to sexual dysfunction were captured as individual
event terms. These event terms have been aggregated and the overall
incidence was as follows. In male patients the overall incidence was 3%,
4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day,
respectively, compared to 2% in placebo. In female patients, the overall
incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day,
15 mg/day, 20 mg/day, respectively, compared to <1% in placebo.
Because voluntarily reported adverse sexual reactions are known to be
underreported, in part because patients and physicians may be reluctant
to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated
measure designed to identify sexual side effects, was used prospectively in
seven placebo-controlled trials. The ASEX scale includes five questions that
pertain to the following aspects of sexual function: 1) sex drive, 2) ease of
arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease
of reaching orgasm, and 5) orgasm satisfaction.
The presence or absence of sexual dysfunction among patients entering
clinical studies was based on their ASEX scores. For patients without sexual
dysfunction at baseline (approximately 1/3 of the population across all
treatment groups in each study), Table 3 shows the incidence of patients
that developed treatment-emergent sexual dysfunction when treated with
BRINTELLIX or placebo in any fixed dose group. Physicians should routinely
inquire about possible sexual side effects.
The presence or absence of sexual dysfunction among patients entering
clinical studies was based on their ASEX scores. For patients without sexual
dysfunction at baseline (approximately 1/3 of the population across all
treatment groups in each study), the following values from Table 3 of the
BRINTELLIX Full Prescribing Information show the ASEX incidence of
patients who developed treatment-emergent sexual dysfunction when
treated with BRINTELLIX or placebo in any fixed-dose group. The incidence in
female patients treated with BRINTELLIX 5 mg (N=65), 10 mg (N=94), 15 mg
(N=57), 20 mg (N=67) or placebo (N=135), respectively was 22%, 23%, 33%,
34% vs. 20%. For male patients, the incidence of treatment-emergent sexual
dysfunction when treated with BRINTELLIX 5 mg (N=67), 10 mg (N=86), 15 mg
(N=67), 20 mg (N=59) or placebo (N=162), respectively was 16%, 20%, 19%,
29% vs. 14%. Incidence was based on the number of subjects with sexual
dysfunction during the study / number of subjects without sexual dysfunction
at baseline. Sexual dysfunction was defined as a subject scoring any of the
following on the ASEX scale at two consecutive visits during the study:
1) total score ≥19; 2) any single item ≥5; 3) three or more items each with a
score ≥4. The sample size for each dose group was the number of patients
without sexual dysfunction at baseline. Physicians should routinely inquire
about possible sexual side effects.
Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX
Treatment
Discontinuation symptoms have been prospectively evaluated in patients
taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the
Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials.
Some patients experienced discontinuation symptoms such as headache,
muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny
nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day
and 20 mg/day.
Laboratory Tests
BRINTELLIX has not been associated with any clinically important changes in
laboratory test parameters in serum chemistry (except sodium), hematology
and urinalysis as measured in the 6 to 8 week placebo-controlled studies.
Hyponatremia has been reported with the treatment of BRINTELLIX
[see Warnings and Precautions]. In the 6-month, double-blind, placebo-
controlled phase of a long-term study in patients who had responded to
BRINTELLIX during the initial 12-week, open-label phase, there were no
clinically important changes in lab test parameters between BRINTELLIX
and placebo-treated patients.
Weight
BRINTELLIX had no significant effect on body weight as measured by the
mean change from baseline in the 6 to 8 week placebo-controlled studies.
In the 6-month, double-blind, placebo-controlled phase of a long-term study
in patients who had responded to BRINTELLIX during the initial 12-week,
open-label phase, there was no significant effect on body weight between
BRINTELLIX and placebo-treated patients.
Vital Signs
BRINTELLIX has not been associated with any clinically significant effects
on vital signs, including systolic and diastolic blood pressure and heart rate,
as measured in placebo-controlled studies.
Other Adverse Reactions Observed in Clinical Studies
The following listing does not include reactions: 1) already listed in previous
tables or elsewhere in labeling, 2) for which a drug cause was remote,
3) which were so general as to be uninformative, 4) which were not
considered to have significant clinical implications, or 5) which occurred at
a rate equal to or less than placebo.
Ear and labyrinth disorders — vertigo
Gastrointestinal disorders — dyspepsia
Nervous system disorders — dysgeusia
Vascular disorders — flushing
DRUG INTERACTIONS
CNS Active Agents
Monoamine Oxidase Inhibitors
Adverse reactions, some of which are serious or fatal, can develop in
patients who use MAOIs or who have recently been discontinued from
an MAOI and started on a serotonergic antidepressant(s) or who have
recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI
[see Contraindications and Warnings and Precautions].
Serotonergic Drugs
Based on the mechanism of action of BRINTELLIX and the potential for
serotonin toxicity, serotonin syndrome may occur when BRINTELLIX
is coadministered with other drugs that may affect the serotonergic
neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol,
and tryptophan products etc.). Closely monitor symptoms of serotonin
syndrome if BRINTELLIX is co-administered with other serotonergic drugs.
Treatment with BRINTELLIX and any concomitant serotonergic agents should
be discontinued immediately if serotonin syndrome occurs [see Warnings
and Precautions].
Other CNS Active Agents
No clinically relevant effect was observed on steady state lithium exposure
following coadministration with multiple daily doses of BRINTELLIX.
Multiple doses of BRINTELLIX did not affect the pharmacokinetics or
pharmacodynamics (composite cognitive score) of diazepam. A clinical study
has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase
the impairment of mental and motor skills caused by alcohol (single dose
of 0.6 g/kg). Details on the potential pharmacokinetic interactions between
BRINTELLIX and bupropion can be found in Section 7.3, Potential for Other
Drugs to Affect BRINTELLIX.
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Serotonin release by platelets plays an important role in hemostasis.
Epidemiological studies of case-control and cohort design have demonstrated
an association between use of psychotropic drugs that interfere with serotonin
reuptake and the occurrence of upper gastrointestinal bleeding. These studies
have also shown that concurrent use of an NSAID or aspirin may potentiate
this risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs and SNRIs are coadministered
with warfarin.
Following coadministration of stable doses of warfarin (1 to 10 mg/day) with
multiple daily doses of BRINTELLIX, no significant effects were observed in
INR, prothrombin values or total warfarin (protein bound plus free drug)
pharmacokinetics for both R- and S-warfarin [see Drug Interactions].
Coadministration of aspirin 150 mg/day with multiple daily doses of
BRINTELLIX had no significant inhibitory effect on platelet aggregation
or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions].
