(Oxford Psychiatry Library) Raymond W. Lam - Depression-Oxford University Press (2018)

O P L
OX F O R D PSYCH IATRY LIB RARY
Depression
O P L
OX F O RD P S YC HIATRY LIB RARY
Depression
THIRD EDITION
Raymond W. Lam
Professor and BC Leadership Chair in Depression Research
Department of Psychiatry, University of British Columbia
Vancouver, British Columbia, Canada
1
1
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Preface to the Third Edition
Despite some initial controversy, DSM-5 (Diagnostic and Statistical Manual of
Mental Disorders, 5th edn) has been accepted and adopted by most clinicians as
an incremental advance for the field. This new edition now incorporates DSM-5
as well as recent revisions in treatment guidelines for depression. The CANMAT
206 Clinical Guidelines for the Management of Adults with Major Depressive
Disorder were published as a theme issue in the Canadian Journal of Psychiatry,
and are available for free download at http://www.canmat.org, accessed 
October 207. The CANMAT guidelines provide much of the reference material
used to summarize new evidence and recommendations for the dizzying array
of available treatments for depression, ranging from mindfulness-based psycho-
therapies to novel antidepressant medications, to neurostimulation and exercise.
All the key references in this edition have been updated to reflect the latest evi-
dence. I want to thank, again, my CANMAT colleagues (nearly 50 strong) for their
dedicated leadership in producing these internationally used guidelines, especially
my guidelines’ co-lead, Dr Sidney Kennedy. Their efforts contribute to making this
book clinically useful.
Progress usually advances incrementally, but medicine is at the tipping point
for the next great revolution—a digital personalized one. The emergence of
data science with ‘big data’ artificial intelligence and machine learning algorithms
heralds a real promise of precision medicine. Biomarker studies have given way
to biosignature research incorporating panels of integrated clinical, neuroimag-
ing, and molecular markers. Predicting individual response to treatment using
crowdsourced EEG (electroencephalographic) and clinical information; personal-
ized alerts for relapse with apps that analyze voice modulation, text messages,
and geographic location patterns; reprogramming neural circuits with individual-
ized brain games; adapting the lighting at home to optimize sleep and circadian
rhythms—these possibilities are no longer science fiction even if, for now, they
are not yet ready for prime-time clinical use. I have no doubt that this innova-
tive research will soon transform the diagnosis, management, and treatment of
depression. I look forward to incorporating these discoveries in a major rewrite
for the next edition of this book.
Raymond W. Lam, MD, FRCPC

Preface to the Second Edition
Progress is inevitable. In the 3 years since publication of the first edition, a num-
ber of advances have occurred in the management of depression. Several new
antidepressants have entered the clinical market. Second generation antipsychotic
medications are now clearly beneficial as adjunctive therapy (and, for one, as
monotherapy) for major depressive disorder. Mindfulness-based cognitive ther-
apy has strengthened its evidence base for prevention of depressive relapse.
Technology-assisted psychotherapy has come of age and transcranial magnetic
stimulation has become clinically available in many centres. The ketamine story
may herald a new frontier for understanding the pathophysiology of depression
as well as offering the promise of a truly rapid acting antidepressant.
It is because of these advances that a revision and second edition of this book
was necessary. Several new sections have been added and the key references have
been updated throughout. Some of these developments were summarized in the
CANMAT Clinical Guidelines for Management of Major Depressive Disorder,
published in 2009 and widely distributed and accessed all over the world.
The next revision will likely be necessary after the upcoming publication and
dissemination of the DSM-5 in 203 (www.dsm5.org). Although the section on
mood disorders will not undergo major modification, there are many planned
changes in other diagnoses and in the overall structure and ‘look and feel’ of
DSM-5. Many of the proposed revisions remain controversial. It will be important
to update clinical management in response to these changes. In the meantime,
I dedicate the second edition of this book to the patients and families who are our
partners in the recovery process from major depressive disorder.

Preface to the First Edition
All the recent new research and knowledge about depression makes it a daunt-
ing task to summarize the vast amounts of information into manageable, yet still
relevant, portions. Much of the work of this volume arose from my involvement
with the Canadian Network for Mood and Anxiety Treatments (CANMAT) in
developing Canadian clinical practice guidelines for depression. I am indebted to
my expert CANMAT colleagues for their many hours of thought-provoking dis-
cussion about all aspects of depression and its treatment. I especially want to
thank Dr Sidney H. Kennedy, Professor of Psychiatry at the University of Toronto
and Chief of Psychiatry at the University Health Network, for his support and
collaboration over many years.
Throughout this book we have tried to simplify the diagnosis and management
of what is a complex disorder, to make the evidence relevant, and to illustrate
the art and the science. Our intent is to provide a practical reference to help ‘at
the bedside’ (or, at least, at the nursing station). We hope that clinicians will find
this book useful.

Contents
Abbreviations x
. Introduction 1
2. Epidemiology and burden 3
3. Pathogenesis 11
4. Clinical features and diagnosis 23
5. Associated clinical features 35
6. Clinical management 45
7. Psychological treatments 53
8. Pharmacological treatments 63
9. Somatic treatments 85
0. Special populations 95
Appendix: Sample rating scales 3

Index 3
Abbreviations
5-HT 5-hydroxytryptamine (serotonin)
ACTH adrenocorticotropic hormone
AIDS acquired immune deficiency syndrome
ASRI allosteric serotonin reuptake inhibitor
BA behavioural activation
BDNF brain-derived neurotrophic factor
BT behaviour therapy
CAM complementary and alternative medicine
cAMP cyclic adenosine monophosphate
CANMAT Canadian Network for Mood and Anxiety Treatments
CANTAB Cambridge Neuropsychological Test Automated Battery
CBASP cognitive behavioural-analysis system of psychotherapy
CBT cognitive–behavioural therapy
CDM chronic disease management
CNS central nervous system
CNS-VS CNS Vital Signs
CREATE Cardiac Randomized Evaluation of Antidepressant and Psychotherapy
Efficacy (trial)
CRF/CRH corticotropin-releasing factor/hormone
CT cognitive therapy
DBS deep brain stimulation
Dex/CRH dexamethasone suppression test in combination with the
CRH-stimulation test
DLPFC dorsolateral prefrontal cortex
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edn
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edn
DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edn (text
revision)
ECT electroconvulsive therapy
EEG electroencephalograph
ENRICHD Enhancing Recovery in Coronary Heart Disease (study)
EPDS Edinburgh Postnatal Depression Scale
FDA US Food and Drug Administration
GI gastrointestinal
G×E gene by environment
abbreviations • xi
HADS Hospital Anxiety and Depression Scale
HAM-D Hamilton Depression Rating Scale
HPA hypothalamic-pituitary-adrenal
5-HTTLPR 5-hydroxytryptamine (serotonin) transporter linked
polymorphic region
ICD-0 International Classification of Diseases (version 0)
INR international normalized ratio
IPT interpersonal psychotherapy
K-DEPACS Korean Depression in Acute Coronary Syndrome (study)
LEAPS Lam Employment Absence and Productivity Scale
LED light-emitting diode
MADRS Montgomery–Åsberg Depression Rating Scale
MAO monoamine oxidase
MAOI monoamine oxidase inhibitor
MBCT mindfulness-based cognitive therapy
MDD major depressive disorder
MDE major depressive episode
MI myocardial infarction
MINI Mini International Neuropsychiatric Interview
MT melatonin
NDRI noradrenaline–dopamine reuptake inhibitor
NMDA N-methyl-D-aspartate
NNT number needed to treat
NRI noradrenaline reuptake inhibitor
NSAID non-steroidal anti-inflammatory drugs
OCD obsessive-compulsive disorder
PDQ-D-5 Perceived Deficits Questionnaire—Depression, 5 item
PHQ-9 Patient Health Questionnaire
PRIME-MD Primary Care Evaluation of Mental Disorders
PST problem-solving therapy
QIDS-SR Quick Inventory of Depressive Symptomatology (self-rated)
QTc corrected QT interval
RCT randomized controlled trial
RDoC Research Domain Criteria
REM rapid eye movement
RIMA reversible inhibitor of MAO-A
rTMS repetitive transcranial magnetic stimulation
SAD-HART Sertraline AntiDepressant Heart Attack Randomized Trial

xii • abbreviations
SAM-e S-adenosylmethionine
SCID Structured Clinical Interview for DSM-IV-TR
SERT serotonin transporter
SGA second-generation antipsychotic
SIGMA structured interview guide for the Montgomery–Åsberg Depression
Rating Scale
SNRI serotonin and noradrenaline reuptake inhibitor
SRI serotonin reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
STAR*D Sequenced Treatment Alternatives to Relieve Depression (study)
SWA slow-wave activity
SWS slow-wave sleep
TADS Treatment for Adolescents with Depression Study
TCA tricyclic antidepressant
TRD treatment-resistant depression
TSD total sleep deprivation
VNS vagus nerve stimulation
WHO World Health Organization

Chapter 1
Introduction
Key points
• Depression is a common and disabling psychiatric condition that must be
recognized by all physicians and health professionals.
• The principles of care for major depressive disorder include: thorough
assessment and diagnosis, selection of appropriate and evidence-based
treatments, and careful follow up using measurement-based care.
A 36 year old janitor who has insomnia and is fatigued all the time. A 24 year old
with diabetes who has stopped taking her insulin. A 40 year old homemaker who
cries and cannot cope at home. A 69 year old seen in the emergency room with
his second heart attack within 3 months. A 32 year old executive who is procras-
tinating about making decisions at work. A 7 year old high-school student who
cannot stop thinking about ending her life. What do all these various people have
in common? They are all suffering from depression, one of the most common of
all medical conditions, yet one of the most difficult to recognize.
Depression is ubiquitous, but the number and range of physical and cognitive
symptoms associated with major depressive disorder (MDD) means that many
people do not present with emotional symptoms. Although one in seven people
will suffer psychosocial impairment from MDD, many will not be diagnosed des-
pite repeated healthcare visits. And, it is not only family physicians, psychiatrists
and mental health clinicians that need to diagnose depression. The high preva-
lence of MDD with other medical illnesses means that other health profession-
als and physicians, whether internists or oncologists or surgeons or cardiologists
or neurologists or any other specialist, must also recognize and manage clinical
depression in their patients. After all, as some authors have noted, there is ‘no
health without mental health’.
Governments and healthcare payers are now finally appreciating the hidden
socioeconomic burden that results from MDD. Depression is a huge drain on
the economy, with exceedingly high rates of disability and reduced productivity.
The World Health Organization announced in 207 that depression had become
the leading medical cause of functional disability worldwide. The concentration,
memory, and decision-making problems associated with depression are particu-
larly damaging to workforces in knowledge-based industries, a major issue for
many countries trying to convert from resource-based economies.
chapter 1
2 • introduction
But, recognizing depression is not enough. The good news is that there are very
effective treatments for depression. Evidence-based psychotherapies abound,
there are many effective antidepressant medications, and several non-invasive
somatic treatments also are available. With appropriate treatment, most patients
are able to promptly recover from a depressive episode and return to their usual
functioning. And, there is an explosion of new research and new methodolo-
gies to expand our understanding of the pathophysiology of depression, with the
promise of new, more effective, and better tolerated treatments to come.
The bad news, however, is that many patients with depression are still not able
to access these treatments, whether psychotherapy or new medications or new
technologies. Even when available, the current systems of health care often do
not achieve best practices for treating MDD, so that the ‘usual care’ of depression
is not good enough. For those patients whose depression can be regarded as a
chronic or persistent condition, collaborative disease management programmes
that include a focus on self-management and functional improvement, instead of
symptom resolution, will further engage patients and clinicians to optimize care.
Mobile and internet technologies also herald promise in terms of access to both
educational information and evidence-based treatments. And, we are getting
closer to identifying clinically useful biomarkers to personalize treatment recom-
mendations for patients with MDD.
This book seeks to succinctly address the diagnostic and treatment issues
that clinicians will encounter when dealing with patients with MDD. The princi-
ples of care for depression can be quite simple. Attention to early recognition,
careful assessment, selection of appropriate evidence-based treatments, and
measurement-based follow up will help our patients get the best care possible.
Further Reading
Lam RW, Kennedy SH, Parikh SV, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 Clinical Guidelines for the Management of Adults with
Major Depressive Disorder: Introduction and methods. Can J Psychiatry 61: 506–9.
Prince M, Patel V, Saxena S, et al. (2007) No health without mental health. Lancet
370: 859–77.
Summergrad P (206) Investing in global mental health: the time for action is now. Lancet
Psychiatry 3: 390–.
World Health Organization (207) Depression and Other Common Mental Disorders.
Geneva: WHO Document Production Services.
chapter 1
Chapter 2
Epidemiology and burden

Key points
• Depression is a highly prevalent condition—about one in seven people will
experience a depressive episode during their lifetime.
• Many people with depression will have a recurrent or chronic course, leading to
substantial impairment in psychosocial function.
• Depression is now the leading cause of years lived with disability worldwide.
• The economic costs of depression are staggering, both in direct medical
costs of treating depression and in indirect costs of work absence and loss of
productivity.
• Depression remains severely undertreated, but scaling up depression treatment
brings US$5 of economic return for every US$ spent.
2.1 Prevalence
2.. Current trends
Depressive disorders are very common conditions as the lifetime risk for expe-
riencing major depressive disorder (MDD) is approximately 5% (Table 2.).
Depression also contributes significantly to disability, with estimates that depres-
sion accounts for .3–4.4% of all disability and premature deaths worldwide. Two
major epidemiological trends are occurring with respect to depressive disorders.
First, the lifetime risk of developing depression in those born after the Second
World War is increasing, although some studies suggest this increase began as far
back as 925. Second, in both women and men, the age of onset for depression
is becoming increasingly younger, which corresponds to the rise in psychiatric
hospitalizations amongst adolescents.
2..2 Sex
The lifetime prevalence of MDD is .6–3. times more common in women than
men, with a greater disparity found in the USA and Western Europe. The dispar-
ity begins at the age of puberty and it is common to find worsening of depressive
symptoms in women coinciding with the onset of menses. Other hypothesized
causes of increased depressive episodes in women include hormonal differences,
psychosocial stressors, and childbirth. The disparity between the sexes appears
to be narrowing in studies involving younger cohorts, and the gap also decreases
after the age of 50–55 years as women enter menopause.
chapter 2
4 • epidemiology and burden
Table 2. Prevalence of DSM-IV MDD in general populations

Prevalence rates (%)
Location 2 month Lifetime

Brazil (Sao Pâulo) 0.4 8.4
USA 8.3 9.2
New Zealand 5.7 5.8
France 5.9 2.0
Netherlands 4.9 7.9
Australia 4.8 2.8
Spain 4.0 0.6
Mexico 4.0 8.0
Canada* 3.9 9.9
China (Shenzen) 3.8 6.5
Germany 3.0 9.9
Japan 2.2 6.6
Source data from: BMC Medicine, 9, Bromet E, Andrade LH, Hwang I et al., Cross-national
epidemiology of DSM-IV major depressive episode, 20; Canadian Journal of Psychiatry, 60, Patten SB,
Williams J, Lavorato DH, et al., Descriptive epidemiology of major depressive disorder in Canada in
202, 205, pp. 23–30.
* Data on Canada is from the Canadian Community Health Survey.
2..3 Age
In worldwide population samples aged 8–64 years, the average age for the
onset of depression varies from 24 to 35 years, with a mean age of 27 years.
There is currently a trend of an increasingly younger age of depression onset. For
example, 40% of depressed individuals have their first depressive episode prior
to the age of 20, 50% have their first episode between the ages of 20–50, and the
remaining 0% after 50 years of age.
Depressive symptoms also vary with age. Childhood depression tends to involve
more somatic complaints combined with irritability and social withdrawal, and ado-
lescents experience more ‘atypical’ features of depression (e.g. overeating, hyper-
somnia), while elderly depressed patients are most likely to have depressive features
of melancholia (e.g. loss of interest or pleasure, lack of reactivity, insomnia).
2.2 Course and prognosis

2.2. Course
About half of individuals with first- episode depression experience a pro-
dromal period during which significant depressive symptoms are present. These
chapter 2
epidemiology and burden • 5
symptoms, which can be present for weeks to years prior to diagnosis, include
anxiety and other mild depressive symptoms. The length of an untreated depres-
sive episode varies from 4 to 30 weeks for a mild–moderate depression, while
severe episodes have an average length of 6–8 months. Nearly 25% of individuals
with severe depressive episodes will endure symptoms for more than 2 months.
Treated depressive episodes last on average 3 months; however, stopping anti-
depressants prior to 3 full months of use almost always results in the return of
symptoms.
2.2.2 Prognosis
For many patients, MDD can be a chronic, relapsing illness. Relapse within the
first 6 months of recovery occurs in 25% of patients, 58% will relapse within the
first 5 years, and 85% will relapse within 5 years of initial recovery. Moreover,
those individuals that have had two previous depressive episodes have a 70%
probability of a third, and having three previous depressive episodes incurs a 90%
likelihood of relapse. As the disease progresses, the interval between depressive
episodes becomes shorter and the severity of each episode becomes greater.
Over a 20-year span, depressive recurrences occur on average five to six times.
A significant proportion of depressed individuals remain chronically ill with
varying levels of symptoms. About two-thirds of patients with a major depressive
episode will fully recover, while one-third of depressed patients will either only
partially recover or remain chronically ill. In a study of patients at  year post-
MDD diagnosis, 40% had recovered with no symptoms of depression, 20% con-
tinued to have residual symptoms but did not meet the criteria for MDD, while
40% remained in a major depressive episode. Those individuals that continue to
have residual depressive symptoms are at a high risk of relapse, suicide, poor
psychosocial functioning, and higher mortality from other medical conditions.
In addition to depression, 5–0% of individuals who have experienced a major
depressive episode will subsequently have a manic or mixed episode indicative
of bipolar disorder.
Numerous studies have focused on prognostic indicators which have a pre-
dictive value in terms of the recovery rate and relapse probability in depressed
individuals (Box 2.).
2.3 Burden of illness

2.3. Disability and death
Depression causes substantial impairment in daily functioning. Social functioning
decreases in correlation with increasing depressive severity as 8% of patients
with minor depression were found to have major problems with daily interac-
tions, compared to 52% of patients with seven to nine symptoms of a major
depressive episode. In general, depression has been found to increase the risk of
social disability 23-fold over the general population.
chapter 2
Box 2. Prognostic indicators of a prolonged recovery in patients

with MDD
• Severe depressive episode
• Long duration of depressive episode (>6 months)
• Presence of comorbid illness
• Presence of psychotic features
• Early age of onset
• Alcohol or drug abuse
• History of prior psychiatric illness (e.g. previous depressions or anxiety
disorder)
• Three or more prior hospitalizations
• Poor social support, poor family functioning, and low family income
• Low level of functioning for 5 years prior to illness
Similarly, depressed patients have almost two times greater overall mortality risk
than the general population owing to direct causes (e.g. suicide) and indirect causes
(e.g. medical illness). The risk of death by suicide increases 26-fold in depressed
individuals. However, the lifetime prevalence of suicide for depressed individuals
is 2.2% and suicide represents only % of reported deaths related to depression.
Depressed patients are at a .8 times greater risk of developing a medical
illness  year post-diagnosis. In particular, hospitalized depressed patients with
comorbid cardiovascular disease are at a significantly increased risk for myocar-
dial infarct and death for 0 years post-hospitalization. For example, depressed
patients with unstable angina are at a three times greater risk of death than non-
depressed individuals. The increased risk of cardiovascular death likely is due to
both direct physiological effects (e.g. reduced heart rate variability, increased
platelet aggregation) and indirect effects (e.g. poor compliance with medications,
drug and alcohol abuse, etc.) of depression (see Chapter 0).
2.3.2 Socioeconomic costs

As of 2000, depression was the fourth leading cause (of over 300 causes) of
disability worldwide, representing 2% of all years lived with disability. By 203,
depression had risen to the second leading medical cause of years lived with dis-
ability, behind only low back pain (Figure 2.). In April 207, the World Health
Organization announced that depression had become the first-ranked leading
cause of health-related disability. An estimated 322+ million people were esti-
mated to have depression, representing 4.4% of the world population, leading to
50+ million years lived with disability in 205.
In terms of work productivity, those suffering with depression are three to
four times more likely to take sick days off work than non-depressed individu-
als. In a U.S. survey, the salary-equivalent productivity loss attributed to depres-
sive absenteeism (average US$82–US$395) approached the estimated cost of
chapter 2
Low back pain
Major
depression
Iron deficiency
anaemia
Neck pain
Hearing loss
0 20 40 60 80
Mean years lived with disability (x1,000,000)
Figure 2. The Global Burden of Disease Study. In 203, depression ranked second
in total health-related disability worldwide.
treating depression. Studies have also found that employers, on the whole, have
negative beliefs about mental illness and are less likely to hire depressed individu-
als based on expectations of sub-standard work performance. In fact, depressed
individuals have a perceived increase in self-rated productivity when they experi-
ence fewer and less severe depressive symptoms, suggesting that early treatment
of depression would economically benefit employers.
The astounding economic costs of depression are due to a combination of dir-
ect treatment of depression, premature mortality (e.g. by suicide), and reduced
productivity and absenteeism. The total annual costs of depression in the United
States are estimated at US$44 billion: US$2.4 billion in direct costs of treat-
ment (hospitals, medications, doctors’ fees), US$8 billion in premature death,
and US$24 billion in absenteeism and reduced productivity in the workplace. In
Canada, the indirect costs of depression (premature mortality and reduced prod-
uctivity) are estimated at C$5 billion, and represent 58% of the overall economic
cost of depression. These approximations, however, underestimate the overall
cost of depression because they do not include out-of-pocket family expenses,
and costs of minor and untreated depression, excessive hospitalization, general
medical services, and diagnostic tests.
2.3.3 Costs of untreated depression

Depression increases the risk for both social and physical disability, and as a
result, increases the costs for other medical services. Nevertheless, an even
greater strain on the medical system originates from the cost of undiagnosed and
untreated depression. Individuals with depressive symptoms, who have not been
diagnosed with a depressive disorder, utilize more medical services and attempt
chapter 2
suicide more often than MDD-diagnosed patients. In a U.S. study, patients diag-
nosed with depression recovering from surgery stay on average 0 days longer in
hospital than non-depressed patients. However, those individuals with untreated
depressive symptoms stayed 26 days longer than non-depressed patients. In fact,
individuals with untreated depression account for the majority of ‘high utilizers’
of general medical services. Thus, diagnosing and treating these individuals should
lessen the burden on the medical system.
2.3.4 Costs of treatment

Depression remains severely undertreated worldwide, but especially so in lower
income countries, where there are also very low rates of perceived need for treat-
ment (Figure 2.2). Effective treatment of depression has been found to improve
patient social functioning, lower risks of other medical illnesses, decrease lost
and unproductive work days, and consequently reduce disability costs. Moreover,
the use of pharmacotherapy and psychotherapy in the treatment of depres-
sion reduces the overall cost to the entire healthcare system. In primary care
settings, the implementation of collaborative care and chronic disease manage-
ment programmes also has been shown to cost-effectively improve outcomes of
depressed patients. Unfortunately, even higher income countries have low rates
of adequate treatment for depression (Figure 2.2). The economic savings for
100
Perceived need for treatment Received any treatment Received adequate treatment
90
80
70
% of people with MDD
60
50
40
30
20
10
0
USA France Germany Spain Brazil* Mexico Bulgaria Iraq China* Columbia Peru
6.7% 5.6% 3.1% 3.8% 10.1% 3.7% 3.0% 3.9% 2.0% 5.3% 2.7%
Higher income Upper-middle income Lower-middle income
* Data from individual city surveys for Brazil (Sao Pâulo) and China (Beijing/Shanghai).
Percentages below country label indicate the 12-month prevalence rate of MDD.
Figure 2.2 Proportion of people with MDD who perceived a need for treatment,
received any treatment, and received adequate treatment in the WHO World
Mental Health Survey.
Source data from The WHO World Mental Health Surveys: Global Perspectives on the Epidemiology of
Mental Disorders, Kessler R.C and Ustun T.B (eds.), 2008.
chapter 2
scaling up treatment services for depression are considerable, with a global study
estimating a US$5 return on investment for every US$ spent.
Further Reading
Bromet E, Andrade LH, Hwang I, et al. (20) Cross-national epidemiology of DSM-IV
major depressive episode. BMC Medicine 9: 90.
Chesney E, Goodwin GM, Fazel S (204) Risks of all-cause and suicide mortality in mental
disorders: a meta-review. World Psychiatry Rep 13: 53–60.
Chisolm D, Sweeny K, Sheehan P, et al (206) Scaling-up treatment of depression and
anxiety: a global return on investment analysis. Lancet Psychiatry 3: 45–24.
Coventry PA, Hudson JL, Kontopantelis E, et al. (204) Characteristics of effective
collaborative care for treatment of depression: a systematic review and meta-regression
of 74 randomised controlled trials. PLoS One 9: e084.
Donohue JM, Pincus HA (2007) Reducing the societal burden of depression: a review of
economic costs, quality of care and effects of treatment. Pharmacoeconomics 25: 7–24.
Global Burden of Disease Study 203 Collaborators (205) Global, regional, and national
incidence, prevalence, and years lived with disability for 30 acute and chronic diseases
and injuries in 88 countries, 990–203: a systematic analysis for the Global Burden of
Disease Study 203. Lancet 386: 743–800.
Kessler RC (202) The costs of depression. Psychiatr Clin North Am 35: –4.
Lam RW, McIntosh D, Wang JL, et al. (206) Canadian Network for Mood and Anxiety
Major Depressive Disorder: Section . Disease burden and principles of care. Can J
Psychiatry 61: 50–23.
Thornicroft G, Chatterji S, Evans-Lacko S, et al. (207) Undertreatment of people with
major depressive disorder in 2 countries. Br J Psychiatry 210: 9–24.
World Health Organization (207) Depression and Other Common Mental Disorders.
Geneva: WHO Document Production Services.
chapter 2
Chapter 3
Pathogenesis
Key points
• There are likely multiple processes to explain the aetiology and pathophysiology
of depression, with involvement of biological, psychological, and social factors.
• Circadian rhythmicity, stressful life events, and stress reactivity can modify
genetic and biological processes (gene–environment interactions) to contribute
to depression.
• Endophenotypes, or genetic expressions of neural systems involved in
depression, are important in the study of the pathogenesis of depression and
the development of novel treatments.
3.1 Introduction
The exact pathophysiology of major depressive disorder (MDD) remains
unknown, but the aetiology has always been presumed to be heterogeneous
since the diagnosis of MDD is only descriptive and likely consists of a number
of syndromes with related symptoms. Biological, psychological, and social factors
all influence MDD, and each has reciprocal relationships with the others (Figure
3.). New research in genetics, neuroimaging, and molecular biology has clarified
some of the relationships between these broad forces, particularly in the modu-
lation of stress and life events on genetic and neurobiological processes. There is
increasing emphasis on endophenotypes, defined as endogenous phenotypes that
are not evident to the unaided eye that fill the gap between genes and a complex
disease, to advance our classification of depressive disorders and to guide treat-
ment selection (Figures 3.2 and 3.3). This chapter will highlight some of these
recent advances.
3.2 Genetics
3.2. Family, twin, and adoption studies
Family studies indicate at least two or three times increased relative risk (5–25%)
for MDD in first-degree relatives of MDD probands, with early age of onset
and recurrent depression conferring greater risk. Adoption studies, most from
Scandinavia, found that biological relatives of depressed adoptees were much
more likely to have depression than the adoptive relatives. Twin studies, by
comparing monozygotic to dizygotic twins, allow the dissection of genetic from
chapter 3
12 • pathogenesis
Biological Psychological Social
Relationships,
Genetics Personality
Work/Leisure
Circadian
Rhythms
Neurohormones,
Neurochemicals,
Person
with depression
Neuroinflammation
Physical illnesses, Life experiences,

Medications/drugs Life stresses
Figure 3. Relationships between biological, psychological, and social factors in the
pathophysiology of depression.
environmental influences on disease risk. Estimates from twin studies of genetic

heritability of depression range from 33% to 70%, independent of gender. The
consistent results from these varied studies indicate a substantial genetic basis
for MDD.
3.2.2 Linkage and association studies

Linkage analysis studies have not produced replicated results, mainly because
complex disorders such as MDD are not likely to be due to abnormalities in a
single gene locus. Large samples (at least ,000 affected sibling pairs) are needed
to reliably detect a locus that causes even a 30% increase in risk. Genome scan-
ning is a powerful new tool used to detect genetic associations, but results from
genome scans are prone to false-positive errors and need to be replicated in
other large samples.
Candidate gene strategies involving association analysis to genes coding for
particular elements of neurotransmitter function have been more informative
(Figures 3. and 3.2). Particular attention has been focused on functional poly-
morphisms, which are variations in DNA sequences that alter expression and/or
functioning of gene products. Initial enthusiasm was generated for an association
of MDD with the polymorphism involving the short allele of the promoter region
of the serotonin transporter gene, 5-HTTLPR (5-hydroxytryptamine (serotonin)
transporter linked polymorphic region), and with response to SSRIs (selective
serotonin reuptake inhibitors), but subsequent studies and meta-analyses have
not replicated these findings. However, other evidence suggests that 5-HTTLPR
polymorphisms are associated with neurotic traits and response to stressful life
chapter 3
pathogenesis • 13
Neuroanatomical abnormalities in major depression
Major depression
Increased stress
Depressed mood sensitivity (Gender
(Mood bias toward specific)
negative emotions)
Anhedonia
Impaired learning
(Impaired reward
and memory
Stress function)
Stress
Increased amygdala
activity/decreased Reduced Reduced Decreased
amygdala volume hippocampal ACC subgenual PFC
volume volume activity
CREB
NMDAR BDNF bcl-2 ?

