Depression

Section Editor
Barbara Turner, MD, MSED
Sankey Williams, MD
Darren Taichman,
MD, PhD
Physician Writer
Tonya L. Fancher, MD
Richard L. Kravitz, MD

Screening

page ITC5-2

Diagnosis

page ITC5-3

Treatment

page ITC5-6

Practice Improvement

page ITC5-12

CME Questions

page ITC5-16

The content of In the Clinic is drawn from the clinical information and
education resources of the American College of Physicians (ACP), including
PIER (Physicians Information and Education Resource) and MKSAP (Medical
Knowledge and Self-Assessment Program). Annals of Internal Medicine
editors develop In the Clinic from these primary sources in collaboration with
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PIER and MKSAP provide expert review of the content. Readers who are
interested in these primary resources for more detail can consult
http://pier.acponline.org, http://www.acponline.org/products_services/
mksap/15/?pr31, and other resources referenced in each issue of In the Clinic.
CME Objective: To review current evidence for the screening, diagnosis, and
treatment of depression
The information contained herein should never be used as a substitute for
clinical judgment.
2010 American College of Physicians

in the clinic

in the clinic

epression affects 5% to 10% of primary care patients (1) on average;

however, this varies widely among clinical populations (2, 3). Only about
half of depressed patients receive treatment (4). Untreated depression
may prevent effective treatment of common co-occurring illnesses, such as diabetes (5). Depression causes disability similar to that of other chronic medical
conditions (6, 7). Effective treatment reduces symptoms and improves quality of
life (8). Asking about depression is sometimes viewed as opening Pandoras box,
but primary care clinicians can efficiently identify and manage most cases.

D
Screening

1. Pignone MP, Gaynes

BN, Rushton JL, et al.
Screening for depression in adults: a summary of the evidence
for the U.S. Preventive
Services Task Force.
Ann Intern Med.
2002;136:765-76.
[PMID:12020146]
2. Lustman PJ, Anderson
RJ, Freedland KE, et al.
Depression and poor
glycemic control: a
meta-analytic review
of the literature. Diabetes Care.
2000;23:934-42.
[PMID: 10895843]
3. Miranda J, Chung JY,
Green BL, et al. Treating depression in
predominantly lowincome young minority women: a randomized controlled
trial. JAMA.
2003;290:57-65.
[PMID: 12837712]
4. Gonzlez HM, Vega
WA, Williams DR, et al.
Depression care in
the United States: too
little for too few. Arch
Gen Psychiatry.
2010;67:37-46.
[PMID:20048221]
5. Katon WJ, Schoenbaum M, Fan MY, et
al. Cost-effectiveness
of improving primary
care treatment of
late-life depression.
Arch Gen Psychiatry.
2005;62:1313-20.
[PMID:16330719]
6. Hays RD, Wells KB,
Sherbourne CD, et al.
Functioning and
well-being outcomes
of patients with depression compared
with chronic general
medical illnesses.
Arch Gen Psychiatry.
1995;52:11-9.
[PMID:7811158]
7. Remick RA. Diagnosis
and management of
depression in primary
care: a clinical update
and review. CMAJ.
2002;167:1253-60.
[PMID:12451082]

2010 American College of Physicians

Which patients are at especially

high risk for depression?
Risk factors for depression include
older age (9) and associated neurologic conditions, female sex, alcohol
dependence, comorbid medical and
psychiatric conditions (10, 11), personal or family history of depression,
recent childbirth (12), and stressful
life events (13) (Box). Although specific biological factors predisposing
to depression may emerge, no clinically useful biological markers of depression have been identified.
A meta-analysis of the interaction between
the serotonin transporter gene (5-HTTLPR)
and stressful life events yielded no association with risk for depression (14).

Should clinicians screen for

depression?
Depression screening instruments
do not diagnose depression but can
accurately identify patients at risk.
A 2009 U.S. Preventive Services
Task Force guideline recommends
screening adults for depression
when staff-assisted depression care
supports are in place to assure accurate diagnosis, effective treatment,
and follow-up (15). Such supports
include outreach personnel and depression educators. Follow-up by
the clinician after diagnosis and beginning of treatment is critical.

Clinicians should consider screening patients with identified risk

factors or who present with unexplained somatic symptoms, comorbid psychological conditions (for
example, panic disorder), substance
abuse, chronic pain, or nonreponse
to effective treatments for medical
conditions (16).
A meta-analysis of screening studies suggested that screening is associated with a
9% absolute reduction in the proportion of
patients with persistent depression at 6
months. Assuming a prevalence of 10%,
110 primary care patients would need to
be screened for depression to produce
1 additional remission (1).

However, the absolute reduction,

and therefore the utility of screening for depression, is highly
dependent on the prevalence of
the illness in the population being
assessed. The optimum interval for
rescreening is unknown.
What methods should clinicians
use to screen for depression?
A positive response to a 2-item
instrument (Box) had a sensitivity
of 96% and a specificity of 57%,
similar to longer instruments (17).
A meta-analysis of 9 case-finding instruments in 18 studies and a head-to-head
study of screening instruments showed
that the 2-question instrument performed
as well as many of the longer ones (18).

Risk Factors for Depression

Age
Alcohol dependence
Comorbid conditions
Female sex
Personal or family history of depression
Recent childbirth
Recent stressful events

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In the Clinic

Screening Questions for Depression

Over the past 2 weeks have you felt
down, depressed, hopeless?
Over the past 2 weeks have you felt
little interest or pleasure in doing
things?

Annals of Internal Medicine

4 May 2010

Patients with a positive response to 1

or both questions should have a
more complete assessment to determine whether they meet the criteria
for depression disorders according to
the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (19).
Other screening tools, such as the
Beck Depression Inventory Scales
II, the Center for Epidemiologic
Studies Depression Scale-Revised,
and the Zung Self-Rating Depression Scale are also used. The Edinburgh Postnatal Depression
Scale was developed to assess
postpartum depression (18, 20,
21). In elderly persons, the Geriatric Depression Rating Scale (22)

can be used, but clinicians should

also assess with the Mini-Mental
State Examination, because cognitive impairment requires a specific
instrument (such as the interviewer
-administered Cornell Scale for
Depression in Dementia [23]).
The Hopkins Symptom Checklist25 has been validated in refugee
populations and is available in
many languages. These instruments are designed to assess the
severity of depressed mood, not
the diagnostic criteria for Major
Depressive Disorder as defined in
DSM-IV Text Revision. The
Patient Health Questionnaire
(PHQ-9) is both a diagnostic and
severity rating instrument (24).

Screening... Clinicians should screen for depression as the first step in a systematic evaluation of mood disorders in all adults. Adults who are older, are postpartum, have personal or family history of depression, or have comorbid medical
illness are at increased risk. Little evidence recommends one screening method
over another, so physicians can choose the method that best suits their patient
population and practice setting. The 2-question instrument is more efficient and
performs as well as longer instruments.

CLINICAL BOTTOM LINE

Diagnosis
What are the diagnostic criteria
for depression?
Depression is diagnosed when 5 or
more DSM-IV symptoms occur in
the same 2 weeks with a change
from previous functioning (Table 1)
(19). One symptom must be either
depressed mood or anhedonia. The
core symptoms of DSM-IV major
depression describe a specific depression syndrome and do not necessarily represent a severity index. Only a
clinical interview or use of 1 of the
previously described instruments can
assess severity.

depression responds equally well to

medication or psychotherapy (26).
Patients with severe major depressive disorder benefit more from
medication alone or combined with
psychotherapy than from psychotherapy alone.

How can clinicians determine the

severity of depression?
Assessment of depressive symptom
severity helps guide treatment.
Mild depression may not require
medication (25). Mild-to-moderate

How can clinicians and patients

distinguish between normal
reactions to life events and
depression?
Subsyndromal depression is characterized by 2 to 4 DSM-IV

4 May 2010

Annals of Internal Medicine

The PHQ-9 is easily scored to

quantify the severity of depression
(Table 2) (24). Like suicidality, severe functional impairment, such as
inability to bathe or eat, may suggest the need for psychiatric consultation or hospitalization (27).