Patients receiving other drugs that interfere with hemostasis should be
carefully monitored when BRINTELLIX is initiated or discontinued [see
Warnings and Precautions].
Potential for Other Drugs to Affect BRINTELLIX
Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g.,
bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider
increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin,
carbamazepine, phenytoin) is coadministered. The maximum dose is not
recommended to exceed three times the original dose (Figure 1).
Figure 1. Impact of Other Drugs on Vortioxetine PK
Potential for BRINTELLIX to Affect Other Drugs
No dose adjustment for the comedications is needed when BRINTELLIX
is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6,
CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinid), CYP2C9 (e.g.,
S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine),
CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose
adjustment for lithium, aspirin, and warfarin is necessary.
Vortioxetine and its metabolites are unlikely to inhibit the following CYP
enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As
such, no clinically relevant interactions with drugs metabolized by these CYP
enzymes would be expected.
In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human
hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the
metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a
series of clinical drug interaction studies, coadministration of BRINTELLIX
with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin),
and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the
pharmacokinetics of these substrates (Figure 2).
Because vortioxetine is highly bound to plasma protein, coadministration
of BRINTELLIX with another drug that is highly protein bound may increase
free concentrations of the other drug. However, in a clinical study with
coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to
10 mg/day), a highly protein-bound drug, no significant change in INR was
observed [see Drug Interactions].
Figure 2. Impact of Vortioxetine on PK of Other Drugs
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of BRINTELLIX in pregnant
women. Vortioxetine caused developmental delays when administered during
pregnancy to rats and rabbits at doses 15 and 10 times the maximum
recommended human dose (MRHD) of 20 mg, respectively. Developmental
delays were also seen after birth in rats at doses 20 times the MRHD of
vortioxetine given during pregnancy and through lactation. There were
no teratogenic effects in rats or rabbits at doses up to 77 and 58 times,
the MRHD of vortioxetine, respectively, given during organogenesis. The
incidence of malformations in human pregnancies has not been established
for BRINTELLIX. All human pregnancies, regardless of drug exposure, have
a background rate of 2 to 4% for major malformations, and 15 to 20% for
pregnancy loss. BRINTELLIX should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed
complications requiring prolonged hospitalization, respiratory support and tube
feeding. Such complications can arise immediately upon delivery. Reported
clinical findings have included respiratory distress, cyanosis, apnea, seizures,
temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia,
hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying.
These features are consistent with either a direct toxic effect of these classes
of drugs or possibly, a drug discontinuation syndrome. It should be noted
that in some cases, the clinical picture is consistent with serotonin syndrome
[see Warnings and Precautions]. When treating a pregnant woman with
BRINTELLIX during the third trimester, the physician should carefully consider Figure 3. Impact of Intrinsic Factors on Vortioxetine PK
the potential risks and benefits of treatment.
Neonates exposed to SSRIs in pregnancy may have an increased risk
for persistent pulmonary hypertension of the newborn (PPHN). PPHN
occurs in one to two per 1,000 live births in the general population and is
associated with substantial neonatal morbidity and mortality. Several recent
epidemiologic studies suggest a positive statistical association between
SSRI use in pregnancy and PPHN. Other studies do not show a significant
statistical association.
A prospective longitudinal study was conducted of 201 pregnant women
with a history of major depression, who were either on antidepressants or
had received antidepressants less than 12 weeks prior to their last menstrual
period, and were in remission. Women who discontinued antidepressant
medication during pregnancy showed a significant increase in relapse of their
major depression compared to those women who remained on antidepressant
medication throughout pregnancy. When treating a pregnant woman with
BRINTELLIX, the physician should carefully consider both the potential risks
of taking a serotonergic antidepressant, along with the established benefits
of treating depression with an antidepressant.
Animal Data
In pregnant rats and rabbits, no teratogenic effects were seen when
vortioxetine was given during the period of organogenesis at oral doses
up to 160 and 60 mg/kg/day, respectively. These doses are 77 and
58 times, in rats and rabbits, respectively, the maximum recommended
human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen
as decreased fetal body weight and delayed ossification, occurred in rats and
rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times
the MRHD, respectively) in the presence of maternal toxicity (decreased
food consumption and decreased body weight gain). When vortioxetine was
administered to pregnant rats at oral doses up to 120 mg/kg (58 times the
MRHD) throughout pregnancy and lactation, the number of live-born pups
was decreased and early postnatal pup mortality was increased at 40 and
120 mg/kg. Additionally, pup weights were decreased at birth to weaning
at 120 mg/kg and development (specifically eye opening) was slightly
delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg
(5 times the MRHD).
Nursing Mothers
It is not known whether vortioxetine is present in human milk. Vortioxetine
is present in the milk of lactating rats. Because many drugs are present
in human milk and because of the potential for serious adverse reactions
in nursing infants from BRINTELLIX, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Clinical studies on the use of BRINTELLIX in pediatric patients have not DRUG ABUSE AND DEPENDENCE
been conducted; therefore, the safety and effectiveness of BRINTELLIX in BRINTELLIX is not a controlled substance.
the pediatric population have not been established.
OVERDOSAGE
Geriatric Use
No dose adjustment is recommended on the basis of age (Figure 3). Results Human Experience
from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young There is limited clinical trial experience regarding human overdosage with
(24 to 45 years old) subjects demonstrated that the pharmacokinetics were BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited
generally similar between the two age groups. to patients who accidentally or intentionally consumed up to a maximum
dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg
Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was
and over, which included subjects from a placebo-controlled study specifically associated with increased rates of nausea, dizziness, diarrhea, abdominal
in elderly patients. No overall differences in safety or effectiveness were discomfort, generalized pruritus, somnolence, and flushing.
observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the Management of Overdose
elderly and younger patients. No specific antidotes for BRINTELLIX are known. In managing over dosage,
consider the possibility of multiple drug involvement. In case of overdose,
Serotonergic antidepressants have been associated with cases of clinically call Poison Control Center at 1-800-222-1222 for latest recommendations.
significant hyponatremia in elderly patients, who may be at greater risk for
this adverse event [see Warnings and Precautions]. Distributed and marketed by:
Use in Other Patient Populations Takeda Pharmaceuticals America, Inc.
No dose adjustment of BRINTELLIX on the basis of race, gender, ethnicity, Deerfield, IL 60015
or renal function (from mild renal impairment to end-stage renal disease) is Marketed by:
necessary. In addition, the same dose can be administered in patients with Lundbeck
mild to moderate hepatic impairment (Figure 3). BRINTELLIX has not been Deerfield, IL 60015
studied in patients with severe hepatic impairment. Therefore, BRINTELLIX BRINTELLIX is a trademark of H. Lundbeck A/S and is used under license by
is not recommended in patients with severe hepatic impairment. Takeda Pharmaceuticals America, Inc.