5-HTTLPR MR
Figure 3.2 Example of how neurochemical abnormalities may relate to candidate

genes and to key components of major depression. Not all functional directions
are indicated for the sake of clarity for the figure. Abbreviations: 5-HTTLPR, 5-
HT (serotonin) transporter promoter region gene; ACC, anterior cingulate cor-
tex; bcl-2, B-cell lymphoma-2 gene; BDNF, brain-derived neurotrophic factor; CREB,
cAMP response element binding protein; MR, mineralocorticoid receptor; NMDAR,
NMDA receptor; PFC, prefrontal cortex.
Reprinted by permission from Macmillan Publishers LTD: Hasler G, Drevets WC, Manji HK,
et al. Discovering endophenotypes for depression. Neuropsychopharmacology 2004; 29:765–8,
copyright 2004.
events, suggesting that this transporter gene modifies stress reactivity rather
than causing MDD, per se. Other candidate genes being investigated in MDD
include tryptophan hydroxylase-2, brain-derived neurotrophic factor (BDNF),
cAMP-responsive element-binding protein (CREB)-, and genes involved in the
circadian clock.
3.3 Neurobiology
3.3. Monoamines
The monoamine hypothesis has been the foundation of neurobiological theories
for depression for the past half century. Initially based upon observations of the
mechanism of action of antidepressants, this hypothesis postulates that depres-
sion results from deficits in key brain areas in serotonin (5-HT) or noradrenaline
synaptic neurotransmission. Antidepressants were thought to act by blocking the
chapter 3
14 • pathogenesis
Figure 3.3 Example of how neurochemical abnormalities may relate to candidate

genes and to key components of major depression. Not all functional directions
are indicated for the sake of clarity for the figure. Abbreviations: 5-HTAR, 5-HT
(serotonin) A receptor; 5- HT2AR, 5- HT (serotonin)-2A receptor; 5- HTTLPR,
5-
HT (serotonin) transporter promoter region gene; CHRM2, cholinergic mus-
carinic-2 receptor; COMT, catechol-O-methyltransferase; CREB, cAMP response
element binding protein; CRH, corticotropin-releasing hormone; CRH-R, CRH-
 receptor; DBH, dopamine-beta-hydroxylase; GR, glucocorticoid receptor; HPA,
hypothalamic-pituitary-adrenal axis; MAO-A , monoamine oxidase-A ; MR, mineralo-
corticoid receptor; REM, rapid eye movement; SERT, serotonin transporter; TPH2,
tryptophan hydoxylase-2.
Reprinted by permission from Macmillan Publishers LTD: Hasler G, Drevets WC, Manji HK,
et al. Discovering endophenotypes for depression. Neuropsychopharmacology 2004; 29:765–8,
copyright 2004.
serotonin transporter (SERT), leading to increased availability of neurotransmit-

ter within the synaptic cleft. However, this theory did not account for the lag time
for onset of therapeutic effects of antidepressants, given that increases in synaptic
neurotransmitters occur immediately with reuptake inhibitors. Tryptophan and
catecholamine depletion studies also have not produced any evidence in support
of a simple deficit of neurotransmitter levels or function in MDD.
Newer models, incorporating various interdisciplinary neuroscience
approaches, have extended past the synapse to focus on the importance of pre-
synaptic and postsynaptic receptors and processes (Figure 3.4). For example,
chapter 3
pathogenesis • 15
Figure 3.4 Characterization of antidepressant effects using an interdisciplinary

approach. Abbreviations: 5-
HT, serotonin; GPCR, G- protein coupled receptor;
HPLC, high-performance liquid chromatography; IC, ion channel; SERT, serotonin
transporter.
Adapted from: Millan MJ. The role of monoamines in the actions of established and “novel” antidepres-
sive agents: a critical review. European Journal of Pharmacology 2004; 500:37–84.
delayed desensitization of presynaptic 5-HTA autoreceptors and downregulation

of postsynaptic α2-adrenergic receptors and/or 5-HT2 receptors have been pro-
posed to explain the delayed response to antidepressants.
3.3.2 Beyond monoamines

There is increasing evidence that non- monoamine neurotransmitters are
involved in the pathophysiology of depression. For example, glutamate is
a major excitatory neurotransmitter that acts via N- methyl- D-
aspartate
(NMDA) and other receptors to help regulate neurotrophic factors and neu-
roplasticity, including BDNF-mediated synaptogenesis (Figure 3.5). Ketamine,
an NMDA antagonist used primarily as an intravenous anaesthetic agent, has
been shown to induce rapid relief of depressive symptoms in people with
treatment- resistant depression. The mechanism of rapid ketamine action
involves a glutaminergic cascade that results in synaptogenesis and synaptic
potentiation. A novel melatonergic antidepressant, agomelatine, acts as an
agonist at melatonin- and -2 receptors and as an antagonist at 5-HT2C recep-
tors. The chronobiotic effects of agomelatine may be integral to its antidepres-
sant mechanism of action.
chapter 3
16 • pathogenesis
Figure 3.5 Mechanisms for cellular plasticity and neurogenesis and therapeutic effects
of standard and novel antidepressants. Abbreviations: α2AR, α2 adrenergic recep-
tor; 5-HT, serotonin; AC, adenyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptor; Bcl-2, B-cell lymphoma 2 protein; BDNF,
brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CREB,
cAMP response element binding; CRH, corticotropin-releasing hormone; GC, gluco-
corticoids; Glu, glutamate; GR, glucocorticoid receptor; HPA, hypothalamic pituit-
ary adrenal; MAPK, mitogen-activated protein kinase; NE, norepinephrine; NMDAR,
N-methyl-D-aspartate (NMDA) receptor; PKA, protein kinase A; TrkB, receptor
tyrosine kinase B.
This figure depicts the multiple targets by which neuroplasticity and cellular resilience can be increased in
mood disorders. (a) Phosphodiesterase inhibitors increase the levels of pCREB; (b) MAP kinase modula-
tors increase the expression of the major neurotrophic protein Bcl-2; (c) mGluR II/III agonists modu-
late the release of excessive levels of glutamate; (d) drugs such as lamotrigine and riluzole act on Na+
channels to attenuate glutamate release; (e) AMPA potentiators upregulate the expression of BDNF;
(f ) NMDA antagonists like ketamine and memantine enhance plasticity and cell survival; (g) novel drugs
to enhance glial release of trophic factors and clear excessive glutamate may have utility for the treatment
of depressive disorders; (h) CRF antagonists and (i) glucocorticoid antagonists attenuate the deleterious
effects of hypercortisolemia, and CRF antagonists may exert other beneficial effects in the treatment of
depression via non-HPA mechanisms; (j) agents which upregulate Bcl-2 (e.g., pramipexole, shown to be
effective in bipolar depression). These distinct pathways have convergent effects on cellular processes
such as bioenergetics (energy metabolism), neuroplasticity, neurogenesis, resilience, and survival.
Adapted from: Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood
disorders. Neuropsychopharmacology 2008; 33:2080–2092.
chapter 3
pathogenesis • 17
Other molecular biology studies have shifted attention from immediate pre-or
postsynaptic events to delayed post-receptor signalling pathways in the mech-
anism of action of antidepressants. The activation of postsynaptic receptors
initiates a cascade of biochemical effects mediating signal transduction, involv-
ing G-protein-coupled stimulation of cAMP (cyclic adenosine monophosphate)
or Ca2+ cascades. Activation of CREB results in increased expression of BDNF,
which acts to promote neurogenesis and cellular plasticity, and which may account
for the therapeutic effects of antidepressants. These neuroplasticity and cellular
resilience pathways provide novel targets for antidepressant drug development
(Figure 3.5).
3.3.3 Hypothalamic-pituitary-adrenal-immune axis

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis have long been rec-
ognized to be associated with MDD. The biological effects of stress are mediated
via secretion of corticotropin-releasing factor/hormone (CRF/CRH), leading
to increased secretion of adrenocorticotropic hormone (ACTH) and release
of glucocorticoids. Glucocorticoids alter noradrenergic receptor sensitivity via
regulation of the beta-adrenoreceptor-coupled adenylate cyclase system in the
brain. Chronic stress results in hypersensitivity of the HPA axis, and MDD is
associated with increased concentrations of CRF in cerebrospinal fluid, increased
CRF immunoreactivity and gene expression of CRF in the hypothalamic paraven-
tricular nucleus, and downregulation of CRF-R receptors in the frontal cortex.
Prolonged glucocorticoid secretion has neurotoxic effects, particularly on neuro-
genesis in the hippocampus (Figure 3.5).
The dexamethasone suppression test in combination with the CRH-stimulation
test (dex/CRH) is the most sensitive neuroendocrine measure of impaired cor-
tisol response and HPA sensitivity. Although it has good sensitivity for detect-
ing MDD, the dex/CRH still lacks sufficient specificity (to distinguish MDD from
other conditions such as schizophrenia and panic disorder) to be used as a diag-
nostic test. Other clinical implications of increased CRF and glucocorticoid pro-
duction in MDD include the possibility that dampening the CRF response may
have therapeutic effects, and several novel CRF and glucocorticoid antagonists
are in early-phase clinical trials as antidepressants.
There is also increasing evidence that disturbances in immune function and
neuroinflammatory mechanisms play a role in the pathogenesis of MDD. Acute
and chronic stress can activate the immune-inflammatory system, with produc-
tion of inflammatory proteins including C-reactive protein and proinflammatory
cytokines such as IL-6 and TNF-α. Bidirectional pathways to the brain can enable
these peripheral proinflammatory mediators to influence neural activity via activa-
tion of brain-resident microglia to produce depressive symptoms and behaviours.
Consequently, anti-inflammatory agents are also being investigated as novel anti-
depressant medications.
chapter 3
18 • pathogenesis
Box 3. Polysomnographic abnormalities of sleep in major depressive

disorder
• Early onset of rapid eye movement (REM) sleep (i.e. shortened REM latency)
• Increased time in REM sleep
• Increased REM density
• Decreased slow-wave sleep (SWS)
• Shift of SWS away from the early part of the night
• Disturbances in slow-wave activity (SWA)
3.3.4 Sleep and circadian rhythms

Sleep complaints (insomnia, hypersomnia) have long been considered cardinal
features of clinical depression, so it is not surprising that biological studies have
focused on dysregulation of sleep in MDD. Polysomnography has been used to
detect many abnormalities of sleep in MDD, and indeed offers some of the most
robust biological markers in depression (Box 3.). There remains controversy
over whether depression causes sleep changes, or vice versa. There is increasing
evidence that sleep changes are trait markers, predate onset of depression, and
predict relapse in remitted patients, thereby suggesting a pathogenetic role for
sleep in MDD.
Theories of sleep involve both homeostatic and circadian factors. The two-
process model suggests an interactive balance between the homeostatic need
for sleep, which increases with longer time awake, and a circadian propensity
for sleep, which shows a circadian pattern for sleepiness and attention. The
human circadian system is controlled by a biological pacemaker located in the
suprachiasmatic nucleus of the hypothalamus. This biological clock is regulated
by external zeitgebers (synchronizers), including the light/dark cycle, external
bright light, and social cues. Many circadian rhythms, such as cortisol, melatonin,
and thyroid-stimulating hormone, are disrupted in depression, with evidence
for both circadian phase shifts and decreased amplitude of rhythms. These
disturbances may be caused by primary dysfunction of the circadian clock or
by secondary disruption of zeitgebers such as stress-induced changes in sleep,
photic (light) exposure, or social behaviour (Figure 3.6). Circadian theories are
also intimately associated with seasonal affective disorder—particularly, phase-
delayed circadian rhythms that are corrected by appropriately timed bright light
exposure (see Chapter 9).
3.4 Neuropsychology
3.4. Cognition and memory
Patients with depression demonstrate a number of cognitive and memory defi-
cits, especially in selective attention and explicit (working) memory. In addition,
chapter 3
pathogenesis • 19
Behaviour Environment Biology Disorder
Photic Sleep
zeitgebers functioning
Rhythmic Depressive
social symptoms
behavior
Non-photic Circadian
zeitgebers functioning
Predisposition/
genetics
Figure 3.6 Model of sleep and circadian rhythm dysfunction in depression.
there are deficits in long-term storage and retrieval of declarative memory,

and in executive cognitive functioning such as selecting strategies and monitor-
ing performance. Finally, depression is also associated with disturbances in ‘hot’
cognition, or emotion-dependent cognitive processing. Many of the cognitive
problems have been associated with reduced cerebral blood flow and metabol-
ism to dorsolateral prefrontal cortex and dorsal anterior cingulate cortex. These
findings are of clinical importance for mechanisms of cognitive–behavioural ther-
apy for depression (see Chapters 5 and 7).
The hippocampus is critically involved in memory formation, as part of the cir-
cuit involved in information processing and creation of emotional and declarative
memories. Hippocampal volume is decreased in patients with depression, espe-
cially with recurrent or chronic episodes or a past history of trauma. Impaired
neurogenesis has been invoked to explain this finding, as increased glucocorticoid
secretion from prolonged stress is particularly neurotoxic to hippocampal neu-
rons (Figure 3.5). The neurogenesis theory also accounts for therapeutic effects
of antidepressants, since these drugs activate the cAMP cascade to release BDNF
and CREB, which serve to increase neurogenesis in hippocampus.
Functional neuroimaging studies have highlighted disturbances in higher order
organization and interconnectivity of brain regions involving specific neural cir-
cuits (Figure 3.7). These circuits link lower order subcortical functions and regions
(autonomic and regulatory) to those involving reward systems (limbic and paral-
imbic systems) and higher cortical function (cognition). In depression, network
dysfunction involving these limbic-cortical circuits—with underactivity in cortical
regions (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex) and
overactivity in the limbic (amydala, hippocampus, nucleus accumbens), paralimbic
(ventral anterior cingulate cortex, ventromedial prefrontal cortex), and integra-
tive cortical regions—are hypothesized to result in the mood and behavioural
symptoms and associated hypothalamic dysregulation.
chapter 3
20 • pathogenesis
DL PFC
Dorsal ACC
Cortical Rostral PFC SCC

OM PFC (Cg25)
Ventral ACC Amygdala

Hippocampus
Limbic VM PFC
N. Accumbens
Hypothalamus
Figure 3.7 Limbic- cortical dysregulation model. Regions in light shading indi-
cate overactivity and regions in dark shading indicate underactivity. Abbreviations:
ACC, anterior cingulate cortex; DL, dorsolaeral; N, nucleus; OM, orbitomedial;
PFC, prefrontal cortex; SCC (Cg25), subcallosal (subgenual) cingulate cortex; VM,
ventromedial.
The emotion-dependent ‘hot’ cognitive deficits in depression include negatively

biased responses in attention and working memory, hypersensitivity to negative
feedback, and excessive self-focus and rumination. In contrast to the circuitry of
‘cold’ cognitive dysfunction, the neural circuits for hot cognitive deficits primarily
involve connections between ventromedial prefrontal cortex and emotional pro-
cessing areas such as amydala.
In the limbic-cortical dysregulation model, alterations at various levels may
produce therapeutic effects. For example, cognitive–behavioural therapy may
modify cortical circuits, while antidepressant drugs may selectively affect circa-
dian or other limbic circuits; the net effect of both interventions may produce the
same adaptive changes in the entire system. One particularly interesting region
is the white matter subcallosal cingulate (subgenual cingulate, Brodmann area
Cg25), which modulates negative mood and shows hyperactivity in depressed
states, while response to varied antidepressant treatment is associated with
reduced activity in this region. This is one area targeted for deep brain stimulation
in treatment-refractory depression (see Chapter 9).
3.4.2 Environment and life events

Depression often follows a major psychosocial stressor, especially with the first
or second depressive episode. Adverse childhood experiences such as maltreat-
ment, loss of a parent, and inadequate social support are also common amongst
depressed patients. Increasing evidence has determined that stress and trauma
chapter 3
pathogenesis • 21
can affect biological systems of interest in depression. For example, animal stud-
ies have shown that early maternal deprivation leads to hypersensitivity of the
HPA axis in adulthood, with decreased hippocampal cell proliferation similar to
the reduced hippocampal volumes found in neuroimaging studies of patients with
depression and childhood trauma. This may have implications for treatment, as
studies have shown that patients with MDD and a history of early childhood
maltreatment have poorer outcomes in general, and better responses to psycho-
therapy than to antidepressant monotherapy.
Twin studies have shown an interaction between genetic risk and life events for
developing depression. However, not all stressful life events precipitate depres-
sion, and certain depressive episodes are not associated with stressors. A gene-
by-environment (G×E) interaction hypothesis, in which genetic vulnerability
influences the likelihood that exposure to stress will result in psychopathology,
may explain this discrepancy (Figure 3.8). Stressful life events have been shown
Normal
Level of Functioning
Impaired
Low High
Environmental stress
Genetically resilient (G main effect) – no effect of stress

Genetically neutral/‘wild-type’ (E main effect) – stress decreases function
Genetically vulnerable (G × E interaction) – stress decreases function
Genetically impaired (G main effect) – no effect of stress
Figure 3.8 Model of gene–environment (G×E) interactions. This figure illustrates

the potential interaction effects of environmental stress and genetic vulnerability.
Functioning is normal under conditions of low environmental stress, but impaired
under conditions of high environmental stress (curved line). Although high environ-
mental stress alone will degrade functioning (solid line), G×E interactions involve
a genetically determined increase in vulnerability to such environmental effects. In
contrast, genetically determined resilience (grey dashed line) or impairment (black
dashed line) are associated with normal or impaired functioning, respectively, inde-
pendent of levels of environmental stress.
Reproduced with permission from: Nugent NR, Tyrka AR, Carpenter LL, et al. Gene–environment
interactions: early life stress and risk for depressive and anxiety disorders. Psychopharmacology 20;
214:75–96
chapter 3
22 • pathogenesis
to have no effect on risk of developing a depression in women with the lowest
genetic vulnerability, but life events had increasing effects on depression risk in
those with increasing genetic loading for depression. These findings suggest that
environmental events, even those that happened in the past, can alter neurobio-
logical function for a long time.
The biological effects of early childhood adversity and life stressors may also
be mediated via epigenetic mechanisms, which involve functional modifications of
the genome that are influenced by environmental factors. MicroRNAs, small units
of non-coding RNA that help regulate gene function by influencing the translation
of target mRNAs, are also emerging targets for antidepressant drug discovery.
Further Reading
Abdallah CG, Sanacora G, Duman RS, et al. (205) Ketamine and rapid-acting
antidepressants: a window into a new neurobiology for mood disorder therapeutics.
Annu Rev Med 66: 505–23.
Cai S, Huang S, Hao W (205) New hypothesis and treatment targets of depression: an
integrated view of key findings. Neurosci Bull 31: 6–74.
Goldstein BL, Klein DN (204) A review of selected candidate endophenotypes for
depression. Clin Psychol Rev 34: 47–27.
Gudayol-Ferré E, Peró-Cebollero M, González-Garrido AA, et al. (205) Changes in
brain connectivity related to the treatment of depression measured through fMRI: a
systematic review. Front Hum Neurosci 9: 582.
Harvey AG (20) Sleep and circadian functioning: critical mechanisms in the mood
disorders? Annu Rev Clin Psychol 7: 297–39.
Hasler G, Drevets WC, Manji HK, et al. (2004) Discovering endophenotypes for
depression. Neuropsychopharmacology 29: 765–8.
Hasler G, Northoff G (20) Discovering imaging endophenotypes for major depression.
Mol Psychiatry 16: 604–9.
Kupfer DJ, Frank E, Phillips ML (202) Major depressive disorder: new clinical,
neurobiological and treatment perspectives. Lancet 379: 045–55.
Nugent NR, Tyrka AR, Carpenter LL, et al. (20) Gene–environment interactions: early
life stress and risk for depressive and anxiety disorders. Psychopharmacology
214: 75–96.
Rosenblat C, McIntyre RS, Alves GS, et al. (205) Beyond monoamines–novel targets
for treatment-resistant depression: A comprehensive review. Curr Neuropharmacol
13: 636–55.
Taylor C, Fricker AD, Devi LA, et al. (2005) Mechanisms of action of
antidepressants: from neurotransmitter systems to signaling pathways. Cell Sig
17: 549–57.
Wohleb ES, Franklin T, Iwata M, et al. (206) Integrating neuroimmune systems in the
neurobiology of depression. Nat Rev Neurosci 17: 497–5.
chapter 3
Chapter 4
Clinical features and diagnosis

Key points
• Depression is associated with a number of physical, emotional, and cognitive
symptoms.
• Sub-typing of major depressive disorder has implications for treatment choice
and selection.
• The differential diagnosis of depression includes bereavement, bipolar disorder,
and other medical or substance-induced conditions.
4.1 Clinical features

4.. Overview
Depression is associated with many different types of symptoms which can result
in a variable presentation in any given person. The features of depression can
be physical (sleep, energy, appetite, libido), emotional (low mood, anxiety, cry-
ing), or cognitive (guilt; pessimism; suicidal thoughts; problems with concentra-
tion, memory, and decision-making). Table 4. presents a common mnemonic for
depressive symptoms.
4..2 Symptoms
Low mood: While depressed people describe feelings of low mood, the emo-
tional misery experienced during a depression is qualitatively different from nor-
mal periods of sadness or grief that everyone experiences. Some have crying
spells, or feel like crying, while others describe a complete lack of emotional
response.
Interest/Pleasure: Loss of interest and pleasure (anhedonia) in activities or
social interactions which previously were pleasurable is another cardinal feature
of depression. Anhedonia also may show as indifference or boredom, and can be
present even when the person does not endorse low mood. Loss of sexual inter-
est, desire, or functioning is also common, which can lead to difficulty in intimate
relationships and marital conflict.
Sleep: Most depressed patients experience sleeping difficulties. The classic
presentation is waking from sleep early in the morning and being unable to fall
asleep again (terminal insomnia), but restless sleep and frequent waking during
the night (middle insomnia) are also common. Difficulty falling asleep at the begin-
ning of the night (early insomnia) is usually seen when anxiety also is present.
chapter 4
24 • clinical features and diagnosis
Table 4. SIGECAPS mnemonic for the clinical features of depression

Depressive symptom Presentation
(SIG: E-CAPS)
Sleep • insomnia or hypersomnia (atypical)
Interest/Pleasure • reduced pleasure (anhedonia), lack of motivation, loss
of interest
Guilt • guilt and self-blame, irrational/delusional thoughts
Energy • low energy, tired, fatigued
Concentration • inattentive, indecisive, distractible
Appetite • decreased or increased (atypical), weight loss or gain
(atypical)
Psychomotor activity • agitation or retardation
Suicide • hopelessness, suicidal thoughts, plans, attempts
In contrast, hypersomnia or oversleeping also can be a symptom of ‘atypical’

depression.
Energy: Low energy and/or fatigue are frequent complaints in depression,
as is difficulty in getting started or initiating tasks. The fatigue experienced can
be physical or mental, and may be associated with poor sleep and appetite. In
severe cases, routine activities such as daily hygiene, grooming, or eating may
be impaired. An extreme form of fatigue is ‘leaden paralysis’, in which patients
describe a feeling like their limbs are made of lead, or that they are walking
through water.
Guilt: Feelings of worthlessness and guilt can often consume an individual’s
thoughts during a depressive episode. Depressed patients may misinterpret triv-
ial daily events and take responsibility for negative events out of their control;
these can sometimes be of delusional proportion. Excessive worry and anxiety
can accompany and exacerbate guilt.
Concentration: Difficulty with concentration and decision-making is often
experienced in depression. Memory complaints are usually due to problems with
attention and distractibility. In elderly patients, the cognitive complaints may be
misdiagnosed as early dementia. Problems with concentration, memory, and
indecisiveness can greatly impair work functioning, especially in ‘white collar’
workers.
Appetite/Weight: Loss of appetite, taste, and enjoyment in eating can lead
to significant weight loss, and some patients may need to ‘force’ themselves to eat.
However, other patients may crave carbohydrates and sweets when depressed,
or self-treat by ‘comfort’ eating. Overeating, accompanied by decreased activity
and exercise, can lead to weight gain and metabolic syndrome. Changes in weight
may also impact on self-image and self-esteem.
chapter 4
clinical features and diagnosis • 25
Psychomotor activity: Psychomotor changes, which are subjective changes
in motor function without objective abnormalities on testing, are commonly seen
in depression. Psychomotor retardation consists of slowing (slowed body move-
ments, lack of facial expression, long latency of speech response) which, at its
extreme, can manifest as mute or catatonic presentations. Anxiety can also present
as psychomotor agitation (talking quickly, pacing, restlessness, inability to sit still).
Racing thoughts may be a symptom of mania, but is also a descriptor for anxiety.
Suicide: Some type of suicidal ideation, ranging from fleeting thoughts of wishing
everything would end to elaborate plans for suicide, is present in nearly two-thirds
of people with depression. Even when suicidal thoughts are serious, depressed
patients often lack the energy and motivation to attempt suicide. However, suicide
remains a significant issue as 0–5% of hospitalized depressed individuals eventu-
ally die by suicide. A period of high risk for suicide is during initial treatment, when
energy and motivation may improve before the cognitive symptoms (e.g. hope-
lessness), making it possible for suicidal patients to act on their thoughts and plans.
Other symptoms: Although not formally indicated as criteria for the diagno-
sis, a number of other symptoms and signs, including anxiety, irritability, cognitive
dysfunction, and pain, are associated with depression. These are discussed fur-
ther in Chapter 5.
4.2 Classification and diagnosis of depression

4.2. Classification of depression
The major classification systems used in clinical practice, DSM- 5 (Diagnostic
and Statistical Manual of Mental Disorders, 5th edn) and ICD-0 (International
Classification of Diseases, version 0), categorize diagnoses based primarily on
symptoms, course, and prognosis. However, it should be noted that alternative
classification systems, such as the Research Domain Criteria (RDoC) developed
by the National Institute of Mental Health in the United States, are attempting to
classify psychiatric conditions based on existing and emerging knowledge about
neural systems in the brain.
The DSM- 5 outlines three major sub- classifications for depression: major
depressive disorder (MDD), persistent depressive disorder, and other depressive
disorders. Figure 4. outlines a simple algorithm to distinguish these depressive
disorders from bipolar disorder.
4.2.2 Major depressive disorder

MDD is characterized by the presence of one or more major depressive episodes
(Box 4.). The diagnostic criteria require a threshold number of symptoms that
must be present much of the time, most days, for at least 2 weeks, although the
duration is usually much longer by the time that help is sought. The symptoms
also must significantly impair functioning or cause significant distress. Finally, other
causes of depressive symptoms must be excluded.
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Yes 5 out of 9 Yes Prior manic/ No Persistent Yes Persistent

Sad mood or
symptoms hypomanic symptoms depressive
low interest?
now? episode? >2 years? disorder
No
No Yes
5 out of 9 Yes Prior manic/ Yes Major

Bipolar
symptoms in hypomanic depressive
disorder
past? episode? disorder
No
No
Dysthymia Major
Persistent Yes (Persistent depressive
symptoms
depressive disorder with
>2 years?
disorder) residual
symptoms
No Other
specified
depressive
disorders
Figure 4. Differential diagnosis of depression.
MDD is identified as either single episode or recurrent, with the latter consist-
ing of two or more major depressive episodes with a remission interval of at
least 2 months. MDD can also be ‘sub-typed’ according to several specifiers and
by severity; these sub-types can be used to differentiate presentations of depres-
sion that have implications for recognition (distinctive symptoms or pattern),
prognosis, or treatment selection.
4.2.3 Persistent depressive disorder

Persistent depressive disorder, with symptoms present for at least 2 years,
encompasses chronic MDD with full syndromic criteria, MDD in partial remission,
and dysthymia. Dysthymia, or dysthymic disorder, is a chronic, low-grade mood
disorder during which the full criteria for a major depressive episode (MDE) are
not met (Box 4.2). Dysthymic symptoms can develop slowly, often unrecog-
nized by the individual, and persist for a minimum of two years (median 5 years).
Individuals with dysthymia often develop episodes of major depression (termed
‘double depressions’), which may prompt them to seek treatment.
However, persistent depressive disorder now includes both chronic MDEs,
with full symptom criteria for 2 years, and MDEs with residual symptoms that
persist longer than 2 years. Specifiers for persistent depressive disorder include
‘with pure dysthymic syndrome’ (when criteria for an MDE have not been met
within the last 2 years) and ‘with persistent major depressive episode’ (when full
criteria for MDE have been met throughout the last 2 years).
4.2.4 Other depressive disorders

Several other disorders are now included under ‘Depressive Disorders’ in DSM-5
(Box 4.3). Depressive disorders that occur secondary to substance use and other
medical conditions are described in sections 4.4.2 and 4.4.3.
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Box 4. Summary of DSM-5 criteria used to diagnose a major depressive

episode
• Five or more of the following nine symptoms present nearly every day for at
least 2 weeks, with at least one symptom including depressed mood or loss
of interest or pleasure, and associated with significant distress or impairment
in psychosocial functioning:
•depressed mood (feeling down, blue, tearful)
•fatigue or poor energy levels
•prominent and/or recurrent thoughts of death or suicide
•problems with concentration, memory, or decision-making
•insomnia or hypersomnia
• significant loss of interest in usual activities, or loss of pleasure/enjoyment
(anhedonia)
•marked feelings of guilt or self-blame (which may be delusional)
•loss of appetite or weight, or increased appetite or weight. In children,
this may present as failure to achieve a typical weight for their age.
•observable psychomotor agitation or retardation.
• There has never been a manic or hypomanic episode.
• The episode is not better explained by other diagnoses, including substance
use (e.g. illicit drugs or medications), other medical conditions (e.g. hypothy-
roidism), or other psychiatric conditions (e.g. schizoaffective disorder, schizo-
phrenia, or other psychotic disorders).
Source data from American Psychiatric Association, Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition DSM-5, 203, American Psychiatric Association
4.3 Sub-types of depression

4.3. Specifiers of major depressive disorder
Several specifiers (sub-types) of MDD have been established based on clinical
features and patterns of depressive episodes. These DSM-5 depressive speci-
fiers sub-classify depression with the intent to improve treatment selection and/
or predict prognosis. Table 4.2 outlines the depressive specifiers along with their
key features.
4.3.2 Severity
Both the DSM-5 and the ICD-0 categorize three separate levels of sever-
ity for MDD: mild, moderate, and severe (Table 4.3). The DSM-5 distinguishes
the severity based on the number and severity of symptoms and the extent of
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Box 4.2 Summary of DSM-5 criteria used to diagnose persistent depressive

disorder
• Depressed mood for most days for at least 2 years (in children and adoles-
cents, this can present as irritable mood with a duration of at least  year),
accompanied by two or more of the following 6 symptoms, and associated
with significant distress or impairment in psychosocial functioning:
•feelings of hopelessness
• low self-esteem
•problems with concentration, memory or decision-making
•fatigue or low energy
•insomnia or hypersomnia
•loss of appetite or increased appetite.
• During the 2 years of symptoms ( year for children and adolescents), there has
never been a 2-month period in which symptoms have been absent. Full symp-
tom criteria for a major depressive episode may be present during the 2 years.
• There has never been a manic or hypomanic episode.
• The episode is not better explained by other diagnoses, including substance
use (e.g. illicit drugs or medications), other medical conditions (e.g. hypothy-
roidism), or other psychiatric conditions (e.g. cyclothymic disorder, schizoaf-
fective disorder, schizophrenia, or other psychotic disorders).
Box 4.3 Other disorders classified as depressive disorders in DSM-5

Disruptive mood dysregulation disorder: This is a disorder of childhood
(age 6–8 years) characterized by persistent irritable or angry mood and severe
temper outbursts or acts of physical aggression. These behaviours are out of
proportion to a situation, not consistent with the developmental level, and not
part of a hypomanic or manic episode.
Premenstrual dysphoric disorder: In most menstrual cycles during the
previous year, symptoms regularly occurred during the last week of the luteal
phase and remitted within a few days of the onset of menses.
Other specified depressive disorders: These include presentations such as
minor depression (sub-syndromal episodes with insufficient symptoms), recur-
rent brief depression, and short-episode (i.e. 4–3 days) depressive episode.
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Table 4.2 DSM-5 specifiers (sub-types) of MDD

Sub-type DSM-5 specifier Key features
Melancholic With melancholic Non-reactive mood, anhedonia,
depression features weight loss, guilt, psychomotor
retardation or agitation, morning
worsening of mood, early morning
awakening
Atypical With atypical features Reactive mood, oversleeping,
depression overeating, leaden paralysis,
interpersonal rejection sensitivity
Psychotic With psychotic features Hallucinations or delusions,
(delusional) either mood-congruent or
depression mood-incongruent
Catatonic With catatonic features Catalepsy (waxy flexibility), catatonic
depression excitement, negativism or mutism,
mannerisms or stereotypies, echolalia
or echopraxia. This sub-type is
uncommon in clinical practice.
Anxious With anxious distress Symptoms of anxiety including feeling
depression tense or unusually restless, difficulty
concentrating because of worry,
fearing that something terrible may
happen, and worry about losing
control
Mixed episodes With mixed features Sub-syndromal hypomanic symptoms
including elevated mood, inflated self-
esteem or grandiosity, racing thoughts
or flight of ideas, talking more than
usual or pressured speech, increased
energy or activity, decreased need
for sleep, impulsive and reckless
behaviours
Seasonal With seasonal pattern Regular onset and remission of
affective depressive episodes during a particular
disorder (SAD) season (usually autumn/winter onset)
Peripartum With peripartum onset Onset of depressive episode
depression during pregnancy or within 4 weeks
postpartum
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Table 4.3 Depression severity criteria

Depression DSM-5 criteria ICD-0 criteria
severity
Mild . Minimal number of criterion . Two typical symptoms
symptoms with mild distress and 2. Two other core symptoms
manageable intensity
2. Minor impairment in social/
occupational functioning
Moderate . Number of symptoms, distress, . Two typical symptoms
and intensity between mild 2. Three or more other core
and severe symptoms
2. Moderate impairment in social/
occupational functioning
Severe . Most criterion symptoms are . Three typical symptoms
present with serious distress and 2. Four or more other core
unmanageable intensity symptoms
2. Marked impairment in social/ Also sub-typed as with or
occupational functioning without psychotic symptoms
Source data from: American Psychiatric Association, Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition DSM-5, 203, American Psychiatric Association; International Classification of
Diseases (ICD), version 0, 992, World Health Organization.
associated impairment in social and/or occupational functioning. The ICD-0,

however, differentiates the severity of depression based on the number and type
of symptoms present in the depressed individual. While these criteria may be of
heuristic value, validated depression rating scales are more clinically useful for
assessing severity (see Chapter 6 and Appendix).
Severity of depression may influence treatment choices. For example, psycho-
therapy is as effective as pharmacotherapy for mild-to-moderate depression, but
severe depression shows better response to combination treatment. Emerging
evidence also suggests that some antidepressants may be more effective than
others for severe depression (see Chapter 8).
4.4 Differential diagnosis