In the Clinic

ITC5-3

8. Heiligenstein JH, Ware

JE Jr, Beusterien KM,
et al. Acute effects of
fluoxetine versus
placebo on functional health and well-being in late-life depression. Int
Psychogeriatr. 1995;7
Suppl:125-37.
[PMID:8580388]
9. McDonald WM,
Richard IH, DeLong
MR. Prevalence, etiology, and treatment of
depression in Parkinsons disease. Biol
Psychiatry.
2003;54:363-75.
[PMID:12893111]
10. Kendler KS, Gardner
CO, Prescott CA.
Clinical characteristics of major depression that predict risk
of depression in relatives. Arch Gen Psychiatry. 1999;56:3227. [PMID:10197826]
11. Runeson B, Asberg
M. Family history of
suicide among suicide victims. Am J
Psychiatry.
2003;160:1525-6.
[PMID:12900320]
12. Beck CT. Predictors
of postpartum depression: an update.
Nurs Res.
2001;50:275-85.
[PMID:11570712]
13. Person C, Tracy M,
Galea S. Risk factors
for depression after a
disaster. J Nerv Ment
Dis. 2006;194:659-66.
[PMID:16971817]
14. Risch N, Herrell R,
Lehner T, et al. Interaction between the
serotonin transporter gene (5-HTTLPR), stressful life
events, and risk of
depression: a metaanalysis. JAMA.
2009;301:2462-71.
[PMID:19531786]
15. OConnor EA, Whitlock EP, Beil TL, et al.
Screening for depression in adult patients in primary
care settings: a systematic evidence review. Ann Intern
Med. 2009;151:793803.
[PMID:19949145]
16. Terre L, Poston WS,
Foreyt J, et al. Do somatic complaints
predict subsequent
symptoms of depression? Psychother
Psychosom.
2003;72:261-7.
[PMID:12920330]
17. Whooley MA, Avins
AL, Miranda J, et al.
Case-finding instruments for depression. Two questions
are as good as many.
J Gen Intern Med.
1997;12: 439-45.
[PMID: 9229283]

2010 American College of Physicians

Table 1. Criteria for Major Depressive Episode, Based on the Diagnostic and Statistical Manual of
Mental Disorders*

18. Mulrow CD, Williams

JW Jr, Gerety MB, et
al. Case-finding instruments for depression in primary
care settings. Ann
Intern Med.
1995;122:913-21.
[PMID:7755226]
19. Diagnosis and Statisitical Manual of
Mental Disorders 4th
Edition. Washington,
DC: American
Pyschiatric Association; 1994.
20. Beck AT, Steer RA,
Brown GK. BDI-II,
Beck Depression Inventory: Manual.
2nd ed. Boston: Harcourt-Brace; 1996.
21. Georgiopoulos AM,
Bryan TL, Yawn BP, et
al. Population-based
screening for postpartum depression.
Obstet Gynecol.
1999;93:653-7.
[PMID:10912961]
22. Yesavage JA. Geriatric Depression
Scale. Psychopharmacol Bull.
1988;24:709-11.
[PMID: 3249773]
23. Alexopoulos GS,
Abrams RC, Young
RC, et al. Cornell
Scale for Depression
in Dementia. Biol
Psychiatry.
1988;23:271-84.
[PMID:3337862]
24. Lwe B, Untzer J,
Callahan CM, et al.
Monitoring depression treatment outcomes with the patient health
questionnaire-9.
Med Care.
2004;42:1194-201.
[PMID:15550799]
25. Fournier JC,
DeRubeis RJ, Hollon
SD, et al. Antidepressant drug effects
and depression
severity: a patientlevel meta-analysis.
JAMA. 2010;303:4753. [PMID:20051569]
26. Thase ME, Greenhouse JB, Frank E, et
al. Treatment of major depression with
psychotherapy or
psychotherapy-pharmacotherapy combinations. Arch Gen
Psychiatry.
1997;54:1009-15.
[PMID:9366657]
27. Depression in primary care: detection,
diagnosis, and treatment. Agency for
Healthcare Policy
and Research. Clin
Pract Guidel Quick
Ref Guide Clin.
1993;5:1-20.

Five or more of the following symptoms (one of which is depressed mood or loss of interest or pleasure) have occurred together for a 2-wk period and represent a change from previous functioning:
Depressed mood most of the day, nearly every day as self-reported or observed by others
Diminished interest or pleasure in all or almost all activities most of the day, nearly every day
Significant weight loss when not dieting, or weight gain; or decrease or increase in appetite nearly every day
Insomnia or hypersomnia nearly every day
Psychomotor agitation or retardation nearly every day
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive or inappropriate guilt nearly every day
Diminished ability to think or concentrate nearly every day
Recurrent thoughts of death, recurrent suicidal ideation without a specific plan.
The symptoms do not meet criteria for a mixed episode.
The symptoms cause clinically significant distress or impairment in social, occupational, or other areas of functioning.
The symptoms are not due to the direct physiologic effects of a substance (drug or medication) or a general medical
condition (hypothyroidism).
The symptoms are not better accounted for by bereavement, or the symptoms persist for more than 2 mo or are
characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
* From American Psychiatric Association. Guidelines for the Treatment of Patients with Major Depressive Disorder. Washington, DC: American Psychiatric Publishing; 1994.

Table 2. Patient Health Questionnaire-9*

Over the last 2 wk, how often have you been bothered by any of the following problems? (0 = not at all;
1 = several days; 2 = more than one half the days; 3 = nearly every day)
1. Little interest or pleasure in doing things
2. Feeling down, depressed, or hopeless
3. Trouble falling or staying asleep or sleeping too much
4. Feeling tired or having little energy
5. Poor appetite or overeating
6. Feeling bad about yourself or that you are a failure or have let yourself or your family down
7. Trouble concentrating on things, such as reading the newspaper or watching television
8. Moving or speaking so slowly that other people have noticed or the opposite (i.e., being so fidgety or restless that
you have been moving around a lot more than usual)
9. Thoughts that you would be better off dead or hurting yourself in some way
10. If you have checked off any problems, how difficult have these problems made it for you to do your work, take
care of things at home, or get along with other people?
* The 9 items reflect the 9 DSM-IV criteria. Item 10 assesses functional impairment. Like symptom severity, severe functional impairment may suggest the need for hospitalization and psychiatric consultation. 1999 Pfizer Inc. All rights reserved. Reproduced with permission.`
Items 1 through 9 are summed to yield a scale score ranging from 0 to 27. On this scale, 0 to 4 is considered nondepressed,
5 to 9 is considered minor depression, 10 to 14 is considered mild depression, 15 to 19 is considered moderately severe depression, and 20 to 27 is considered severe depression.

2010 American College of Physicians

depressive symptoms, including depressed mood or anhedonia, for

more than 2 weeks (Table 1). Situational adjustment reaction with
depressed mood (adjustment disorder) is subsyndromal depression
with a clear precipitant. Adjustment
disorder must abate within 6 months
of the resolution of the stressor, and
careful observation and supportive

counseling are indicated. If the patient meets criteria for major depression, having a stressor does not alter
the diagnosis; however, the clinician
may chose careful watchful waiting
if the major depressive syndrome
occurred only after a defined event.

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Annals of Internal Medicine

In the Clinic

Differentiating normal grieving and

pathologic grief from depression can

4 May 2010

be difficult. Major depression may

be transiently present in normal
grief; however, sadness without the
complete syndrome is more common. In some cultures, transient and
limited hallucinations (hearing or
seeing the deceased person) or passive suicidal thoughts (feeling that
one would be better off dead or
should have died with the deceased
person) may be part of normal grief.
The boundaries of normal grief are
shaped by sociocultural factors.
Symptoms of clinical depression beyond normal grief include inappropriate guilt, persistent thoughts of
death, morbid preoccupation with
worthlessness, marked psychomotor
retardation, prolonged functional
impairment, and hallucinations or
delusions. Symptoms persisting beyond 2 months should raise concern
about major depression.

kill themselves for a particular timeframe and to seek immediate care if

suicide is seriously considered or
planned.
A recent meta-analysis showed that there is
no evidence for the utility of these safety
contracts and that they afford the physician
little, if any, medicolegal protection (33).