©2013 Takeda Pharmaceuticals America, Inc.
LUN205P R1_Brf. September 2013
90243 L-LUN-0913-2
 MAINE
The Central Maine Medical Group is seeking a board certified
psychiatrist to develop, lead, and direct adult inpatient and
outpatient behavioral health services at Central Maine Medical
Center. This full time position provides the opportunity to create
and direct the behavioral health resources for this growing
facility and involves both direct patient care and administrative
responsibilities. Central Maine Medical Center is the flagship
hospital of Central Maine Healthcare. The medical center has
250 inpatient beds and offers a broad range of services that
include, among many, a Level II trauma center, cardiovascular
medicine, vascular and cardiac surgery, medical and radiation
oncology, and bariatric surgery. The Central Maine Medical
Group comprises approximately 350 providers, approximately
half of which are in primary care. The group delivers care
across almost 3600 sq miles at numerous outpatient sites and
four hospitals.
Close to the ocean, lakes and mountains this opportunity offers
the outdoor enthusiast unlimited recreational possibilities.
Combine your talent and skills with our established excellent
reputation of the best physician care.
Interested candidates, send CV to:
Babette Irwin
Central Maine Medical Center
300 Main Street; Lewiston, Maine 04240
Fax: 207-795-5696, E-mail: BIrwin@cmhc.org, or call: 800/445-7431
Not a J1 opportunity.
Intermountain Healthcare has openings for
Psychiatrists:
Adult Inpatient - Salt Lake City, Utah
Adult Outpatient - St. George, Utah
Adult Inpatient – Provo, Utah
Employment with Intermountain Medical
Group. Competitive salary and incentive
recognition bonuses. Signing bonus. Loan
repayment money available. Full Intermountain
benefits to include defined pension, 401k
match & CME. Relocation provided up to 15k.
Intermountain Healthcare is frequently
referenced nationally as one of the leaders in
delivering high quality/low
cost health care.
Contact Intermountain Healthcare
Physician Recruiting.
800-888-3134 Fax: 801-442-3388
PhysicianRecruit@imail.org
http://physicianjobsintermountain.org
Psychiatry Opportunities
Correctional Medicine
PENNSYLVANIA Some of the unique benefits of
Statewide Psychiatry Director - FT correctional healthcare include:
Staff Psychiatrists - FT, PT, PD & Interim
$$ Loan Repayment Available $$ • Innovative healthcare environment
Scranton, Wilkes-Barre, Harrisburg, free of administrative hassles
Pittsburgh, Williamsport & Bloomsburg • Diverse patient population with
clinically interesting caseloads
MINNESOTA • Exciting and rewarding career in
Lino Lakes, Moose Lake, Red Wing, Shakopee, one of the fastest-growing areas of
Stillwater & St. Cloud - FT, PT & PD healthcare
$$ Loan Repayment Available $$ • Having a positive impact on public
NEW HAMPSHIRE health
Concord & Goffstown - FT MHM provides its employees with
MISSOURI an excellent benefits package that
Bowling Green - FT, PT & PD includes competitive salaries, health/
Farmington, Jefferson City, St. Joseph & dental/life/vision insurance, 401K plan
Mineral Point - PT & PD with company contributions, tuition
reimbursement, generous paid days
MICHIGAN off, company-paid holidays, paid
Ann Arbor, Adrian & Jackson - FT, PT & PD malpractice coverage and a supportive,
MARYLAND team-oriented atmosphere.
Baltimore & Jessup - FT, PT & PD
EOE M/F/D/V
MASSACHUSETTS
Bridgewater, Framingham & Gardner - FT
ALABAMA Contact: Vikkie Schill, (877) 282-5811
Montgomery & Birmingham - FT & PT Vikkie@mhmcareers.com
www.mhm-services.com
MHM Blog: www.correctionalpsych.com
Outpatient Psychiatrist
Minneapolis, MN
Park Nicollet is seeking an Adult Psychiatrist to join our
growing Mental Health department in desirable western
suburban Minneapolis. Position is straight outpatient or a
blended position with our Consult-Liaison office. We have a
highly competitive and comprehensive compensation and
benefits package, including pension, paid malpractice and
yearly CME funds of $4,000.
Our integrated healthcare system, including Park Nicollet
Clinic and Methodist Hospital, is recognized locally and
nationally for great care and leadership. Share your expertise
in an environment that supports new treatments and
innovations while embracing a strong work-life balance.
The Minneapolis area is famous for its cultural attractions,
healthcare and educational systems, natural beauty and
overall quality of life.
Send CV to J. Bredeson, Clinician Recruitment, at
bredej@parknicollet.com, phone 952-993-2804 or apply
online at http://www.parknicollet.com/Careers.
We are proud to be an EEO/AA employer M/F/D/V.

Psychiatry Opportunities
Spectrum Health Medical Group
Grand Rapids, Michigan
Spectrum Health Medical Group has opportunities for
BC/BE candidates in the following specialties:
t
Child & Adolescent Psychiatry
Focus on Eating Disorders and ADHD/ADD
t
Neuropsychiatry
Completion of UCNS accredited Behavioral
Neurology & Neuropsychiatry Fellowship required
t
Psychosomatic Medicine
Completion of Psychosomatic Medicine Fellowship
desired
For more information on Spectrum Health, please visit
spectrumhealth.org, shmg.org and HelloWestMichigian.com
For consideration, please contact:
Beth Brackenridge, Physician Recruiter
at 616.486.6604
or e-mail: beth.brackenridge@spectrumhealth.org
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HR@youinc.org
Y.O.U., Inc.
is proud to be an EEO/AA employer
The James J. Peters
VA Medical Center
COMBINED CLINICAL & RESEARCH
FELLOWSHIP PROGRAMS IN PSYCHIATRY
The James J Peters VA Medical Center, an affiliate of the Icahn School of Medicine at Mount
Sinai in New York City, is soliciting applications for its Fellowship Programs in Psychiatry
Research. In addition to training in clinical psychiatry, fellows will participate in research
aimed at improving outcomes in serious mental illness in veterans and/or understanding
the pathophysiology of serious mental illness. The program offers a wide range of clinical,
translational and basic research opportunities. Start dates are flexible. More information
on programs and faculty is available at
http://www.mirecc.va.gov/visn3/education.asp;
http://www.mssm.edu/departments-and-institutes/psychiatry/educational-programs and
http://www.va.gov/oaa/archive/NeuroscienceRFP_AY2009.pdf
Applicants must have completed ACGME-accredited training in psychiatry, be board
eligible or board certified, and have an active license to practice medicine in the
U.S. International medical graduates must also have a current visa and a valid ECFMG
certificate. Applicants on a J-1 visa must have current ECFMG sponsorship.