4.4. Bereavement
Bereavement or grief over loss of relationships can share similar symptoms
(e.g. intense sadness, insomnia, poor appetite) with a major depressive epi-
sode. However, bereavement is no longer an explicit exclusion criterion for
an MDE because it often cannot be distinguished from other types of stresses,
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such as loss of a job. Instead, the severity and duration of symptoms and their
impact on psychosocial functioning can help distinguish between grief and MDD
(Table 4.4).
4.4.2 Depressive disorder due to another medical condition

Depressive symptoms can result from the direct physiological effects of a specific
pre-existing medical condition. Conversely, the physical symptoms of a primary
medical illness may obscure the diagnosis of a comorbid MDD (see Chapter 0).
The Hospital Anxiety and Depression scale (HADS) is a useful screening tool
for medically ill patients in that it uses questions that focus on cognitive symp-
toms rather than somatic ones. MDD is prevalent in numerous chronic illnesses
(Table 4.5), but may be particularly common in diabetes, cardiovascular disease
(e.g. post-myocardial infarction), thyroid disease, and neurological disorders (e.g.
Parkinson’s disease, multiple sclerosis, dementia).
4.4.3 Substance/medication-induced depressive disorder

Side effects of drugs (whether prescribed or illicit) can also lead to depressive
symptoms, hence substance-induced mood disorders must be considered in
the differential diagnosis of MDD (Box 4.4). Evidence from the history, physical
examination, or laboratory findings is used to establish whether abuse, depend-
ence, intoxication, or withdrawal states are physiologically inducing a depressive
episode. While substance-induced depressive symptoms usually resolve with dis-
continuation of the substance, some intense forms of withdrawal can last over
a month.
4.4.4 Bipolar disorder

A history of mania or hypomania signifies a bipolar disorder, but since () bipolar
disorder often starts with a depressive episode, and (2) bipolar patients spend
more time in depressive episodes than in mania/hypomania, it is important to
Table 4.4 Features that help distinguish bereavement from a major

depressive episode
Feature Bereavement Major depressive episode
Mood experience Feelings of loss or Persistent sadness or
emptiness anhedonia
Feelings of worthlessness Absent Present
Suicidal ideas Absent Common
Delusions of guilt, etc. Absent Possible
Psychomotor changes Mild agitation Marked slowing
Functional impairment Mild Marked to severe
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Table 4.5 General medical conditions associated

with depressive symptoms
Neurological disorders Endocrine disorders
Alzheimer’s disease Adrenal
Cerebrovascular disease Cushing’s
Cerebral neoplasms Addison’s
Cerebral trauma Hyperaldosteronism
CNS infections Menses related
Dementia Parathyroid disorders
Epilepsy Thyroid disorders
Extrapyramidal diseases Vitamin deficiencies
Huntington’s disease B2/folate
Hydrocephalus Vitamin C
Migraine Niacin
Multiple sclerosis Thiamine
Narcolepsy Other disorders
Parkinson’s disease Acquired immune deficiency
Progressive supranuclear palsy syndrome (AIDS)
Sleep apnoea Cancer
Wilson’s disease Cardiopulmonary disease
Systemic disorders Klinefelter’s syndrome

Viral and bacterial infections Myocardial infarction
Inflammatory disorders Porphyrias

Rheumatoid arthritis Postoperative states
Sjögren’s syndrome Renal disease and uraemia
Systemic lupus erythematosus Systemic neoplasms
Temporal arteritis
carefully rule out bipolarity when diagnosing MDD. In fact, 5–0% of individuals
that experience a major depressive episode will have a manic or hypomanic epi-
sode in their lifetime. Depressive symptoms that suggest bipolarity include racing
thoughts, psychotic symptoms, atypical features (hypersomnia, overeating), early
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Box 4.4 Common drugs of abuse resulting in substance-induced mood

disorders
Alcohol
Amphetamines
Anxiolytics
Cocaine
Hallucinogens
Hypnotics
Inhalants
Opioids
Phencyclidine
Sedatives
age of onset, and recurrent episodes. Bipolar II (with hypomania) disorder is

especially difficult to recognize because patients themselves do not recognize
hypomania as abnormal––they may simply perceive it as ‘feeling good’. Collateral
information from a spouse, close friend, or family member is often essential
to making this diagnosis. Validated screening questionnaires, such as the Mood
Disorder Questionnaire, can also be helpful for identifying hypomania.
The DSM-5 depressive episode specifier, ‘with mixed features’, recognizes
that sub-syndromal manic or hypomanic symptoms may be experienced during
depressive episodes in up to 25% of patients with MDD. These patients warrant
close monitoring during treatment with antidepressants because they may be at
higher risk of a hypomanic/manic switch.
Further Reading
American Psychiatric Association (203) Diagnostic and Statistical Manual of Mental
Disorders, 5th edn. Washington, DC: American Psychiatric Press.
Cuthbert BN (204) The RDoC framework: facilitating transition from ICD/DSM to
dimensional approaches that integrate neuroscience and psychopathology. World
Psychiatry 13: 28–35.
Hirschfeld RM, Williams JB, Spitzer RL, et al. (2000) Development and validation of a
screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire.
Am J Psychiatry 157: 873–5.
Rackley S, Bostwick JM (202) Depression in medically ill patients. Psychiatr Clin North Am
35: 23–47.
Weber AN, Michail M, Thompson A, et al. (207) Psychiatric emergencies: Assessing and
managing suicidal ideation. Med Clin North Am 10: 553–7.
chapter 4
World Health Organization (2005) International Statistical Classification of Diseases
and Health Related Problems (The) ICD-0 Second Edition. Geneva: World Health
Organization.
Yatham LN, Kennedy SH, Parikh SV, et al. (203) 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 disorder: update 203. Bipolar Disord 15: –44.
Zigmond AS, Snaith RP (983) The Hospital Anxiety and Depression Scale. Acta Psychiatr
Scand 67: 36–70.
chapter 4
Chapter 5
Associated clinical features

Key points
• Depression is associated with a number of non-specific clinical features,
including anxiety, fatigue, irritability, anger, cognitive dysfunction, and pain.
• These features may be present as associated symptoms in a depressive episode
or as specific comorbidities.
• The presence of associated clinical features can affect the differential
diagnosis and management of depression, e.g. in the selection and use of an
antidepressant and/or a psychological treatment.
5.1 Associated clinical features

5.. Overview
Patients with depression have a myriad of subjective symptoms and objective
signs. Many of these are captured within the diagnostic criteria for major depres-
sive disorder (MDD), but there are also many other symptoms that are not
diagnosis-specific. Other symptoms associated with depression include anxiety,
irritability and anger, fatigue, cognitive dysfunction, and pain. These clinical fea-
tures are commonly experienced by depressed patients and are important to
consider in the assessment and management of the depressive episode.
5.2 Anxiety
5.2. Anxiety and depression
Anxiety is a ubiquitous symptom in psychiatric disorders, but there is a very close
relationship between depression and anxiety. Indeed, 60–90% of patients with
MDD experience prominent symptoms of anxiety (e.g. excessive worry, tension,
and somatic symptoms) during a depressive episode, and DSM-5 (Diagnostic and
Statistical Manual of Mental Disorders, 5th edn) now includes the episode specifier
‘with anxious distress’ to recognize the importance of assessing anxiety. Many
studies have shown that the presence of significant anxiety is associated with
increased severity of depression, greater functional and psychosocial impairment,
higher suicide risk, and poorer responses to treatment.
Anxiety has both emotional and somatic components. Descriptors of anxiety
include: nervous, stressed, worried, tense, apprehensive, edgy, restless, jittery, on
chapter 5
36 • associated clinical features
edge, jumpy, uneasy, fearful, and panicky. Somatic features can involve multiple
systems, including cardiovascular (chest pain, rapid heartbeat, palpitations, heart
pounding), respiratory (shortness of breath, gasping, hyperventilating), gastro-
intestinal (dry mouth, heartburn, gas, diarrhoea, constipation), musculoskeletal
(stiffness, cramps, twitching), and central nervous system (headaches, tremor, diz-
ziness). Generalized forms of anxiety should be distinguished from phobic anxiety
and panic attacks.
In addition to anxiety as a symptom, anxiety disorders (especially generalized
anxiety disorder, panic disorder, and social anxiety disorder) are also frequently
comorbid with depression. The symptom and functional outcomes are poorer,
and suicide and relapse rates higher, for people with comorbid depressive and
anxiety disorders.
5.2.2 Implications for diagnosis and management

A diagnostic truism is: ‘When depression is present, look for anxiety, and when
anxiety is present, look for depression’. Patients may present with a non-specific
complaint of ‘stress’, which should trigger assessment for both anxiety and
depressive disorders. Sometimes patients will describe their anxiety as ‘racing
thoughts’, and restlessness as ‘hyperactivity’, which need to be distinguished from
hypomanic symptoms.
Depression with prominent anxiety symptoms or comorbid anxiety disorders
usually requires treatment with combined psychotherapy (especially cognitive–
behavioural therapy) and pharmacotherapy. Pharmacotherapy involves selecting
a ‘broad-spectrum’ antidepressant that has proven efficacy for both depressive
and anxiety disorders (see Chapter 8). Patients with anxiety may be especially
prone to experiencing side effects of antidepressants. The maxim used in geriat-
ric psychiatry, ‘Start low, go slow, keep going’—that is, start with lower doses of
the antidepressant and increase slowly to full therapeutic doses—also applies to
anxious patients. Some patients may require symptomatic relief of anxiety with
adjunctive, short-term benzodiazepine treatment. Patients with anxiety should be
monitored carefully for increased agitation and suicidality during treatment with
antidepressants, especially in the early initiation of the treatment phase.
5.3 Irritability and anger

5.3. Irritability, anger, and depression
Irritability and anger are commonly experienced by people with depression, but
these emotions are less studied and understood than other depression-associated
symptoms. They often occur in combination with anxiety and agitation and may
lead to other related phenomena (Table 5.). Irritability can adversely affect rela-
tionships with others, at home and at work, and is often a factor in interpersonal
conflicts and social withdrawal. It can also present as low frustration tolerance,
aggression, or violence; up to 50% of depressed patients report anger attacks.
chapter 5
associated clinical features • 37
Table 5. Irritability and related phenomena

Symptom Description
Irritability A feeling state characterized by reduced control over temper,
which usually results in irascible verbal or behavioural outbursts.
Dysphoria Refers both to depressive mood as well as irritability and may
also be used specifically to refer to a pathological mood state,
‘irritable mood’.
Anger An affect with physiological concomitants which is experienced
as the motivation to act in ways that warn, intimidate, or attack
those who are perceived as challenging or threatening.
Hostility A self-reported attitude of dislike, resentment, or suspicion
towards the world or the objects in it.
Agitation Motor restlessness such as fidgeting and pacing associated with
inner tension.
Aggression A deliberate verbal or physical act, which is interpreted by
others as destructive.
Anger attacks Sudden spells of anger, surge of autonomic arousal, and
symptoms like tachycardia, sweating, flushing, and a feeling of
being out of control. These attacks occur spontaneously or in
response to a provocation and are experienced by the subjects
as uncharacteristic of themselves and inappropriate to the
situation.
Episodic dyscontrol Violent outbursts with loss of control over aggressive behaviour
upon minor provocation.
Adapted from European Archives of Psychiatry and Clinical Neuroscience, 255, Painuly N, Sharan P,
Mattoo SK. Relationship of anger and anger attacks with depression: a brief review, pp. 25–22.
© Steinkopff-Verlag 2005, with permission from Springer.
Irritability is a particularly common presenting complaint in children and youth.

In the DSM-5 (but not the ICD-0 (International Classification of Diseases, ver-
sion 0)), irritability is a primary criterion for the diagnosis of major depression
in children and adolescents. The importance of irritability in children was demon-
strated in a 20-year follow-up study of a community-based cohort in which irrit-
ability was significantly predictive of progression to depression, dysthymia, and
generalized anxiety disorder, but not to phobias, personality, or bipolar disorder.

The major differential diagnoses for irritability and anger are bipolar disorder,
especially type II and mixed states, and personality disorders, especially border-
line personality disorder. In bipolar disorder, irritable mood states are associated
with other manic or hypomanic symptoms, including hyperactivity, impulsivity,
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and pressured thinking and speech. In borderline personality disorder, anger is a
chronic, lifelong symptom, not limited to distinct episodes.
In the management of depressed patients with irritability and anger, assess-
ment must include an evaluation of potential aggression and violence against
self and others. Effective treatments for depression appear to also treat irrit-
ability and anger. As with anxiety, when irritability is a prominent symptom, it
is important to monitor for increased agitation and suicidality with initiation of
antidepressants.
5.4 Cognitive dysfunction

5.4. Cognition and memory
Cognition is often classified as two separate, but inter- related, pro-
cesses: emotion- independent ‘cold’ cognition (attention, processing speed,
memory, executive functioning) and emotion-dependent ‘hot’ cognition (atten-
tional biases with negative-valenced material, negative recall bias, rumination).
These are not mutually exclusive because, for example, depressed people
with hot cognitive dysfunction will overreact to mistakes, which impairs their
performance on cold cognitive tasks. Executive function, usually defined as
the higher level cognitive processes that control and regulate other cognitive
domains, may be particularly important in depression. These higher level pro-
cesses include the abilities to initiate and stop actions, to change and adapt
behaviour to new and novel stimuli and situations, and to plan and prioritize
new behaviours towards an active goal.
Various domains of cognitive functioning can be assessed using specific
neuropsychological tests (Table 5.2). Difficulties in attention are more notice-
able in tasks requiring effort. Psychomotor slowing can be demonstrated using
reaction time tasks. Neuropsychological test results in depression are also
influenced by external factors, such as premorbid intelligence and educational
attainment.
5.4.2 Cognitive deficits in depression

Cognition and memory are central to both biological and psychological theories
of depression and increasingly recognized as important in the clinical manage-
ment of patients. Cognition is associated with a number of neuroanatomical and
neurocircuitry pathways that are also implicated in the pathogenesis of depres-
sion (see Chapter 3).
Concentration and memory complaints are commonly reported by depressed
patients and are included in the diagnostic criteria for major depressive dis-
order. Patients describe cognitive symptoms in many different ways (Table 5.2).
Attention frequently overlaps with memory in patient descriptors. Executive
function is often described in terms of difficulties with multi-tasking, decision-
making, and problem-solving.
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Table 5.2 Cognitive domains, patient descriptions, and

neuropsychological tasks
Cognition Examples of patient Examples of neuropsychological
domain descriptions tests
Attention Unable to focus, poor • Digit span forwards
concentration, confused, • Spatial span backwards
scattered, unmotivated, brain • Choice reaction time
clouded, lose train of thought,
absent-minded, distracted
Memory Forgetful, can’t remember, • Digit span and spatial span
make mistakes, can’t keep backwards
things in my head • CNS-VS verbal and visual
memory test
• Rey Auditory Verbal Learning
Test—Total & Delayed Recall
• Wechsler Memory Scale—
Visual Memory Index
Psychomotor Feel slowed down, tough • Finger tapping
speed getting started, low energy, • Trail Making Test A
slow motion, foggy, lethargic, • Symbol digit coding
mental block, ‘cotton brain’ • Digit Symbol Substitution Test
Executive Indecisive, problem with • Trail Making Test B
function multi-tasking, easily confused, • Tower of London Test
overwhelmed by tasks, • Wisconsin Card Sorting Test
procrastinating • Stroop Test
• CANTAB Intradimensional/
extradimensional Shift Test
Emotion- Easily flustered by • Emotional Stroop Test
dependent mistakes, negative thinking, • Emotional faces task
processing (‘hot’ catastrophizing, rumination • Affective Go/No-Go Test
cognition) • Attentional interference task
Objective cognitive dysfunction, however, may not be well correlated with sub-
jective complaints, which can be confounded by the negative cognitive bias seen in
depression. Cognitive deficits in depression appear to be less prevalent and less
severe, whether in acute phase or in remission phase, than in schizophrenia or bipo-
lar disorder. People with depression can have severe global cognitive problems,
focal deficits in specific cognitive domains, or no cognitive dysfunction. Cognitive
deficits in one or more domains can be identified in 20–60% of depressed patients,
depending on the population studied and the definition of deficit. Cognitive dys-
function can be demonstrated in first-episode depression, but certain subsets of
depressed patients have higher risk of cognitive deficits, including those with psych-
otic features, those with chronic or severe depression, and those of older age.
chapter 5
Deficits in cognition and memory would be expected to play a major role
in functional impairment, whether at work or at home. In particular, executive
dysfunction has great impact on quality of life and functionality since executive
functions control many aspects of our daily lives, such as problem-solving and
decision-making. Cognitive deficits would also affect the ability to cope, make it
more difficult to adhere to treatment, and increase the risk of relapse.

Problems with cognition and attention should be differentiated from distract-
ibility in the differential diagnosis with bipolar disorder and adult attention def-
icit disorder. In the elderly, cognitive deficits can be mistaken for early dementia,
although depression is also recognized as an early symptom of dementia and
as a risk factor for developing dementia (see Chapter 0). A thorough cogni-
tive assessment should include both subjective measures (cognitive question-
naires such as the PDQ-D-5 (Perceived Deficits Questionnaire—Depression, 5
item), see Appendix) and objective measures (neuropsychological tests such as
the THINC-it screening tool, http://thinc.progress.im) because both types of
measures yield different types of information.
There is evidence that cognitive dysfunction improves with treatment, but
some studies find residual cognitive deficits even when patients were in symptom
remission after treatment. These residual deficits are associated with poorer func-
tional outcomes. Some investigators have suggested the cognitive or executive
function impairment may be a trait marker or vulnerability risk factor for depres-
sion. Other studies have shown that cognitive deficits as a residual symptom may
herald depressive relapse. Hence, it is important to assess cognitive functioning
during management of depression.
In pharmacotherapy, studies show that cognitive functioning generally improves
with antidepressant treatment, although there may be less effect on some domains
such as executive functioning. Some antidepressants, such as the multimodal anti-
depressant vortioxetine, may show specific benefits for cognitive dysfunction in
MDD compared with others. Other antidepressants, especially those with greater
anticholinergic activity (e.g. amitriptyline, mirtazapine, paroxetine), can worsen
cognition. It is possible that some adjunctive treatments, for example stimulant
or modafinil augmentation, may improve cognition in treatment-resistant depres-
sion, but there is, as yet, little supporting evidence. Cognitive functioning should
be routinely monitored during electroconvulsive therapy (see Chapter 9).
Psychological treatments may also specifically target cognition. While there is
still little information on the neuropsychological effects of cognitive–behavioural
therapy, it may address some of the negative cognitive biases in MDD. Cognitive
remediation or retraining programmes that specifically address cognitive deficits
are effective for schizophrenia, and preliminary studies of cognitive remediation
for MDD show promising results.
chapter 5
5.5 Pain
5.5. Pain and depression
Pain commonly accompanies depression. Depression can magnify painful
symptoms, including headaches, muscle aches, and back pain. Chronic pain
conditions may also precipitate and exacerbate depression, and some pain
conditions (e.g. fibromyalgia) are commonly associated with depressive
disorders.
There is much evidence for cognitive and neural modulation of pain, and
several specific brain structures that are implicated in the pathophysiology
of depression are also involved in pain. For example, the anterior cingulate
cortex, insular cortex, thalamus, nucleus accumbens, and hippocampus are all
involved in pain processing, especially the affective response to pain. In add-
ition, depression and pain share a common dysfunction of neurotransmitter
systems involving both serotonergic and noradrenergic mechanisms, with sig-
nificant cross-talk between systems. Hence, it is not surprising that pathological
changes in neurotransmitters and neurocircuitry in one condition would affect
another.

Patients with chronic pain conditions should be screened for the presence of
depression (see Chapter 6). As with other somatic conditions, diagnostic assess-
ment should focus on non-physical symptoms of depression, as pain can con-
found assessment of sleep and appetite.
Both psychological and pharmacotherapy approaches have been helpful in
depression-associated pain and in comorbid pain and depression. Some antide-
pressants (e.g. tricyclic antidepressants (TCAs) such as amitriptyline, and sero-
tonin and noradrenaline reuptake inhibitors (SNRIs) such as duloxetine) may have
specific effects on pain and may be approved for pain indications, such as fibro-
myalgia and painful diabetic neuropathy.
When using medications for both pain and depression, additive side effects
can occur. For example, patients may experience oversedation with con-
current use of sedating antidepressants (e.g. amitriptyline, mirtazapine) and
sedating analgesics (e.g. opioids). Potential drug interactions mediated by
the cytochrome P450 system must also be considered (see Chapter 8). For
example, codeine is metabolized to morphine via cytochrome P450 2D6;
antidepressants that significantly inhibit 2D6 (e.g. fluoxetine, paroxetine) can
reduce the efficacy of codeine. Another important drug interaction involves
amitriptyline, which is often used in lower doses for pain relief. Amitriptyline
is primarily metabolized by 2D6; hence, concurrent use of the 2D6 inhibitor
antidepressants can increase serum levels of low-dose amitriptyline to poten-
tially cardiotoxic levels.
chapter 5
5.6 Fatigue and low energy

5.6. Fatigue in depression
Fatigue and low energy are often used synonymously. Fatigue (and energy) can be
both mental and physical. Although fatigue is a core symptom in MDD, it warrants
specific attention because it is one of the key symptoms that patients describe
as most interfering with home and work functioning. Up to 40% of patients with
MDD continue to experience fatigue as a residual symptom after treatment,
and when present it predicted relapse at -year, 4-year, and 0-year follow up.
Chronic fatigue conditions may also precipitate and exacerbate depression and
may be related to both the disease and its treatments. Finally, fatigue can be a side
effect of medication treatment.

Patients with higher pretreatment levels of fatigue have greater severity of func-
tional impairment and are less likely to achieve symptom remission with treat-
ment. Conversely, ensuring remission of fatigue and low energy during treatment
has been shown to improve overall functioning and quality of life. There is some
suggestion that SSRI (selective serotonin reuptake inhibitor) antidepressants are
associated with higher rates of fatigue as a residual symptom, and that SNRIs (e.g.
desvenlafaxine and levomilnacipran) and bupropion have lower rates. Stimulant
medications as adjunctive treatment for treatment- resistant depression have
been shown to have therapeutic effects on fatigue.
Further Reading
Beblo T, Sinnamon G, Baune BT (20) Specifying the neuropsychology of affective
disorders: Clinical, demographic and neurobiological factors. Neuropsychol Rev
21: 337–59.
Fava M, Ball S, Nelson JC, et al. (204) Clinical relevance of fatigue as a residual symptom
in major depressive disorder. Depress Anxiety 31: 250–7.
Jaracz J, Gattner K, Jaracz K, et al. (206) Unexplained painful physical symptoms in
patients with major depressive disorder: Prevalence, pathophysiology and management.
CNS Drugs 30: 293–304.
McIntyre RS, Xiao HX, Syeda K, et al. (205) The prevalence, measurement, and
treatment of the cognitive dimension/domain in major depressive disorder. CNS Drugs
29: 577–89.
Painuly N, Sharan P, Mattoo SK (2005) Relationship of anger and anger attacks with
depression: A brief review. Eur Arch Psychiatry Clin Neurosci 255: 25–22.
chapter 5
Robinson MJ, Edwards SE, Iyengar S, et al. (2009) Depression and pain. Front Biosci
14: 503–5.
Roiser JP, Elliot R, Sahakian BJ (202) Cognitive mechanisms of treatment in depression.
Neuropsychopharmacology 37: 7–36.
Schaffer A, McIntosh D, Goldstein BI, et al. (202) The CANMAT task force
recommendations for the management of patients with mood disorders and comorbid
anxiety disorders. Ann Clin Psychiatry 24: 6–22.
chapter 5
Chapter 6
Clinical management
Key points
• Clinical management of depression includes screening, assessment, developing
a therapeutic alliance, selecting treatment(s), monitoring, and follow up.
• The treatment of depression has two phases: the acute phase to achieve full
remission of symptoms, and the maintenance phase to prevent relapse and
recurrence.
• Self-management is an important component of disease management
programmes for depression.
6.1 Introduction
Clinical management for patients with depression involves following general
principles of care: careful assessment, developing a therapeutic alliance, select-
ing evidence-based treatments, monitoring outcomes, and following up appro-
priately. Understanding that treatment of depression has two phases, acute and
maintenance, will ensure that patients not only get well, but stay well. For many
patients, depression can be considered a recurrent and/or chronic illness, so fol-
lowing principles of chronic disease management (CDM) will also help improve
outcomes. CDM, which is widely used for medical conditions such as diabetes
and arthritis, includes elements of screening, self- management, monitoring,
collaborative care, and rehabilitation. CDM also incorporates the concept of
‘stepped care’, progressing first from lower intensity and lower cost treatments
in milder, less complicated cases, to more intensive and expensive treatments in
more severe and/or refractory cases.
6.2 Assessment
6.2. Screening
Depression is not easily diagnosed, especially in primary care settings, because
often the presenting complaint is physical (e.g. body aches, fatigue, insomnia).
Some depressed individuals are unaware of sad mood, or are feeling lack of emo-
tion. In these cases, asking about loss of interest or pleasure can be diagnostic.
People with high-risk factors should be screened for a depressive illness (Box 6.).
chapter 6
46 • clinical management
Box 6. Patients with the following factors are at high risk for major
depressive disorder and should be screened
• Chronic pain
• Chronic physical illness (diabetes, heart disease, etc.)
• Unexplained somatic symptoms
• Frequent visits to primary care setting
• Postpartum state
• Recent psychosocial stressors
If these risk factors are present, a two-question ‘quick screening tool’ can be
used. An answer of ‘Yes’ to either question indicates that a more detailed assess-
ment is required.
) In the last month, have you been bothered by little interest or pleasure in
doing things?
2) In the last month, have you been feeling down, depressed, or hopeless?
6.2.2 Diagnostic tools

There are no specific laboratory tests to guide diagnosis, so the diagnostic inter-
view remains the ‘gold standard’ in psychiatry. However, semi-structured inter-
views and questionnaires can help a busy clinician to more efficiently establish
the diagnostic criteria and to ensure a complete functional inquiry. Examples
of such instruments include the PRIME-MD (useful in primary care settings),
the Structured Clinical Interview for DSM-V (SCID-5, used in many psychiatric
research studies), and the Mini International Neuropsychiatric Interview (MINI
v.7.0, more convenient and clinician-friendly).
6.2.3 Suicide assessment

Suicide is one of the most tragic consequences of depression. It is difficult to pre-
dict suicide risk beyond very short time periods. Table 6. lists risk factors for
suicide based on episode characteristics and demographics, but these give only a
general sense of suicide potential. For any given patient, different factors will be
important.
In the assessment of suicidality, attention must be given to social supports,
potential methods, lethality of previous attempts and plans, and personality traits
such as impulsivity. The period of initiating treatment is a time of higher suicide
risk, in part because symptoms tend to be most severe before seeking help, the
patient may be having initial side effects (such as anxiety or agitation) that can
worsen suicidality, and/or patients’ physical symptoms (e.g. energy) may improve
before their cognitive symptoms (e.g. hopelessness) and thereby such patients
may be more likely to act on suicidal impulses.
chapter 6
clinical management • 47
Table 6. Risk factors for suicide

Related to episode Related to demographics
Current suicidal plans Male
Prior attempts Adolescent or elderly
Severe depression Early onset of mood disorder
Hopelessness and guilt Personality disorder (especially Cluster B)
Inpatient or recently discharged Family history of suicide
Bipolarity (especially bipolar II) Adverse childhood experiences (trauma,
Mixed state (with agitation), illness, parental loss)
dysphoric mania Adverse life circumstances
Psychotic features (unemployment, social isolation)
Comorbidity (anxiety, substance abuse, Recent psychosocial stressor

serious medical conditions) Lack of supports
Management of suicidal ideation includes minimizing available methods for suicide

(removing guns, prescribing small amounts of medication), substituting an activity
(going for a walk, doing relaxation exercises, etc.), keeping a list of reasons for living,
and making contingency plans (e.g. contacting a crisis telephone line, calling a friend,
going to the emergency room). Although contracts against suicide (verbal or writ-
ten) are widely used by clinicians, they have not been shown to be effective in the
management of suicidal patients. Documentation of suicidality and management
plans, however, is very important. Some patients with acute and severe suicidality
will require civil committal to hospital under regional mental health legislation.
6.2.4 Monitoring outcomes (measurement-based care)

Measurement-based care is a term used to describe the integration of outcome
assessment in disease treatment. Outcome is best monitored by the use of vali-
dated symptom rating scales, which are psychiatry’s version of laboratory tests.
The benefits of rating scales include comprehensive assessment of symptoms,
reliable measurement of treatment effects, ensuring full remission is achieved, and
aiding patient education and self-management.
Rating scales can be clinician-administered or patient-rated. Self-rated scales
can help improve efficiency for busy clinicians because they can be completed at
home or in the waiting room, and can also be used by patients to monitor their
own mood states. The most widely used clinician-based depression scales are
the Hamilton Depression Rating Scale (HAM-D) and the Montgomery–Åsberg
Depression Rating Scale (MADRS). Commonly used patient-rated scales include
the Beck Depression Inventory II, the Hospital Anxiety and Depression Scale
(HADS), the Patient Health Questionnaire ((PHQ-9), specifically developed for
primary care settings), and the Quick Inventory for Depressive Symptomatology,
chapter 6
self-rated ((QIDS-SR), used in the STAR*D (Sequenced Treatment Alternatives
to Relieve Depression) study; see Chapter 0). Some of these rating scales are
described in the Appendix.
Clinical response is often defined as a 50% or greater reduction from base-
line in depression rating scale scores, which indicates substantial and meaningful
improvement. However, despite this clinical improvement, patients may be left
with residual symptoms of depression. Many studies have shown that residual
symptoms are associated with poorer outcomes, including higher risks of relapse,
chronicity, suicide, and poor social and occupational functioning. Therefore, the
target for treatment should be remission of symptoms, which is defined as a rat-
ing scale score within the normal, not depressed, range (e.g. MADRS score ≤0,
HAM-D score ≤7, QIDS-SR ≤5).
While attention to symptoms is essential, more important to patients are out-
comes such as quality of life and functionality. Interestingly, there is only a moder-
ate correspondence between symptoms and functioning, so separate assessment
of social and occupational functioning should be conducted alongside symptom
assessment. Simple patient-rated scales such as the Sheehan Disability Scale and
the Lam Employment Absence and Productivity Scale (LEAPS) can be helpful in
clinical settings (see Appendix).
Empowering patients to participate in measurement-based care can also help
with self-efficacy and strengthen the therapeutic alliance. This can be done via
websites such as http://www.MoodFx.ca, accessed  October 207, which
allows patients free access to screen, assess, and track their moods and other out-
comes (e.g. quality of life and side-effect burden) using brief, validated self-rated
questionnaires (e.g. PHQ-9, LEAPS). Patients can print their results to show their
clinician and can subscribe to weekly self-management tips for their depression.
6.3 Phases of treatment

The treatment of depression can be divided into two phases, acute and mainten-
ance, with different goals and activities (Table 6.2). For most patients, successful
management of depression takes at least  year, but for some patients, treatment
will need to continue for 2 years or more.
In the acute phase, symptom remission is often considered the target for treat-
ment. However, restoration of functioning is more meaningful to patients and
should be the ultimate goal of treatment. Full recovery of functioning, however,
may take longer to achieve, and is less likely to happen unless symptom remission
occurs.
Maintenance treatment is particularly important for pharmacotherapy, since
relapse or recurrence is likely to occur if medications are stopped too soon.
The maintenance period for medications is 6 months to 2 years or more (see
Chapter 8). Psychotherapy approaches (e.g. mindfulness- based cognitive–
behavioural therapy) may also prevent recurrences and allow earlier discontinu-
ation of medications (see Chapter 7).
chapter 6
Table 6.2 Phases of treatment for depression

Phase Duration Goals Activities
Acute 8–2 weeks Remission of Establish a therapeutic alliance
symptoms; Educate and support
improve social self-management
and occupational
functioning Choose evidence-based
treatment(s)
Manage side effects
Follow up and monitor
outcomes
Maintenance 6–24 months Return to Educate and support
or longer baseline social self-management
and occupational Manage side effects
functioning;
Rehabilitate work and social
prevent relapse and
function
recurrence
Monitor for recurrence
6.4 Clinical management