In the absence of exacerbating factors, when the patient has adequate

social support and is able to give reasons for living, proceed with outpatient treatment and close follow-up.
For poor social support, no clear indication of alliance for safety, or alcohol or drug disorders, choose
emergency referral for hospitalization and psychiatric assessment.

How should clinicians assess a

depressed patients risk for selfharm, including suicide?
Each year, more than 30 000 U.S. citizens die by suicide. Mental health
conditions and addictive disorders,
such as alcohol use disorders, are the
most powerful risk factors for suicide
in all age groups, present in more
than 90% of all suicides (28). In a patient with major depression, previous
suicide attempts are the best predictor
of completed suicide (29). Most patients who die by suicide have seen a
physician in the preceding months.
Clinicians should assess for suicidal
intent at each visit for depression.

When should clinicians consult a

mental health professional for
help diagnosing depression or a
related mood disorder?
Although many mood disorders
can be successfully managed by the
primary care clinician, psychiatric
consultation should be considered
for diagnostic uncertainty, psychiatric comorbid conditions, significant suicidal ideation, or inadequate
response to treatment. Psychiatric
evaluation is warranted if the clinician finds psychotic symptoms
(delusions, hallucinations, disorganized speech, or episodes of catatonia) or substance abuse. Patients
with psychotic symptoms or
comorbid substance abuse are at
greater risk for suicide and warrant
psychiatric evaluation (34).

Asking about and reducing access to

lethal means (especially firearms) can
reduce this risk (30). Close telephone
follow-up by an experienced psychiatrist can reduce the risk for suicide after a previous attempt (31). Accurate
assessment of suicidal risk and the
need for hospitalization is critical. A
psychiatrist should be consulted for
any uncertainty regarding suicidal
risk. Previously, physicians used the
No Harm Contract (32), which is a
verbal or written agreement in which
suicidal patients agree not to harm or

Also, screen patients for history of

manic episodes (days to weeks
marked by unusually high energy,
euphoria, hyperactivity, or impaired
judgment). The Mood Disorders
Questionnaire (MDQ) is a useful
tool to identify a history of bipolar
illness (35). Patients with a depressed
mood and an undiagnosed bipolar
affective disorder may convert to
frank mania if prescribed an antidepressant without a concurrent
mood-stabilizing medication. Consult a psychiatrist for manic or

28. Moscicki EK. Identification of suicide risk

factors using epidemiologic studies.
Psychiatr Clin North
Am. 1997;20:499517. [PMID:9323310]
29. Brody DS, Thompson TL 2nd, Larson
DB, et al. Recognizing and managing
depression in primary care. Gen Hosp
Psychiatry.
1995;17:93-107.
[PMID:7789790]
30. Mann JJ, Apter A,
Bertolote J, et al. Suicide prevention
strategies: a systematic review. JAMA.
2005;294:2064-74.
[PMID:16249421]
31. Vaiva G, Vaiva G,
Ducrocq F, et al. Effect of telephone
contact on further
suicide attempts in
patients discharged
from an emergency
department: randomised controlled
study. BMJ.
2006;332:1241-5.
[PMID:16735333]
32. Stanford EJ, Goetz
RR, Bloom JD. The
No Harm Contract in
the emergency assessment of suicidal
risk. J Clin Psychiatry.
1994;55:344-8.
[PMID:8071303]
33. Garvey KA, Penn JV,
Campbell AL, et al.
Contracting for safety with patients: clinical practice and
forensic implications.
J Am Acad Psychiatry Law. 2009;37:36370. [PMID: 19767501]
34. Karch DL, Barker L,
Strine TW. Race/ethnicity, substance
abuse, and mental
illness among suicide victims in 13 US
states: 2004 data
from the National Violent Death Reporting System. Inj Prev.
2006;12 Suppl 2:ii22ii27. [PMID:
17170166]
35. Hirschfeld RM, Calabrese JR, Weissman
MM, et al. Screening
for bipolar disorder
in the community. J
Clin Psychiatry.
2003;64:53-9. [PMID:
12590624]

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2010 American College of Physicians

4 May 2010

Annals of Internal Medicine

In the Clinic

hypomanic symptoms after starting

an antidepressant. Mania may also
present as a mixed state of depression with significant psychomotor
agitation or racing thoughts. Thus,
agitation after starting antidepressant
treatment is a source of concern.
Delays in starting mood-stabilizing
drug therapy for bipolar disorder,
even when mild, increases the risk

for suicidal behavior, poor social adjustment, and more hospitalization

(36). Adherence to antidepressants
should be assessed, because it affects
response. The physician might obtain data, as needed, for related conditions (for example, thyroid disorders, HIV testing, urine toxicology),
but extensive testing without a clear
indication is not recommended.

Diagnosis... The DSM-IV criteria are the standard for diagnosing major depression. The risk for suicide and comorbid mental and physical illness should be assessed in each patient. If clinicians are uncertain about the diagnosis, risk for
suicide, or need for hospitalization, psychiatric consultation should be considered.

CLINICAL BOTTOM LINE

Treatment

36. Goldberg JF, Ernst

CL. Features associated with the delayed initiation of
mood stabilizers at
illness onset in bipolar disorder. J Clin
Psychiatry.
2002;63:985-91.
[PMID:12444811]
37. Paykel ES, Scott J,
Teasdale JD, et al.
Prevention of relapse in residual depression by cognitive therapy: a
controlled trial. Arch
Gen Psychiatry.
1999;56:829-35.
[PMID: 12884889]
38. Fava GA, Rafanelli C,
Grandi S, et al. Sixyear outcome for
cognitive behavioral
treatment of residual
symptoms in major
depression. Am J
Psychiatry.
1998;155:1443-5.
[PMID:9766780]
39. Kessler D, Lewis G,
Kaur S, et al. Therapist-delivered Internet psychotherapy
for depression in primary care: a randomised controlled
trial. Lancet.
2009;374:628-34.
[PMID:19700005]
40. Warmerdam L, van
Straten A, Twisk J, et
al. Internet-based
treatment for adults
with depressive
symptoms: randomized controlled trial.
J Med Internet Res.
2008;10:e44.
[PMID:19033149]

2010 American College of Physicians

How should clinicians decide

whether to recommend
psychotherapy, drug therapy, or
both?
A recent meta-analysis questions
the benefits of antidepressant medication compared with placebo in
patients with mild or moderate
symptoms (25).

Patients with mild-to-moderate

major depression may benefit
equally from psychotherapy or
medication (26). Combined therapy shows no short-term benefit, although psychotherapy may protect
better against relapse (37). Patient
preference remains the primary factor in choosing initial therapy.
Therapist availability and insurance
policies can also be barriers to care.
Severely depressed patients benefit
more from antidepressant medication, alone or in combination with
psychotherapy, than from psychotherapy alone (26).

What types of behavioral

interventions and psychotherapy
are most likely to be effective for
depression?
Three types of psychotherapeutic
options have proven to be effective:
cognitive behavioral therapy (CBT),
interpersonal therapy (IPT), and
problem-solving therapy (PST). The
aim of CBT is to modify thoughts
and behaviors to yield positive emotions. It is also used to treat residual
symptoms after drug therapy and
may help prevent relapse in patients
with a history of recurrent depression
(38). IPT targets conflicts and role
transitions contributing to the depressive episode. It is only useful when
the patient has the capacity for psychological insight and is committed
to longer-term therapy. In PST, patients learn to cope better with specific everyday problems. Sophisticated
behavioral interventions and psychotherapy require specialized training, but primary care clinicians can
often employ basic tenets of these
therapies, such as asking a patient to
keep a journal about situations in
which they feel more depressed to review at monitoring visits. Therapists
often combine all 3 techniques. Webbased CBT and PST lessons are effective and may provide another

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Annals of Internal Medicine

Fournier and colleagues examined individual patient-level data from 6 randomized,

controlled trials and found that the magnitude of benefit from antidepressants
increased with the severity of depression
symptoms and may be minimal (or nonexistent) in patients with mild or moderate
symptoms (25).