For further information, contact
William Byne, M.D., Ph.D. at (718) 584-9000, ext 6041
or email william.byne@mssm.edu
We are an Equal Opportunity Employer.
DEPARTMENT OF
VETERANS AFFAIRS
OUTPATIENT PSYCHIATRY
OCHSNER HEALTH SYSTEM in BATON ROUGE is seeking
a Board Certified/Board Eligible PSYCHIATRIST for its
outpatient practice.
Ochsner Baton Rouge currently has over 1,400 employees
serving our patients in ten Ochsner Health Centers and
Ochsner Medical Center Baton Rouge, a 151-bed full-service
hospital. We employ more than 130 physicians and mid-level
providers who provide an excellent referral base.
Ochsner Health System is a physician-led, non-profit, academic,
multi-specialty, healthcare delivery system employing over
900 physicians. At Ochsner our mission is to Serve, Heal,
Lead, Educate, and Innovate. The system includes 9 hospitals
and more than 40 health centers. We offer a generous and
comprehensive benefits package. We also enjoy the advantage
of practicing in a favorable malpractice environment in
Louisiana. Please visit us at www.ochsner.org.
Baton Rouge, the State Capital, is a vibrant, modern city-home
to the main campuses of both Louisiana State and Southern
Universities. You’ll find Baton Rouge a beautiful, safe, friendly
place to raise a family with great schools, restaurants, shopping
and an abundance of sports and cultural opportunities. Baton
Rouge is located an hour West of New Orleans and has a
metropolitan area population of over 600,000.
Please e-mail CV to:
profrecruiting@ochsner.org
or call for information:
(800) 488-2240. Ref. # APSYBR09. EOE.
Sorry, no J-1 visa opportunities available.
 Subscription and Business
Information
The American Journal of Psychiatry, ISSN
0002-953X, is published monthly by the
American Psychiatric Association, 1000 Wil-
son Blvd., Suite 1825, Arlington, VA 22209-
3901. Subscriptions (per year): individual
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Extended-Release Tablets
BRIEF SUMMARY. See package insert for full Prescribing Information. For further product information and current
package insert, please visit www.pristiqhcp.com or call Pfizer US Medical Information toll-free at (800) 438-1985.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young
adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and
behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant
use in patients aged 65 and older [see Warnings and Precautions (5.1) in the full prescribing information].
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and
for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close
observation and communication with the prescriber [see Warnings and Precautions (5.1) in the full
prescribing information].
PRISTIQ is not approved for use in pediatric patients [see Use in Specific Populations (8.4) in the full
prescribing information].
INDICATIONS AND USAGE: PRISTIQ, a serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for the
treatment of major depressive disorder (MDD) [see Clinical Studies (14) and Dosage and Administration (2.1) in the
full prescribing information]. The efficacy of PRISTIQ has been established in four short-term (8-week, placebo-
controlled studies) and two maintenance studies in adult outpatients who met DSM-IV criteria for major depressive
disorder.
CONTRAINDICATIONS: Hypersensitivity—Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride
or to any excipients in the PRISTIQ formulation. Angioedema has been reported in patients treated with PRISTIQ
[see Adverse Reactions (6.1) in the full prescribing information]. Monoamine Oxidase Inhibitors—The use of
monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders with PRISTIQ or within 7 days of
stopping treatment with PRISTIQ is contraindicated because of an increased risk of serotonin syndrome. The use
of PRISTIQ within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see
Dosage and Administration (2.6) and Warnings and Precautions (5.2) in the full prescribing information]. Starting
PRISTIQ in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also
contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6) and
Warnings and Precautions (5.2) in the full prescribing information].
WARNINGS AND PRECAUTIONS: Suicidal Thoughts and Behaviors in Adolescents and Young Adults—Patients
with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/
or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not
they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a
known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest
predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in
inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of
treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents,
and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-
term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The
pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder
(OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over
4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders
included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000
patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the
younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable
within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 patients treated) included 14 additional cases of increases among those aged <18, 5 additional
cases of increases among those aged 18 to 24, 1 fewer case of decrease among those aged 25 to 64, and 6 fewer
cases of decrease among those aged ≥65.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not
sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to
longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled
maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of
depression. All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior,
especially during the initial few months of a course of drug therapy, or at times of dose changes, either
increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in
adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other
indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms
and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is
concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to
changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is
persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening
depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s
presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as
rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see
Dosage and Administration (2.4) and Warnings and Precautions (5.7) in the full prescribing information for a
description of the risks of discontinuation of PRISTIQ]. Families and caregivers of patients being treated with
antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual
changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to healthcare providers. Such monitoring should include daily
observation by families and caregivers. Prescriptions for PRISTIQ should be written for the smallest quantity of
tablets consistent with good patient management, in order to reduce the risk of overdose. Screening patients for
bipolar disorder—A major depressive episode may be the initial presentation of bipolar disorder. It is generally
believed (though not established in controlled studies) that treating such an episode with an antidepressant alone
may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether
any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment
with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are
at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of
suicide, bipolar disorder, and depression. It should be noted that PRISTIQ is not approved for use in treating bipolar
depression. Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been
reported with SNRIs and SSRIs, including PRISTIQ, alone but particularly with concomitant use of other serotonergic
drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s
Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat
psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome
symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic
instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular
symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The
concomitant use of PRISTIQ with MAOIs intended to treat psychiatric disorders is contraindicated. PRISTIQ should also
not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports
with methylene blue that provided information on the route of administration involved intravenous administration in
the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such
as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking PRISTIQ. PRISTIQ should
be discontinued before initiating treatment with the MAOI [see Contraindications (4.2) and Dosage and Administration
(2.6) in the full prescribing information]. If concomitant use of PRISTIQ with other serotonergic drugs, including
triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically
warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during
treatment initiation and dose increases. Treatment with PRISTIQ and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Elevated Blood Pressure: Patients receiving PRISTIQ should have regular monitoring of blood pressure since
increases in blood pressure were observed in clinical studies [see Adverse Reactions (6.1) in the full prescribing
information]. Pre-existing hypertension should be controlled before initiating treatment with PRISTIQ. Caution should
be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that
might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate
treatment have been reported with PRISTIQ. Sustained blood pressure increases could have adverse consequences.