6.4. Choice of treatment
Selecting a treatment must include an evaluation of severity of illness, availability of
resources, and patient preference. For depressions of mild-to-moderate severity,
evidence-based psychotherapies are as effective as pharmacotherapy. Hence, for
mild depression a psychological or other non-pharmacological treatment (e.g. exer-
cise) should be first considered. For moderate-to-severe depression, most clinicians
would recommend an antidepressant, with or without psychotherapy. For initial treat-
ment of uncomplicated depressions, there is little evidence that combining pharma-
cotherapy and psychotherapy is superior to either treatment alone. Combined
treatment should be considered when the depression is severe, or comorbid with
other conditions, or when there is inadequate response to monotherapy.
6.4.2 Optimizing adherence

Methods for enhancing adherence to pharmacotherapy include giving some sim-
ple instructions to every patient starting on medications (Box 6.2).
6.4.3 Collaborative care

Collaborative care refers to patients receiving depression care from more than
one provider. In most cases, this will be a physician prescribing medications and
another practitioner (nurse, psychologist, etc.) providing psychotherapy. In some
primary care settings, patients have access to a care manager who provides
chapter 6
Box 6.2 Simple messages to give to patients to improve adherence

to pharmacotherapy
• Antidepressants are not addictive.
• Take your medications every day, as prescribed.
• It may take 2 or 3 weeks before you start feeling better.
• Mild side effects are expected, but should get better with time.
• Call me before you stop the medication.
education, support, and, sometimes, brief psychotherapy. Care management by

telephone has been shown to have similar effects to face-to-face meetings, and is
more convenient and cost-effective to implement across clinical settings. Studies
have shown that these collaborative care programmes, including telephone care
management, lead to improved outcomes, with a favourable cost-offset.
In situations where another health professional is providing psychotherapy, it is
still important for the primary physician to monitor outcomes, so that other treat-
ments (e.g. pharmacotherapy) can be applied if improvement is not seen after an
appropriate follow-up period.
6.4.4 Follow up
Health service studies show that, in primary care settings, an average of three
office visits take place in the first 6 months after a diagnosis of depression is
made. This is not considered adequate follow up for depression management,
and may be a factor in less than optimal outcomes associated with depression
treatment in ‘usual care’. It is especially important to monitor more frequently in
the first weeks of treatment, as this is a period with higher suicide risk, challenges
to adherence, and potential clinical worsening. Follow-up visits may be brief (or
even conducted via telephone or videoconference), but the recommended min
imum frequency is weekly for the first 4 weeks, then monthly for 6 months, then
every 3 months, as needed.
6.4.5 Patient education and self-management

Self-management is an integral focus for CDM approaches. At its simplest, self-
management includes educating patients about the illness and its treatment. At
more complex levels, it includes actively involving patients in their own recovery,
using techniques taken primarily from CBT and recovery models. Patient self-help
and support groups are also important resources that are often available locally.
Bibliotherapy, including workbooks for patients and information from reliable
internet sites (Table 6.3), is effective as monotherapy for patients with mild
depression, and can be used as adjunctive treatment for more severe cases.
The internet is becoming increasingly important as a source of information
for self-management of medical conditions. Table 6.3 lists some resources for
self-management.
chapter 6
Table 6.3 Resources for self-management

Recommended books:
Antidepressant Skills at Work, by Dan Bilsker, PhD, Merv Gilbert, PhD, and Joti Samra,
PhD. BC Mental Health and Addiction Services, 2009; Available for free download
at: http://www.comh.ca/antidepressant-skills/work/, accessed  October 207
Mind Over Mood, 2nd edition, by David Greenberger, PhD, and Christine Padesky, PhD.
New York, Guildford Press, 205. Translations available in 22 languages; a Clinician’s
Guide is also available.
Feeling Good: The New Mood Therapy, by Dr David D. Burns. HarperCollins, 2008.
Recommended internet sites:
http://www.bluepages.anu.edu.au, Blue Pages, Australia (public info)
accessed  October 207
http://www.canmat.org, accessed  Canadian Network for Mood and Anxiety
October 207 Treatments (CANMAT) (guidelines,
public info)
http://www.cmha.ca/mental-health/ Canadian Mental Health Association
understanding-mental-illness/depression/ (CMHA) (public info)
, accessed  October 207
http://www.depressionalliance.org, Depression Alliance, UK (public info)
http://www.nami.org/Learn-More/ National Alliance on Mental Illness
Mental-Health-Conditions/Depression, (NAMI), USA (public info)
http://www.nimh.nih.gov, accessed  National Institute of Mental Health
October 207 (NIMH), USA (public info)
http://www.psychcentral.com, accessed PsychCentral, USA (public info)
 October 207
Mobile health (mHealth) via smartphones and tablet devices is also gaining
traction, with many mobile applications (apps) now available to screen and track
symptoms and to deliver information and psychological treatments (e.g. self-
management). At this time, most apps have not been rigorously evaluated, and
given the rapid changes in this field, recommendations are not listed.
Further Reading
Archer J, Bower P, Gilbody S, et al. (202) Collaborative care for depression and anxiety
problems. Cochrane Database Syst Rev 10: CD006525.
Cozine EW, Wilkinson JM (206) Depression screening, diagnosis, and treatment across
the lifespan. Prim Care 43: 229–43.
chapter 6
Guo T, Xiang YT, Xiao L, et al. (205) Measurement-based care versus standard care
for major depression: A randomized controlled trial with blind raters. Am J Psychiatry
172: 004–3.
IsHak WW, Greenberg JM, Balayan K, et al. (20) Quality of life: The ultimate outcome
measure of interventions in major depressive disorder. Harv Rev Psychiatry 19: 229–39.
Kupfer DJ, Frank E, Phillips ML (202) Major depressive disorder: New clinical,
neurobiological and treatment perspectives. Lancet 379: 045–55.
Lam RW, Filteau MJ, Milev R (20) Clinical effectiveness: The importance of psychosocial
functioning outcomes. J Affect Disord 132(Suppl ): S9–S3.
Lam RW, Michalak EE, Swinson RP (2005) Assessment Scales in Depression, Mania and
Anxiety. London: Taylor and Francis.
Trivedi MH (203) Evaluating and monitoring treatment response in depression using
measurement-based assessment and rating scales. J Clin Psychiatry 74: e4.
Van Ameringen M, Turna J, Khalesi Z, et al. (207) There is an app for that! The current
state of mobile applications (apps) for DSM-5 obsessive-compulsive disorder,
posttraumatic stress disorder, anxiety and mood disorders. Depress Anxiety 34: 526–39.
chapter 6
Chapter 7
Psychological treatments
Key points
• Evidenced-based psychological treatments for depression include problem-
solving therapy, behavioural activation, cognitive–behavioural therapy,
interpersonal psychotherapy, and the cognitive behavioural-analysis system of
psychotherapy.
• For mild-to-moderate severity of depression, evidence-based psychological
treatments are first-line treatments and are as effective as pharmacotherapy.
• For more severe, chronic, or comorbid depressions, combined treatment with
psychotherapy and pharmacotherapy is indicated.
• Mindfulness-based cognitive therapy, developed as a maintenance treatment,
also has benefit in acute depressive episodes.
7.1 Introduction
7.. Efficacy
Evidenced-based psychological treatments are those which have shown empirical
evidence of efficacy in randomized controlled trials (RCTs) in defined populations
of patients with major depressive disorder (MDD). Table 7. lists the evidence-
based psychotherapies and their key features. Although these psychotherapies
have different principles, areas of focus, and techniques, they also share many
common elements, including their short-term nature, active participation by both
therapist and patient, and use of pragmatic strategies. Other psychotherapies
(e.g. long-term or brief psychodynamic psychotherapy) may also be effective but
have been less systematically studied in MDD, and so are considered second-or
third-line recommendations.
Many therapists in the community use an assortment of techniques from dif-
ferent types of psychotherapy in what is sometimes termed ‘eclectic psychother-
apy’. However, some evidence suggests that the more experienced the therapist,
and the greater the integrity of the therapist to the structure of a particular psy-
chotherapy, the better is the outcome. Access to evidence-based psychothera-
pies remains a major problem for patients, as the availability of qualified therapists
is limited, and psychotherapy is often not funded by public health systems.
chapter 7
54 • psychological treatments
Table 7. Key features of evidence-based psychotherapies for depression

Psychotherapy Main principles Duration Comments
Problem-solving Identify problems 4–6 Developed for
therapy (PST) Develop problem-solving sessions primary care
skills settings
Cognitive therapy Identify patterns of negative 2–6 Often used with
(CT) thinking and attitudes sessions BA as cognitive–
behavioural therapy
Challenge faulty beliefs
(CBT)
Substitute more rational
thoughts
Behavioural Identify maladaptive 8–2 Often used with
activation (BA) patterns of behaviour sessions CT as cognitive–
Reinforce positive coping behavioural therapy
behaviours (CBT)
Use social skills training
Mindfulness-based Promote mindful attention 8–2 Initially developed
cognitive therapy and acceptance sessions as maintenance
(MBCT) treatment to
Interrupt habitual cognitive
prevent depressive
patterns associated with
episodes, but also
relapse
effective in acute
episodes
Interpersonal Identify major 2–6 Uses cognitive/
psychotherapy interpersonal issues sessions behavioural and
(IPT) Use practical strategies to psychodynamic
deal with one or two issues techniques
Cognitive Analyze specific situations 6–20 Developed

behavioural- which led to interpersonal sessions specifically for
analysis system problems chronic depression
of psychotherapy
Use problem-solving
(CBASP)
techniques to develop
alternative ways of dealing
with interpersonal situations
7..2 Choice of psychotherapy

There are very few comparison studies of the evidence-based psychothera-
pies. Meta-analyses have shown that CBT (cognitive–behavioural therapy)
and IPT (interpersonal psychotherapy) have similar effect sizes and perform
chapter 7
psychological treatments • 55
equally well in MDD. There is also little information about clinical factors
that might predict better outcomes with a specific psychotherapy. In one of
the few large trials comparing cognitive therapy (CT) and IPT, the predictive
factors found for response were counter-intuitive––namely, that patients did
better with CT when they had fewer negative cognitions, while patients did
better with IPT when they had less social impairment. Several studies have
shown that investigator allegiance to a particular psychotherapy also influ-
ences outcomes.
7..3 Psychotherapy and pharmacotherapy

Most comparisons of psychotherapies with pharmacotherapy have been con-
ducted in patients with MDD of mild-to-moderate severity. The overall conclu-
sion from RCTs and meta-analyses is that evidence-based psychotherapies are
as effective as antidepressants for these patients. There are few studies of psy-
chotherapy for severe depression, but CT was found to be of similar efficacy to
paroxetine use (with or without augmentation using lithium and desipramine) in
one recent trial (although pharmacotherapy showed numerically higher response
and remission rates). Most clinicians would still recommend combined treatment
with psychotherapy and pharmacotherapy for severe, comorbid, and/or chronic
depression. Sequential treatment (starting with pharmacotherapy and adding psy-
chotherapy later) is also an effective strategy.
Non-response to either psychotherapy or to pharmacotherapy does not imply
general refractoriness to treatment. That is, patients who have not responded
to psychotherapy will show typical response rates to pharmacotherapy, and vice
versa. It does not appear that psychotherapy and pharmacotherapy target the
same mechanisms.
7.2 Problem-solving therapy

Problem-solving therapy (PST) is a brief treatment that was developed for use
in primary care settings and is closely related to CBT. PST consists of four to six
sessions of 20–30 minutes each that teaches a structured approach to identify-
ing problems and using pragmatic problem-solving techniques. These include
breaking down problems into manageable components, sorting priorities,
brainstorming solutions, and listing advantages and disadvantages for potential
solutions. Several large, pragmatic RCTs have shown superior outcomes with
PST compared to treatment as usual for MDD in primary care practices. One
advantage of PST is that it can be delivered by healthcare workers who do not
specialize in mental health (such as nurses, family physicians, and care manag-
ers), and only brief training is required. Therefore, PST could become more
widely available than other therapies that need more extensive training and
experience.
chapter 7
7.3 Cognitive and behavioural therapies

7.3. Cognitive therapy
CT is the most validated psychosocial treatment in psychiatry, with numerous
RCTs and meta-analyses showing evidence for efficacy in MDD. In CT, automatic
negative thoughts associated with depression are believed to underlie the depres-
sive feelings and affect. These negative thoughts are formulated into dysfunctional
attitudes about the self, others, and the world. CT seeks to systematically identify
these thinking patterns (such as, I’m always a failure) and then rationally challenge
them (e.g. How can you tell if you are a failure? What evidence is there that you
are a failure? Is there any evidence that you are not a failure?). Table 7.2 illustrates
other examples of negative cognitions.
Techniques of CT include keeping track of automatic thoughts, assessing the
affect associated with them, and then reassessing feelings after an intervention
such as a rational challenge. The therapist uses an active Socratic questioning style
to teach the client how to substitute more rational thoughts. Homework assign-
ment and review is an integral part of CT.
CT also appears to have enduring effects beyond acute treatment. In studies
of treatment discontinuation, patients who stopped CT after acute treatment
had lower relapse rates on long-term follow up than those who were discontin-
ued from medications. The relapse/recurrence rates following CT given only in
the acute phase of treatment were found to be similar to the rates for patients
who had continued on maintenance medications. Similarly, CT has been shown
to reduce relapse/recurrence when given after an acute course of antidepres-
sants, even if the medication is discontinued. Thus, it appears that CT reduces
Table 7.2 Examples of negative cognitions

Minimizing/maximizing I never have any fun any more; winning the lottery just
means more people will come after me for money.
Catastrophizing If I don’t go to the office party, no one at work will
speak to me again.
Negative inference My boss didn’t give me a good assignment, which
proves that he doesn’t like me.
Over-generalizing I heard someone say that I am shy, so I can’t make any
friends.
Dichotomous (black and If I don’t get an A for this report, I’m not worthy of
white) thinking graduate school.
Over-personalization If my daughter loses the spelling contest, I must be a
bad father.
chapter 7
vulnerability to further depression, while medications appear to provide only
symptomatic relief. It is unclear whether this is due to compensatory mechanisms
(e.g. learning new ways to adapt to depressive symptomatology) or whether
there is a fundamental change in the processes that are causal for depression (e.g.
changing negative cognitive schemas).
7.3.2 Mindfulness-based cognitive therapy

Mindfulness refers to the inner experience of being aware of the present moment
and taking a non-evaluative and non-judgmental approach to thoughts and feel-
ing states. Mindfulness-based cognitive therapy (MBCT) is a variant of CT that
incorporates meditation and mindfulness techniques to deal with chronic feel-
ings of unhappiness and depression. Focusing attention on the present moment
(instead of guilt over the past or worries about the future) can prevent the
spiralling of negative thoughts into depressive feeling states. MBCT was devel-
oped initially as a maintenance treatment to prevent episodes in patients with
recurrent MDD. More recent studies have shown that MBCT is also effective in
acute depressive episodes.
7.3.3 Behavioural activation

Behaviour therapy, or behavioural activation (BA), is also a widely validated
treatment for MDD. BA is based on the principle that depression is associated
with a decrease in goal-directed behaviours and reduction of positive reinforcing
activities. This sets up a ‘vicious circle’ in which reduced activity leads to more
inertia, which in turn further limits activity. In BA, the inertia and reduction in goal-
directed activities are addressed to facilitate new learned behaviours. Negative
behaviours (such as crying or angry tirades) are also targeted. Various activation
techniques are used, including increasing the number of pleasurable activities,
tracking moods, and undergoing relaxation exercises and social skills training. The
emphasis is on mastery of situations and skills. As in CT, monitoring mood and
affect and doing homework are essential components of BA. One advantage of
BA is that training of therapists is less intensive than that for CT. In one RCT for
severe depression, BA was found to be as effective as antidepressant medication,
and both were superior to CT alone.
7.3.4 Cognitive–behavioural therapy

Cognitive therapy and behaviour therapy/ behavioural activation are often
used together as cognitive–behavioural therapy (CBT), especially in community
practice. CBT is also widely used in other psychiatric and medical conditions.
Workbooks and patient guides relating to CBT have long been available, but CBT
has now expanded to digital delivery via computer programs, interactive internet
sites, and mobile applications (apps). Meta-analyses have shown that these are
effective interventions for mild-to-moderate MDD.
chapter 7
Table 7.3 Issues and strategies in interpersonal psychotherapy

Interpersonal issue Strategies
Unresolved grief Encourage reminiscing; undergo mourning;
consider future planning.
Relationship conflict (e.g. marital Problem solve; learn communication and
problems) conflict resolution skills.
Role transition (e.g. empty-nesters, Consider both losses and benefits of transition;
divorce, loss of job, retirement) use activation techniques.
Social isolation Learn and practise social skills.
7.4 Interpersonal psychotherapy

IPT is based on the observation that people with depression, whether as a con-
tributory cause or a consequence, often have disturbed interpersonal relation-
ships. IPT was developed in conjunction with pharmacotherapy and uses an
explicit medical model for illness. In IPT, the therapeutic focus is on four common
interpersonal issues (Table 7.3). The initial stage of IPT begins with an extensive
interpersonal history to identify which of these problems is/are relevant for the
patient, and to decide on which one or two issues to work on. IPT is much less
structured than CBT, but the focus on pragmatic methods means that many cog-
nitive and behavioural techniques are used in IPT.
7.5 Cognitive behavioural-analysis system

of psychotherapy
The cognitive behavioural-analysis system of psychotherapy (CBASP) was devel-
oped specifically for chronic depression and includes elements of both CBT and
psychodynamic psychotherapy. CBASP is based on the assumption that patients
with chronic depression are perceptually disconnected from their environmental
situations so that consequences are not appropriately reinforcing behaviours.
The first phase of CBASP is a detailed personal history of interpersonal rela-
tionships, often identifying traumatic events and stressful relationships. Using a
technique termed situational analysis, the therapist helps the patient to identify
the effects of their behaviours on others, and also uses the therapist–patient
interaction to illustrate these effects. The therapy then uses behavioural skills
training and rehearsal to modify the consequences of behaviours and change the
interpersonal dynamic.
In a large (N = 68), 20-week RCT of patients with chronic MDD, CBASP
was found to be as effective as an antidepressant (nefazodone, unfortunately no
longer available owing to problems with liver toxicity), but the combination of
antidepressant plus CBASP was significantly better than either monotherapy (75%
chapter 7
remission rates compared to less than 50% for the monotherapies). Therefore,
patients are encouraged to use pharmacotherapy as they undergo CBASP.
7.6 Group psychotherapies

Most of the individual psychotherapies can be adapted to couples or group set-
tings, and both CBT and IPT are available in group formats. Marital therapy, which
usually incorporates CBT or IPT techniques, also has been shown to be effect-
ive for MDD. The advantages of group psychotherapy are that participants have
more sources for support and encouragement during stressful situations, a group
offers the opportunity to practise interpersonal techniques and receive feedback,
and groups may be more cost-effective. Some of the potential disadvantages of
group psychotherapy are that often patients will prefer individual therapy (which
may, in part, be a consequence of their depressive symptoms, i.e. social isolation
and anxiety), individual therapy may be more effective, and it is more difficult to
engage patients and schedule appointments for groups.
7.7 Technology-assisted psychotherapy

Even though the foundation of psychotherapy is the relationship between ther-
apist and client, the ever-expanding availability of computers, mobile devices,
and access to the internet has generated interest in novel uses of technology
for psychotherapeutic treatments. The technologies range from self-management
or interactive CBT programmes by DVD or computer or over the internet, to
structured psychotherapy delivered by clinicians by telephone or videoconference
(e.g. via Skype). A number of RCTs and meta-analyses have shown good effects
of computer-or internet-delivered interactive CBT and self-management pro-
grammes (Table 7.4), although the effect sizes and adherence rates appear larger
when these are supported by a clinician. These programmes seem to be most
beneficial for motivated people with mild or sub-threshold symptoms, rather
than those who are clinically depressed. Beating the Blues is an example of a
computer-assisted program with clinician support that has been approved by the
U.K. National Health Service for use in primary care clinics.
More recently, mobile health (mHealth) has become prevalent, with numer-
ous applications (apps) available for smartphones and tablet devices. While
mobile apps show great promise for incorporating reminder systems, using pas-
sive tracking for monitoring, and delivering psychological treatments such as self-
management, there remains little rigorous evaluation of their effectiveness.
Mental health clinicians can also provide manualized CBT over the telephone.
Telephone-delivered CBT has many advantages, including convenience (appoint-
ments can be scheduled in the evening or at weekends and the need for travel
is eliminated) and increased capacity and access (especially important for rural
areas because clinicians do not need to be in the same geographic location).
Telephone-delivered CBT has also been found to be acceptable and effective for
chapter 7
Table 7.4 Examples of technology-assisted therapy programs

Programme and website Description
Bounce Back Online No charge, internet-based CBT programme and
http://www.vchbb.com, print materials with modules for depression, anxiety,
accessed  October 207 and other mental health issues.
Living Life To The Full No charge, interactive, internet-based CBT
http://www.llttf.com, intervention consisting of five modules. Offers
accessed  October 207 practitioner training workshops.
MoodGYM No charge, interactive, internet-based CBT
https://www.moodgym.com. intervention consisting of five modules, each taking
au/, accessed  October 207 20–40 minutes to complete. Pitched to a younger
audience.
Big White Wall Online community offering 24/7 peer support with
http://www.bigwhitewall.com, professionally trained ‘wall guides’ to ensure safety
accessed  October 207 and anonymity. Free in many areas of the UK and
small charge to others.
Beacon Internet portal to online applications for mental and
http://www.beacon.anu.edu. physical disorders, reviewed and rated by health
au, accessed  October 207 experts.
many patients, although again the effect sizes may be somewhat smaller than with
in-person psychotherapy. While they may not help everyone with depression, the
use of these technologies will no doubt make psychotherapy accessible to many
more people and will help to stream those who need more intensive treatment
to the appropriate services.
7.8 Maintenance and prevention

CT has been shown to have some enduring effects after acute treatment to
reduce relapse and prevent recurrences, but IPT has not shown such effects.
Maintenance forms of both CBT and IPT have been developed (e.g. using
‘booster’ sessions once a month) to prevent loss of therapeutic effect, but these
have yet to be systematically evaluated. Sequential application of CBT follow-
ing treatment with antidepressants has also shown benefits in converting partial
remitters to full remitters, helping to discontinue antidepressants, and prevent-
ing relapse after stopping medications. MBCT has also been shown to prevent
relapses and recurrences following an acute episode.
chapter 7
Further Reading
Barth J, Munder T, Gerger H, et al. (203) Comparative efficacy of seven
psychotherapeutic interventions for patients with depression: A network meta-analysis.
PLoS Med 10: e00454.
Beck AT, Rush AJ, Shaw BF, et al. (979) Cognitive Therapy of Depression.
New York: Guilford Press.
Chiesa A, Serretti A (20) Mindfulness based cognitive therapy for psychiatric
disorders: A systematic review and meta-analysis. Psychiatry Res 187: 44–53.
Ekers D, Webster L, Van Straten A, et al. (204) Behavioural activation for depression; an
update of meta-analysis of effectiveness and sub group analysis. PLoS One 9: e0000.
Gratzer D, Khalid-Khan F (206) Internet-delivered cognitive behavioural therapy in the
treatment of psychiatric illness. CMAJ 188: 263–72.
McCullough JP (2000) Treatment for Chronic Depression: Cognitive behavioral analysis system
of psychotherapy (CBASP). New York: Guilford Press.
Parikh SV, Quilty L, Ravitz P, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 guidelines for the management of major depressive
disorder in adults. Section 2. Psychological treatments. Can J Psychiatry 61: 524–39.
Segal ZV, Walsh KM (206) Mindfulness-based cognitive therapy for residual depressive
symptoms and relapse prophylaxis. Curr Opin Psychiatry 29: 7–2.
Weissman MM, Markowitz JC, Klerman GL (2000) A Comprehensive Guide to Interpersonal
Psychotherapy. New York: Basic Books.
chapter 7
Chapter 8
Pharmacological treatments
Key points
• The newer antidepressants (SSRIs, SNRIs, other agents) are first-line
medications owing to improved safety and tolerability over first-generation
medications (TCAs, MAOIs).
• Selection of an antidepressant must be personalized to an individual patient and
must take into account efficacy, side-effect profile, safety, specific symptoms,
comorbid conditions, concurrent medications, simplicity of use, and cost.
• Switching antidepressants must take into account side effects, discontinuation
effects, potential drug interactions, and rapidity of switch.
8.1 Selecting an antidepressant

Note: This chapter categorizes medications (e.g. tricyclic antidepressants (TCAs))
using the older, traditional taxonomy because it is still widely used clinically.
Several international neuropsychopharmacology organizations, however, have
jointly proposed a newer nomenclature system that is based on pharmacology
and mode of action rather than structure and clinical indication (see http://www.
nbnomenclature.org, accessed  October 207).
Selecting an antidepressant requires consideration of both patient and medi-
cation factors. There are only small differences in efficacy among the antide-
pressants, so efficacy alone cannot be the only factor in selecting a medication.
Other factors that must be considered include safety, tolerability, simplicity of
use, comorbid conditions, potential drug interactions, clinical presentation, and
cost. For most clinical situations, there is usually no single medication of choice,
and side-effect profile tends to be the factor given highest priority by clinicians in
selecting an antidepressant.
Most of the newer, second-generation antidepressants are considered first-
line medications (Table 8.) because they are safer and better tolerated than the
older, first-generation TCAs. The second-generation antipsychotic (SGA) agent,
quetiapine-XR, is also a second-line recommendation because of its side-effect
profile and limited comparative data with other antidepressants. Similarly, newer
medications, including levomilnacipran and vilazodone, are considered second-line
agents because they do not have, as yet, comparative and maintenance data. The
monoamine oxidase inhibitors (MAOIs) are regarded as third-line medications
because of safety, tolerability, and drug interaction issues. However, MAOIs may
chapter 8
64 • pharmacological treatments
Table 8. CANMAT antidepressant recommendations

First-line medications Second-line medications Third-line
medications
Agomelatine (MT, MT2 Amitriptyline, clomipramine, Phenelzine (MAOI)
agonist; 5-HT2 antagonist) others (TCA) Reboxetine (NRI)
Bupropion (NDRI) Levomilnacipran (SNRI) Tranylcypromine
Citalopram (SSRI) Moclobemide (reversible (MAOI)
Desvenlafaxine (SNRI) inhibitor MAO-A)
Duloxetine (SNRI) Quetiapine (SGAc)
Escitalopram (ASRI) Selegiline transdermal
(irreversible inhibitor MAO-B)
Fluoxetine (SSRI)
Trazodone (SRI; 5-HT2
Fluvoxamine (SSRI)
antagonist)
Mianserin (α2-adrenergic,
Vilazodone (multimodal)
5-HT2 antagonist)
Milnacipran (SNRI)
Mirtazapine (α2-adrenergic,
5-HT2 antagonist)
Paroxetine (SSRI)
Sertraline (SSRI)
Venlafaxine (SNRI)
Vortioxetine (multimodal)
5-HT, serotonin; ASRI, allosteric serotonin reuptake inhibitor; CANMAT, Canadian Network for
Mood and Anxiety Treatments; MAO, monoamine oxidase; MAOI, monoamine oxidase inhibitor;
MT, melatonin; NDRI, noradrenaline and dopamine reuptake inhibitor; NRI, noradrenaline reuptake
inhibitor; SGA, second-generation antipsychotic; SNRI, serotonin and noradrenaline reuptake
inhibitor; SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA; tricyclic
antidepressant.
still be helpful in cases of treatment-resistant depression (TRD; see Chapter 0).

Reboxetine is included as a third-line recommendation because of evidence that
it is less effective than other antidepressants.
Given that anxiety and depression are frequently comorbid, antidepressants
with broad-spectrum efficacy—that is, that are effective for both depressive and
anxiety disorders—carry an advantage for clinical use. The selective serotonin
reuptake inhibitors (SSRIs), escitalopram, and venlafaxine have good evidence for
efficacy in a number of anxiety disorders.
8.2 Comparative efficacy

Most antidepressants have proven efficacy against placebo, but there is little infor-
mation on differences in efficacy among them. A major methodological problem
is that it is much more difficult to power studies to detect the smaller, but still
chapter 8
pharmacological treatments • 65
clinically relevant, differences between two active drugs than to find the larger
differences between drug and placebo. Statistical calculations show that a rand-
omized controlled trial (RCT) requires over 400 patients in each group to dem-
onstrate a 0% difference in efficacy between two active drugs; there are no
antidepressant studies with those sample sizes. Consequently, there is increas-
ing use of meta-analysis, a statistical technique to combine results from studies
involving smaller samples, to investigate comparative efficacy. There are several
limitations to this approach. For example, establishing equivalent doses among
the different medications is difficult. Some of these meta-analyses group together
classes of medications (e.g. SSRIs), but this may not be appropriate since it is not
clear whether all these medications, even within the SSRI class, have the same
efficacy profile (e.g. non-response to one SSRI does not predict non-response to
another, and vice versa).
With these limitations in mind, there is reasonable evidence from meta-analyses
that venlafaxine, particularly at higher doses, has a greater likelihood of producing
remission than SSRIs. Meta-analyses have consistently shown 7–0% superiority
in remission rates for venlafaxine compared to those for SSRIs (primarily fluoxet-
ine), leading to a ‘number needed to treat’ (NNT) of 0–2 (i.e. need to treat ten
patients with venlafaxine to achieve one more remission than treating with an SSRI;
or, for every 00 patients treated with venlafaxine, ten more will go into remission
than with SSRIs). The superiority of venlafaxine has not been shown against other
agents such as bupropion, duloxetine, escitalopram, or mirtazapine. Meta-analyses
also show that escitalopram is consistently superior to citalopram and other SSRIs,
with an effect size and NNT similar to those of venlafaxine/SSRI comparisons
(i.e. for every 00 patients treated with escitalopram,  more will go into remis-
sion than with citalopram). Other antidepressants with some evidence to support
superior efficacy include agomelatine, duloxetine, mirtazapine, and sertraline.
In the subpopulation of patients with more severe illness (and its proxy, hos-
pitalized patient samples), the TCA clomipramine was found to be superior to
SSRIs and moclobemide. Meta-analyses show that the clomipramine results do
not extend to other TCAs such as amitriptyline and imipramine. In prospective
head-to-head RCTs, escitalopram also shows superiority to citalopram and par-
oxetine in severe depression.
8.3 Safety
The newer antidepressants have superseded TCAs and MAOIs in clinical use
because of their superior tolerability and safety profile. The absence of cardio-
vascular side effects makes SSRIs and other new agents much safer in both over-
dose and in potential drug interactions. However, there has been increasing public
and professional attention regarding the possibility that antidepressants, particu-
larly SSRIs and other second-generation agents, may worsen suicidal ideation and
behaviours. While this issue was first raised in the paediatric trials (see Chapter 0),
suicidality with antidepressants has also been queried in adult populations.
chapter 8
Reviews of meta-analyses and large-sample naturalistic database studies, how-
ever, do not show evidence of any excess suicidality associated with specific anti-
depressants in adult populations. In fact, analysis of suicide items on depression
rating scales shows marked improvement in suicidal ideas with antidepressant
treatment, especially in older age samples. Pharmacoepidemiology studies also
have shown decreasing suicide rates associated with increasing rates of anti-
depressant prescriptions. However, overdose with venlafaxine carries a greater
risk for death than overdose with SSRIs, but not as great a risk as with TCAs.
In summary, unlike the youth age group (see Chapter 0), in adults there is no
evidence that antidepressants cause an increase in suicidality overall, and in older
age groups these medications show protective effects on suicidality. Regardless,
it is certainly possible that antidepressants can worsen suicidality in a small subset
of patients, perhaps by worsening anxiety and agitation. Therefore, it is import-
ant to carefully monitor clinical status, including suicidality, when initiating treat-
ment. This is a period of high risk because patients are at high symptom severity,
may not yet be feeling better from treatment, and instead may be experiencing
troublesome side effects that contribute to suicidality.
8.4 Drugs, doses, and common side effects