In the Clinic

4 May 2010

Table 3. Drug Treatment for Depression

Agent, Daily Dose*

Benefits

Side Effects and Notes

Second-generation
antidepressants

As a class: Effective,
well tolerated

Bupropion, 300450 mg
(75225 mg)

Less weight gain than other

second-generation agents, fewer
sexual side effects. Approved for
smoking cessation

Citalopram, 2060 mg
(1040 mg)
Duloxetine, 3060 mg

Few drug interactions

As a class: Nausea, diarrhea, decreased appetite, nervousness, insomnia,

somnolence, sweating, impaired sexual function; hyponatremia in the
elderly. Contraindicated with MAOIs. Potential for drug interactions
with drugs metabolized in liver. Delicate risk/benefit calculus in
pregnancy.
Lowers seizure threshold. Relatively contraindicated in patients with
history of seizures, family history of seizures, or head trauma. Missed
doses should not be taken with next dose. Use with caution with other
drugs that may lower seizure threshold and in patients with impaired
hepatic function or anorexia/bulimia.
See class effects. Relatively selective 5-HT reuptake inhibitor, but clinical
implications unclear.
Agitation, urinary retention. Withdrawal symptoms may occur.

May be effective in comorbid

pain and depression
Escitalopram, 520 mg (510 mg) Few drug interactions
Fluoxetine, 2060 mg (540 mg)
Longest clinical experience.
Long half-life mitigates effects of
missed doses. Withdrawal
symptoms rare
Mirtazapine, 1545 mg
Faster onset of action than
(7.530 mg)
citalopram, fluoxetine,
paroxetine or sertraline
Paroxetine, 2050 mg (540 mg) Long clinical experience

Sertraline, 50200 mg
(25150 mg)
Trazodone, 50400 mg

Less effective in doses <300 mg

Venlafaxine, 75350 mg
(50225 mg)

Similar efficacy to other

second-generation antidepressants

First-generation
antidepressants

As a class: Effective

Amitriptyline, 25300 mg

May aid with sleep. Low doses

effective for neuropathic pain
May be effective in
psychotic depression
Possibly useful in comorbid
anxiety, panic disorders
See class effects
Potent antihistaminic properties
may have advantages in allergic
syndromes
See class effects
See class effects
See class effects

Amoxapine, 50300 mg
Clomipramine, 25250 mg
Desipramine, 25300 mg
Doxepin, 25300 mg

Imipramine, 25300 mg
Protriptyline, 1560 mg
Trimipramine, 50300 mg

Long clinical experience

See class effects. Similar to citalopram.

See class effects. Among the first newer antidepressants on the market.

Increased appetite, somnolence. Both may be an advantage in

hospitalized patients. Use caution with renal impairment. Avoid
concomitant benzodiazepines and alcohol.
More weight gain and sexual adverse events. Withdrawal syndrome not
uncommon. Long-acting formulations may be less prone to withdrawal
syndrome.
Higher incidence of diarrhea. Generally well-tolerated.
Somnolence, rare priapism in young men. Used in low doses
(50100 mg) sleeping aid in patients taking more stimulating
antidepressants.
Higher incidence of nausea, vomiting, dry mouth, sexual side effects,
hypertension. Occasional hypertensive urgencies.
As a class: Dry mouth, dizziness, nausea, sedation, anticholinergic
effects, orthostatic hypotension. Contraindicated with MAOIs. Do
not use with prolonged QT interval. Use with caution in patients
with cardiovascular disease or predisposition to urinary retention or
narrow angle glaucoma. Follow ECGs and orthostatic blood pressure
changes.
Highly sedating and anticholinergic. See class effects.
See class effects. Rarely used in United States.
See class effects. Especially prone to serious interactions with MAOIs,
which should be strictly avoided.
See class effects.
Dry mouth, sedation. May be slightly less potent than imipramine.

See class effects.

See class effects.
See class effects.

5-HT = 5-hydroxytryptophan (serotonin); ECG = electrocardiogram; MAOI = monoamine oxidase inhibitor.

* Dose range for geriatric patients is in parentheses.
Wright SK, Schroeter S. Hyponatremia as a complication of selective serotonin reuptake inhibitors. J Am Acad Nurse Pract. 2008;20:47-51.
[PMID: 18184165]
Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry.
2009;31:206-19. [PMID: 19410099]

Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants to treat depressive
disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:725-33. [PMID: 19017591]

4 May 2010

Annals of Internal Medicine

In the Clinic

ITC5-7

2010 American College of Physicians

approach for patients to access psychotherapeutic interventions (39, 40).

41. Clinical Efficacy Assessment Subcommittee of American
College of Physicians. Using secondgeneration antidepressants to treat
depressive disorders:
a clinical practice
guideline from the
American College of
Physicians. Ann Intern Med.
2008;149:725-33.
[PMID:19017591]
42. Cipriani A, La Ferla T,
Furukawa TA, et al.
Sertraline versus
other antidepressive
agents for depression. Cochrane Database Syst Rev.
2010:CD006117.
[PMID: 20091586]
43. Williams JW Jr, Mulrow CD, Chiquette E,
et al. A systematic
review of newer
pharmacotherapies
for depression in
adults: evidence report summary. Ann
Intern Med.
2000;132:743-56.
[PMID:10787370]
44. STAR*D Study Team.
Medication augmentation after the
failure of SSRIs for
depression. N Engl J
Med. 2006;354:124352. [PMID:16554526]
45. Lin EH, Von Korff M,
Katon W, et al. The
role of the primary
care physician in patients adherence to
antidepressant therapy. Med Care.
1995;33:67-74.
[PMID:7823648]
46. Wells KB, Sherbourne C, Schoenbaum M, et al. Impact of
disseminating quality improvement programs for depression in managed
primary care: a randomized controlled
trial. JAMA.
2000;283:212-20.
[PMID:10634337]
47. Dubicka B, Hadley S,
Roberts C. Suicidal
behaviour in youths
with depression
treated with newgeneration antidepressants: metaanalysis. Br J
Psychiatry.
2006;189:393-8.
[PMID:17077427]
48. Stone M, Laughren
T, Jones ML, et al.
Risk of suicidality in
clinical trials of antidepressants in
adults: analysis of
proprietary data
submitted to US
Food and Drug Administration. BMJ.
2009;339:b2880.
[PMID:19671933]

2010 American College of Physicians

How should clinicians select from

the many antidepressant drug
therapies?
Clinicians face a wide array of antidepressant drug options (Table 3).
The most commonly prescribed
drugs are the second-generation
antidepressants: selective serotonin
reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and bupropion.
First-generation antidepressants
(tricyclic antidepressants [TCAs]
and monoamine oxidase inhibitors
[MAOIs]) may offer similar effectiveness, but with more toxicity
(41). Generally, TCAs are avoided
because of considerable dry mouth,
constipation, and dizziness. TCAs
are relatively contraindicated in
patients with coronary artery disease, congestive heart failure, and
arrhythmias. They are also potentially fatal in overdose. MAOIs are
also used infrequently, even by psychiatric specialists, because of the
many dietary restrictions and the
potential for hypertensive crisis (except for the newer selegeline patch).
Primary care clinicians should consult with a psychiatrist before considering MAOI therapy.
Drug selection is based on tolerability, safety, evidence of effectiveness in the patient or a first-degree
relative, and cost.

A recent review of 59 mostly low-quality

studies found a trend in favor of sertraline
over other antidepressants in terms of efficacy and acceptability (42).

Regardless of the drug, most patients treated with antidepressants

experience improvement by 6
weeks (43). However, relatively few
achieve baseline levels of mood and
functioning at this point (44), and
many require dose adjustment,
switching to another drug, augmentation with a second agent, or
the addition of psychotherapy.
How should clinicians monitor
response to drug therapy?
Treatment for depression requires at
least 6 to 9 months with close follow-up (Table 4). The first 2 weeks
of drug therapy are often the most
challenging. The pessimism and
hopelessness intrinsic to depression
and the relatively rapid onset of side
effects can lead to nonadherence:
28% of depressed primary care
patients stop taking their medication in the first month, and 44%
stop within 3 months (45).
Clinicians should follow up patients within 1 to 2 weeks of starting therapy to ask about acceptance
of medication, reinforce educational
messages, reassess suicidality, and
address adverse events. Telephone
follow-up by a trained nurse is also
effective (46). Addressing specific
adverse effects is critical to

Table 4. Follow-up for Depression*

Depression Severity

Suggested Follow-up

Minor
Mild (PHQ-9 score of 1014)

Watchful waiting, re-evaluate in 48 wk

Contact by phone or in-person monthly
(whether or not antidepressants are prescribed)
Contact by phone or in-person every 24 wk
Contact by phone or in-person every 24 wk
until PHQ-9 score improved by at least 5 points
Contact by phone or in-person every 23 mo
after remission

Moderate (PHQ-9 score of 1519)

Severe (PHQ-9 score of 20)
If no active treatment, receiving on-going
stable antidepressants or counseling
PHQ-9 = Patient Health Questionnaire.