For patients who experience a sustained increase in blood pressure while receiving PRISTIQ, either dose reduction or
discontinuation should be considered [see Adverse Reactions (6.1) in the full prescribing information]. Abnormal
Bleeding: SSRIs and SNRIs, including PRISTIQ, may increase the risk of bleeding events. Concomitant use of aspirin,
nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and
epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs
that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of PRISTIQ and NSAIDs,
aspirin, or other drugs that affect coagulation or bleeding. Narrow-angle Glaucoma: Mydriasis has been reported in
association with PRISTIQ; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle
glaucoma (angle-closure glaucoma) should be monitored. Activation of Mania/Hypomania: During all MDD phase
2 and phase 3 studies, mania was reported for approximately 0.02% of patients treated with PRISTIQ. Activation of
mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were
treated with other marketed antidepressants. As with all antidepressants, PRISTIQ should be used cautiously in
patients with a history or family history of mania or hypomania. Discontinuation Syndrome: Discontinuation
symptoms have been systematically and prospectively evaluated in patients treated with PRISTIQ during clinical
studies in Major Depressive Disorder. Abrupt discontinuation or dose reduction has been associated with the
appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety,
fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer
duration of therapy. During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs
(Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation,
dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache,
lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting,
there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms
when discontinuing treatment with PRISTIQ. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose, but at a more gradual rate [see Dosage and Administration (2.4) and
Adverse Reactions (6.1) in the full prescribing information]. Seizure: Cases of seizure have been reported in pre-
marketing clinical studies with PRISTIQ. PRISTIQ has not been systematically evaluated in patients with a seizure
disorder. Patients with a history of seizures were excluded from pre-marketing clinical studies. PRISTIQ should be
prescribed with caution in patients with a seizure disorder. Hyponatremia: Hyponatremia may occur as a result of
treatment with SSRIs and SNRIs, including PRISTIQ. In many cases, this hyponatremia appears to be the result of the
syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L
have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also,
patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations
(8.5) and Clinical Pharmacology (12.6) in the full prescribing information]. Discontinuation of PRISTIQ should be
considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion,
weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute
cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Interstitial Lung Disease
and Eosinophilic Pneumonia: Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the
parent drug of PRISTIQ) therapy have been rarely reported. The possibility of these adverse events should be
considered in patients treated with PRISTIQ who present with progressive dyspnea, cough, or chest discomfort. Such
patients should undergo a prompt medical evaluation, and discontinuation of PRISTIQ should be considered.
ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the label:
Hypersensitivity [see Contraindications (4)], Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see
Warnings and Precautions (5.1)], Serotonin Syndrome [see Warnings and Precautions (5.2)], Elevated Blood Pressure
[see Warnings and Precautions (5.3)], Abnormal Bleeding [see Warnings and Precautions (5.4)], Narrow-Angle
Glaucoma [see Warnings and Precautions (5.5)], Activation of Mania/Hypomania [see Warnings and Precautions
(5.6)], Discontinuation Syndrome [see Warnings and Precautions (5.7)], Seizure [see Warnings and Precautions
(5.8)], Hyponatremia [see Warnings and Precautions (5.9)], Interstitial Lung Disease and Eosinophilic Pneumonia [see
Warnings and Precautions (5.10)]. Clinical Studies Experience: Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient exposure—
PRISTIQ was evaluated for safety in 4,158 patients diagnosed with major depressive disorder who participated in
multiple-dose pre-marketing studies, representing 1,677 patient-years of exposure. Among these 4,158 PRISTIQ
treated patients; 1,834 patients were exposed to PRISTIQ in 8-week, placebo-controlled studies at doses ranging
from 50 to 400 mg/day. Out of the 1,834 patients, 687 PRISTIQ treated patients continued into a 10-month open-
label study. Of the total 4,158 patients exposed to at least one dose of PRISTIQ; 1,320 were exposed to PRISTIQ for
6 months, representing 1,058 patient-years of exposure, and 274 were exposed for one year, representing 241
patient-years of exposure. Adverse reactions reported as reasons for discontinuation of treatment—In the pooled
8-week placebo-controlled studies in patients with MDD, 12% of the 1,834 patients who received PRISTIQ (50
to 400 mg) discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated
patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for PRISTIQ
(4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of PRISTIQ the discontinuation rate due
to an adverse reaction was 8.7%. The most common adverse reactions leading to discontinuation in at least 2%
and at a rate greater than placebo of the PRISTIQ treated patients in the short-term studies, up to 8 weeks, were:
nausea (4%); dizziness, headache and vomiting (2% each); in the longer-term studies, up to 11 months, the most
common was vomiting (2%). Common adverse reactions in placebo-controlled MDD studies—The most commonly
observed adverse reactions in PRISTIQ treated MDD patients in short-term fixed-dose studies (incidence ≥ 5% and