8.4. Selective serotonin reuptake inhibitors
The SSRIs are the most commonly prescribed antidepressants owing to their
tolerability, safety, simplicity of use, and broad-spectrum efficacy (Table 8.2).
Although they share a common mechanism of action, the drugs in this class
are not interchangeable for clinical efficacy or for side-effect profile. This may
be due to the different secondary receptor binding properties among these
drugs. Fluoxetine and its active metabolite, norfluoxetine, have long half-lives
(about 7 days, compared to 24 hours for other SSRIs). Sertraline is associated
with higher rates of diarrhoea than other SSRIs. The SSRIs are generally weight
neutral in acute trials, but paroxetine has greater weight gain with long-term
use. Sexual side effects can occur in up to 40% of patients, especially ejacu-
lation delay in men and orgasm delay in women, with more noticeable effects
occurring with fluoxetine and paroxetine and fewer effects with citalopram and
escitalopram.
Escitalopram, the S-enantiomer of racemic citalopram, is an SSRI with an add-
itional mechanism of action. While it binds to the primary binding site on the
serotonin transporter protein in the same way as other SSRIs, escitalopram is
unique in that it also binds to an allosteric site on the transporter protein. The
result of this allosteric binding is a more efficient inhibition of serotonin reuptake
that increases serotonin availability in the synapse (leading some to call it an allo-
steric serotonin reuptake inhibitor, or ASRI). The presence of R-citalopram in the
racemic citalopram interferes with this allosteric binding. This additional mechan-
ism may explain the superior therapeutic effect of escitalopram over citalopram
chapter 8
Table 8.2 SSRIs
Mechanism of action Common side effects (bold Drugs, usual daily doses Comments
indicates >30%)
• Selective inhibition • GI (distress, nausea, • Citalopram, 20–40 mg • Mild side-effect profile; low potential for drug
of serotonin vomiting, diarrhoea) interactions
reuptake • CNS (headache, agitation, • Doses of 60 mg and above are associated with
sleep disturbance, tremor) prolonged QTc—caution with use of other drugs that
• Drowsiness, sedation, affect QTc
dry mouth
• Fluoxetine, 20–60 mg • Longer half-life; markedly inhibits CYP 2D6; fewer
• Sexual side effects
discontinuation symptoms
• Fluvoxamine, 00–300 mg • More GI effects (GI distress, nausea) and sedation;
markedly inhibits CYP A9
• Paroxetine, 20–50 mg • More weight gain with long-term use; markedly inhibits
CYP 2D6; more discontinuation symptoms (less so with
CR formulation)
• Sertraline, 50–200 mg • More diarrhoea; medium potential for drug
interactions
• Inhibition of • Similar to SSRIs • Escitalopram, 0–20 mg • More effective than SSRIs, especially for more severely
serotonin reuptake ill, mild side effects; low potential for drug interactions
• Allosteric binding • Also known as an allosteric serotonin reuptake inhibitor
to transporter • Not associated with QT prolongation to doses of 30
protein mg (unlike citalopram)
• Inhibition of • Similar to SSRIs. • Vilazodone, 40 mg • Metabolized by CYP 3A4; should be taken with food;
serotonin reuptake should titrate to therapeutic dose
• 5-HTA agonism
and other SSRIs. The side-effect profile, however, is no different from that of
citalopram.
Citalopram has an additional caution for its dose-dependent increase in QTc
interval, with most regulatory agencies revising down the therapeutic dose to
20–40 mg/day in adults. However, there is no indication that this is a clinically
relevant effect because rates of arrhythmia are no different for citalopram than
for other antidepressants, and other known cardiac risk factors are usually pre-
sent in reports of citalopram-associated arrhythmias. Similarly, there appear to
be no clinically important QTc issues with escitalopram, and no dose adjustments
are required.
8.4.2 Serotonin and noradrenaline reuptake inhibitors

Duloxetine, desvenlafaxine, levomilnacipran, milnacipran, and venlafaxine are
examples of SNRIs, which selectively inhibit serotonin and noradrenaline reuptake
(Table 8.3). Venlafaxine has a dose-dependent effect, with greater efficacy than
SSRIs demonstrated when higher doses are used, perhaps because noradrenaline
reuptake occurs only with doses greater than 50 mg/day. However, compared
to SSRIs, venlafaxine has more side effects and discontinuations because of side
effects, especially at higher doses. The extended-release version has fewer of
these effects. Venlafaxine is also associated with greater toxicity in overdose than
other second-generation antidepressants, owing to more cardiovascular effects
(although this is not seen with therapeutic doses). Desvenlafaxine, the active
metabolite of venlafaxine, has a narrower dose range (50–00 mg) and does not
appear to have the same problem with side effects and discontinuation. Duloxetine
and milnacipran have not shown the same evidence for superiority to SSRIs, but
they have shown efficacy in studies of neuropathic pain and fibromyalgia, as well
as alleviating pain complaints associated with depression. Levomilnacipran, the
l-enantiomer of milnacipran, has a more balanced ratio of serotonin and nor-
adrenaline reuptake inhibition. It is associated with small increases in blood pres-
sure and is not recommended in people with uncontrolled hypertension, active
cardiovascular disease, or recent history of myocardial infarction.
8.4.3 Other reuptake inhibitors

Bupropion is a noradrenaline and weak dopamine reuptake inhibitor (Table 8.4).
Because it has no effects on serotonin, its side-effect profile is distinct from SSRIs,
with fewer gastrointestinal and sexual side effects. It tends to be more activating,
and unlike other antidepressants, does not show efficacy for anxiety disorders.
Bupropion was previously associated with increased risk of seizures in patients
with risk factors, but this has not been noted with the sustained and extended-
release formulations.
Reboxetine is a selective noradrenaline reuptake inhibitor showing efficacy in
depression, but meta-analyses show that it is less effective than other antidepres-
sants. Atomoxetine is another selective noradrenaline reuptake inhibitor that is
chapter 8
Table 8.3 SNRIs
Mechanism of action Common side effects Drugs, usual Comments
(bold indicates >30%) daily doses
• Inhibition of serotonin • GI (distress, nausea, • Desvenlafaxine, • Active metabolite of venlafaxine; low rate of sexual side effects;
reuptake vomiting, diarrhoea) 50–00 mg low potential for drug interactions
• Inhibition of • CNS (headache, agitation,
• Duloxetine, • Effective in neuropathic pain and fibromyalgia
noradrenaline sleep disturbance)
60–90 mg
reuptake • Sweating
• Sexual side effects • Levomilnacipran, • Titrate to therapeutic dose; small increases in blood pressure—
(some SNRIs) 40–20 mg not recommended for certain cardiovascular conditions
• Milnacipran, • Effective in fibromyalgia; shorter half-life, should titrate to

50–00 mg b.i.d. therapeutic dose; higher rates of nausea; low potential for drug
interactions
• Venlafaxine, • More effective than SSRIs
75–225 mg • More GI distress and other side effects than SSRIs; dose-
related increased blood pressure; more discontinuation
symptoms (less so for XR formulation)
• Less safe in overdose
Table 8.4 Other reuptake inhibitors

Mechanism of Common side effects Drugs, usual Comments
action (bold indicates >30%) daily doses
• Inhibition of • Insomnia, agitation, • Bupropion- • Slight increased
noradrenaline dry mouth, blurred SR, -XL, risk for seizures at
reuptake vision, constipation, 300–400 mg higher doses; low
• Possible weak sweating, tremor, GI rate of sexual side
inhibition of distress effects
dopamine • Moderately
reuptake inhibits CYP 2D6
• Inhibition of • Dry mouth, • Reboxetine, • At higher doses,
noradrenaline constipation, 4–0 mg urinary retention
reuptake insomnia, dizziness, may occur
tremor, sweating, • Less efficacy than
urinary hesitancy, other second-
tachycardia generation
antidepressants,
therefore
indicated as third-
line antidepressant
effective in attention deficit hyperactivity disorder, but there are no published

studies in depression.
8.4.4 Multimodal and other receptor agents

A number of medications are now available that primarily act on pre-or postsyn-
aptic receptors (Table 8.5). These medications include mirtazapine and mianserin,
which antagonize α2-adrenergic autoreceptors, leading to increased release of
serotonin and noradrenaline, and also block 5-HT2C receptors, which may explain
the lack of sexual and sleep side effects. Mirtazapine is also a potent histamine-
receptor antagonist, which may help insomnia but also can result in anticholinergic
side effects. Mirtazapine is associated with more sedation, and greater appetite
and weight gain, than other second-generation antidepressants.
Agomelatine is a novel antidepressant that is an agonist of melatonin- and -
2 receptors, and an antagonist of 5-HT2C receptors. In addition to efficacy for
depressive symptoms, agomelatine shows greater beneficial effects on sleep
architecture and symptoms than SSRIs and SNRIs, accompanied by a side-
effect profile similar to that of placebo. Agomelatine also has fewer sexual side
effects than SSRIs. The melatoninergic effects of agomelatine may also help
regulate the sleep–wake cycle and other circadian rhythms. Preliminary studies
suggest that agomelatine may have superior efficacy compared to certain SSRIs.
Other antidepressants have multimodal effects—that is, they act as reuptake
inhibitors and as receptor agents. Multimodal agents include vilazodone and
chapter 8
Table 8.5 Multimodal and other receptor agents
Mechanism of action Common side effects (bold Drugs, usual daily doses Comments
indicates >30%)
• Melatonin -and 2-receptor • Dizziness, nausea, headache • Agomelatine, 25–50 mg • Beneficial effects on sleep; mild
agonism • Profile similar to placebo side-effect profile; low rate of
• 5-HT2C antagonism sexual side effects
• May have chronobiotic
properties
• α2-adrenergic autoreceptor • Fatigue, drowsiness, blurred • Mirtazapine, 5–45 mg • Affects both serotonin and
antagonism vision, dry mouth, constipation, • Mianserin, 30–90 mg noradrenaline; beneficial effects
• 5-HT2C antagonism weight gain on sleep; fewer sexual side
effects than SSRIs
• Antihistaminic properties result
in increased appetite and weight
gain; daytime sedation
• Inhibition of serotonin reuptake • Nausea, diarrhoea, headaches • Vilazodone, 20–40 mg (should • Titrate from 0 mg; low rate of
• 5-HTA agonism be taken with food) sexual side effects
• Inhibition of serotonin reuptake • Nausea • Vortioxetine, 0–20 mg • Beneficial effects on cognition;
• 5-HTA agonism low rate of sexual side effects
• 5-HTB partial agonism • Half-life approximately 66 hours
• 5-HTD, 5-HT3, 5-HT7
antagonism
vortioxetine. Vilazodone is a serotonin reuptake inhibitor that also acts as a par-
tial agonist of 5-HTA receptors. It is unclear whether the 5-HTA agonist activity
offers any clinical advantage and there are no comparative studies against other
antidepressants or maintenance/relapse prevention studies. Vortioxetine also
exhibits moderate serotonin reuptake inhibition, as well as effects at multiple
serotonin receptors: agonist at 5-HTA, partial agonist at 5-HTB, and antagonist at
5-HTD, 5-HT3, and 5-HT7. These multiple effects appear to have post-receptor
downstream effects on other neurotransmitters, including glutamate, and may
explain vortioxetine’s beneficial effects on cognitive dysfunction.
8.4.5 Second-generation antipsychotics

There is now abundant evidence that several SGAs, also known as atypical antip-
sychotics, are efficacious as add-on treatment to antidepressants in TRD (see
Chapter 0). However, one SGA––quetiapine-XR––has demonstrated efficacy as
a monotherapy in acute and maintenance treatment of non-psychotic MDD and
generalized anxiety disorder. Quetiapine-XR is also efficacious as monotherapy
for bipolar depression and as an adjunctive agent for TRD. However, the anti-
depressant properties of quetiapine-XR may not represent a class effect for all
SGAs, because other SGAs have not shown efficacy as monotherapy for MDD
(e.g. olanzapine) or bipolar depression (e.g. aripiprazole, ziprasidone).
The side effects associated with quetiapine-XR include sedation, somnolence,
weight gain, and metabolic effects, but these may be less problematic in MDD than
in other conditions, partly because the adverse effects seem dose-dependent.
The doses used (50–300 mg/day) in MDD are lower than those used for bipo-
lar depression (300–600 mg/day) and for mania/psychosis (800–,000 mg/day).
In contrast to SSRIs and SNRIs, quetiapine-XR also has beneficial effects on sleep
and low rates of sexual side effects. Regardless, because of the relative side-effect
burden and lack of comparative data with other antidepressants, quetiapine-XR is
recommended as a second-line medication for patients who show poor response
or intolerability to first-line antidepressants (Table 8.6).
8.4.6 Tricyclic antidepressants

TCAs are still widely used but have many limiting side effects and can be cardiotoxic
even at therapeutic doses, and so are now usually considered second-or third-line
choices. The tertiary amine TCAs (amitriptyline, imipramine) have more side effects
because they also have active metabolites (nortriptyline and desipramine, respect-
ively). One advantage for TCAs is that plasma drug concentrations have been cor-
related to therapeutic response and thus can be used to aid dose titration. Most
have a minimum plasma concentration to achieve clinical response, but nortriptyline
demonstrates a ‘therapeutic window’ in that plasma levels above and below the
therapeutic range are associated with lower response. Plasma drug concentration
should not be used as a clinical indicator in TCA overdose because of poor correl-
ation with cardiotoxicity; electrocardiogram monitoring of QRS duration is a better
predictor although it has, at best, moderate sensitivity and specificity (Table 8.7).
chapter 8
Table 8.6 Second-generation antipsychotics

Mechanism of Common Drugs, usual Comments
action side effects daily doses
(bold indicates
>30%)
• Inhibition of • Sedation, • Quetiapine- • Side-effect profile greater
noradrenaline weight gain, XR, 50– than other second-
reuptake dry mouth, 300 mg generation antidepressants,
(active constipation, therefore indicated as
metabolite) dizziness, second-line treatment
• 5-HT2 tremor, • Low rate of sexual side
antagonism sweating, effects; beneficial effects
• 5-HTA partial urinary on sleep
agonism hesitancy, • Also effective as
• Dopamine tachycardia monotherapy for bipolar
D2 partial depression and generalized
agonism/ anxiety disorder
antagonism
8.4.7 Monoamine oxidase inhibitors and related agents

These drugs inhibit monoamine oxidase (MAO) A and B, which contribute to the
metabolism of serotonin, noradrenaline, and dopamine. MAOIs are considered
by many clinicians to be superior drugs for treatment-resistant depression, but
the required dietary restrictions and potentially fatal drug interactions make them
more difficult to use in clinical practice. Without MAO, tyramine—found in certain
foods (ripe cheese, red wine)—is not metabolized, and can result in hyperten-
sive crises. ‘Serotonin syndrome’ has also occurred from combining MAOIs with
serotonergic antidepressants and other agents. Because they irreversibly inhibit
MAO, a 2-week washout is necessary when switching from a MAOI to another
antidepressant to allow for regeneration of MAO. Similarly, a -week washout
(5 weeks for fluoxetine) is required when switching from an antidepressant to
a MAOI.
Moclobemide is a reversible and selective inhibitor of MAO-A, and does not
require the same dietary restrictions because MAO-B is still available for metabo-
lizing tyramine. Moclobemide has a benign side-effect profile, but many clinicians
do not regard it as efficacious as MAOIs.
Selegiline (also known as deprenyl) is a selective, irreversible MAO-B inhibitor
that is available as a transdermal delivery system (skin patch). At lower doses it
does not require dietary restrictions, but at higher doses (and with overdose)
selegiline loses selectivity and acts as a MAOI, thereby requiring a tyramine-free
diet. Both selegiline and moclobemide carry the same cautions for drug interac-
tions as for the MAOIs (Table 8.8).
chapter 8
Table 8.7 TCAs
Mechanism of action Common side effects Drugs, usual daily doses Comments
(bold indicates >30%)
• Inhibition of • Side effects vary with drug— Secondary amines • Fewest anticholinergic/cardiovascular
serotonin reuptake secondary amine TCAs have fewer • Nortriptyline, 75–50 mg effects
• Inhibition of side effects than tertiary amine TCAs • Therapeutic window for plasma level
noradrenaline • Anticholinergic (blurred vision,
• Desipramine, 75–225 mg • More activating
reuptake dry mouth, constipation, urinary
• Minimum therapeutic plasma level
• Affects many retention, sweating, confusion)
other receptors • Antihistaminic (drowsiness, • Dosulepin, 75–300 mg • Similar to desipramine
(e.g. histamine, sedation, weight gain) • Most sedating; used in low doses as
Tertiary amines
acetylcholine, • Cardiovascular (dizziness, postural
• Amitriptyline, 75–200 mg hypnotic; used for pain
α2-adrenergic) hypotension, antiarrhythmic effects, • Minimum therapeutic plasma level
QRS prolongation)
• GI (nausea, vomiting) • Imipramine, 00–300 mg • Very sedating
• CNS (tremor, headaches, seizures, • Minimum therapeutic plasma level
insomnia) • Clomipramine, 00–250 mg • More effective in severe depression,
• Sexual dysfunction
used for OCD, very sedating
• Minimum therapeutic plasma level
Heterocyclics • Lowers seizure threshold
• Maprotiline, 00–225 mg
• Amoxapine, 200–400 mg • Dopaminergic; may be useful in
psychotic depression, but also more
likely to cause extrapyramidal symptoms
• Lofepramine, 40–20 mg • Although it is metabolized to
desipramine, it has a safe cardiovascular
profile, even in overdose
Table 8.8 MAOIs and related agents
Mechanism of Common side effects Drugs, usual daily doses Comments
action (bold indicates >30%)
• Irreversible • Hypertensive crises • Phenelzine, 45–90 mg • Phenelzine more sedating; tranylcypromine more
inhibition of • Drowsiness, agitation, • Tranylcypromine 20–60 mg activating
MAO (A and B) hyperreflexia, headache, (in the UK, close supervision • MAOIs require tyramine-free diet
sweating, GI distress, weight gain, is recommended for doses • Caution for drug interactions (see Table 7.7)
sleep disturbance, orthostatic above 30 mg) • Requires 2-week washout before switching to
hypotension, oedema another drug
• Isocarboxazid, 20–60 mg • Milder side effects compared to other MAOIs
• Reversible • Insomnia, agitation, headache, • Moclobemide, 300–600 mg • Mild side-effect profile; dietary restrictions
inhibition of sedation, dry mouth, not needed
MAO-A constipation, nausea, dizziness • Same cautions for drug interactions as for MAOIs
• Selective • Application site reactions, • Selegiline transdermal patch, • At higher doses and in overdosage, selegiline also
irreversible insomnia, headache, dry mouth, 6–2 mg inhibits MAO-A, thereby acting as a MAOI
inhibition of diarrhoea • Dietary restrictions not needed for 6 mg dose,
MAO-B but tyramine-free diet recommended for 9–2
mg dose
• Same cautions for drug interactions as for MAOIs
8.5 Uncommon but serious side effects

There are some uncommon but serious side effects associated with antidepres-
sants. All antidepressants can affect liver function and elevate serum levels of
liver enzymes. In the elderly, hyponatremia can be seen with SSRIs. The older
TCA and MAOI medications can have cardiotoxic effects, sometimes even at
therapeutic doses. Some second-generation antidepressants, especially SSRIs and
SNRIs, are associated with increased risks of gastrointestinal (GI) bleeding (espe-
cially when taken with concomitant non-steroidal anti-inflammatory drugs—or
NSAIDs), osteoporosis, and bone fractures. The increased risk of GI bleeding
with SSRIs may be ameliorated by acid-suppressing drugs such as proton pump
inhibitors (PPIs).
8.6 Drug interactions

Some antidepressants can inhibit a specific cytochrome P450 (CYP) isoenzyme,
thereby leading to increased blood levels of concurrent drugs that are metab-
olized by that isoenzyme (Table 8.9). For example, fluoxetine and paroxetine
markedly inhibit CYP 2D6, which extensively metabolizes several TCAs. If these
TCAs are concurrently taken with fluoxetine or paroxetine, plasma TCA levels
can increase by as much as five to ten times usual for a given dose. Thus, a 200
mg dose essentially becomes equivalent to a 2,000 mg dose, which can be car-
diotoxic. Therefore, lower TCA doses must be prescribed and plasma TCA levels
carefully monitored when used concurrently with fluoxetine or paroxetine.
Pharmacogenetic testing for CYP isoenzymes is increasingly available. These
tests can help identify rapid metabolizers (which lead to lower than expected
drug levels in blood, and presumably less likelihood of a therapeutic response)
and poor metabolizers (which lead to higher than expected drug levels in blood,
and presumably a higher likelihood of safety or side effects), and may be useful in
situations where side effects interfere with attainment of therapeutic doses, or in
cases of treatment-resistant depression. However, given the still-limited evidence
for clinical utility, routine pharmacogenetic testing and/or therapeutic drug level
monitoring is not recommended.
8.7 Switching antidepressants

Many patients will need to be switched from one antidepressant to another for
non-response or intolerance. Switching involves consideration of potential side
effects, discontinuation effects, drug interactions, and need for rapidity of switch.
It is usually not necessary to stop the first antidepressant before starting the sec-
ond (the ‘V approach’, Figure 8.). Instead, the first antidepressant can be tapered
down while the second is tapered up (the ‘X approach’). The advantage of the X
approach is that it takes much less time. The disadvantages include the possibility
chapter 8
Table 8.9 Clinically significant interactions of antidepressants with common drugs*
Drug Mechanism Interacts with Comments
Agomelatine • Substrate for • cimetidine • Reduce dose when used with CYP A2 inhibitors
CYP A2 • ciprofloxacin
• fluvoxamine
Bupropion • Moderate • TCAs • Usually not a clinically relevant effect, but caution with
inhibition of CYP • beta blockers (metoprolol, propranolol) higher doses
2D6 • codeine and other opioids (reduces
effect)
Duloxetine • Moderate • TCAs • Usually not a clinically relevant effect, but caution with
inhibition of • beta blockers (metoprolol, propranolol) higher doses
CYP 2D6 • codeine and other opioids (reduces • Reduce dose when used with CYP 3A4 inhibitors
• Substrate for effect)
CYP 3A4
Fluoxetine • Marked • TCAs • Can potentially increase serum TCA levels to
inhibition of CYP • beta blockers (metoprolol, propranolol) cardiotoxic levels
2D6 • codeine and other opioids (reduces • Long half-life of fluoxetine means that inhibition of CYP
effect) 2D6 can occur for up to 5 weeks after discontinuation
Fluvoxamine • Marked • buspirone • Increased statin levels can cause rhabdomyolysis
inhibition of • clozapine • Monitor INR carefully when warfarin used
CYP A2 • diazepam
• Moderate • quinidine
inhibition of • warfarin
CYP 3A4 • statin drugs
• Moderate • sildenafil
inhibition of CYP • vardenafil
2C9 • phenytoin
• cyclosporine (cyclosporin A)
(continued)
Table 8.9 Continued
Drug Mechanism Interacts with: Comments
MAOIs • Inhibits MAO • high tyramine-containing foods • Potentially fatal reactions with sympathomimetics or
(isocarboxazid, metabolism of • sympathomimetic agents (e.g. tyramine due to hypertensive crises
phenelzine, noradrenaline, pseudoephedrine) • Delirium, confusion, seizures, coma, death reported after
tranylcypromine) serotonin, and • meperidine ingestion of meperidine or other narcotics (including
dopamine • dextromorphan dextromorphan), and with serotonergic agents
• other antidepressants • Avoid disulfiram (Antabuse) with isocarboxazid
• other serotonergic agents
Moclobemide • Inhibits MAO • same as for MAOIs (except dietary • Theoretical risk of serotonin syndrome when combined
metabolism of interactions) with other antidepressants
noradrenaline,
serotonin, and
dopamine
Paroxetine • Marked • TCAs • Can potentially increase serum TCA levels to cardiotoxic
inhibition of CYP • beta blockers (metoprolol, propranolol) levels
2D6 • codeine and other opioids (reduces
effect)
Quetiapine-XR • Substrate for CYP • ketoconazole • Reduce dose when used with CYP 3A4 inhibitors
3A4 • erythromycin
Selegiline • Inhibits MAO • same as for MAOIs (except dietary • Theoretical risk of serotonin syndrome when combined
metabolism of interactions at lower doses) with other antidepressants
noradrenaline,
serotonin, and
dopamine
TCAs • Substrate for CYP • fluoxetine • Can potentially increase serum TCA levels to cardiotoxic
2D6 • paroxetine levels
• bupropion (less likely)
• duloxetine (less likely)
Vilazodone • Substrate for CYP • ketoconazole • Reduce dose when used with CYP 3A4 inhibitors
3A4 • erythromycin
Vortioxetine • Substrate for CYP • fluoxetine • Reduce dose when used with CYP 2D6 inhibitors
2D6 • paroxetine
Marked = >50% increase in blood levels; moderate = 50–50% increase in blood levels.
*
Not a comprehensive list of interactions; only a selection of commonly used drugs.
V Approach X Approach
Drug 1 Drug 2 Drug 1 Drug 2
Dose
Time
Figure 8. Switching approaches for antidepressants.
of additive side effects and difficulty in differentiating discontinuation symptoms

(from the first drug) from side effects of the second drug.
Washout periods are usually not required for switching between most antide-
pressants, especially the SSRIs and newer medications (Table 8.0). The excep-
tion is switching to or from MAOIs. When switching to a MAOI, the first drug
should be washed out (at least  week for most antidepressants, 3 weeks for vor-
tioxetine, and 5 weeks for fluoxetine). When switching from a MAOI to another
antidepressant, a 2-week washout is necessary to ensure that endogenous MAO
is regenerated. For the reversible inhibitor of MAO-A (RIMA), moclobemide, and
the selective MAO-B inhibitor, selegiline, only  week is necessary for washout
when switching to another antidepressant. A useful internet resource for switch-
ing medications (antidepressants and antipsychotics) may be found at http://
www.SwitchRx.ca, accessed  October 207.
8.8 Maintenance pharmacotherapy

Stopping medications too soon is a major challenge for adherence. Meta-analyses
have shown that maintenance antidepressants can reduce relapse rates to 0–20%,
compared to 50% or higher rates with placebo. For uncomplicated depressive epi-
sodes, maintenance of 6 months after symptom remission appears sufficient, but
a period of 2 or more years is recommended when risk factors are present (Box
8.). Some patients will need lifelong maintenance antidepressant treatment.
8.9 Discontinuation
Some patients will experience transient discontinuation symptoms, usually of mild
severity, when antidepressants are abruptly stopped (Box 8.2). Sensory distur-
bances can include tingling or ‘electric shock’-like sensations. Paroxetine, venlafax-
ine, and TCAs are most likely to be associated with discontinuation symptoms (but
less so with the controlled and extended-release preparations), while fluoxetine
is the least likely, in part owing to its long half-life. Other drugs with low propen-
sity for discontinuation symptoms include agomelatine, bupropion, citalopram,
chapter 8
Table 8.0 Washout periods required for switching between antidepressants
Switching to: SSRIs, SNRIs, and Multimodal and other TCAs/SGAs MAOIs Moclobemide
other reuptake receptor agents Selegiline
inhibitors
Switching from:
SSRIs, SNRIs, and None (watch for None (watch for None (watch for  week (5 weeks for  week (5 weeks for
other reuptake additive serotonergic/ additive serotonergic/ additive serotonergic/ fluoxetine) fluoxetine)
inhibitors noradrenergic effects) noradrenergic effects) noradrenergic effects)
Multimodal and other None (watch for None (watch for None (watch for  week (3 weeks for  week (3 weeks for
receptor agents additive serotonergic/ additive serotonergic/ additive serotonergic/ vortioxetine) vortioxetine)
noradrenergic effects) noradrenergic effects) noradrenergic effects)
TCAs/SGAs None (watch for None (watch for None (watch for  week  week
additive serotonergic/ additive serotonergic/ additive serotonergic/
noradrenergic effects) noradrenergic effects) noradrenergic effects)
MAOIs 2 weeks 2 weeks 2 weeks 2 weeks 2 weeks
Moclobemide  week  week  week  week  week
Selegiline
Box 8. Maintenance pharmacotherapy recommendations

. All patients should continue pharmacotherapy for at least 6 months following
remission of symptoms.
2. Patients with the following risk factors should be maintained on pharmaco-
therapy for at least 2 years (up to lifetime for some patients):
• Severe episodes (including psychosis and suicidality)
• Chronic episodes
• Comorbid (psychiatric or medical) episodes
• Difficult-to-treat episodes
• Residual symptoms during current episode
• Frequent and recurrent episodes
• Older age.
desvenlafaxine, escitalopram, levomilnacipran, moclobemide, quetiapine-XR, and

sertraline.
While discontinuation symptoms are not true withdrawal syndromes and the
symptoms are usually transient, they may be quite uncomfortable. Whenever
possible, tapering medications slowly (by one dose-level every week) is prudent.
If necessary, reinstating the dose will ameliorate the symptoms. For those patients
who have difficulty stopping the drug even when on the minimum dose, tapering
to alternate-day dosing may be helpful.
8.10 Complementary and alternative medicine

treatments
Complementary and alternative medicine (CAM) includes such diverse treat-
ments as natural health products (e.g. St John’s wort), dietary supplements (e.g.
Box 8.2 FINISH mnemonic for antidepressant discontinuation symptoms

F Flu-like symptoms
I Insomnia
N Nausea
I Imbalance (dizziness)
S Sensory disturbances
H Hyperarousal (agitation)
Reproduced from Journal of Clinical Psychiatry, 59, Berber MJ, FINISH: Remembering the
discontinuation syndrome. Flue-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbance,
and hyperarousal (anxiety/agitation), p. 255. Copyright (998) with permission from Physicians
Postgraduate Press, Inc
chapter 8
Box 8.3 Caveats and consideration for the use of complementary and
alternative treatments
• There is little RCT evidence for many CAM treatments.
• Many of the conducted RCTs have significant methodological limitations,
including small sample size; lack of placebo controls; inadequate allocation
concealment and blinding; variability in diagnostic and inclusion/exclusion cri-
teria; lack of standardization of doses, potency, and concentration of treat-
ments; and few systematic evaluations of side effects.
• Most of the studies have included patients with mild-to-moderate depressive
severity.
• Few long-term and maintenance studies have been conducted.
• Few comparative studies with standard antidepressants or treatments have
been conducted.
• Although CAM treatments may be widely available (e.g. sold at health food
and grocery stores), manufacturing standards and regulations vary.
• There is little information about interactions with standard medications.
omega-3 fatty acids, S-adenosylmethionine (SAM-e)), vitamins (e.g. methylfolate,

vitamin D), and physical/meditation treatments (e.g. yoga, acupuncture). Many
patients are using CAM treatments with or without the knowledge of their physi-
cians. Although physicians are often wary or sceptical of such treatments, several
CAM treatments have good evidence to support their efficacy in MDD. Side-
effect burden is generally low for these treatments. However, even for those
CAM treatments with reasonable evidence, several caveats about their use
should be considered (Box 8.3).
CAM treatments with good supporting evidence (including meta-analyses) for
efficacy in MDD include St John’s wort (also called hypericum, 500–,800 mg/
day), omega-3 fatty acids (3–9 g/day) and oral SAM-e (800–,600 mg/day in
divided doses). These can be recommended as adjunctive agents to standard treat-
ments, including psychotherapy. In particular, hypericum appears to have good effi-
cacy and tolerability as monotherapy, especially for mild-to-moderate depression.
However, drug interactions with St John’s wort have been reported, so caution is
required if combining with standard antidepressants and medications. Yoga also
has some promising efficacy data, but further study is required. Other CAM treat-
ments do not yet have adequate support for first-or second-line use in MDD.
Further Reading
Bauer M, Pfennig A, Severus E, et al. (203) World Federation of Societies of Biological
Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders,
part : Update 203 on the acute and continuation treatment of unipolar depressive
disorders. World J Biol Psychiatry 14: 334–85.
chapter 8
Cleare A, Pariante CM, Young AH, et al. (205) Evidence-based guidelines for treating
depressive disorders with antidepressants: A revision of the 2008 British Association for
Psychopharmacology guidelines. J Psychopharmacol 29: 459–525.
Procyshyn RM, Bezchlibnyk-Butler KZ, Jeffries JJ (207) Clinical Handbook of Psychotropic
Drugs, 22nd edn. Toronto: Hogrefe and Huber.
Cipriani A, Furukawa TA, Salanti G, et al. (2009) Comparative efficacy and acceptability
of 2 new-generation antidepressants: A multiple-treatments meta-analysis. Lancet
373: 746–58.
Kennedy SH, Lam RW, McIntyre RS, et al. (206) Canadian Network for Mood and
Anxiety Treatments (CANMAT) 206 guidelines for the management of major
depressive disorder in adults. Section 3. Pharmacological treatments. Can J Psychiatry
61: 540–60.
Ravindran AV, Balneaves L, Faulkner G, et al. (206) Canadian Network for Mood
and Anxiety Treatments (CANMAT) 206 guidelines for the management of major
depressive disorder in adults. Section 5. Complementary and alternative medicine
treatments. Can J Psychiatry 61: 576–87.
Stahl SM (203) Stahl’s Essential Psychopharmacology, 4th edn. Cambridge: Cambridge
University Press.
chapter 8
Chapter 9
Somatic treatments
Key points
• Wake therapy, exercise, and light therapy are non-invasive and clinically useful
treatments.
• Electroconvulsive therapy remains an effective, safe, and well-tolerated
treatment for patients with severe, psychotic, or medication-resistant
depression.
• Repetitive transcranial magnetic stimulation now has good evidence for acute
efficacy, but with limited data about long-term management.
• Surgical treatments with novel neuromodulation techniques may become
clinically useful for some patients with difficult-to-treat depression.
9.1 Introduction
Psychiatry has a long history of using physical or somatic treatments that purport
to address the biological pathogenesis of depression. One of the earliest and best
known of these somatic treatments is electroconvulsive therapy (ECT), which,
despite the negative popularized depictions of its use, remains one of the saf-
est and most effective treatments for severe and treatment-resistant depression
(TRD; see Chapter 0). Others, such as insulin shock, are no longer used because
the risks of treatment outweighed any proven benefits. Somatic treatments, how-
ever, vary from non-invasive (wake therapy, exercise, light therapy) to more inva-
sive methods (transcranial magnetic stimulation) and to the most invasive (those
that involve surgery such as vagus nerve stimulation, limbic neurosurgery).
A major problem for evaluating somatic treatments is that, since a physical
treatment is used, designing a suitable placebo control condition for randomized
controlled trials (RCTs) is challenging, and blinding of conditions is often very dif-
ficult to achieve. Hence, the evidence base for these somatic treatments is not as
robust as for medication treatments (Table 9.).
9.2 Wake therapy (sleep deprivation)