* Adapted from The MacArthur Initiative in Depression and Primary Care (www.depression-primarycare.org).

ITC5-8

In the Clinic

Annals of Internal Medicine

4 May 2010

maintaining adherence until

patients respond. In addition, antidepressants may be associated with
an increased risk for suicide in children, adolescents, and young adults.
A meta-analysis of 2741 patients age 6 to
18 years showed an increased relative risk
for self-harm or suicide-related events in
patients treated with newer-generation
antidepressants compared with those given placebo (4.8% vs. 3.0%; P = 0.01; number-needed-to-treat for harm, 55). Because
actual suicide is rare in such studies, the increase in risk for suicide, rather than for suicidal behaviors, can only be inferred (47).

The U.S. Food and Drug Administration (FDA) has issued a

Public Health Advisory recommending close monitoring of all
patients treated with antidepressants, particularly in the first 1 to
2 months of treatment. A warning
statement regarding a possible increased risk for suicide has been
added to FDA Patient Information Sheets for citalopram, duloxetine, venlafaxine, escitalopram,
fluvoxamine, paroxetine, fluoxetine, mirtazapine, bupropion, and
sertraline. Clinicians should ask
about agitation, irritability, or
unusual changes in behavior.
Compared with placebo, adults
younger than 25 years have an
increased risk for suicidal behavior
(odds ratio, 2.3) (48). The FDA
recommends weekly follow-up in
these patients for the first month,
biweekly for the next month, and
monthly thereafter. Most evidence
suggests that, when properly
administered, antidepressants
avert many more suicides than
they cause (49).
If response to medication is inadequate after 6 to 8 weeks of therapy,
treatment should be modified. Recurrence of depression after a first
episode is common. Clinicians
should educate patients and their
families to self-assess for symptoms
and risk for recurrent episodes.
Surveillance for recurrence or relapse should continue indefinitely.

4 May 2010

Annals of Internal Medicine

How long should clinicians treat

depressed patients with drugs, and
when should they consider longterm maintenance on drug
therapy?
The goal of treatment is complete
remission of symptoms and return to
normal functioning. For the first
episode, antidepressant treatment may
take 1 to several months until remission is achieved and should be continued for another 4 to 9 months.
Although not strictly evidence-based,
some clinicians advocate treatment
for at least 1 year to maintain remission for a full annual cycle of holidays
and anniversaries. For multiple
episodes of depression, an even longer
duration of therapy may be beneficial
(41). For older patients (>70 years)
with major depression who respond
to an SSRI, consider treating for 2
years to prevent recurrence (50).
When should clinicians consider
switching drugs because of a
suboptimum response to initial
drug therapy?
Most patients starting antidepressant therapy do not achieve complete remission, so increasing the
dose of the current medication or
changing drugs is often necessary.
STAR*D (Sequenced Treatment Alternatives to Relieve Depression) randomly assigned patients to 1 of several treatment
sequences, all starting with 12 weeks of
citalopram. The study showed that 30% of
patients achieved complete remission after 12 weeks of citalopram. Of those who
did not improve with citalopram, about
25% responded to an alternative agent
(sertraline, venlafaxine, or bupropion) and
another one-third responded to augmentation with bupropion (44)

For a partial response, the dose of

the initial agent should be maximized as tolerated before switching
to another medication or adding
a second drug. When a partial
response continues, the clinician can
refer for psychotherapy, change antidepressants, or augment treatment
with bupropion, mirtazapine, or a
nontraditional agent.

In the Clinic

ITC5-9

49. Grunebaum MF, Ellis

SP, Li S, et al. Antidepressants and suicide risk in the United States,
1985-1999. J Clin
Psychiatry.
2004;65:1456-62.
[PMID:15554756]
50. Reynolds CF 3rd,
Dew MA, Pollock BG,
et al. Maintenance
treatment of major
depression in old
age. N Engl J Med.
2006;354:1130-8.
[PMID:16540613]
51. Spier SA. Use of
bupropion with SRIs
and venlafaxine. Depress Anxiety.
1998;7:73-5.
[PMID:9614595]
52. Carpenter LL, Jocic
Z, Hall JM, et al. Mirtazapine augmentation in the treatment
of refractory depression. J Clin Psychiatry. 1999;60:45-9.
[PMID:10074878].
53. Shelton RC, Papakostas GI. Augmentation of antidepressants with
atypical antipsychotics for treatment-resistant major
depressive disorder.
Acta Psychiatr
Scand. 2008;117:2539. [PMID:18190674]
54. Candy M, Jones L,
Williams R, et al. Psychostimulants for
depression.
Cochrane Database
Syst Rev.
2008:CD006722.
[PMID:18425966]
55. Hardy SE.
Methylphenidate for
the treatment of depressive symptoms,
including fatigue
and apathy, in medically ill older adults
and terminally ill
adults. Am J Geriatr
Pharmacother.
2009;7:34-59.
[PMID:19281939]
56. Obrocea G. Thyroid
hormone augmentation in treatment
resistant depression.
Clin Pyschopharmacol Neurosci.
2008;6:3-10
57. Cooper-Kazaz R,
Lerer B. Efficacy and
safety of triiodothyronine supplementation in patients
with major depressive disorder treated
with specific serotonin reuptake inhibitors. Int J Neuropsychopharmacol.
2008;11:685-99.
[PMID:18047754]

2010 American College of Physicians

58. Carney RM, Freedland KE, Rubin EH, et

al. Omega-3 augmentation of sertraline in treatment of
depression in patients with coronary
heart disease: a randomized controlled
trial. JAMA.
2009;302:1651-7.
[PMID:19843899]
59. Golden RN, Gaynes
BN, Ekstrom RD, et
al. The efficacy of
light therapy in the
treatment of mood
disorders: a review
and meta-analysis of
the evidence. Am J
Psychiatry.
2005;162:656-62.
[PMID:15800134]
60. Mead GE, Morley W,
Campbell P, et al. Exercise for depression.
Cochrane Database
Syst Rev.
2009:CD004366.
[PMID:19588354]
61. Morgan AJ, Jorm AF.
Self-help interventions for depressive
disorders and depressive symptoms:
a systematic review.
Ann Gen Psychiatry.
2008;7:13.
[PMID:18710579]
62. Nurnberg HG, Hensley PL. Selective
phosphodiesterase
type-5 inhibitor
treatment of serotonergic reuptake inhibitor antidepressant-associated
sexual dysfunction: a
review of diagnosis,
treatment, and relevance. CNS Spectr.
2003;8:194-202.
[PMID:12595814]
63. Wright SK, Schroeter
S. Hyponatremia as a
complication of selective serotonin reuptake inhibitors. J
Am Acad Nurse
Pract. 2008;20:47-51.
[PMID:18184165]
64. Osteoporotic Fractures in Men Study
Group. Association
of low bone mineral
density with selective serotonin reuptake inhibitor use by
older men. Arch Intern Med.
2007;167:1246-51.
[PMID: 17592097]
65. Smoller JW, Allison
M, Cochrane BB, et
al. Antidepressant
use and risk of incident cardiovascular
morbidity and mortality among postmenopausal women
in the Womens
Health Initiative
study. Arch Intern
Med. 2009;169:212839. [PMID:20008698]

2010 American College of Physicians

Compared with withdrawing one

drug and starting another, combination therapy offers faster effects, potential for synergistic or complementary effects, and avoidance of
withdrawal symptoms when stopping the first agent. But with a more
complex regimen, drug interactions
and adverse effects can increase.
Adding bupropion to an SSRI or
venlafaxine therapy may enhance
response or treat side effects in
many patients (51). Similar response rates occur when adding
mirtazapine to SSRI treatment
(52). Combinations of MAOIs and
either SSRIs or TCAs are not recommended, because of increased
risk for the serotonin syndrome
(with confusion, nausea, autonomic
instability, and hyperreflexia).
Adding atypical antipsychotics,
psychostimulants, and thyroid hormone remains controversial. Antipsychotics added to SSRIs for
treatment-resistant depression show
some benefit but also carry significant risks, so their use should be
limited to psychiatrists (53).
A Cochrane review of psychostimulants
(dexamphetamine, methylphenidate, methylamphetamine, demoline, modafinil) for
moderate-to-severe depression found shortterm improvement in depression symptoms
and fatigue (54). A second review of 19 controlled trials on adults older than 65 years
supported this recommendation for methylphenidate; however, dosing, when to initiate
therapy, and how to monitor side effects remains unclear (55).