at least twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis,
constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders. The incidence
of common adverse reactions that occurred in ≥2% of PRISTIQ-treated MDD patients and twice the rate of placebo
at any dose in the pooled 8-week, placebo-controlled, fixed-dose clinical studies (placebo, n=636; PRISTIQ 50 mg,
n=317; PRISTIQ 100 mg, n=424; PRISTIQ 200 mg, n=307; PRISTIQ 400 mg, n=317) included Cardiac disorders:
Blood pressure increased (1% placebo, 1% PRISTIQ 50 mg, 1% PRISTIQ 100 mg, 2% PRISTIQ 200 mg, 2% PRISTIQ
400 mg); Gastrointestinal disorders: Nausea (10% placebo, 22% PRISTIQ 50 mg, 26% PRISTIQ 100 mg, 36% PRISTIQ
200 mg, 41% PRISTIQ 400 mg), Dry mouth (9% placebo, 11% PRISTIQ 50 mg, 17% PRISTIQ 100 mg, 21% PRISTIQ
200 mg, 25% PRISTIQ 400 mg), Constipation (4% placebo, 9% PRISTIQ 50 mg, 9% PRISTIQ 100 mg, 10% PRISTIQ
200 mg, 14% PRISTIQ 400 mg), Vomiting (3% placebo, 3% PRISTIQ 50 mg, 4% PRISTIQ 100 mg, 6% PRISTIQ 200
mg, 9% PRISTIQ 400 mg); General disorders and administration site conditions: Fatigue (4% placebo, 7% PRISTIQ 50
mg, 7% PRISTIQ 100 mg, 10% PRISTIQ 200 mg, 11% PRISTIQ 400 mg), Chills (1% placebo, 1% PRISTIQ 50 mg, <1%
PRISTIQ 100 mg, 3% PRISTIQ 200 mg, 4% PRISTIQ 400 mg), Feeling jittery (1% placebo, 1% PRISTIQ 50 mg, 2%
PRISTIQ 100 mg, 3% PRISTIQ 200 mg, 3% PRISTIQ 400 mg); Metabolism and nutrition disorders: Decreased appetite
(2% placebo, 5% PRISTIQ 50 mg, 8% PRISTIQ 100 mg, 10% PRISTIQ 200 mg, 10% PRISTIQ 400 mg); Nervous
system disorders: Dizziness (5% placebo, 13% PRISTIQ 50 mg, 10% PRISTIQ 100 mg, 15% PRISTIQ 200 mg, 16%
PRISTIQ 400 mg), Somnolence (4% placebo, 4% PRISTIQ 50 mg, 9% PRISTIQ 100 mg, 12% PRISTIQ 200 mg, 12%
PRISTIQ 400 mg), Tremor (2% placebo, 2% PRISTIQ 50 mg, 3% PRISTIQ 100 mg, 9% PRISTIQ 200 mg, 9% PRISTIQ
400 mg), Disturbance in attention (<1% placebo, <1% PRISTIQ 50 mg, 1% PRISTIQ 100 mg, 2% PRISTIQ 200 mg,
1% PRISTIQ 400 mg); Psychiatric disorders: Insomnia (6% placebo, 9% PRISTIQ 50 mg, 12% PRISTIQ 100 mg,
14% PRISTIQ 200 mg, 15% PRISTIQ 400 mg), Anxiety (2% placebo, 3% PRISTIQ 50 mg, 5% PRISTIQ 100 mg, 4%
PRISTIQ 200 mg, 4% PRISTIQ 400 mg), Nervousness (1% placebo, <1% PRISTIQ 50 mg, 1% PRISTIQ 100 mg, 2%
PRISTIQ 200 mg, 2% PRISTIQ 400 mg), Abnormal dreams (1% placebo, 2% PRISTIQ 50 mg, 3% PRISTIQ 100 mg, 2%
PRISTIQ 200 mg, 4% PRISTIQ 400 mg); Renal and urinary disorders: Urinary hesitation (0% placebo, <1% PRISTIQ
50 mg, 1% PRISTIQ 100 mg, 2% PRISTIQ 200 mg, 2% PRISTIQ 400 mg); Respiratory, thoracic and mediastinal
disorders: Yawning (<1% placebo, 1% PRISTIQ 50 mg, 1% PRISTIQ 100 mg, 4% PRISTIQ 200 mg, 3% PRISTIQ 400
mg); Skin and subcutaneous tissue disorders: Hyperhidrosis (4% placebo, 10% PRISTIQ 50 mg, 11% PRISTIQ 100
mg, 18% PRISTIQ 200 mg, 21% PRISTIQ 400 mg); Special Senses: Vision blurred (1% placebo, 3% PRISTIQ 50 mg,
4% PRISTIQ 100 mg, 4% PRISTIQ 200 mg, 4% PRISTIQ 400 mg), Mydriasis (<1% placebo, 2% PRISTIQ 50 mg, 2%
PRISTIQ 100 mg, 6% PRISTIQ 200 mg, 6% PRISTIQ 400 mg), Vertigo (1% placebo, 2% PRISTIQ 50 mg, 1% PRISTIQ
100 mg, 5% PRISTIQ 200 mg, 3% PRISTIQ 400 mg), Tinnitus (1% placebo, 2% PRISTIQ 50 mg, 1% PRISTIQ 100 mg,
1% PRISTIQ 200 mg, 2% PRISTIQ 400 mg), Dysgeusia (1% placebo, 1% PRISTIQ 50 mg, 1% PRISTIQ 100 mg, 1%
PRISTIQ 200 mg, 2% PRISTIQ 400 mg); Vascular disorders: Hot flush (<1% placebo, 1% PRISTIQ 50 mg, 1% PRISTIQ
100 mg, 2% PRISTIQ 200 mg, 2% PRISTIQ 400 mg).
Sexual function adverse reactions—The incidence of sexual function adverse reactions that occurred in ≥ 2% of
PRISTIQ treated MDD patients in any fixed-dose group (pooled 8-week, placebo-controlled, fixed and flexible-dose,
clinical studies) included Men only (placebo, n=239; PRISTIQ 50 mg, n=108; PRISTIQ 100 mg, n=157; PRISTIQ 200
mg, n=131; PRISTIQ 400 mg, n=154): Anorgasmia (0% placebo, 0% PRISTIQ 50 mg, 3% PRISTIQ 100 mg, 5%
PRISTIQ 200 mg, 8% PRISTIQ 400 mg), Libido decreased (1% placebo, 4% PRISTIQ 50 mg, 5% PRISTIQ 100 mg, 6%
PRISTIQ 200 mg, 3% PRISTIQ 400 mg), Orgasm abnormal (0% placebo, 0% PRISTIQ 50 mg, 1% PRISTIQ 100 mg,
2% PRISTIQ 200 mg, 3% PRISTIQ 400 mg), Ejaculation delayed (<1% placebo, 1% PRISTIQ 50 mg, 5% PRISTIQ 100 with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
mg, 7% PRISTIQ 200 mg, 6% PRISTIQ 400 mg), Erectile dysfunction (1% placebo, 3% PRISTIQ 50 mg, 6% PRISTIQ event [see Warnings and Precautions (5.9) in the full prescribing information]. Renal Impairment—In subjects
100 mg, 8% PRISTIQ 200 mg, 11% PRISTIQ 400 mg), Ejaculation disorder (0% placebo, 0% PRISTIQ 50 mg, 1% with renal impairment the clearance of PRISTIQ was decreased. In subjects with severe renal impairment (24-hr
PRISTIQ 100 mg, 2% PRISTIQ 200 mg, 5% PRISTIQ 400 mg), Ejaculation failure (0% placebo, 1% PRISTIQ 50 mg, CrCl <30 mL/min, Cockcroft-Gault) and end-stage renal disease, elimination half-lives were significantly prolonged,
0% PRISTIQ 100 mg, 2% PRISTIQ 200 mg, 2% PRISTIQ 400 mg), Sexual dysfunction (0% placebo, 1% PRISTIQ 50 increasing exposures to PRISTIQ; therefore, dosage adjustment is recommended in these patients [see Dosage and
mg, 0% PRISTIQ 100 mg, 0% PRISTIQ 200 mg, 2% PRISTIQ 400 mg); Women only (placebo, n=397; PRISTIQ 50 mg, Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment—The
n=209; PRISTIQ 100 mg, n=267; PRISTIQ 200 mg, n=176; PRISTIQ 400 mg, n=163): Anorgasmia (0% placebo, 1% mean terminal half life (t1/2) changed from approximately 10 hours in healthy subjects and subjects with mild hepatic
PRISTIQ 50 mg, 1% PRISTIQ 100 mg, 0% PRISTIQ 200 mg, 3% PRISTIQ 400 mg). impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose
Other adverse reactions observed in clinical studies: Other infrequent adverse reactions, not described elsewhere in patients with moderate to severe hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not
in the label, occurring at an incidence of <2% in MDD patients treated with PRISTIQ were: Cardiac disorders— recommended [see Clinical Pharmacology (12.3) in the full prescribing information].