Since disturbances in the sleep–wake cycle are cardinal symptoms of major
depressive disorder (MDD), it is not surprising that manipulation of the sleep–
wake cycle has been investigated as a treatment. What may be surprising, how-
ever, is that although depressed patients complain of insomnia and resulting
chapter 9
86 • somatic treatments
Table 9. Level of evidence supporting efficacy of somatic treatments

Somatic treatment Level of evidence available*
Wake therapy (sleep deprivation) RCTs (not sham-controlled)
Exercise RCTs (sham-controlled); meta-analyses
Light therapy RCTs (sham-controlled); meta-analyses
Repetitive transcranial magnetic RCTs (sham-controlled); meta-analyses
stimulation
Electroconvulsive therapy RCTs (sham-controlled); meta-analyses
Vagus nerve stimulation One RCT; large prospective cohort studies
Deep brain stimulation Two RCTs (sham-controlled); small-sample
case series
Limbic neurosurgery Prospective case series
* RCTs, randomized controlled trials.
daytime fatigue, keeping them awake all night can result in a clear improvement
in mood that continues through the next day. Total sleep deprivation (TSD, now
known as wake therapy to better describe the active intervention) can result
in dramatic changes in mood, with many patients feeling a return to baseline.
Although it is difficult to design placebo-controlled studies, the fact that wake
therapy is so counterintuitive to patients (most of whom think they will feel better
if only they had more sleep) makes a placebo response less likely.
Unfortunately, the mood improvement after TSD is not long lived. The majority
of patients relapse after a recovery sleep the next day after TSD. Several reviews of
sleep deprivation studies found the clinical response rate to TSD averaged about
60%, but 80–85% of patients relapsed the the day after the recovery sleep. Relapse
can occur even after brief naps. However, it is intriguing that up to 5% of patients
appear to have sustained responses to TSD even after a recovery sleep. Newer
techniques have suggested that wake therapy, in combination with medications
such as lithium or antidepressants, or with bright light therapy, can help sustain
response in a good proportion of patients. The main problem with wake therapy is
adherence, since many patients do not have the motivation to stay awake all night.
A regimen in which an all-night sleep deprivation is alternated with nights of regular
sleep may make it easier to perform as an outpatient. Alternatively, partial sleep
deprivation, in which patients are allowed to sleep from 0 p.m. to 2 a.m., may
also be effective and may make it easier for patients to comply with wake therapy.
Clinical summary: Given the non-invasive, easily conducted nature of wake
therapy, it can be considered as adjunctive treatment for patients with MDD,
especially those who require rapid response and can be monitored (e.g. hospital-
ized patients, acutely suicidal patients).
chapter 9
somatic treatments • 87
9.3 Exercise
Exercise has been shown to improve mood and reduce depressive symptoms in
various populations, with now many RCTs conducted in MDD. Several system-
atic reviews and meta-analyses have shown that exercise is effective and well-
tolerated compared to control conditions in mild-to-moderate MDD, with effect
sizes similar to antidepressants and psychotherapy. Both aerobic (cardiovascular)
and anaerobic (resistance) exercise are effective, without clear evidence to sup-
port superiority of either. The recommended regimen for MDD is similar to the
general public health recommendations: at least 30 minutes of moderate intensity
(an activity level in which you can still talk) at least three times weekly for at least
9 weeks. This regimen should be tailored to the physical status of the patient, and
supervised exercise has more benefit than unsupervised.
Clinical summary: Although there remain some methodological limitations
to the RCT evidence, given the lack of side effects and the other medical benefits,
supervised exercise can be recommended as monotherapy for mild-to-moderate
MDD and as adjunctive treatment for more severe MDD.
9.4 Light therapy

Light therapy consists of daily exposure to bright, artificial light, usually admin-
istered with a fluorescent light box (Figure 9.). Light therapy has been found
to be effective in seasonal affective disorder (in DSM-5 terminology: recurrent
major depressive episodes with a seasonal pattern) and has been studied in other
conditions such as non-seasonal depression, bulimia nervosa, and premenstrual
depressive disorder.
The standard protocol for light therapy is 0,000 lux white, fluorescent light
(with ultraviolet wavelengths blocked) for 30 minutes a day in the early morn-
ing upon arising from sleep. Newer light treatment devices include those using
light-emitting diodes (LEDs). These have the advantages of long life, portability
(can be battery-powered), and wavelength differences (which may be more effi-
cient). Light therapy devices (costing about US$20–US$300) are available for
purchase at local pharmacies or medical equipment stores or on the internet.
Several websites offer professional information about light therapy (e.g. http://
www.UBCsad.ca, accessed  October 207, http://www.CET.org, accessed 
October 207).
The effect of light therapy is mediated through the eyes to the brain via the reti-
nohypothalamic tract. Major hypotheses for its therapeutic effect involve circadian
rhythm regulation (light is the strongest synchronizer of the circadian pacemaker
in the brain, located in the suprachiasmatic nucleus of the hypothalamus) and/or
effects on neurotransmitter dysregulation (particularly serotonin and/or dopa-
mine). The circadian effects of light are transmitted via melanopsin, a photopigment
in retinal ganglion cells which is sensitive to lower-intensity blue light. However,
there is as yet little evidence comparing the antidepressant effects of bright white
chapter 9
Figure 9. Example of fluorescent light box used for light therapy.
Source: Image provided by Compass Health Brands.
light with dimmer blue light. Several systematic reviews of RCTs have shown that
bright light is effective in the treatment of seasonal depression, with some trials
showing the effects of light to be comparable to those with SSRI antidepressants.
There is emerging evidence for efficacy of light therapy in other conditions, includ-
ing non-seasonal depression. For non-seasonal MDD, the combination of light and
SSRI antidepressant appears to be more efficacious than either monotherapy alone.
Adverse effects reported for light therapy are generally mild, but include head-
ache, nausea, eye strain, agitation, and insomnia. There are also case reports of
manic induction with bright light so that patients with bipolar disorder should use
the same cautions as with other antidepressants. Relative contraindications to
using bright light include pre-existing retinal disease, macular degeneration, and
use of retinal photosensitizing drugs (e.g. thioridazine, lithium, melatonin).
Clinical summary: Light therapy is a first-line treatment for seasonal affect-
ive disorder. Although the evidence base for efficacy in non-seasonal depression
is limited, given the non-invasive nature, tolerability, and low cost of light therapy
it can be considered as a first-line treatment for patients with mild-to-moderate
depression severity when standard treatments are not tolerated, or as adjunctive
treatment with antidepressants.
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9.5 Transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a technique in which a brief,
high-intensity magnetic field is generated and used to stimulate cortical neurons.
The advantage of rTMS is that it is a non-invasive treatment which can be applied
while patients are awake, and in which adverse effects are minimal. Compared
to ECT, there are no cognitive side effects and no anaesthesia is required. In the
mid-990s, rTMS, in which a ‘train’ of sequential pulses is applied in one session,
began to be evaluated as a treatment for MDD and other neuropsychiatric condi-
tions. Since then, dozens of RCTs, systematic reviews, and meta-analyses have
found statistically and clinically significant effects of active rTMS over sham con-
trol conditions. In ‘real-world’ studies, the response rate for rTMS in depressed
patients is about 50%, while the remission rate is about 30%. A consistent pre-
dictor for rTMS response is the degree of treatment resistance—the more failed
trials of medications, the lower the response to rTMS. Also consistent with this
finding is that ECT is superior to rTMS in direct comparisons.
High-frequency stimulation is considered excitatory in neuronal regions, while
low-frequency stimulation is inhibitory. Studies of rTMS parameters have shown
efficacy for high-frequency stimulation over the left dorsolateral prefrontal cortex
(DLPFC), low-frequency stimulation over the right DLPFC, and bilateral rTMS
using both. Other rTMS parameters are being studied, including deep rTMS and
both intermittent and continuous theta-burst stimulation. The usual course for
rTMS consists of daily treatments (five times per week) for 4–6 weeks. Each
treatment takes 5–45 minutes, depending on the stimulation protocol, although
theta-burst stimulation protocols only take –3 minutes per session. Side effects
can include mild scalp pain during stimulation and transient headache.
The major limitation of the evidence for rTMS is the lack of long-term follow-
up and maintenance data. The studies of rTMS have been short—generally 2–4
weeks in duration—and the durability of response is variable—between 2 and
2 months. As with ECT, most patients relapse within 6 months after response
to an acute course. Studies using different maintenance rTMS schedules are being
conducted, but there remains insufficient evidence to make recommendations.
Clinical summary: rTMS is a non-invasive treatment with few side effects,
and efficacy is demonstrated in short-term studies. Overall, rTMS can be recom-
mended as a first-line acute treatment for patients who have failed at least one
antidepressant trial. It should be considered earlier in the treatment algorithm
than ECT, as rTMS is not a substitute for ECT. The limiting clinical factors include
lack of availability, the inconvenience of daily visits to the clinic for 4–6 weeks, and
limited information on longer term outcomes and maintenance strategies.
9.6 Electroconvulsive therapy

ECT remains one of the most effective treatments in psychiatry, with response
rates of 60–90%, and recent developments in ECT have optimized the treatment
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Box 9. Indications for electroconvulsive therapy (ECT) in depression

• High suicide potential
• Deteriorating physical status (e.g. inability to eat or drink)
• Psychotic features (especially delusional depression)
• Previous good response to ECT
• Poor response to antidepressants
• Inability to tolerate antidepressants
• Pregnancy
• Patient preference.
parameters while reducing cognitive side effects. ECT also appears to work faster
than antidepressants, especially for elderly patients and/or those with psychotic
depression. Systematic reviews have highlighted the strong evidence for efficacy
compared to sham treatments, and recent RCTs have also shown clear acute
benefits of ECT. Unfortunately, there remain only a few comparisons of ECT with
second-generation antidepressants and combinations.
Indications for ECT are shown in Box 9.. High-dose (three to eight times the
dose needed for seizure threshold) unilateral electrode placement has similar effi-
cacy to bilateral placement with fewer cognitive side effects. In addition, some
evidence exists that bifrontal electrode placement, which requires lower electrical
dose to achieve seizures, also has similar efficacy to the traditional bitemporal
placement, with fewer cognitive side effects. Ultrabrief pulse stimulation appears
to have less severe short-term cognitive side effects than brief pulse stimulation,
but at the cost of slightly less efficacy. Seizure duration is commonly monitored
using EEG analysis or the blood pressure cuff method (for seizure-induced motor
activity), but there is no good definition of an ‘adequate’ seizure. The usual course
of treatment consists of six to 2 sessions administered three times weekly, but
less frequent sessions are associated with fewer cognitive side effects.
ECT is a safe treatment. With careful pre-anaesthesia examination, the mortality
rate approximates that of general anaesthesia. There is no evidence for any long-
term neural damage due to ECT; indeed, there are animal studies suggesting that
electroconvulsive shock can lead to enhanced neurogenesis.
The common side effects of ECT relate to recovery from the general anaes-
thetic and the brief seizure, including nausea, headache, and muscle aches. These
resolve spontaneously or with symptomatic treatment. Less common are mus-
culoskeletal and dental injuries, persistent myalgia, and cardiovascular events.
The cognitive side effects of ECT include a post-ECT confusional state (due to
post-ictal and post-anaesthetic effects) that resolves quickly, and a short-term
retrograde memory loss that resolves more slowly. Although there are anecdotal
reports of severe and permanent memory loss, neuropsychological studies show
no sustained cognitive deficits upon testing 6 months after ECT. In fact, one meta-
analysis showed recovery or improvement in neuropsychological tests 3–5 days
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after a course of ECT. Some loss of memory for events surrounding the time
of ECT may linger, but longer term cognitive effects seem to be selective for
impersonal autobiographical memories (such as public events) that do not affect
functioning. In addition, the majority of patients show improvement in cognitive
functioning because their depression-related memory problems improve.
Most guidelines have recommended stopping ineffective pre-ECT antidepres-
sants before or during a course of ECT, as they will not likely be effective for
maintenance treatment and their continued use may have additive side effects.
One RCT showed that concurrent use of nortriptyline with ECT was associated
with better response and fewer cognitive side effects than use of either placebo
or venlafaxine. Therefore, commencement of a new agent can be considered
either before or during the ECT course.
Without maintenance treatment, the relapse rate following successful ECT is
high, ranging from 50% to 80% within 6 months. Greater severity and degree of
medication resistance is associated with a higher rate of relapse. Limited data on
maintenance options exist, but the combination of lithium and nortriptyline has
been found to be superior to nortriptyline alone, and the combination of lithium
and venlafaxine was as effective as lithium and nortriptyline in preventing relapse.
In addition, continuation ECT (starting at twice a month and then tapering to once
a month) was as effective as the lithium–nortriptyline combination.
Clinical summary: ECT is a safe and effective treatment that should be con-
sidered in the treatment algorithm for TRD and psychotic depression. ECT can
also be a first-line recommended treatment for severely compromised patients—
for example, those with extreme suicidality, severe dysfunction, and physical
deterioration. The transient memory disturbance associated with ECT can be
minimized using high-dose unilateral or lower-dose bifrontal electrode placement,
or ultrabrief pulse stimulation. Maintenance strategies, including antidepressants,
combination lithium–nortriptyline, and continuation ECT, are important to pre-
vent relapse following ECT.
9.7 Surgical treatments

9.7. Vagus nerve stimulation
Vagus nerve stimulation (VNS) involves surgical implantation of an electrode
around the left vagus nerve in the neck, connected to a stimulator/battery pack,
similar to a pacemaker implanted under the chest wall. Electrical stimulation to
the vagus nerve is continuously applied in a cycle of 30 seconds on, then 5 min-
utes off. A major advantage of VNS is that compliance to treatment is 00%.
VNS is an effective and approved treatment for medication-refractory epilepsy,
but when study patients were found to have improved mood independent of
effects on seizures, VNS was investigated for TRD. Initial open-label pilot studies
were encouraging, but an 8-week double-blind RCT found no effects of active
VNS compared to the inactivated form. However, patients with activated VNS
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continued to improve over a -to 2-year naturalistic follow up, and outcomes
were better than with a matched cohort of patients with TRD that received usual
care without VNS. Based on these results, VNS is currently approved for TRD in
the United States and Canada.
The therapeutic mechanism(s) of VNS is not known, but the vagus nerve is
a major afferent pathway to the brain. Neuroimaging studies suggest that VNS
results in changes in neural circuitry similar to those seen with antidepressants
and ECT. Side effects of VNS include mild voice changes (due to proximity to the
larynx and laryngeal nerve) and infections.
9.7.2 Deep brain stimulation

Deep brain stimulation (DBS) is an approved treatment for tremor in Parkinson’s
disease unresponsive to medication, and is being investigated for TRD and other
psychiatric conditions. In DBS, electrodes are inserted into the brain using stereo-
tactic neurosurgery and connected to a battery/stimulator implanted under the
chest wall which is similar to that used in VNS. Continuous electrical stimulation
is then applied to specific brain areas.
Based on neuroimaging and neural circuitry hypotheses of depression, several
target sites have been proposed, including a site of metabolic overactivity in the
white matter of the anterior cingulate cortex (the subgenual cingulate region,
Brodmann’s area 25). By electrically stimulating this area, brain activity can be
inhibited in a manner similar to ablative limbic neurosurgery, leading to improve-
ment in depressive symptoms. The advantage of DBS over limbic neurosurgery is
that, presumably, no damage is done to brain tissue and the procedure is poten-
tially reversible in that the electrodes can be removed if desired.
Several case series have shown that patients with chronic refractory depres-
sion (defined as failing numerous medication trials and ECT) had good responses
to DBS. The original series of 20 patients with subgenual cingulate DBS main-
tained a 64% response rate after 3–6 years of follow up. However, two 6-month,
sham-controlled RCTs were both negative, with no benefit evident for active
over sham DBS. Other targeted areas now being investigated for DBS include the
internal capsule/ventral striatum, the nucleus accumbens, and the medial fore-
brain bundle.
9.7.3 Limbic neurosurgery

Neurosurgical treatments such as prefrontal lobotomy have a history steeped
in notoriety in psychiatry, but modified forms of neurosurgery are still used in
patients with the most refractory depressive and anxiety disorders. These tech-
niques, including capsulotomy and cingulotomy, now involve stereotactic neuro-
surgery targeting very small areas for ablation. Double-blind studies are obviously
not possible with limbic neurosurgery, but long-term follow up of patients has
shown reasonable outcomes (with about one-third substantially improved) with
few adverse effects (although some changes in personality and cognition are
possible).
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Clinical summary: Given the invasive nature of surgical interventions, VNS
can be recommended for patients who have not responded to standard treat-
ments, including pharmacotherapy, psychotherapy, and ECT, and/or for those
who refuse—or are intolerant to—ECT. However, the lack of robust efficacy
data must be factored into this decision. Limbic surgery is reserved for the most
chronic and refractory patients, while DBS remains an experimental treatment.
Further Reading
Andrade C, Arumugham SS, Thirthalli J (206) Adverse effects of electroconvulsive
therapy. Psychiatr Clin North Am 39: 53–30.
Bewernick B, Schlaepfer TE (205) Update on neuromodulation for treatment-resistant
depression. F000Res 4: pii: F000 Faculty Rev-389.
Brown ED, Lee H, Scott D, et al. (204) Efficacy of continuation/maintenance
electroconvulsive therapy for the prevention of recurrence of a major depressive
episode in adults with unipolar depression: A systematic review. J ECT 30: 95–202.
Brunoni AR, Chaimani A, Moffa AH, et al. (207) Repetitive transcranial magnetic
stimulation for the acute treatment of major depressive episodes: A systematic review
with network meta-analysis. JAMA Psychiatry 74: 43–52.
Lam RW, Levitt AJ, Levitan RD, et al. (206) Efficacy of bright light treatment, fluoxetine,
and the combination in patients with nonseasonal major depressive disorder: A
randomized clinical trial. JAMA Psychiatry 73: 56–63.
Lam RW, Tam EM (2009) A Clinician’s Guide to Using Light Therapy. Cambridge: Cambridge
University Press.
McClintock SM, Reti IM, Carpenter LL, et al. (207) Consensus recommendations for
the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the
treatment of depression. J Clin Psychiatry 207 May 23. doi: 0.4088/JCP.6cs0905
Milev RV, Giacobbe P, Kennedy SH, et al. (206) Canadian Network for Mood and
depressive disorder in adults. Section 4. Neurostimulation treatments. Can J Psychiatry
61: 56–75.
Nyström MB, Neely G, Hassmén P, et al. (205) Treating major depression with physical
activity: A systematic overview with recommendations. Cogn Behav Ther 44: 34–52.
Tor PC, Bautovich A, Wang MJ, et al. (205) A systematic review and meta-analysis of
brief versus ultrabrief right unilateral electroconvulsive therapy for depression. J Clin
Psychiatry 76: e092–8.
Wirz-Justice A, Benedetti F, Berger M, et al. (2005) Chronotherapeutics (light and wake
therapy) in affective disorders. Psychol Med 35: 939–44.
chapter 9
Chapter 10
Special populations
Key points
• The keys to optimal management of treatment-resistant depression and
depression in special populations include careful assessment, and selection
of evidence-based treatments tailored to the individual, along with ongoing
monitoring of response and outcome.
• Given the still limited evidence base, use and selection of antidepressants
depend on an individual risk–benefit assessment in elderly patients, those with
other medical illnesses, pregnant and breastfeeding women, and children and
adolescents.
10.1 Treatment-resistant depression

0.. Definition and assessment
While most patients with depression respond to initial treatment, up to one-third
will not show a clinical response and another 20–30% may not achieve full remis-
sion of symptoms. There is unfortunately little high-quality evidence available on
how to best manage patients with limited or partial responses, and even less
information on optimal sequencing of treatments. Thus, clinical management for
these situations is often based only on expert opinion and consensus.
Treatment-resistant depression (TRD) is the term used to describe limited
response after several treatments (usually pharmacotherapy). The usual defin-
ition for TRD is failure to demonstrate a clinical response to adequate trials of
two or more antidepressants, usually from different classes. Clinical response is
usually defined as 50% or greater reduction from baseline score using a depres-
sion rating scale. An adequate trial usually means that antidepressant treatment
has been ‘optimized’ by increasing the dose to the maximum approved dose (or
until limited by side effects) for at least 4–6 weeks of treatment. However, this
definition of TRD does not take into account partial responses or residual symp-
toms, and by assuming the first strategy for poor response is switching to another
monotherapy, it does not capture failure of other strategies such as augmentation
and combination. Hence, findings from studies of TRD may not be generalizable
to patients with limited treatment response seen in clinical practice.
The evaluation of patients with TRD involves reassessment of diagnostic and
treatment/adherence issues (Box 0.). Psychoeducation and self-management
should be encouraged (see Chapter 6) and an effort to identify psychological
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96 • special populations
Box 0. Evaluation for patients with depression that are not responding
to treatment
• Reassess adherence to treatment (side effects, taking medication
properly, etc.)
• Reassess the diagnosis (especially hypomania, psychotic or seasonal depres-
sion, persistent depression)
• Reassess for comorbidity (especially anxiety disorder, substance abuse, per-
sonality disorder, attention deficit hyperactivity disorder, physical conditions)
• Reassess medication profile (any drug–drug interactions?)
• Determine degree of response/non-response (using a rating scale)
• Consider psychological treatment options
• Consider pharmacological treatment options
• Consider transcranial magnetic stimulation, electroconvulsive therapy, and
other somatic treatments.
targets for intervention may also be beneficial at this stage. Because there is lim-
ited information on approaches to the patient who has not responded to psycho-
therapy, the remainder of this section will focus on pharmacotherapy strategies
for TRD.
0..2 Pharmacological treatment strategies

Pharmacotherapy strategies for TRD include switching (to another antidepressant
monotherapy), augmenting (adding another medication which, by itself, is not an
antidepressant), and combining (adding a second antidepressant). However, the
definition of an antidepressant is now blurring (e.g. quetiapine-XR was initially
considered to be an augmentation agent but is now recognized as an antidepres-
sant in monotherapy) and the terms augmenting and combining are often used
interchangeably. Hence, the term ‘augmentation/combination’ is usually replaced
by ‘add-on’ or ‘adjunctive’, which does not infer the type of agent being added.
Adjunctive strategies have many potential advantages compared to monotherapy
switch, but there are also disadvantages (Table 0.). Although it may seem that
side effects should be higher when two drugs are used, combining can often be
done using lower doses of each drug, so the overall side effect burden may actu-
ally be less than with a high dose of a single drug.
Unfortunately, there remains limited evidence to support efficacy for many of
these strategies, and even less information on sequencing of strategies (Table
0.2). However, using a systematic approach (e.g. the CANMAT treatment algo-
rithm, Figure 0., or the Texas Medication Algorithm) with careful documenta-
tion and evaluation of response can lead to improved outcomes. Switching from
one selective serotonin reuptake inhibitor (SSRI) to another seems to have similar
efficacy to switching to another class, perhaps because these medications have
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special populations • 97
Table 0. Advantages and disadvantages of pharmacotherapy strategies

for TRD
Strategy Advantages Disadvantages
Switch to • Simple • May lose partial
monotherapy • Better adherence benefits of first
with another • May be cheaper* medication
antidepressant • May have fewer side effects* • Possible
• No drug interactions discontinuation
symptoms from
stopping first
medication
• Lag time to response
with second
medication
Add-on treatment • Retains therapeutic optimism • When combining,
(augment or (by not ‘giving up’ on the first never sure if
combine) medication) the second
with another • Allows longer time on first antidepressant would
medication/ medication have worked by itself
antidepressant • May enlist additional mechanisms • May have more side
of action effects*
• Builds on partial responses • May have drug
• Faster response than with interactions*
switching* • May be more
• May be able to target specific expensive*
residual symptoms
• May be able to treat side effects of
first medication
• No problem with discontinuation
symptoms
*
Depends on doses and medications used.
differences in secondary binding properties. For tips on switching and discontinu-

ing antidepressants, see Chapter 8.
Most clinicians prefer to use adjunctive agents rather than switch when there is
partial response to the first medication, in order to not lose any benefits from the
first medication. Second-generation antipsychotics (SGAs), such as aripiprazole,
brexpiprazole, olanzapine, quetiapine-XR, and risperidone, now have the best-
quality evidence as adjunctive agents. The evidence for lithium (at therapeutic
serum levels of 0.5–.0 meq/L) is primarily in augmenting tricyclic antidepres-
sants (TCAs), with less evidence in newer antidepressants. Similarly, the evidence
for triiodothyronine is primarily with TCAs, but it has fewer side effects and is
easier to use than lithium. Psychostimulants (d-amphetamine, methylphenidate,
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Table 0.2 Evidence for pharmacotherapy strategies for TRD

Strategy Medication(s) Level of evidence*
Switch • within same class (SSRIs) • Level 2
• to another class • Level 2
Add-on (Augment) • second-generation antipsychotics • Level 
• lithium • Level 2
• triiodothyronine • Level 2
• modafinil • Level 2
• other psychostimulants • Level 3
Add-on (Combine) • bupropion • Level 2
• mirtazapine/mianserin • Level 2
• TCAs, e.g. desipramine (caution • Level 2
with CYP 2D6 interactions) • Level 3
*
Level  = meta-analysis or large, placebo-controlled, replicated RCTs; Level 2 = at least one
placebo-controlled RCT with ≥30 patients per condition; Level 3 = small-sample RCT or
uncontrolled or open-label studies; Level 4 = expert opinion.
lisdexamfetamine) have not generally shown overall efficacy as add-on agents, but
may be more useful in targeting fatigue and/or cognitive symptoms. However, the
wake-promoting agent, modafinil, has Level 2 evidence to support its use as an
adjunctive agent.
Another advantage of adjunctive treatment is that it may be possible to target
specific symptoms or side effects with the second agent. For example, mirtazap-
ine/mianserin/quetiapine-XR may be particularly beneficial for residual symp-
toms of anxiety and/or insomnia, triiodothyronine/modafinil/psychostimulants
for fatigue and low energy, and bupropion for treating SSRI-induced sexual dys-
function. However, there is as yet little evidence to support any targeted adjunct-
ive treatment.
0..3 STAR*D (Sequenced Treatment Alternatives to Relieve

Depression) study
The STAR*D study is an important, large-scale (N = 3,67 patients), pragmatic
effectiveness study funded by the National Institute of Mental Health in the
United States which was designed to provide information on sequencing of treat-
ments for major depressive disorder (MDD) after non-remission with a standard
antidepressant (2 weeks of citalopram, 20–60 mg/day). STAR*D incorporates
many state-of-the-art features, including a focus on remission as the primary out-
come, use of real-world patients (e.g. without excluding for comorbidity or sub-
stance abuse/dependence) from primary care and specialist settings, large sample
size, incorporation of patient preference, and use of measurement-based care.
Various levels of treatment were studied, with non-remitters progressing to the
next step corresponding to increasing treatment resistance. Although patients
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Select and initiate a
first-line
antidepressant
Early No 2 3 Consider factors for 3

improvement
after 2–4 switch vs. add-on
weeks?
Yes 4
Switch to another
Add-on an
Switch to a 2nd or 3rd first-line antidepressant,
adjunctive
line antidepressant preferably with
medication
superior efficacy
Early
Continue Yes No
improvement
treatment for
after 2–4
6–8 weeks
weeks?
No 6 7
Symptom
remission?
Yes
Figure 0. CANMAT treatment algorithm for managing limited response to an ini-
tial antidepressant.
Reproduced from: Kennedy SH, Lam RW, McIntyre RS, et al. (206) Canadian Network for Mood and
Anxiety Treatments (CANMAT) 206 guidelines for the management of major depressive disorder in
adults. Section 3. Pharmacological treatments. Canadian Journal of Psychiatry 61: 540–60.
Notes for Figure 0..
() Monitor outcomes using measurement-based care. Early improvement (defined as ≥20% reduction
in symptom score) to a first-line antidepressant should be apparent within 2–4 weeks of achieving a
therapeutic dose.
(2) If there is not at least initial improvement and the drug is well tolerated, increase the dose. If there is
still limited improvement, reassess diagnosis (especially comorbidity), degree of improvement (such as
number and type of residual symptoms), adherence, and tolerability.
(3) At any step, especially with early treatment resistance, consider adding an evidence-based, non-
pharmacological treatment (e.g. cognitive–behavioural therapy, exercise, light therapy) or switching to
a neurostimulation treatment (such as transcranial magnetic stimulation or electroconvulsive therapy).
(4) Generally, consider second-line antidepressants only after trying two or more first-line agents.
(5) For more resistant depressions, consider a longer period to evaluate benefit.
(6) Depending on tolerability, increase to maximum dose.
(7) For more chronic and resistant depressions, consider a chronic disease management approach, with
less emphasis on reducing symptoms and more emphasis on improving functioning and quality of life.
could select the sub-study for participation at each level, they were randomized
to treatments within the sub-study.
Table 0.3 summarizes the overall results. The remission rates were lower than
those seen in efficacy RCTs (randomized controlled trials), because the patient
population was more severe and challenging to treat. About two-thirds of patients
achieved full symptom remission after four treatment levels. Most of the treat-
ment options were indistinguishable from each other, but unfortunately, by Step
3 the sample sizes were too small to detect meaningful differences. Some differ-
ences in tolerability of treatments were observed. For example, citalopram com-
bined with bupropion was better tolerated than when combined with buspirone,
and citalopram combined with triiodothyronine was better tolerated than lithium
augmentation. The sub-study with cognitive therapy was smaller than expected,
but the remission rates were similar to those of medication options. Overall, this
study shows that remission is achievable for the majority of patients—even those
with challenging MDD—with increasing intensity of treatments. However, there
remain unresolved questions about the comparative efficacy of many of the treat-
ment options studied. Another major limitation of STAR*D is that the SGAs, now
the best-evidenced treatments for TRD, were not studied.
0..4 Second-generation antipsychotics