Studies are conflicting about the effectiveness of adding thyroid hormone (triiodothyronine [T3] and
levothyroxine [T4]) to antidepressants. (56, 57). More research is needed before these therapies can be recommended for use in primary care.
Augmentation with other nontraditional agents has also shown mixed
results: omega-3 fatty acids added to
sertraline in patients with coronary
heart disease did not improve depressive outcomes (58), whereas light
therapy (6000 to 10 000 lux for 30 to

ITC5-10

In the Clinic

90 minutes each morning) for winter

depression (59), yoga, self-help books,
exercise (60), relaxation therapy (61),
and acupuncture seem useful.
What are the common adverse
effects of antidepressant drugs
and how should clinicians manage
these effects?
Specific types of side effects are
more common with particular
drugs and should guide choice of
medications (Table 3). Sexual side
effects of SSRIs include decreased
libido or interest (men and
women), anorgasmia (women), and
delayed ejaculation (men). To address these side effects, consider
pretreatment counseling, switching
to a drug with a different mechanism of action (for example, bupropion or mirtazapine), or using
sildenafil for SSRI-associated erectile dysfunction if no contraindications (62). Switching to bupropion
can reduce undesired weight gain.
Agitation or excessive activation,
most commonly with fluoxetine,
warrants switching to another SSRI
and considering mixed mania.
Adding a low-dose tricyclic agent,
mirtazapine, trazodone, or a sedative-hypnotic may reduce insomnia
early in the course of treatment.
During SSRI initiation, clinicians
may also provide a short course of
benzodiazepines to counter anxiety
with major depression or early
SSRI treatment. SSRIs are associated with hyponatremia in elderly
persons (63) and may promote
osteoporosis (64).
Analysis from the Womens Health Initiative found that although antidepressant
use did not increase the risk for coronary
heart disease, SSRI use was associated with
an increased risk for hemorrhagic and fatal stroke and that both SSRI and TCA were
associated with increased mortality (65).
Conversely, OConnor and colleagues studied 1006 patients with clinical heart failure
and reported that depression, and not antidepressant use, was associated with increased mortality (66).

Annals of Internal Medicine

4 May 2010

When should clinicians consult a

psychiatrist for help in managing
drug therapy?
Treatment-resistant depression is
common and may require psychiatric
consultation. Referral may be necessary for patients who have not responded to agents familiar to the
primary care provider, have repeated
failures, or have side effects that are
difficult to manage. The threshold
for referral should be lower for more
severely impaired patients. The
Agency for Healthcare Research and
Policy recommends a psychiatric
consult for severe symptoms; heightened suicide risk; comorbid, psychiatric, or substance abuse problems;
or lack of response to appropriate
treatment (27).
Electroconvulsive therapy can be
considered for depressed patients
who have psychotic features, suicidal thoughts, no response to antidepressants, or who cannot tolerate
antidepressants. Electroconvulsive
therapy should be managed by a
psychiatrist (7).
When should clinicians consider
hospitalizing depressed patients?
Hospitalization should be considered
for significant suicidal ideation or intent without safeguards in the family
environment, express intent to hurt
others, requirement for close observation (to assess self-care and adherence), detoxification or substance
abuse treatment, electroconvulsive
therapy candidates, or dysfunctional
family systems worsening the depressive disorder or interfering with
treatment. When a patients life is in
jeopardy, hospitalization against their
wishes is necessary. The conditions
of such involuntary hospitalization
are governed by state-specific legal
requirements.
What should clinicians advise
patients about
complementaryalternative
treatments for depression?
St. Johns wort (Hypericum) may be
beneficial for subsyndromal

4 May 2010

Annals of Internal Medicine

depression or for patients who are

unwilling or cannot take conventional therapy for mild depression.

If a patient relapses after

cessation of depression treatment,
should clinicians resume previously
effective therapy or select a new
therapy?
Recurrence of major depression
requires long-term maintenance
therapy with the same antidepressant that previously led to remission. Lifetime therapy may be
required for patients with 3 or
more depressive episodes or with
first recurrence and risk factors for
more recurrences (family history of

66. OConnor CM, Jiang

W, Kuchibhatla M, et
al. Antidepressant
use, depression, and
survival in patients
with heart failure.
Arch Intern Med.
2008;168:2232-7.
[PMID:19001200]
67. Linde K, Berner MM,
Kriston L. St Johns
wort for major depression. Cochrane
Database Syst Rev.
2008:CD000448.
[PMID:18843608]
68. Obach RS. Inhibition
of human cytochrome P450 enzymes by constituents of St. Johns
Wort, an herbal
preparation used in
the treatment of depression. J Pharmacol Exp Ther.
2000;294:88-95.
[PMID:10871299]
69. de Maat MM,
Hoetelmans RM,
Math RA, et al. Drug
interaction between
St Johns wort and
nevirapine. AIDS.
2001;15:420-1.
[PMID:11273226]
70. Ondrizek RR, Chan
PJ, Patton WC, et al.
Inhibition of human
sperm motility by
specific herbs used
in alternative medicine. J Assist Reprod
Genet. 1999;16:8791. [PMID:10079411]
71. Pies R. Handbook of
Essential Psychopharmacology,
second ed. American Psychiatric Publishing; 2005.
72. Chambers CD, Hernandez-Diaz S, Van
Marter LJ, et al. Selective serotonin-reuptake inhibitors
and risk of persistent
pulmonary hypertension of the newborn. N Engl J Med.
2006;354:579-87.
[PMID:16467545]
73. U.S. Food and Drug
Administration. FDA
Public Health Advisory: Treatment
Challenges of Depression in Pregnancy. 2006. Accessed at
www.fda.gov/Drugs/
DrugSafety/PublicHealthAdvisories/ucm124348.ht
m on 25 March
2010.
74. Einarson A, Pistelli A,
DeSantis M, et al.
Evaluation of the risk
of congenital cardiovascular defects associated with use of
paroxetine during
pregnancy. Am J
Psychiatry.
2008;165:749-52.
[PMID: 18381907]

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2010 American College of Physicians

A Cochrane review suggests that Hypericum extracts are as effective as standard

antidepressants for mild depression and
have fewer side effects (67).

St. Johns wort should not be used

for moderate-to-severe major
depression, because of lack of benefit.
Although St. Johns wort has mixed
results in randomized, placebocontrolled trials, serious adverse
effects are uncommon. Many trials
with positive findings have used
standardized doses of 0.3% hypericin, 300 mg three times a day (67).
There are important caveats to the
use of St Johns wort. To avoid
symptoms of serotonin excess, do
not use with SSRIs. Through activation of the cytochrome P450 system, St. Johns wort may reduce
plasma concentration of digoxin,
theophylline, simvastatin, and warfarin (68). Severe drug interactions
have also been reported with antiretroviral therapy; St. Johns wort
can decrease concentrations of protease inhibitors and nonnucleoside
reverse transcriptase inhibitors (69).
At high concentrations, St. Johns
wort may harm sperm cells and lead
to decreased fertility (70). The National Institute of Healths National
Center for Complementary and Alternative Medicine is a good resource for more information (http://
nccam.nih.gov/health/stjohnswort).

In the Clinic

bipolar disorder, recurrence <1 year,

onset in adolescence, severe depression, suicide attempt, and sudden
onset of symptoms) (71).

in labeling for this agent (73).