Tachycardia; General disorders and administration site conditions—Asthenia; Investigations—Weight increased, DRUG ABUSE AND DEPENDENCE: Controlled Substance—PRISTIQ is not a controlled substance.
liver function test abnormal, blood prolactin increased; Musculoskeletal and connective tissue disorders— OVERDOSAGE: Human Experience with Overdosage—There is limited clinical trial experience with
Musculoskeletal stiffness; Nervous system disorders—Syncope, convulsion, dystonia; Psychiatric disorders— desvenlafaxine succinate overdosage in humans. However, desvenlafaxine (PRISTIQ) is the major active metabolite
Depersonalization, bruxism; Renal and urinary disorders—Urinary retention; Skin and subcutaneous tissue of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of PRISTIQ) is presented below; the
disorders—Rash, alopecia, photosensitivity reaction, angioedema. In clinical studies, there were uncommon reports identical information can be found in the Overdosage section of the venlafaxine package insert. In postmarketing
of ischemic cardiac adverse reactions, including myocardial ischemia, myocardial infarction, and coronary occlusion experience, overdose with venlafaxine (the parent drug of PRISTIQ) has occurred predominantly in combination with
requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in
these events during PRISTIQ treatment as compared to placebo. level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram
Laboratory, ECG and vital sign changes observed in MDD clinical studies—The following changes were observed changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia,
in placebo-controlled, short-term MDD studies with PRISTIQ. Lipids—Elevations in fasting serum total cholesterol, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been
LDL (low density lipoproteins) cholesterol, and triglycerides occurred in the controlled studies. Some of these reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased
abnormalities were considered potentially clinically significant. The percentage of patients who exceeded a risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic
predetermined threshold value included: Total Cholesterol increase of ≥50 mg/dl and an absolute value of ≥261 antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing
mg/dl (2% placebo, 3% PRISTIQ 50 mg, 4% PRISTIQ 100 mg, 4% PRISTIQ 200 mg, 10% PRISTIQ 400 mg), LDL burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of
Cholesterol increase ≥50 mg/dl and an absolute value of ≥190 mg/dl (0% placebo, 1% PRISTIQ 50 mg, 0% PRISTIQ fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s)
100 mg, 1% PRISTIQ 200 mg, 2% PRISTIQ 400 mg), Triglycerides, fasting, ≥327 mg/dl (3% placebo, 2% PRISTIQ 50 of venlafaxine-treated patients, is not clear. Management of Overdosage—No specific antidotes for PRISTIQ are
mg, 1% PRISTIQ 100 mg, 4% PRISTIQ 200 mg, 6% PRISTIQ 400 mg). known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call
Proteinuria—Proteinuria, greater than or equal to trace, was observed in the fixed-dose controlled studies. This Poison Control Center at 1-800-222-1222 for latest recommendations.
proteinuria was not associated with increases in BUN or creatinine and was generally transient. The percentage of
patients with proteinuria in the fixed-dose clinical studies were 4% placebo, 6% PRISTIQ 50 mg, 8% PRISTIQ 100 This brief summary is based on PRISTIQ Prescribing Information LAB-0452-8.0, revised February 2013.
mg, 5% PRISTIQ 200 mg, 7% PRISTIQ 400 mg.
Vital sign changes—Mean changes observed in placebo-controlled, short-term, fixed-dose, pre-marketing,
controlled studies with PRISTIQ in patients with MDD included Blood pressure: Supine systolic bp (-1.4 mm Hg © 2013 Pfizer Inc. All rights reserved. March 2013
placebo, 1.2 mm Hg PRISTIQ 50 mg, 2.0 mm Hg PRISTIQ 100 mg, 2.5 mm Hg PRISTIQ 200 mg, 2.1 mm Hg PRISTIQ
400 mg); Supine diastolic bp (-0.6 mm Hg placebo, 0.7 mm Hg PRISTIQ 50 mg, 0.8 mm Hg PRISTIQ 100 mg, 1.8 mm
Hg PRISTIQ 200 mg, 2.3 mm Hg PRISTIQ 400 mg); Pulse rate: Supine pulse (-0.3 bpm placebo, 1.3 bpm PRISTIQ 50
mg, 1.3 bpm PRISTIQ 100 mg, 0.9 bpm PRISTIQ 200 mg, 4.1 bpm PRISTIQ 400 mg); Weight: (0.0 kg placebo, -0.4 kg
PRISTIQ 50 mg, -0.6 kg PRISTIQ 100 mg, -0.9 kg PRISTIQ 200 mg, -1.1 kg PRISTIQ 400 mg).
Treatment with PRISTIQ at all doses from 50 mg/day to 400 mg/day in controlled studies was associated with
sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and
≥10 mm Hg above baseline for 3 consecutive on-therapy visits. The proportion of patients with sustained elevation of
supine diastolic blood pressure included 0.5% placebo, 1.3% PRISTIQ 50 mg, 0.7% PRISTIQ 100 mg, 1.1% PRISTIQ
200 mg, 2.3% PRISTIQ 400 mg. Analyses of patients in PRISTIQ short-term controlled studies who met criteria
for sustained hypertension revealed a consistent increase in the proportion of patients who developed sustained
hypertension. This was seen at all doses with a suggestion of a higher rate at 400 mg/day.