There is increasing evidence to support the use of SGAs as adjunctive agents in
TRD (Table 0.4). Several meta-analyses and a Cochrane Systematic Review have
summarized the clinical trial data supporting the efficacy of aripiprazole, olan-
zapine (combined with fluoxetine), risperidone, and quetiapine-XR as adjunctive
treatment for non-responders to SSRIs and SNRIs (serotonin and noradren-
aline reuptake inhibitors). Brexpiprazole was approved for adjunctive treatment
on the basis of two positive RCTs. The recommended doses of these agents
for MDD and TRD are generally lower than those for bipolar disorder, which
in turn are lower than those for psychosis/schizophrenia. It is unclear whether
the antidepressant effects of the SGAs represent a class effect. For example,
only quetiapine-XR has good evidence as monotherapy for both MDD and bipo-
lar depression, while aripiprazole and ziprasidone are not effective for bipolar
depression.
The side effects of the various SGAs are well known, including (depending on
the agent) sedation, somnolence, weight gain, metabolic effects, extrapyramidal
side effects including akathisia, and prolactin release. However, SGA side effects
may be dose-dependent, and so may be less problematic with the lower doses
used in MDD/TRD compared to the doses used in bipolar disorder and schizo-
phrenia. Weight gain and metabolic effects limit the use of olanzapine to second-
line recommendation as an adjunctive treatment.
In summary, the most consistent evidence substantiates the use of aripiprazole,
quetiapine-XR, and risperidone as first-line adjunctive agents for TRD, with more
limited support for brexpiprazole and olanzapine. Unfortunately, as with most of
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Table 0.3 Summary of STAR*D results
Level & sample size Sub-studies and intervention(s) Remission rate Cumulative remission2
Step  • Citalopram 36.8% 36.8%
N = 3,67
Step 23 • SWITCH to: venlafaxine or bupropion or sertraline 30.6% 56.%
N = ,439 • COMBINE citalopram with: bupropion or buspirone
• SWITCH to or COMBINE with: cognitive therapy
Step 33 • SWITCH to: nortriptyline or mirtazapine 3.7% 62.%
N = 390 • AUGMENT with: lithium or triiodothyronine
Step 4 • SWITCH to: tranylcypromine or mirtazapine plus venlafaxine 3.0% 67.0%
N = 23

Combined remission rates from all sub-studies within treatment level.
2
By QIDS-SR criteria.
3
Patients could choose the sub-study for participation, but were randomized to treatments within the sub-study.
Table 0.4 Dosing recommendations for second-generation antipsychotics

for TRD
Agent Initiate Maintenance
Aripiprazole 2–5 mg/day Increase to 0–5 mg if
needed
Brexpiprazole 0.5 mg/day Increase to –3 mg if
needed
Olanzapine (combined with 5 mg at bedtime Increase to 7.5–0 mg
fluoxetine) if needed
Risperidone 0.25 mg at bedtime Increase to .5 mg at
bedtime if needed
Quetiapine-XR 50 mg at bedtime × 2 days; Increase to 300 mg at
50 mg at bedtime on day 3 bedtime if needed
the adjunctive strategies, few long-term data are available and the risk–benefit
ratio must continue to be considered for an individual patient.
10.2 Elderly and medically ill

0.2. Diagnostic issues
There are many similarities in diagnosing and treating depression in the elderly
and medically ill populations. Mood disorders in the geriatric age group are fre-
quently precipitated by medical illness and are associated with an increased risk of
mortality and longer hospital stays; up to one-half of hospitalized elderly patients
have depression. Common treatment considerations include age-and/or disease-
related pharmacokinetic changes, potential drug–drug interactions resulting from
polypharmacy, increased sensitivity to side effects, and difficulty differentiating
side effects from physical symptoms of the medical condition.
Dementia in elderly patients can present with similar symptoms to those
observed in MDD (e.g. apathy, psychomotor retardation). A thorough history
and evaluation which examines the onset, course, duration, and treatment
response of an individual can help to differentiate between MDD and dementia.
The repeated use of cognitive tests (e.g. mini-mental state exam) can also help
to distinguish between depression and dementia. For example, early dementia
often presents with gradually declining cognitive function, while individuals with
a major depressive episode often show an abrupt cognitive decline coinciding
with the onset of depressive symptoms. However, depression and dementia
can also co-exist, and the progressing symptoms of dementia subsequently can
mask the depressive symptoms (e.g. psychomotor retardation masking decreased
concentration).
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Numerous studies have also demonstrated that MDD is more common in
medically ill individuals than in the general population (Figure 0.2), but it is both
under-diagnosed and under-treated. A common barrier to diagnosis is the mis-
taken notion that ‘reactive depression’ is not pathological and that treatment is
unnecessary and/or ineffective. Reluctance to stigmatize patients with a psychi-
atric diagnosis may also play a role. Diagnosis is further complicated by the diffi-
culty in differentiating neurovegetative symptoms of depression (e.g. poor sleep,
loss of energy and appetite, fatigue) from physiological symptoms associated with
the medical condition. Certain screening tools such as the Hospital Anxiety and
Depression Scale have tried to simplify this by focusing on the cognitive symptoms
of depression.
0.2.2 Pharmacotherapy issues

Meta-analyses have shown that pharmacotherapy is safe and generally well-
tolerated for MDD in the elderly and in those with various medical illnesses. The
maxim, ‘Start low, go slow, keep going, stay longer’ can be applied to the use of
antidepressants in these populations (Box 0.2). To minimize side effects, it is
generally advisable to begin with a low dosage and gradually titrate up accord-
ing to clinical response. However, full therapeutic doses of the medications are
usually required, although a slower treatment response may be seen. In addition,
comorbidity and older age are risk factors for relapse with discontinuation of
antidepressants, so maintenance treatment of 2 years or longer is recommended
(see Chapter 8).
Selection of antidepressants requires consideration of safety, side effect, and
drug-interaction issues (Box 0.2). Most second-generation antidepressants are
Pain
Dementia
Obesity
Cancer
Cardiac
Diabetes
HIV/AIDS
Cerebrovascular
General Population
0 10 20 30 40 50 60
Prevalence Rates for Depression (%)
*Highest rates shown from reported data ranges.
Figure 0.2 Prevalence* of MDD in other medical conditions.
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Box 0.2 Antidepressant selection in the elderly or medically ill

• Avoid antidepressants that have potential safety issues that can worsen an
underlying medical condition, e.g. arrhythmogenic and hypotensive effects of
TCAs in cardiac patients.
• Avoid antidepressants with side effects that may worsen the symptoms of the
medical condition, e.g. SSRIs or SNRIs in gastrointestinal bleeding; venlafaxine
or levomilnacipran in hypertension; and mirtazapine or TCAs in diabetes.
• Avoid antidepressants that may interact with other drugs that patients may
be using for the medical condition, e.g. fluvoxamine with warfarin; fluoxetine
and paroxetine with codeine; and TCAs with quinidine.
• Be aware of age-and illness- related changes in pharmacokinetics; for
example, liver disease and hepatic dysfunction may reduce metabolism and
increase serum levels of antidepressants.
• ‘Start low, go slow, keep going, stay longer’: start with lower than usual doses,
titrate up slowly to usual therapeutic doses, and maintain on medications for
a longer duration.
effective in these populations, but TCAs are usually avoided because of greater
side-effect burden due to anticholinergic, antihistaminic, and cardiovascular
effects. However, these patients may also have difficulty tolerating certain side
effects of the second- generation antidepressants— for example, the gastro-
intestinal side effects of SSRIs. SSRIs are also associated with hyponatremia in
some patients, which may be particularly problematic for the elderly, and with a
small increased risk of falls (not due to orthostatic hypotension) and gastrointes-
tinal bleeding (particularly with concurrent use of NSAIDs (non-steroidal anti-
inflammatory drugs), although the use of acid-suppressing drugs may mitigate this
risk). Overall, however, SSRIs are still considered first-line antidepressants for eld-
erly and medically ill patients.
Electroconvulsive therapy (ECT) can be the treatment of choice for some
medically ill and/or elderly patients because it is fast acting and bypasses the
problem of medication side effects and interactions. For example, the depressed
older person with inability or refusal to eat or drink may have physical deterior-
ation that requires rapid treatment with ECT (see Chapter 8).
0.2.3 Psychotherapy issues

Despite the advances being made in psychopharmacology, psychotherapy remains
an integral part of managing depression in medically ill patients. Some goals of
psychotherapy include improving self-esteem, correcting misconceptions about
the illness, and facilitating expression of fears and concerns. It should also enable
patients to acknowledge their physical limitations and eventually accept loss and
disability. Family therapy is often necessary to expedite communication, prepare
the family for change, and alleviate guilt and shame in both parties. Group therapy
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can decrease social isolation and help patients find meaning in life, despite their
illness.
Evidence-based psychotherapies such as cognitive–behavioural therapy (CBT)
and interpersonal psychotherapy (IPT) have been demonstrated to be benefi-
cial in many comorbid conditions, including cancer, HIV/AIDS, and cardiovascular
disease. In addition, CBT and self-management strategies are now widely used in
chronic disease management programmes as well as for adjunctive treatment of
many medical conditions (e.g. insomnia, cancer, diabetes, arthritis, fibromyalgia),
even when MDD is not comorbid.
0.2.4 Depression and cardiovascular disease

Recent attention has focused on the relationship between MDD and cardiac dis-
ease, and several recent large clinical trials have been conducted, so it is useful to
consider this as an example of medical comorbidity. Up to 25% of patients with
angiographic evidence of coronary artery disease will meet criteria for MDD.
Indeed, depression is now recognized as an independent risk factor for sudden
cardiovascular death, comparable to any of the traditional cardiac risk factors,
such as obesity, tobacco use, and hypercholesterolemia. Similarly, 20% of patients
surviving a myocardial infarction (MI) will also have a depressive disorder. The
mortality risk following MI is 5.7 times higher when MDD is present, making
depression a greater risk factor for death post-MI than other cardiac factors such
as smoking, history of previous MI, and poor left ventricular function. Several
mechanisms have been proposed to explain the relationship of depression to
cardiovascular disease and mortality (Table 0.5).
Table 0.5 Potential mechanisms to explain the relationship

between depression and cardiovascular mortality and morbidity
Behavioural Physiological
• Poor concentration and adherence • Hyperactivity of the HPA axis, resulting
to medication regimens in elevated catecholamine secretion and
• Lack of motivation to adhere to inflammatory cytokines, with detrimental
lifestyle changes (e.g. good diet, effects on the heart, blood vessels, and
exercise) platelets
• Increased prevalence of habits with • Augmented platelet responsiveness or
negative health consequences (e.g. activation, increasing the risk of clot
smoking, binge-eating) formation and atherosclerosis
• Reduced activity and social • Altered 5-HT2 receptor density on platelets,
isolation/anxiety, making it thereby increasing platelet aggregation and
more difficult to participate in coronary artery vasoconstriction
rehabilitation programmes. • Disrupted circadian rhythms and
reduced heart rate variability, leading to
arrhythmogenesis.
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Several large clinical trials have been conducted in patients with cardiac dis-
ease and MDD, and two of these examined patients with MDD who were post-
MI. The SAD-HART (Sertraline AntiDepressant Heart Attack Randomized
Trial) study showed the efficacy of sertraline in improving depression symp-
toms compared to placebo, the ENRICHD (Enhancing Recovery in Coronary
Heart Disease) study found that CBT (augmented by sertraline when depres-
sion was severe or with non-response after 5 weeks) was modestly effect-
ive in reducing depression scores compared to usual care (which may have
included antidepressants), and the CREATE (Cardiac Randomized Evaluation
of Antidepressant and Psychotherapy Efficacy) trial examined citalopram,
IPT, and the combination of both in patients with coronary artery disease.
Citalopram was superior to placebo, but IPT alone was not, and the combin-
ation was not significantly more effective than citalopram. Note that citalo-
pram (but not other SSRIs) is associated with dose-dependent increase in QTc
prolongation, so doses higher than 20 mg/day should be avoided in patients
with cardiovascular disease. Finally, the Korean Depression in Acute Coronary
Syndrome (K-DEPACS) study found improved quality of life in patients treated
with escitalopram versus placebo.
These studies show that SSRIs such as citalopram, escitalopram, and sertra-
line are safe and effective for patients with cardiovascular disease, and that CBT
(but not IPT) also offers benefit. Unfortunately, while all were large sample trials
for depression studies, none had a sample that was sufficiently large to detect
changes in mortality or cardiac events. Further study is needed to determine
whether treatment of MDD in these patients has direct effects on cardiovascular
outcomes.
10.3 Peri-and post partum

0.3. Prevalence
The peripartum period includes pregnancy and the first 4 weeks post partum.
Depressive symptoms are commonly experienced in the peripartum and post-
partum periods, but the risk for MDD is also high. For example, ‘postpartum
blues’ with mild self-limiting depressive symptoms occurs in up to 50% of women,
with up to 30% experiencing postpartum MDD (see Chapter 4). Postpartum
psychosis, a severe condition requiring emergency treatment, is less common,
occurring in two out of ,000 deliveries. Risk factors for postpartum depression
include a previous history of postpartum depression, previous history of MDD,
depressive symptoms during pregnancy, positive family history, and poor social
supports and relationships. Given the high prevalence, screening for depression
has been recommended for all women in the postpartum period; the Edinburgh
Postnatal Depression Scale (EPDS) has been widely used for both screening and
monitoring outcome (see Appendix).
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0.3.2 Treatment approaches
There is evidence that non-pharmacological treatments such as IPT and CBT are
effective during pregnancy and post partum, so they should be considered as first-
line treatments for mild-to-moderate MDD. However, there remain significant
barriers to access for these evidence-based psychotherapies (see Chapter 7).
There is always concern about using medications during pregnancy and post
partum because of potential adverse effects on the fetus, and drug transmission
to the infant by breastfeeding. It must be remembered, however, that untreated
depression clearly results in poor outcomes for both mother and child, including
premature birth, low birth weight, increased neonatal distress, and relationship
problems. Discontinuing antidepressants during pregnancy is also not recom-
mended, since the risk of relapse may be as high as 70%.
0.3.3 Antidepressants in pregnancy and breastfeeding

Although the clinical database is not large, the second-generation antidepres-
sants are considered to be relatively safe for use during pregnancy. Citalopram,
escitalopram, and sertraline are recommended first-line antidepressants, while
bupropion, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine,
and venlafaxine are considered second-line antidepressants. Meta-analyses have
shown that the risk for major malformations in women taking most SSRIs (citalo-
pram, escitalopram, fluoxetine, sertraline) is no higher than the base rate of –
3%. However, first-trimester exposure to paroxetine, particularly at doses higher
than 25 mg/day, is associated with a small increased risk of cardiac defects.
Exposure to SSRIs (and other antidepressant classes) is associated with a
small increase in the rate of spontaneous abortions and preterm births, although
depression itself may contribute to this risk. The use of SSRIs and SNRIs in the
third trimester is also associated with a transient adaptation syndrome in 5–30%
of neonates (compared to 3–0% in non-exposed neonates), consisting of jitteri-
ness, shivering, increased muscle tone, agitation, and mild respiratory distress.
The cause of these symptoms is not known, but it may be related to discon-
tinuation effects, since resolution usually occurs within 2 weeks. In regards to
longer term effects on infants, two studies have examined neurodevelopmen-
tal measures (language, IQ, distractibility, behaviour problems) in children aged
6–86 months after exposure to fluoxetine in utero. Neither found any differ-
ences compared to unexposed children of mothers without depression. Finally,
pharmacoepidemiological studies have inconsistently found associations between
antenatal SSRI use and autism spectrum disorders, but large cohort studies have
consistently shown lack of significant association, and suggest that prepregnancy
maternal illness may explain any association.
Antidepressants are variably excreted in breast milk. Serum levels were
undetectable or negligible in infants whose mothers were taking citalopram,
paroxetine, sertraline, and nortriptyline. Maternal use of fluoxetine does lead
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to detectable serum levels in infants; however, there have been no behavioural
effects noted in infants with low serum levels of antidepressants.
In summary, paroxetine has been associated with slightly more neonatal prob-
lems than other medications, but other SSRIs appear to be safe in pregnancy,
although neonates should be monitored for adaptation syndrome. Most antide-
pressants show low rates of transmission to infants via breast milk, but thera-
peutic drug monitoring in the infant may be reassuring to mothers since most will
have no detectable drug levels. Given the limited database, selection of medica-
tion for women in pregnancy and post partum is still based on an individualized
risk–benefit assessment.
10.4 Children and adolescents

0.4. Treatment controversies
There has been considerable media, public, and professional controversy about
the treatment of depression in youth (children and adolescents), centred around
the issue of antidepressant efficacy and safety, especially association with suicidal-
ity. This is a complex issue because suicidal thoughts and behaviours are intimately
associated with the underlying condition, making it difficult to tease out the rela-
tionship between a worsening symptom and medication side effects (Box 0.3;
see Chapter 6).
Unlike childhood anxiety disorders, where there is excellent evidence for effi-
cacy of psychotherapy, there remains only limited information about the efficacy
of CBT and IPT in youth with depression. While generally positive, many of the
studies did not enrol patients with MDD, and most involved samples with milder
Box 0.3 Potential causes for worsening suicidality when starting

an antidepressant
• Worsening of depression in the natural course of illness, since patients gen-
erally come to attention when the severity of their depression is highest
• Initial improvement in physical symptoms of depression (e.g. energy) before
cognitive symptoms (e.g. hopelessness), so that suicidal thoughts can be
actualized
• Unforeseen psychosocial stressor (e.g. breakup of relationship, family
conflict)
• Demoralization from lack of treatment response
• Non-specific side effects of antidepressant (e.g. nausea, insomnia) causing
increased worry and anxiety
• Specific side effects of antidepressant (e.g. agitation, activation syndrome)
• Antidepressant-induced hypomania or mixed state in a patient with an unrec-
ognized bipolar disorder.
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severity. In the one trial with a more severe and comorbid study sample, the
Treatment for Adolescents with Depression Study (TADS), CBT was no better
than pill placebo while fluoxetine was significantly superior to both. However,
there was indication that the best outcomes were achieved with combined fluox-
etine and CBT treatment.
0.4.2 Safety and efficacy of antidepressants

Previous studies had shown that TCAs were not effective in youth with MDD,
but several individual studies with SSRIs found evidence for efficacy of fluox-
etine, sertraline, citalopram, and escitalopram (in adolescents). A Cochrane
systematic review found small effect sizes overall in reducing depression
symptom severity, response, and remission. Fluoxetine had the most consist-
ent effects, with the estimated effect size showing that an excess of 20–25
patients will respond for every 00 patients treated with fluoxetine instead
of placebo.
Given the limited evidence for benefits of the second-generation antidepres-
sants, the issue of safety becomes even more important. Meta-analyses of pub-
lished and unpublished RCTs have shown slightly increased risks of suicidality
(worsening suicidal thoughts and/or attempts) with second-generation antide-
pressants compared to placebo. Of individual drugs, only venlafaxine carried a
significantly higher risk, while paroxetine had a trend to significance. However,
there were no deaths by suicide within the entire Food and Drug Administration
database. The overall small relative risk of .58 for suicidality translates into –3
excess cases of emergent suicidality for every 00 patients treated with a non-
TCA antidepressant (other than fluoxetine, which carries the lowest risk). In the
TADS trial, combination treatment with CBT seemed to further reduce the small
risk of suicidality associated with fluoxetine.
These RCTs (other than TADS) have been critiqued because of their high pla-
cebo responses, low severity of patients, and limited generalizability of results.
Other types of studies have not supported increased suicidality or deaths by sui-
cide with antidepressants in youth. For example, database studies of naturalistic
treatment have not found greatly increased risks for suicidality, toxicology studies
have shown that youths that die by suicide do not show the presence of SSRIs in
their blood, and pharmacoepidemiology studies show that increasing prescription
rates for SSRIs are associated with declining suicide rates, which would not be
expected if suicide was associated with antidepressants.
In summary, antidepressants should be used cautiously in youth with MDD,
with careful evaluation of risk–benefit for individual patients (Box 0.4). There is
a suggestion of a small risk of suicidality (ideation and behaviours, but not com-
pleted suicide) based on placebo-controlled RCTs, but little additional evidence
to corroborate this finding. Regardless, it is possible that antidepressants worsen
suicidality in a small subset of vulnerable patients, so it is prudent to carefully
monitor patients, particularly early in treatment when they are at highest risk
for suicide.
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Box 0.4 Recommendations for children and adolescents with MDD

• For MDD of mild-
to-
moderate severity, evidence-
based psychotherapy
(CBT or IPT) alone should be used, whenever possible.
• For MDD of marked or worse severity, antidepressants are indicated.
Fluoxetine is the only first-line antidepressant recommended because of its
proven efficacy and safety profile. Combining with psychotherapy may also
improve efficacy and reduce the risk of medication-associated suicidality.
• Other SSRIs such as escitalopram, citalopram, and sertraline, despite a slightly
increased risk of worsening suicidality, can be used as second-line treatments,
especially when depression is severe, chronic, or associated with comorbid-
ity, and when psychosocial treatments have not helped.
• Other novel agents (agomelatine, bupropion, duloxetine, mirtazapine) are
considered third-line medications because of limited evidence for efficacy
and/or side-effect burden.
• TCAs, venlafaxine, and paroxetine are not recommended based on lack of
evidence for efficacy and increased risk for suicidality.
• Close monitoring (e.g. at least weekly contact for the first month of treat-
ment) for treatment response and suicidality is important, particularly in the
early phases of treatment when the suicide risk is highest.
• Discussion with patient and family about potential side effects (e.g. suicidality,
agitation, anxiety, irritability, hypomania, and activation syndrome) should be
done prior to initiation of treatment.
Further Reading
Hetrick SE, McKenzie JE, Cox GR, et al. (202) Newer generation antidepressants
for depressive disorders in children and adolescents. Cochrane Database Syst Rev
11: CD00485.
Huang AX, Delucchi K, Dunn LB, et al. (205) A systematic review and meta-analysis of
psychotherapy for late-life depression. Am J Geriatr Psychiatry 23: 26–73.
Isacsson G, Rich CL (204) Antidepressant drugs and the risk of suicide in children and
adolescents. Paediatr Drugs 16: 5–22.
Kennedy SH, Lam RW, McIntyre RS, et al. (206) Canadian Network for Mood and
depressive disorder in adults. Section 3. Pharmacological treatments. Can J Psychiatry
61: 540–60.
McIntyre RS, Filteau MJ, Martin L, et al. (204) Treatment-resistant depression: Definitions,
review of the evidence, and algorithmic approach. J Affect Disord 156: –7.
MacQueen GM, Frey BN, Ismail Z, et al. (206) Canadian Network for Mood and Anxiety
Treatments (CANMAT) 206 guidelines for the management of major depressive
disorder in adults. Section 6. Special populations: Youth, women, and the elderly. Can J
Psychiatry 61: 588–603.
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March J, Silva S, Petrycki S, et al. (2004) Fluoxetine, cognitive-behavioral therapy, and
their combination for adolescents with depression: Treatment for Adolescents with
Depression Study (TADS) randomized controlled trial. JAMA 292: 807–20.
Mulsant BH, Blumberger DM, Ismail Z, et al. A systematic approach to pharmacotherapy
for geriatric major depression. Clin Geriatr Med 30: 57–34.
Nulman I, Koren G, Rovet J, et al. (202) Neurodevelopment of children following
prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated
maternal depression. Am J Psychiatry 169: 65–74.
Ramasubbu R, Taylor VH, Samaan Z, et al. (202) The Canadian Network for Mood and
Anxiety Treatments (CANMAT) task force recommendations for the management
of patients with mood disorders and select comorbid medical conditions. Ann Clin
Psychiatry 24: 9–09.
Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006) Acute and longer-term outcomes in
depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J
Psychiatry 163: 905–7.
Seligman F, Nemeroff CB (205) The interface of depression and cardiovascular
disease: Therapeutic implications. Ann N Y Acad Sci 1345: 25–35.
Stewart DE, Vigod S (206) Postpartum depression. N Engl J Med 375: 277–86.
Thase ME (206) Adverse effects of second-generation antipsychotics as adjuncts to
antidepressants: Are the risks worth the benefits? Psychiatr Clin North Am 39: 477–86.
Vigod SN, Wilson CA, Howard LM (206) Depression in pregnancy. BMJ 352: i547.
chapter 10
APPENDIX
Sample rating scales
Sample rating scales 14
Hamilton Depression Rating Scale, 7-item version (HAM-D) 5
Montgomery–Åsberg Depression Rating Scale (MADRS) 8
Quick Inventory of Depressive Symptomatology (Self-Rated)
(QIDS-SR) 21
Patient Health Questionnaire (PHQ-9) 24
Perceived Deficits Questionnaire—Depression, 5 item (PDQ-D-5) 25
Lam Employment Absence and Productivity Scale (LEAPS) 26
Edinburgh Postnatal Depression Scale (EPDS) 28
Appendix
Sample rating scales
Sample rating scales are provided in Table A..
Table A. Various rating scales

Rating scale Key features/limitations Done by Length and time
Hamilton Depression Rating Scale Most widely used outcome measure in clinical trials; Clinician 7–24 items, 20–30 minutes
(HAM-D) not all DSM-5 symptoms covered
Montgomery–Åsberg Depression Widely used in clinical trials, specialized training not Clinician 0 items, 5 minutes
Rating Scale (MADRS) required, sensitive to change; not all DSM-5 symptoms
covered
Quick Inventory of Depressive Used in the STAR*D effectiveness trial; all DSM-5 Patient 7 items, 0 minutes
Symptomatology, Self-Rated symptoms covered
(QIDS-SR)
Patient Health Questionnaire (PHQ-9) Brief, validated in primary care settings; follows Patient 9 items, 5 minutes
the DSM-5 symptom criteria; useful for screening,
diagnosis, and monitoring outcomes
Perceived Deficits Questionnaire— Brief version of the PDQ-D-20 for assessing subjective Patient 5 items, 3 minutes
Depression, 5 item (PDQ-D-5) cognitive symptoms
Lam Employment Absence and Brief, depression-specific scale for assessing and Patient 0 items, 3–5 minutes
Productivity Scale (LEAPS) monitoring work functioning and productivity
Edinburgh Postnatal Depression Scale Screens for postpartum depression; validated in Patient 0 items, 7 minutes
(EPDS) primary care settings; not all DSM-5 symptoms covered
appendix: sample rating scales • 115
Hamilton Depression Rating Scale, 17-item version (HAM-D)
See Box A..
Box A. Hamilton Depression Rating Scale

1. Depressed mood
0 = Absent
 = These feeling states indicated only on questioning
2 = These feeling states spontaneously reported verbally
3 = Communicates feeling states non-verbally—i.e. through facial expression,
posture, voice, and tendency to weep
4 = Patient reports virtually only these feeling states in his spontaneous verbal
and non-verbal communication
2. Work and activities

0 = No difficulty
 = Thoughts and feelings of incapacity, fatigue, or weakness related to activi-
ties, work or hobbies
2 = Loss of interest in activities, hobbies or work—either directly reported by
patient, or indirect in listlessness, indecision, and vacillation (feels he has to
push self to work or activities)
3 = Decrease in actual time spent in activities or decrease in productivity. In
hospital, rate 3 if patient does not spend at least 3 hours a day in activities
(hospital job or hobbies) exclusive of ward chores.
4 = Stopped working because of present illness. In hospital, rate 4 if patient
engages in no activities except ward chores, or if patient fails to perform
ward chores unassisted.
3. Genital symptoms
0 = Absent
 = Mild
2 = Severe
4. Somatic symptoms—gastrointestinal
0 = None
 = Loss of appetite but eating without staff encouragement; heavy feelings in
abdomen
2 = Difficulty eating without staff urging. Requests or requires laxatives or medi-
cation for bowels or medication for gastrointestinal symptoms
Appendix
116 • appendix: sample rating scales
5. Loss of weight
0 = No weight loss
 = Probable weight loss associated with present illness
2 = Definite (according to patient) weight loss
6. Insomnia—early
0 = No difficulty falling asleep
 = Complains of occasional difficulty in falling asleep—i.e. takes more than
half an hour
2 = Complains of nightly difficulty in falling asleep
7. Insomnia—middle
0 = No difficulty
 = Patient complains of being restless and disturbed during the night
2 = Waking during the night—any getting out of bed rates 2 (except for pur-
poses of voiding)
8. Insomnia—late
0 = No difficulty
 = Wakes in early hours of the morning but goes back to sleep
2 = Unable to fall asleep again if he/she gets out of bed
9. Somatic symptoms—general
0 = None
 = Heaviness in limbs, back, or head; backaches, headache, muscle aches; loss
of energy and fatiguability
2 = Any clear-cut symptom rates 2
10. Feelings of guilt

0 = Absent
 = Self-reproach; feels he/she has let people down
2 = Ideas of guilt or rumination over past errors or sinful deeds
3 = Present illness is a punishment; delusions of guilt
4 = Hears accusatory or denunciatory voices and/or experiences threatening
visual hallucinations
11. Suicide
0 = Absent
 = Feels life is not worth living
Appendix
2 = Wishes he/she were dead or any thoughts of possible death to self

3 = Suicide ideas or gestures
4 = Attempts at suicide (any serious attempt rates 4).
12. Anxiety—psychic
0 = No difficulty
 = Subjective tension and irritability
2 = Worrying about minor matters
3 = Apprehensive attitude apparent in face or speech
4 = Fears expressed without questioning
13. Anxiety—somatic
0 = Absent
 = Mild
2 = Moderate
3 = Severe
4 = Incapacitating
14. Hypochondriasis
0 = Not present
 = Self-absorption (bodily)
2 = Preoccupation with health
3 = Frequent complaints, requests for help, etc.
4 = Hypochondriacal delusions
15. Insight
0 = Acknowledges being depressed and ill
 = Acknowledges illness but attributes cause to bad food, climate, over-work,
virus, need for rest, etc.
2 = Denies being ill at all
16. Motor retardation

0 = Normal speech and thought
 = Slight retardation at interview
2 = Obvious retardation at interview
3 = Interview difficult
4 = Complete stupor
17. Agitation
0 = None
 = Fidgetiness
2 = Playing with hands, hair, etc.

3 = Moving about; can’t sit still
4 = Hand wringing, nail biting, hair pulling, biting of lips
17-item HAM-D total:______________
Montgomery–Åsberg Depression Rating Scale (MADRS)

The rating should be based on a clinical interview moving from broadly phrased
questions about symptoms to more detailed ones which allow a precise rating of
severity. The rater must decide whether the rating lies on the defined scale steps (0,
2, 4, 6) or between them (, 3, 5). A structured interview guide is now available and
is the preferred means to administer the MADRS (Williams JB, Kobak KA (2008)
Development and reliability of a structured interview guide for the Montgomery–
Åsberg Depression Rating Scale (SIGMA). Br J Psychiatry 92: 52–58).
Table A.2 describes the Montgomery–Åsberg Depression Rating Scale. Circle
the score which best characterizes the patient at this time.
Table A.2 MADRS scale

Item Explanation
. Apparent 0 No sadness
sadness 
2 Looks dispirited but does brighten up without difficulty
3
4 Appears sad and unhappy most of the time
5
6 Looks miserable all the time; extremely despondent
2. Reported 0 Occasional sadness in keeping with the circumstances
sadness 
2 Sad or low but brightens up without difficulty
3
4 Pervasive feelings of sadness or gloominess; mood still
influenced by external circumstances
5
6 Continuous unvarying sadness, misery, or despondency
3. Inner tension 0 Placid; only fleeting inner tension

2 Occasional feelings of edginess and ill-defined discomfort
3
4 Continuous feelings of inner tension or intermittent panic
which the patient can only master with some difficulty
5
6 Unrelenting dread or anguish; overwhelming panic
Table A.2 Continued

Item Explanation
4. Reduced sleep 0 Sleeps as usual

2 Slight difficulty dropping off to sleep or slightly reduced,
light, or fitful sleep
3
4 Sleep reduced or broken by at least 2 hours
5
6 Less than 2 or 3 hours’ sleep
5. Reduced 0 Normal or increased appetite
appetite  Slightly reduced appetite
2 No appetite; food is tasteless
3 Needs persuasion to eat at all
6. Concentration 0 No difficulties in concentrating
difficulties 
2 Occasional difficulties in collecting one’s thoughts
3
4 Difficulties in concentrating and sustaining thought, which
reduces ability to read or hold a conversation
5
6 Unable to read or converse without great difficulty
7. Lassitude 0 Hardly any difficulty in getting started; no sluggishness

2 Difficulties in starting activities
3
4 Difficulties in starting simple routine activities, which are
carried out with effort
5
6 Complete lassitude; unable to do anything without help
8. Inability to feel 0 Normal interest in the surroundings and other people

2 Reduced ability to enjoy usual interests
3
4 Loss of interest in the surroundings; loss of feelings for
friends and acquaintances
5
6 The experience of being emotionally paralysed; inability to
feel anger, grief, or pleasure; and a complete or even painful
failure to feel for close relatives and friends
(continued)
Appendix
Table A.2 Continued

Item Explanation
9. Pessimistic 0 No pessimistic thoughts
thoughts 
2 Fluctuating ideas of failure, self-reproach, or
self-deprecation
3
4 Persistent self-accusations, or definite but still rational ideas
of guilt, or sin; increasingly pessimistic about the future
5
6 Delusions of ruin, remorse, or unredeemable sin; self-
accusations which are absurd and unshakable
0. Suicidal 0 Enjoys life or takes it as it comes

thoughts 
2 Weary of life; only fleeting suicidal thoughts
3
4 Probably better off dead; Suicidal thoughts are common,
and suicide is considered as a possible solution, but without
specific plans or intention
5
6 Explicit plans for suicide when there is an opportunity;
active preparations for suicide
TOTAL SCORE ________
Reproduced from British Journal of Psychiatry, 34, Montgomery SA, Asberg M, A new depression
scale designed to be sensitive to change, pp. 382-389. Copyright (979) The Royal College of
Psychiatrists
Appendix
Quick Inventory of Depressive Symptomatology
(Self-Report) (QIDS-SR)
See Figure A..
Figure A. Quick Inventory of Depressive Symptomatology.