Paroxetine is the only SSRI with a
class D rating for pregnancy; all
others are class C.

How should clinicians advise

women receiving drug therapy for
depression who are or who wish
to become pregnant?
In 2006, the FDA issued a warning concerning SSRI use during
pregnancy. A casecontrol study
showed that persistent pulmonary
hypertension was 6 times more
common in babies whose mothers
received an SSRI after the 20th
week of gestation than in those
whose mothers did not (72). The
absolute risk for persistent pulmonary hypertension was low
(about 6 to 12 per 1000 women).
However, this study adds to concerns from previous reports that
infants of mothers taking SSRIs
late in pregnancy may have irritability, difficulty feeding, and (in
very rare cases) difficulty breathing.

A recent review of over 3000 births to

women receiving paroxetine during the
first trimester showed no increase in cardiac malformations (74).

The teratogenic potential of SSRIs

is probably low overall, but 2 epidemiologic studies of paroxetine
in early pregnancy prompted the
FDA in late 2005 to order a change

Stopping antidepressants carries its

own risks.
In 201 pregnant women with history of
major depression before pregnancy, relapse of depression was more common in
those who stopped their medication than
in those who continued (68% vs. 26%, hazard ratio, 5.0; P < 0.001) (75).

Tricyclic antidepressants are not

strictly contraindicated in pregnancy.
However, the neonatal withdrawal
syndrome may occur, and these
drugs should be tapered before delivery (71). If a TCA is chosen, desipramine or nortriptyline may be
preferred, because they cause fewer
side effects and because drug levels
can be monitored (76). Clinicians
should help patients make an informed decision and should check
for signs of postpartum depression
4 to 6 weeks after delivery.

Treatment... Primary care physicians play an important role in treating affective

disorders. Depression is highly treatable and has many treatment options; clinicians familiar with 2 SSRIs (such as citalopram, sertraline), an SNRI (such as
extended-release venlafaxine), and sustained-release bupropion are well equipped
to treat most cases. However, clinicians should not hesitate to refer patients to a
psychiatrist for evaluation or comanagement. Familiarity with local psychotherapy options and options for addressing common side effects is also helpful.

CLINICAL BOTTOM LINE

Practice
Improvement

2010 American College of Physicians

What can clinicians do to

encourage adherence to therapy
for patients with depression?
Patient education and slowly increasing medication doses to minimize side effects are the first lines
of defense against nonadherence to
antidepressant therapy.

Among 155 depressed patients, those

receiving the following educational
messages were more likely to adhere to
therapy during the first month: take the
medication daily, antidepressants must
be taken for 2 to 4 weeks for a noticeable effect, continue to take medicine
even if feeling better, do not stop taking
antidepressant medication without

ITC5-12

Annals of Internal Medicine

In the Clinic

4 May 2010

checking with the physician, and resolve questions regarding antidepressants and potential side effects with the
physician (45).

A meta-analysis of 37 RCTs showed that

collaborative care is more effective than
standard care in improving depression
outcomes (83).

Nonadherence often begins in the

first weeks of therapy and is related to
beliefs about the illness, concerns over
side effects, ineffectiveness of treatment, cost of medications, and diverse
cultural and attitudinal factors (77).
Clinicians should routinely ask patients and their families about their
beliefs. Personalizing educational
messages to address the patients beliefs will enhance the benefit. Whenever possible, family involvement may
improve acceptance of and support
for the patients condition and may
enhance response. Patients and their
families should receive appropriate
written and electronic patient education materials about depression and
its management. Clinicians can improve the effect of printed material by
intensive reinforcement of key educational messages (45).

What criteria are used to judge

the quality of depression care?
The Ambulatory Care Quality Alliance has adopted 2 antidepressant
medication management measures
developed by the National Committee for Quality Assurance: antidepressant therapy for at least 12
weeks after the initial diagnosis and
treatment and continuous anti
depressant therapy for at least 6
months after the initial diagnosis
and treatment. For more information, see www.aqaalliance.org/
performancewg.htm.

How can primary care practices

improve depression care?
Improving outcomes in depression
care requires systems change (78).
Elements shown to support improvement include collaborative
care involving primary care clinicians and mental health specialists,
systematic tracking of outcomes
with decision support, and use of
nurses or office staff to coordinate
follow-up (79, 80). Recommendations to adopt screening strategies
using questionnaires without organizational enhancements may not
be justified (81). Changing physician behavior requires structured
interventions that operate independently of physician initiation.
Most collaborative care models require additional resources, but some
are cost-saving (82), and overall
costs seem commensurate with
demonstrated benefit. Implementation of these approaches requires
initiative at the level of the health
care delivery system rather than in
the doctor-patient relationship.

4 May 2010

Annals of Internal Medicine

The American Psychiatric Association published its Practice Guideline

for the Treatment of Patients with
Major Depressive Disorder in 2002,
and a third edition is under development (www.psych.org/psych
_pract/treatg/pg/MDD2e_05-15
-06.pdf ). Updates to this guideline

75. Cohen LS, Altshuler

LL, Harlow BL, et al.
Relapse of major depression during
pregnancy in
women who maintain or discontinue
antidepressant treatment. JAMA.
2006;295:499-507.
[PMID:16449615]
76. Miller LJ. Psychiatric
medication during
pregnancy: understanding and minizing risks. Psychiatr
Ann. 1994;24:69-75.
77. Delgado PL. Approaches to the enhancement of patient adherence to
antidepressant medication treatment. J
Clin Psychiatry.
2000;61 Suppl 2:6-9.
[PMID:10714617]
78. Ong MK, Rubenstein
LV. Wishing upon a
STAR*D: the promise
of ideal depression
care by primary care
providers. Psychiatr
Serv. 2009;60:1460-2.
[PMID: 19880461]
79. Gilbody S, Bower P,
Fletcher J, et al. Collaborative care for
depression: a cumulative meta-analysis
and review of
longer-term outcomes. Arch Intern
Med. 2006;166:231421. [PMID:17130383]
80. Weissman MM, Olfson M. Translating
intergenerational research on depression into clinical
practice. JAMA.
2009;302:2695-6.
[PMID:20040558]
81. Gilbody S, Sheldon T,
House A. Screening
and case-finding instruments for depression: a metaanalysis. CMAJ.
2008;178:997-1003.
[PMID:18390942]
82. Unutzer J, Katon WJ,
Fan MY, et al. Longterm cost effects of
collaborative care for
late-life depression.
Am J Manag Care.
2008;14:95-100.
[PMID: 18269305]
83. Bower P, Rowland N.
Effectiveness and
cost effectiveness of
counselling in primary care. Cochrane
Database Syst Rev.
2006;3:CD001025.
[PMID:16855955]
84. Sherbourne CD,
Wells KB, Duan N, et
al. Long-term effectiveness of disseminating quality improvement for
depression in primary care. Arch Gen
Psychiatry.
2001;58:696-703.
[PMID:11448378]

ITC5-13

2010 American College of Physicians

A study of 1299 patients in a primary care

HMO compared usual care with 2 qualityimprovement programs: one offered medication-focused management, and the
other emphasized psychotherapy. Both
interventions showed benefit versus usual
care at 6 and 12 months, but only the psychotherapy intervention showed a persistent benefit at 24 months in both clinical
outcomes and mental healthrelated
quality of life (84).

What do professional
organizations recommend
regarding screening for and
managing depression?
In 2009, the U.S. Preventive Services Task Force issued guidelines on
screening for depression (www.ahrq
.gov/clinic/uspstf/ix.htm). The Task
Force recommends screening adults
in clinical practices with staffassisted depression care supports.
The Task Force also issued a guideline on screening for suicide risk in
2004 (www.ahrq.gov/clinic/uspstf
/uspssuic.htm).

In the Clinic

The MacArthur Initiative in Depression and Primary Care, in collaboration with Dartmouth College
and Duke University, has expanded
the work of the AHRQ by developing a comprehensive Web site
that offers provider guidelines and
patient education resources

in the clinic

Tool Kit
Depression

covering all aspects of depression

management. It can be accessed at
www.depression-primarycare.org.
Pharmacologic therapy of major
depression and dysthymia is covered in clinical guidelines from the
American College of Physicians
that were issued in 2008 (www
.annals.org/cgi/content/149/
10/725.abstract).