Orthostatic hypotension—In the short-term, placebo-controlled clinical studies with doses of 50 to 400 mg, systolic
orthostatic hypotension (decrease ≥30 mm Hg from supine to standing position) occurred more frequently in patients
≥65 years of age receiving PRISTIQ (8%, 7/87) versus placebo (2.5%, 1/40), compared to patients <65 years of age
receiving PRISTIQ (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218). Postmarketing Experience—The following
adverse reaction has been identified during post-approval use of PRISTIQ. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure: Skin and subcutaneous tissue disorders—Stevens-Johnson syndrome. DRUG
INTERACTIONS: Monoamine Oxidase Inhibitors (MAOI)—[see Dosage and Administration (2.6), Contraindications
(4) and Warnings and Precautions (5.2) in the full prescribing information]. Serotonergic Drugs—[see Dosage and
Administration (2.6), Contraindications (4) and Warnings and Precautions (5.2) in the full prescribing information].
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)—Serotonin release by platelets plays
an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated
an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate
this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and
SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when
PRISTIQ is initiated or discontinued [see Warnings and Precautions (5.4) in the full prescribing information]. Potential
for Desvenlafaxine to Affect Other Drugs—Clinical studies have shown that desvenlafaxine does not have a
clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. Substrates primarily metabolized by
CYP2D6 (e.g., desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) should
be dosed at the original level when co-administered with PRISTIQ 100 mg or lower. Reduce the dose of these
substrates by one-half if co-administered with 400 mg of PRISTIQ. The substrate dose should be increased to the
original level when 400 mg of PRISTIQ is discontinued. Other Drugs Containing Desvenlafaxine or Venlafaxine—
Avoid use of PRISTIQ with other desvenlafaxine-containing products or venlafaxine products. The concomitant use of
PRISTIQ with other desvenlafaxine-containing products or venlafaxine will increase desvenlafaxine blood levels and
increase dose-related adverse reactions [see Adverse Reactions (6) in the full prescribing information]. Ethanol—A
clinical study has shown that PRISTIQ does not increase the impairment of mental and motor skills caused by ethanol.
However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking PRISTIQ.
USE IN SPECIFIC POPULATIONS: Pregnancy—Pregnancy Category C: Risk summary—There are no adequate and
well-controlled studies of PRISTIQ in pregnant women. In reproductive developmental studies in rats and rabbits with
desvenlafaxine succinate, evidence of teratogenicity was not observed at doses up to 30 times a human dose of 100
mg/day (on a mg/m2 basis) in rats, and up to 15 times a human dose of 100 mg/day (on a mg/m2 basis) in rabbits.
An increase in rat pup deaths was seen during the first 4 days of lactation when dosing occurred during gestation
and lactation, at doses greater than 10 times a human dose of 100 mg/day (on a mg/m2 basis). PRISTIQ should be
used during pregnancy only if the potential benefits justify the potential risks to the fetus. Clinical considerations—A
prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning
of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to
experience a relapse of major depression than women who continued antidepressant medication. Human data—
Neonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin
Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical
findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.
These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation
syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see
Warnings and Precautions (5.2) in the full prescribing information]. Animal data—When desvenlafaxine succinate
was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/
kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed. These doses are 30 times a human
dose of 100 mg/day (on a mg/m2 basis) in rats and 15 times a human dose of 100 mg/day (on a mg/m2 basis) in
rabbits. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with
maternal toxicity at the highest dose, with a no-effect dose 10 times a human dose of 100 mg/day (on a mg/
m2 basis). When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation
and lactation, there was a decrease in pup weights and an increase in pup deaths during the first four
days of lactation at the highest dose of 300 mg/kg/day. The cause of these deaths is not known. The no-
effect dose for rat pup mortality was 10 times a human dose of 100 mg/day (on a mg/m2 basis). Post-
weaning growth and reproductive performance of the progeny were not affected by maternal treatment
with desvenlafaxine succinate at a dose 30 times a human dose of 100 mg/day (on a mg/m2 basis). Nursing
Mothers—Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious
adverse reactions in nursing infants from PRISTIQ, a decision should be made whether to discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use—Safety and
effectiveness in pediatric patients have not been established [see Boxed Warning and Warnings and Precautions
(5.1) in the full prescribing information]. Anyone considering the use of PRISTIQ in a child or adolescent must balance
the potential risks with the clinical need. Geriatric Use—Of the 4,158 patients in clinical studies with PRISTIQ, 6%
were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients
and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of
systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with
PRISTIQ [see Adverse Reactions (6) in the full prescribing information]. For elderly patients, possible reduced renal
clearance of PRISTIQ should be considered when determining dose [see Dosage and Administration (2.2) and Clinical
Pharmacology (12.3) in the full prescribing information]. SSRIs and SNRIs, including PRISTIQ, have been associated
 Major Depressive Disorder (MDD) can make
it all feel overwhelming.

Consider PRISTIQ® (desvenlafaxine) 50 mg for your adult MDD patients

An SNRI with a starting dose that is the proven effective dose* and a low discontinuation rate due to adverse reactions1
Ř Discontinuation rate due to adverse reactions comparable to placebo (4.1% vs 3.8%)2
Ř Most commonly observed adverse reactions vs placebo include nausea (22% vs 10%), dizziness (13% vs 5%), hyperhidrosis (10% vs 4%),
constipation (9% vs 4%), and decreased appetite (5% vs 2%)
*50 mg per day is the recommended dose for most patients. The maximum recommended dose in patients with severe renal impairment (24-hr CrCl less than 30 mL/min, C-G) or
end-stage renal disease (ESRD) is 50 mg every other day. Supplemental doses should not be given to patients after dialysis.

Important Safety Information for PRISTIQ

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents,
and young adults in short-term studies. These studies did not show an increase in the risk
of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was
a reduction in risk with antidepressant use in patients aged 65 and older.
In patients of all ages who are started on antidepressant therapy, monitor closely for
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
caregivers of the need for close observation and communication with the prescriber.
PRISTIQ is not approved for use in pediatric patients.
Contraindications
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References: 1. Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT. An integrated analysis of the efficacy of desvenlafaxine
compared with placebo in patients with major depressive disorder. CNS Spectr. 2009;14(3):144-154. 2. Clayton AH, Kornstein SG, Rosas G,
Guico-Pabia C, Tourian KA. An integrated analysis of the safety and tolerability of desvenlafaxine compared with placebo in the treatment
of major depressive disorder. CNS Spectr. 2009;14(4):183-195. 3. Data on file. Pfizer Inc, New York, NY.
Please see brief summary of full Prescribing Information on adjacent pages.
MORE
THAN 14 MILLION
PRESCRIPTIONS
FILLED3†
To learn more about PRISTIQ, go to www.pristiqhcp.com
†
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PQP566511-02 © 2013 Pfizer Inc. All rights reserved. May 2013