Figure A. Continued.
Appendix
Figure A. Continued.

© UT Southwestern Medical Center, Dallas, Texas
Appendix
Patient Health Questionnaire (PHQ-9)

See Figure A.2.
Figure A.2 PHQ-9.

PHQ9 Copyright © Pfizer Inc.
Appendix
Perceived Deficits Questionnaire—Depression, 5-item
(PDQ-D-5)
See Figure A.3.
Figure A.3 PDQ-D-5.

PDQ-D Copyright © 995 Michael JL Sullivan
Appendix
Lam Employment Absence and Productivity Scale (LEAPS)

See Figure A.4.
Figure A.4 LEAPS scale.
Appendix
Figure A.4 Continued.

© Dr. Raymond W. Lam, 2009; permission for individual clinical use only, queries: r.lam@ubc.ca
Appendix
Edinburgh Postnatal Depression Scale (EPDS)

See Figure A.5.
Figure A.5 EPDS scale.
Appendix
Figure A.5 Continued.
Appendix
Key references
Cox J, Holden J, Sagovsky R (987) Detection of postnatal depression. Development of
the 0-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 150: 782–6.
Fehnel SE, Forsyth BH, DiBenedetti DB, et al. (206) Patient-centered assessment of
cognitive symptoms of depression. CNS Spectr 21: 43–52.
Hamilton M (967) Development of a rating scale for primary depressive illness. Br J Soc
Clin Psych 6: 278–96.
Kroenke K, Spitzer RL, Williams JB (200) The PHQ–9: Validity of a brief depression
severity measure. J Gen Intern Med 16: 606–3.
Lam RW, Michalak EE, Swinson RP (2005) Assessment Scales in Depression, Mania and
Anxiety. London: Taylor and Francis.
Lam RW, Michalak EE, Yatham, LN (2009) A new clinical rating scale for work absence and
productivity: Validation in patients with major depressive disorder. BMC Psychiatry 9: 78.
Leon AC, Olfson M, Portera L, et al. (997) Assessing psychiatric impairment in primary
care with the Sheehan Disability Scale. Int J Psychiatry Med 27: 93–05.
Montgomery SA, Asberg M (979) A new depression scale designed to be sensitive to
change. Br J Psychiatry 134: 382–9.
Trivedi MH, Rush AJ, Ibrahim HM, et al. (2004) The Inventory of Depressive
Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick
Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report
(QIDS-SR) in public sector patients with mood disorders: A psychometric evaluation.
Psychol Med 34: 73–82.
Wilkinson MJ, Barczak P (988) Psychiatric screening in general practice: Comparison of
the general health questionnaire and the hospital anxiety depression scale. J R Coll Gen
Pract 38: 3–3.
Appendix
Index
NUMBERS levomilnacipran 63, 68, 69t
maintenance treatment 80, 82b
atomoxetine 68, 70
attention, patient descriptions
5-HTTLPR polymorphisms 2–3 mechanism of action 20 and neuropsychological
neurogenesis theory 9 tests 39t
A mianserin 7t
mirtazapine 70, 7t
atypical antipsychotics see
second-generation
acute phase of treatment 48, 49t monoamine oxidase antipsychotics
adherence, improvement of inhibitors 73 atypical depression 29t
49, 50b for pain 4 augmentation 96
adjunctive (‘add-on’) therapy reboxetine 68, 70t
96, 97–8 safety 65–6, 09
advantages and second-generation B
disadvantages 97t antipsychotics 72 BDNF (brain-derived
adjunctive agents 97–8 selection of 63–4t neurotrophic factor)
second-generation selective serotonin reuptake 6f, 7
antipsychotics 00, 02t inhibitors (SSRIs) 66–8, 67t Beacon 60t
adolescents selegiline 73, 75t, 78t, 80, 8t Beating the Blues 59
safety and efficacy of serotonin and noradrenaline Beck Depression Inventory 47
antidepressants 09 reuptake inhibitors behavioural activation (BA)
treatment controversies 08–9 (SNRIs) 68 54t, 57
treatment side effects 67t, 69t, 70t, 7t, bereavement 30–
recommendations 0b 73t, 74t, 75t, 76 differentiation from major
see also children in special populations 95 depressive episodes 3t
adoption studies  children and adolescents 09 bibliotherapy 50, 5t
age of onset 3, 4 elderly patients 03–4 Big White Wall 60t
aggression 37t medically ill patients 03–4 biological factors 2f
agitation 37t pregnancy and bipolar disorder 3–3
agomelatine 5, 65, 70, 7t breastfeeding 07–8 irritability and anger 37
drug interactions 77t suicide risk 65–6, 08b borderline personality
amitriptyline 74t young people 09 disorder 38
drug interactions 4 switching agents 76, 80f Bounce Back Online 60t
see also tricyclic antidepressants washout periods 8t breastfeeding 07–8
amoxapine 74t in treatment-resistant brexpiprazole 00
see also tricyclic antidepressants depression 96–8 dosing recommendations 02t
AMPA receptor 6f advantages and broad-spectrum
d-amphetamine 97–8 disadvantages 97t antidepressants 64
anger 36–7t CANMAT guidelines 99f bupropion 68, 70t, 98
implications for diagnosis and STAR*D study 98, 00, 0t drug interactions 77t
management 37–8 tricyclics 72, 74t and fatigue 42
anger attacks 37t venlafaxine 64–9, 80, 9, 07 pregnancy 07
anhedonia 23 vilazodone 70, 7t, 72 burden of illness , 5–9
antidepressants vortioxetine 7t, 72 buspirone, STAR*D study 00
agomelatine 70, 7t anti-inflammatory agents 7
in anxiety disorders 36 anxiety disorders 35–6, 36
atomoxetine 68, 70 implications for diagnosis and C
bupropion 68, 70t management 36 cancer, prevalence of
citalopram 67t, 68, 06–7, 00, pharmacotherapy 64, 98 depression 03f
0t, 09, 0b anxious depression 29t candidate gene studies 2–3
CANMAT appetite changes 24 CANMAT antidepressant
recommendations 64t aripiprazole 00 recommendations 64t
and cognitive function 40 dosing recommendations 02t for limited response to initial
comparative efficacy 64–5 assessment antidepressant 99f
comparison with diagnostic tools 46 capsulotomy 92
psychotherapy 55, 58 monitoring outcomes 47–8 cardiac disease, prevalence of
concurrent use with ECT 9 screening 45–6b depression 03f
desvenlafaxine 69, 69t, 07 of suicidality 46–7 cardiovascular comorbidity
discontinuation 80, 82 associated clinical features 35 6, 05t–6
drug interactions 4, 76, 77t–9t anxiety 35–6 cardiovascular disease risk 6, 05t
duloxetine 65, 68, 69t, 77t, 07 cognitive dysfunction 38–40 catastrophizing 56t
escitalopram 64–8, 06, 07, fatigue and low energy 42 catatonic depression 29t
09, 0b irritability and anger 36–8 cellular resilience
and fatigue 42 pain 4 pathways 6f–7
indications for 49
132 • index
cerebrovascular disease, somatic treatments; delusional (psychotic)
prevalence of treatment-resistant depression 29t
depression 03f depression dementia 40
childhood trauma 20–, 22 clinical response 48, 95 differentiation from
children clomipramine 65, 74t depression 02
antidepressants, safety and see also tricyclic antidepressants prevalence of depression 03f
efficacy 09 codeine, drug interactions 4 deprenyl see selegiline
disruptive mood dysregulation cognitive behavioural analysis desipramine 74t
disorder 28b system of psychotherapy see also tricyclic antidepressants
irritability 37 (CBASP) 54t, 58–9 desvenlafaxine 68, 69t
persistent depressive cognitive–behavioural therapy pregnancy 07
disorder 28b (CBT) 20, 54t, 57 dexamethasone suppression
symptoms 4 in children and adolescents test 7
treatment controversies 08–9 08–9, 0b diabetes 3
treatment effect on cognitive function 40 painful neuropathy 4
recommendations 0b maintenance treatment 60 prevalence of depression 03f
choice of treatment 49 in medical illnesses 05 diagnosis 
psychotherapies 54–5 coronary heart disease 06 elderly patients 02
chronic disease management in peripartum depression 07 medically ill patients 03
(CDM) 45 cognitive deficits 8–20, diagnostic tools 46
chronic illness 5 24, 38–40 dichotomous thinking 56t
chronic pain conditions 4 after ECT 90– differential diagnosis 26f, 30–3
cingulotomy 92 dementia 02 disability 5–6
circadian rhythm implications for diagnosis and discontinuation of
disturbance of 8, 9f management 40 pharmacotherapy 80, 82
effects of light 87 cognitive domains, patient discontinuation symptoms,
citalopram 67t, 68 descriptions and FINISH mnemonic 82b
breastfeeding 07 neuropsychological disruptive mood dysregulation
in children and adolescents tests 39t disorder 28b
09, 0b cognitive therapy (CT) 54t, 56–7 dosulepin 74t
CREATE trial 06 comparison with interpersonal see also tricyclic antidepressants
pregnancy 07 psychotherapy 55 double depressions 26
STAR*D study 00, 0t recurrence prevention 60 drug interactions 4, 76, 77t–9t
see also selective serotonin ‘cold’ cognition 20, 38 DSM-5 (Diagnostic and Statistical
reuptake inhibitors collaborative care 49–50 Manual of Mental
classification of depression 25–6 combination therapy 96 Disorders, 5th edn)
DSM-5 criteria for major comorbidities classification 25
depressive episodes 27b cardiovascular disease 05t–6 criteria for major depressive
severity 30t diagnosis of depression 03 episodes 27b
sub-types 27, 29t–30t pharmacotherapy 03–4 criteria for persistent
clinical features , 23–5, 35 see also medical illness depressive disorder 28b
anxiety 35–6 complementary and alternative other depressive disorders 28b
cognitive dysfunction 38–40 medicine (CAM) 82–3b severity criteria 30t
fatigue and low energy 42 computer-delivered duloxetine 65, 68, 69t
irritability and anger 36–8 psychotherapies 59–60t drug interactions 77t
pain 4 concentration problems 24 pregnancy 07
SIGECAPS mnemonic 24t corticotropin-releasing factor dysphoria 37t
variation with age 4 (CRP) 7 dysthymia (dysthymic
clinical management 45 costs disorder) 26
assessment 45–8 socioeconomic burden , 6–7f
children and adolescents of treatment 8–9
recommendations 0b of untreated depression 7–8 E
safety and efficacy of course of depression 4–5 eclectic psychotherapy 53
antidepressants 09 C-reactive protein 7 economic burden , 6–7f
treatment CREATE (Cardiac Randomized Edinburgh Postnatal Depression
controversies 08–9 Evaluation of Scale 06, 4t, 28–9
choice of treatment 49 Antidepressant and elderly patients
collaborative care 49–50 Psychotherapy Efficacy) diagnostic issues 02
follow up 50 study 06 electroconvulsive therapy 04
optimizing adherence 49, 50b CREB (cAMP response element pharmacotherapy 03–4
patient education and binding) 6f, 7 symptoms 4
self-management 50–t CYP isoenzymes 76 electroconvulsive therapy (ECT)
treatment phases 48–9t 85, 89–90
see also antidepressants; cognitive function 40
complementary and D efficacy 90
alternative medicine; deep brain stimulation in elderly patients 04
pharmacotherapy; (DBS) 20, 92 evidence levels for 86t
psychological treatments; evidence levels for 86t indications for 90b

index • 133
in medically ill patients 04
relapse rate and prevention 9
G K
safety and side effects 90– gene-by-environment ketamine 5
emotion-dependent processing (GxE) interaction Korean Depression in Acute
(‘hot’ cognition) 20, 38 hypothesis 2f–2 Coronary Syndrome
patient descriptions and genetics –3 (K-DEPACS) study 06
neuropsychological genome scanning 2
Global Burden of Disease
tests 39t
energy, lack of 24, 42 Study 7f L
pharmacotherapy 98 glucocorticoids 7 Lam Employment Absence and
ENRICHD (Enhancing Recovery glutamate 5, 6f Productivity Scale (LEAPS)
in Coronary Heart group psychotherapies 59 48, 4t, 26–7
Disease) study 06 medically ill patients 04–5 leaden paralysis 24
environmental factors 20–2 guilt 24 levomilnacipran 63, 68, 69t
epidemiology 3–4t life events 20–2
light therapy 87–8f
prevalence of MDD in other
medical conditions 03f H evidence levels for 86t
prevalence of peripartum Hamilton Depression Rating limbic–cortical dysregulation
depression 06 Scale (HAM-D) 47, model 9–20f
epigenetic mechanisms 22 4t, 5–8 limbic neurosurgery 92
episodic dyscontrol 37t hippocampus 9 evidence levels for 86t
escitalopram 66, 67t, 68 HIV/AIDS, prevalence of linkage analysis studies 2
broad-spectrum action 64 depression 03f lisdexamfetamine 98
in children and adolescents Hospital Anxiety and Depression lithium
09, 0b scale (HADS) 3, 47, 03 as an adjunctive agent 97
efficacy 65 hostility 37t STAR*D study 00
K-DEPACS study 06 ‘hot’ cognition 20, 38 use after ECT 9
pregnancy 07 patient descriptions and Living Life To The Full 60t
see also selective serotonin neuropsychological lofepramine 74t
reuptake inhibitors tests 39t see also tricyclic
evidence-based psychotherapies hypericum (St John’s wort) 83 antidepressants
53, 54t hypersomnia 24 low mood 23
evidence levels for somatic hypomania 33
treatments 86t hypothalamic-pituitary-adrenal-
executive function 38 immune axis 7 M
patient descriptions and maintenance treatment
neuropsychological 48–9t, 82b
tests 39t I after ECT 9
exercise 87 ICD (International Classification pharmacotherapy 80
evidence levels for 86t of Diseases)-0 25 psychotherapies 60
severity criteria 30t major depressive disorder
imipramine 74t (MDD) 25–6
F see also tricyclic antidepressants differentiation from
family studies  immune function disturbances 7 bereavement 3t
family therapy 04 insomnia 23 DSM-5 criteria 27b
fatigue 24, 42 pharmacotherapy 98 severity 27, 30t
pharmacotherapy 98 insulin shock therapy 85 specifiers 27, 29t
fibromyalgia 4 interest, loss of 23 MAPK (mitogen-activated protein
FINISH mnemonic, internet, resources for kinase) 6f
discontinuation self-management 5t maprotiline 74t
symptoms 82b internet-delivered see also tricyclic antidepressants
fluoxetine 66, 67t psychotherapies 59–60t marital therapy 59
breastfeeding 07–8 interpersonal psychotherapy (IPT) maternal deprivation 2
in children and adolescents 54t, 58t maximizing 56t
09, 0b in children and adolescents measurement-based care 47–8
discontinuation 80 08–9, 0b medical illness
drug interactions 76, 77t comparison with cognitive cardiovascular disease 05t–6
pregnancy 07 therapy 55 chronic pain conditions 4
see also selective serotonin CREATE trial 06 depressive symptoms 3, 32t
reuptake inhibitors maintenance treatment 60 diagnosis of depression 03
fluvoxamine 67t in medical illness 05 electroconvulsive therapy 04
drug interactions 77t in peripartum depression 07 pharmacotherapy 03–4
pregnancy 07 irritability 36–7t prevalence of depression 03f
see also selective serotonin implications for diagnosis and psychotherapy issues 04–5
reuptake inhibitors management 37–8 risk of 6
follow up 50 isocarboxazid 75t medication-induced depressive
functionality assessment 48 see also monoamine oxidase disorder 3
functional polymorphisms 2 inhibitors melanopsin 87

134 • index
melancholic depression 29t see also selective serotonin see also monoamine oxidase
memory deficits 8–20, reuptake inhibitors inhibitors
24, 38–40 nortriptyline 74t pleasure, loss of 23
after ECT 90– breastfeeding 07 polysomnography 8
implications for diagnosis and use after ECT 9 postpartum depression
management 40 see also tricyclic antidepressants antidepressants 07–8
patient descriptions and prevalence 06
neuropsychological risk factors 06
tests 39t O treatment approaches 07
meta-analyses of obesity, prevalence of postsynaptic receptors and
antidepressants 65 depression 03f processes 5f
methylphenidate 97–8 olanzapine 00 pregnancy
mianserin 70, 7t, 98 dosing recommendations 02t antidepressants 07
microRNAs 22 omega-3 fatty acids 83 see also peripartum depression;
mild depression 30t outcome monitoring 47–8 postpartum depression
milnacipran 68, 69t overeating 24 premenstrual dysphoric
mindfulness-based cognitive over-generalizing 56t disorder 28b
therapy (MBCT) 54t, 57 over-personalization 56t presynaptic receptors and
recurrence prevention 60 processes 5f
minimizing 56t prevalence 3–4
minor depression 28b P in other medical
mirtazapine 65, 70, 7t, 98 pain 4 conditions 03f
pregnancy 07 pain conditions, prevalence of peripartum depression 06
mixed depressive episodes 29t depression 03f prevention of recurrence see
mobile health (mHealth) 5, 59 paroxetine 66, 67t recurrence prevention
moclobemide 73, 75t breastfeeding 07 problem-solving therapy (PST)
drug interactions 78t discontinuation 80 54t, 55
switching antidepressants 80 drug interactions 76, 78t prognosis 5
washout periods 8t see also selective serotonin prognostic indicators 6b
see also monoamine oxidase reuptake inhibitors proinflammatory cytokines 7
inhibitors pathogenesis  psychological factors 2f
modafinil 98 biological, psychological, and psychological treatments
moderate depression 30t social factors 2f behavioural activation 57
monoamine hypothesis 3–5 genetics –3 choice of treatment 54–5
monoamine oxidase inhibitors neurobiology 3–8 cognitive behavioural
(MAOIs) 63–4, 73 neuropsychology 8–22 analysis system of
doses 75t patient education 50 psychotherapy 58–9
drug interactions 78t Patient Health Questionnaire cognitive–behavioural therapy 57
mechanism of action 75t (PHQ-9) 47, 4t, 24 cognitive therapy 56–7
side effects 75t Perceived Deficits Questionnaire– comparison with
washout periods 80, 8t Depression,5 item pharmacotherapy 55, 58
Montgomery–Åsberg Depression (PDQ-D-5)4t, 25 effect on cognitive function 40
Rating Scale (MADRS) 47, peripartum depression 29t efficacy 53
4t, 8–20 antidepressants 07–8 evidence-based
MoodGYM 60t prevalence 06 psychotherapies 54t
mortality risk 6 treatment approaches 07 group psychotherapies 59
see also suicide risk persistent depressive disorder 26 indications for 49
multimodal agents 70– DSM-5 criteria 28b interpersonal psychotherapy 58t
myocardial infarction (MI) pharmacogenetic testing 76 maintenance and prevention 60
6, 05–6 pharmacotherapy mindfulness-based cognitive
in comorbidities 03–4 therapy 57
problem-solving therapy 55
N comparative efficacy of
antidepressants 64–5 psychodynamic
negative cognitions 56t comparison with psychotherapy 53
negative inference 56t psychotherapy 55, 58 in special groups
neuroanatomical discontinuation 80, 82 children and adolescents
abnormalities 3f in elderly patients 03–4 08–9, 0b
neurobiology 3–8 maintenance medically ill patients 04
neurochemical treatment 80, 82b peripartum depression 07
abnormalities 4f safety 65–6 technology-assisted 59–60t
neurogenesis theory 9 selecting an psychomotor changes 25
neuroplasticity pathways 6f–7 antidepressant 63–4t psychomotor speed, patient
neuropsychology 8–22 in treatment-resistant descriptions and
neurosurgery 92–3 depression 96–8 neuropsychological
NMDA receptor 6f advantages and tests 39t
noradrenaline (norepinephrine) disadvantages 97t psychostimulants 97–8
3, 6f see also antidepressants psychotic (delusional)
norfluoxetine 66 phenelzine 75t depression 29t

index • 135
Q selegiline (deprenyl) 73, 75t
drug interactions 78t
vortioxetine 7t
ECT 90–
QTc interval increase, switching antidepressants 80 second-generation
citalopram 68 washout periods 8t antipsychotics 00
quetiapine-XR 63, 72, 73t, see also monoamine oxidase SIGECAPS mnemonic 24t
98, 00 inhibitors situational analysis 58
dosing recommendations 02t self-management 50– sleep abnormalities 8, 9f, 23
drug interactions 78t resources 5t sleep deprivation (wake
Quick Inventory for Depressive self-rated scales 47–8 therapy) 85–6t
Symptomatology, self- Sequenced Treatment social disability 5
rated (QIDS-SR) 47–8, Alternatives to Relieve social factors 2f
4t, 21–3 Depression (STAR*D) socioeconomic burden , 6–7f
study 98, 00 somatic symptoms 4
R summary of results 0t
serotonin (5-HT) 3, 6f
of anxiety 36
somatic treatments 85
racing thoughts 25 serotonin and noradrenaline deep brain stimulation 92
randomized controlled reuptake inhibitors electroconvulsive
trials (RCTs) of (SNRIs) 68 therapy 89–9
antidepressants 65 doses 69t exercise 87
rating scales 47–8, 4t and fatigue 42 levels of supporting
reactive depression 03 mechanism of action 69t evidence 86t
reboxetine 64, 68, 70t pregnancy 07 light therapy 87–8f
recurrence prevention side effects 69t limbic neurosurgery 92
psychotherapies 56, 60 washout periods 8t transcranial magnetic
see also maintenance treatment serotonin syndrome 73 stimulation 89
relapse rates 5 sertraline 65, 66, 67t vagus nerve stimulation
after ECT 9 breastfeeding 07 9–2, 93
repetitive transcranial magnetic in children and adolescents wake therapy (sleep
stimulation (rTMS) 89 09, 0b deprivation) 85–6t
evidence levels for 86t pregnancy 07 STAR*D (Sequenced Treatment
Research Domain Criteria SAD-HART study 06 Alternatives to Relieve
(RDoC) 25 see also selective serotonin Depression) study 98, 00
risk factors for depression 46b reuptake inhibitors summary of results 0t
postpartum depression 06 severe depression 30t stepped care 45
risperidone 00 severity of depression 27, 30t St John’s wort (hypericum) 83
dosing recommendations 02t sex differences in prevalence 3 stress response 7
sexual problems 23 subcallosal cingulate 20
pharmacotherapy 98 substance-induced mood
S side effects of disorders 3, 33b
SAD-HART (Sertraline antidepressants 66 suicide risk 6, 25
AntiDepressant Heart Sheehan Disability Scale 48 and antidepressants
Attack Randomized short-episode depression 28b 65–6, 08b
Trial) 06 side effects of treatments in young people 09
SAM-e (S-adenosylmethionine) 83 antidepressants 76 assessment of 46
screening 45–6b during adjunctive therapy 96 reduction of 47
in postpartum period 06 agomelatine 7t risk factors 47t
seasonal affective disorder (SAD) bupropion 68, 70t surgical treatments 93
8, 29t citalopram 67t deep brain stimulation 92
light therapy 87–8f desvenlafaxine 69t limbic neurosurgery 92
second-generation antipsychotics in elderly patients 04 vagus nerve
(SGAs) 72, 00, 02t escitalopram 67t stimulation 9–2
dose 73t, 02t levomilnacipran 69t switching antidepressants 76,
mechanism of action 73t management of 98 80f, 96–7
side effects 73t in medical illnesses 04 advantages and
selective serotonin reuptake mianserin 7t disadvantages 97t
inhibitors (SSRIs) mirtazapine 7t washout periods 8t
64, 66, 68 monoamine oxidase symptom rating scales 47–8
in children and adolescents inhibitors 75t symptoms , 23–5
09, 0b quetiapine-XR 72 associated clinical features 35
doses 67t reboxetine 70t anxiety 35–6
and fatigue 42 selective serotonin reuptake cognitive dysfunction 38–40
mechanism of action 67t inhibitors 66, 67t, 68 fatigue and low energy 42
in patients with cardiovascular selegiline 75t irritability and anger 36–8
disease 06 serotonin and noradrenaline pain 4
pregnancy 07 reuptake inhibitors 69t of bipolar disorder 32–3
side effects 67t, 04 tricyclics 72, 74t elderly patients 02
switching agents 96–7 venlafaxine 69t SIGECAPS mnemonic 24t
washout periods 8t vilazodone 7t variation with age 4

136 • index
T alternative medicine;
pharmacotherapy;
overdose 66
pregnancy 07
technology-assisted psychological treatments; use after ECT 9
psychotherapy 59–60t somatic treatments vilazodone 63, 67t, 70, 7t, 72
telephone-delivered CBT 59–60 treatment targets 48 drug interactions 79t
total sleep deprivation (TSD) 85–6t tricyclic antidepressants see also selective serotonin
transcranial magnetic (TCAs) 72 reuptake inhibitors
stimulation 89 adjunctive agents 97 vortioxetine 7t, 72
evidence levels for 86t in children and adolescents drug interactions 79t
tranylcypromine 75t 09, 0b effect on cognitive function 40
see also monoamine oxidase discontinuation 80
inhibitors doses 74t
treatment choice 49 drug interactions 76, 79t W
antidepressants 63–4t mechanism of action 74t wake therapy (sleep
psychotherapies 54–5 side effects 74t, 04 deprivation) 85–6t
Treatment for Adolescents washout periods 8t washout periods 80, 8t
with Depression Study triiodothyronine 97, 98 websites, resources for
(TADS) 09 STAR*D study 00 self-management 5t
treatment phases 48–9t twin studies –2, 2 weight changes 24
treatment-resistant side effects of
depression (TRD) antidepressants 66
assessment 95–6b U
CANMAT guidelines 99f undertreatment 8f
definition 95
pharmacological
untreated depression, costs of 7–8 X
strategies 96–8 X approach, switching
antidepressants 76, 80f
advantages and
disadvantages 97t
V
vagus nerve stimulation (VNS)
second-generation
antipsychotics 00, 02t 9–2, 93 Y
STAR*D study 98, 00, 0t evidence levels for 86t yoga 83
treatments 2 V approach, switching
antidepressants 76, 80f
availability of 8f
costs of 8–9 venlafaxine 68, 69t Z
perceived need for 8f broad-spectrum action 64 zeitgebers 8
see also antidepressants; discontinuation 80 ziprasidone 00
complementary and efficacy 65

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O P L

OX F O R D PSYCH IATRY LIB RARY

Raymond W. Lam, MD, FRCPC

Raymond W. Lam, MD, FRCPC

Raymond W. Lam, MD, FRCPC

Appendix: Sample rating scales 3

Epidemiology and burden

Table 2. Prevalence of DSM-​IV MDD in general populations

Location 2 month Lifetime

* Data on Canada is from the Canadian Community Health Survey.

2.2 Course and prognosis

2.3 Burden of illness

Box 2. Prognostic indicators of a prolonged recovery in patients

2.3.2 Socioeconomic costs

Low back pain

2.3.3 Costs of untreated depression

2.3.4 Costs of treatment

Higher income Upper-middle income Lower-middle income

Biological Psychological Social

Physical illnesses, Life experiences,

environmental influences on disease risk. Estimates from twin studies of genetic

3.2.2 Linkage and association studies

Neuroanatomical abnormalities in major depression

NMDAR BDNF bcl-2 ?

Figure 3.2 Example of how neurochemical abnormalities may relate to candidate

Figure 3.3 Example of how neurochemical abnormalities may relate to candidate

serotonin transporter (SERT), leading to increased availability of neurotransmit-

Figure 3.4 Characterization of antidepressant effects using an interdisciplinary

delayed desensitization of presynaptic 5-​HTA autoreceptors and downregulation

3.3.2 Beyond monoamines

3.3.3 Hypothalamic-​pituitary-​adrenal-​immune axis

Box 3. Polysomnographic abnormalities of sleep in major depressive

3.3.4 Sleep and circadian rhythms

Figure 3.6 Model of sleep and circadian rhythm dysfunction in depression.

there are deficits in long-​term storage and retrieval of declarative memory,

Cortical Rostral PFC SCC

Ventral ACC Amygdala

The emotion-​dependent ‘hot’ cognitive deficits in depression include negatively

3.4.2 Environment and life events

Genetically resilient (G main effect) – no effect of stress

Figure 3.8 Model of gene–​environment (G×E) interactions. This figure illustrates

Clinical features and diagnosis

4.1 Clinical features

Table 4. SIGECAPS mnemonic for the clinical features of depression

In contrast, hypersomnia or oversleeping also can be a symptom of ‘atypical’

4.2 Classification and diagnosis of depression

4.2.2 Major depressive disorder

Yes 5 out of 9 Yes Prior manic/ No Persistent Yes Persistent

5 out of 9 Yes Prior manic/ Yes Major

Figure 4. Differential diagnosis of depression.

4.2.3 Persistent depressive disorder

4.2.4 Other depressive disorders

Box 4. Summary of DSM-​5 criteria used to diagnose a major depressive

4.3 Sub-​types of depression

Box 4.2 Summary of DSM-​5 criteria used to diagnose persistent depressive

Box 4.3 Other disorders classified as depressive disorders in DSM-​5

Table 4.2 DSM-​5 specifiers (sub-​types) of MDD

Table 4.3 Depression severity criteria

associated impairment in social and/​or occupational functioning. The ICD-​0,

4.4 Differential diagnosis

4.4.2 Depressive disorder due to another medical condition

4.4.3 Substance/​medication-​induced depressive disorder

4.4.4 Bipolar disorder

Table 4.4 Features that help distinguish bereavement from a major

Table 2. Prevalence of DSM-IV MDD in general populations

delayed desensitization of presynaptic 5-HTA autoreceptors and downregulation

3.3.3 Hypothalamic-pituitary-adrenal-immune axis

there are deficits in long-term storage and retrieval of declarative memory,

The emotion-dependent ‘hot’ cognitive deficits in depression include negatively

Figure 3.8 Model of gene–environment (G×E) interactions. This figure illustrates

Box 4. Summary of DSM-5 criteria used to diagnose a major depressive

4.3 Sub-types of depression

Box 4.2 Summary of DSM-5 criteria used to diagnose persistent depressive

Box 4.3 Other disorders classified as depressive disorders in DSM-5

Table 4.2 DSM-5 specifiers (sub-types) of MDD

associated impairment in social and/or occupational functioning. The ICD-0,

4.4.3 Substance/medication-induced depressive disorder

Box 4.4 Common drugs of abuse resulting in substance-induced mood

6.2.4 Monitoring outcomes (measurement-based care)

6.4.5 Patient education and self-management

Table 6.3 Resources for self-management

Table 7. Key features of evidence-based psychotherapies for depression

Cognitive Analyze specific situations 6–20 Developed

7.2 Problem-solving therapy

7.3.2 Mindfulness-based cognitive therapy

7.3.4 Cognitive–behavioural therapy

7.5 Cognitive behavioural-analysis system

7.7 Technology-assisted psychotherapy

Table 7.4 Examples of technology-assisted therapy programs

still be helpful in cases of treatment-resistant depression (TRD; see Chapter 0).

• Milnacipran, • Effective in fibromyalgia; shorter half-life, should titrate to

8.4.5 Second-generation antipsychotics

Table 8.6 Second-generation antipsychotics