PIER Modules
http://pier.acponline.org/physicians/diseases/d954/d954.html
Access the PIER module on depression from the American College of
Physicians. PIER modules provide an evidence-based, electronic resource
for clinical recommendations and links to patient information materials at
the point of care.

Depression Scales
www.chcr.brown.edu/pcoc/cesdscale.pdf
Center for Epidemiological Studies Depression Scale
http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf
Zung Self-Depression Scale
www.stanford.edu/~yesavage/GDS.html
Geriatric Depression Scale
www.nelmh.org/downloads/other_info/hopkins_symptom_checklist.pdf
Hopkins Symptom Checklist
www.aap.org/practicingsafety/Toolkit_Resources/Module2/EPDS.pdf
Edinburgh Postnatal Depression Scale

Patient Information
www.doctorsforadults.com/images/healthpdfs/depression.pdf
Downloadable brochure on depression and how internists can help.
www.depression-primarycare.org
Patient education handouts on depression symptoms, management, medications, and psychological counseling.
www.annals.org/intheclinic/toolkit-depression.html
Download an electronic copy of the patient information sheet on the next
page for duplication and use in your office
www.nlm.nih.gov/medlineplus/depression.html
Public-oriented information on depression, including educational information from the National Institutes of Mental Health and other organizations, recent studies, and news. Many resources are available in Spanish.

2010 American College of Physicians

ITC5-14

In the Clinic

in the clinic

are available (www.psych.org/psych

_pract/treatg/pgMDDWatch.pdf ).

Annals of Internal Medicine

4 May 2010

THINGS YOU SHOULD

KNOW ABOUT
DEPRESSION

In the Clinic
Annals of Internal Medicine

Depression makes you feel sad and makes it hard to do

or enjoy anything. Talking to a therapist or taking
the right medicine can make you feel better.

What You Can Do

Dont be afraid to ask for help.
If the doctor gives you medicine, take it every day.
Dont expect your medicine to work for 2 to 4 weeks
after you start it.
Keep taking your medicine even if you feel better.
Dont stop your medicine without checking with
your doctor.
Expect to take your medicine for at least 6 months.
See the doctor 1 to 2 weeks after you start medicine
and then again in 6 weeks.
Ask your doctor about side effectsputting on
weight, feeling nervous, or having trouble with sex.

If you feel bad or need help, call your doctor or 911

or go to the emergency room right away.

Your medicines have too many side effects

You are having strange thoughts or big mood swings

Ask your doctor about seeing a

specialist if:

You feel you may hurt yourself or other people

Your medicines dont seem to be working

You are drinking too much or taking street drugs

For More Information

www.nlm.nih.gov/medlineplus/depression.html

MedlinePLUS
www.nami.org/Template.cfm?Section=By_Illness/TaggedPage/
TaggedPageDisplay.cfm

National Alliance on Mental Illness

www.nimh.nih.gov/publicat/depression.cfm

National Institutes of Mental Health

www.fda.gov

U.S. Food and Drug Administration (search for depression drugs)

www.cancer.gov/espanol/pdq/cuidados-medicos-apoyo/depresion/
patient/

National Cancer Institute (Spanish)

Patient Information

Ask your doctor about the right people to talk to

and how your family can help you.

CME Questions
1. A 25-year-old woman is evaluated for a 2month history of feeling down and
hopeless after her fianc ended their
engagement. She believes that the broken
engagement was somehow her fault. The
patient also reports spending less time with
friends, restricting previously enjoyable
social activities, and having difficulty
concentrating. During the past week, she
has been thinking increasingly about
ending her life and has been fingering a
knife when at home alone while
contemplating cutting her wrists. She lives
at home with her mother and two sisters,
who are concerned and have expressed
feelings of support and willingness to help.
The patient is willing to make a no-harm
contract of calling or going to the
emergency department if suicidal feelings
intensify. She has no history of suicide
attempts. Medical history is unremarkable,
and she takes no medications. Her father
committed suicide several years ago.
Findings on physical examination are
unremarkable.
Which is the most appropriate initial
care for this patient?

A. Corroborate her account by

contacting her former fianc
B. Reassurance and careful follow-up
and observation
C. Start an antidepressant and follow
up in 2 weeks
D. Urgent mental health referral
2. A 70-year-old woman is evaluated
because of depressed mood, anhedonia,
decreased appetite, impaired sleep, and
decreased energy. Although the patient
feels somewhat hopeless about the
future, she adamantly states that she
would never take her own life. Her
judgment seems intact. Medical history
is unremarkable, and she has not had
previous episodes of depression. She is
taking no medications. Findings on
physical examination are unremarkable.
Sertraline, 50 mg/d, is begun. The patient
returns for a follow-up visit 5 weeks later

and reports that she is tolerating the

medication well but has no significant
change in symptoms, which is validated
with a standardized symptom assessment
tool. The sertraline is therefore increased to
100 mg/d. Six weeks later, she again reports
no side effects and no improvement.
Which is most appropriate at this time?

A. Add methylphenidate
B. Discontinue sertraline and begin
citalopram
C. Reassess in 4 weeks
D. Refer for electroconvulsive therapy
3. A 72-year-old woman is evaluated for a
4-month history of insomnia, with
difficulty falling asleep. The patient was
the major caretaker for her husband,
who had advanced heart failure and died
suddenly 4 months ago. She has lost 3.6
kg (8 lb) and does not have much of an
appetite. The patient used to volunteer
at the hospital, but she does not enjoy
going there any more. She also does not
have much energy. The patient is tearful
and says that nearly everything reminds
her of her husband. Medical history is
otherwise unremarkable. The physical
examination is unremarkable.
Which is the most appropriate
management option for this patient?

A.
B.
C.
D.

Begin dextroamphetamine
Begin mirtazapine at bedtime
Begin zolpidem at bedtime
Reassure the patient and schedule a
follow-up appointment in 3 months

4. A 37-year-old woman is evaluated in the

office for major depression that was
diagnosed 3 months ago and treated
with sertraline. Five weeks after
initiation of treatment, she had no
suicidal ideation, and her depressive
symptoms had improved, with a 5-point
decrease in her Patient Health
Questionnaire (PHQ-9) score. During
todays visit, she reports that her
depressive symptoms have continued to
improve, although she has experienced

sexual dysfunction manifested by

bothersome anorgasmia. She is also
overweight and is worried about gaining
more weight.
Blood pressure is 140/80 mm Hg. Her body
mass index is 29 kg/m2. The remainder of
the physical examination is normal.
Which is the most appropriate
alternative treatment option for this
patients depression?

A.
B.
C.
D.

Bupropion
Citalopram
Fluoxetine
Mirtazapine

5. A 29-year-old woman has an 8-month

history of insomnia, difficulty
concentrating, fatigue, and irritability. She
has trouble falling asleep, awakens after 2
or 3 hours, and has difficulty returning to
sleep. The patient is concerned that her
impaired concentration is interfering with
her work as an attorney and has tried to
compensate by spending long hours in the
office. Her social activities have decreased
because of the extended work hours. She
broke up with her boyfriend several months
ago and is concerned that she will soon be
30 years old and that her biological clock
is ticking. She frequently lies awake in bed
wondering if she will make partner at her
law firm as well as whether she will ever
get married and have children. She has
occasional episodes of crampy abdominal
pain, but her appetite is unchanged and her
weight has been stable.
Findings on physical examination are
unremarkable. Body mass index is 24 kg/m2.
Results of routine laboratory studies,
including thyroid function tests, are normal.
The patient refuses to see a psychotherapist
because she finds talk therapy difficult.
Which is the most appropriate
pharmacologic agent at this time?

A.
B.
C.
D.

Alprazolam
Imipramine
Quetiapine
Sertraline

Questions are largely from the ACPs Medical Knowledge Self-Assessment Program (MKSAP, accessed at
http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/
to obtain up to 1.5 CME credits, to view explanations for correct answers, or to purchase the complete MKSAP program.

2010 American College of Physicians

ITC5-16

In the Clinic

Annals of Internal Medicine

4 May 2010