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PSYCHIATRY
Official
Journal
of the
AMERICAN
PSYCHIATRIC
ASSOCIATION
PRACTICE for the Treatment of Patients With
Volume 167 GUIDELINE Major Depressive Disorder, Third Edition
Number 10
October
2010
PRACTICE GUIDELINE FOR THE
Treatment of Patients With
Major Depressive Disorder
Third Edition
This practice guideline was approved in May 2010 and published in October 2010. A guideline watch, summarizing
significant developments in the scientific literature since publication of this guideline, may be available at
http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx.
FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST
The Work Group on Major Depressive Disorder reports reports receiving honoraria from lectureships for Boeh-
the following potentially competing interests for the pe- ringer Ingleheim, Bristol-Myers Squibb, Cyberonics,
riod from May 2005 to May 2010: Forest Pharmaceuticals, Inc., Eli Lilly and Company, and
Dr. Gelenberg reports consulting for Eli Lilly and Com- Schwartz Pharma. He was involved in the creation of
pany, Pfizer, Best Practice, AstraZeneca, Wyeth, Cyber- the Massachusetts General Hospital Psychiatry Academy
onics, Novartis, Forest Pharmaceuticals, Inc., GlaxoSmith- (MGH-PA) and has served as a panelist in four satellite
Kline, ZARS Pharma, Jazz Pharmaceuticals, Lundbeck, broadcast programs. MGH-PA programs that have indus-
Takeda Pharmaceuticals North America, Inc., eResearch try support are always multi-sponsored, and curriculum
Technology, Dey Pharma, PGxHealth, and Myriad Genet- development by the Academy is independent of sponsor-
ics. He reports serving on speakers bureaus for Pfizer, ship; the curricula from January 2005 to March 2009 in-
GlaxoSmithKline, and Wyeth. He reports receiving re- cluded sponsorship support from AstraZeneca, Bristol-
search grant funding from Eli Lilly and Company, Pfizer, Myers Squibb, Cephalon, Eli Lilly and Company, Forest
and GlaxoSmithKline. He reports stock ownership in Pharmaceuticals, Inc., GlaxoSmithKline, Janssen Medical
Healthcare Technology Systems. Affairs LLC, Ortho-McNeil Pharmaceutical, sanofi-
Dr. Freeman reports that she received research support aventis, Shire, and Wyeth. He reports equity holdings in
from the Meadows Foundation, the National Institute for Compellis Pharmaceuticals, MedAvante, and Somaxon.
Mental Health, the U.S. Food and Drug Administration, Dr. Thase reports that he provided scientific consulta-
the Institute for Mental Health Research, Forest, Glaxo- tion to AstraZeneca, Bristol-Myers Squibb, Eli Lilly &
SmithKline and Eli Lilly and Company (investigator- Company, Forest Pharmaceuticals, Inc., Gerson Lehman
initiated trials), and Pronova Biocare (research materials). Group, GlaxoSmithKline, Guidepoint Global, H. Lund-
She received an honorarium for case-based peer-reviewed beck A/S, MedAvante, Inc., Neuronetics, Inc., Novartis,
material for AstraZenecas website. She reports consulting Otsuka, Ortho-McNeil Pharmaceuticals, PamLab, L.L.C.,
for Ther-Rx, Reliant, and Pamlab. She reports receiving Pfizer (formerly Wyeth-Ayerst Laboratories), Schering-
an honorarium for speaking at an APA continuing medical Plough (formerly Organon), Shire U.S., Inc., Supernus
education program that was sponsored by Forest and an Pharmaceuticals, Takeda (Lundbeck), and Transcept Phar-
honorarium for speaking at a continuing medication edu- maceuticals. He was a member of the speakers bureaus for
cation program sponsored by KV Pharmaceuticals. She AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Com-
reports receiving an honorarium from Leerink Swann for pany, GlaxoSmithKline, Pfizer (formerly Wyeth-Ayerst
participating in a focus group. Laboratories), and Schering-Plough (formerly Organon).
Dr. Markowitz reports consulting for Ono Pharma- He received grant funding from Eli Lilly and Company,
ceutical Co., Ltd. (2005). He reports receiving research GlaxoSmithKline, the National Institute of Mental Health,
support from Forest Pharmaceuticals, Inc. (2005). He re- the Agency for Healthcare Research and Quality, and
ports receiving grant support from the National Institute Sepracor, Inc. He had equity holdings in MedAvante, Inc.,
of Mental Health (20052013), the National Alliance for and received royalty income from American Psychiatric
Research in Schizophrenia and Depression (2005), and Publishing, Inc., Guilford Publications, Herald House,
MINT: Mental Health Initiative (2005). He reports re- Oxford University Press, and W.W. Norton and Company.
ceiving royalties from American Psychiatric Publishing, Inc. His wife was employed as the group scientific director for
(20052010), Basic Books (20052010), Elsevier (2005 Embryon (formerly Advogent), which does business with
2010), and Oxford University Press (20072010). Bristol-Myers Squibb and Pfizer/Wyeth.
Dr. Rosenbaum reports attending advisory boards for Dr. Trivedi reports that he was a consultant to or on
Bristol-Myers Squibb, Cephalon, Cyberonics, Forest Phar- speaker bureaus for Abbott Laboratories, Inc., Abdi Ibra-
maceuticals, Inc., Eli Lilly and Company, MedAvante, him, Akzo (Organon Pharmaceuticals, Inc.), AstraZeneca,
Neuronetics, Inc., Novartis, Orexigen Therapeutics, Inc., Bristol-Myers Squibb Company, Cephalon, Inc., Cyber-
Organon BioSciences, Pfizer, Roche Diagnostics, Sanofi- onics, Inc., Eli Lilly and Company, Evotec, Fabre Kramer
aventis, Shire, and Wyeth. He reports consulting for Aus- Pharmaceuticals, Inc., Forest Pharmaceuticals, Glaxo-
pex Pharmaceuticals, Compellis Pharmaceuticals, EPIX SmithKline, Janssen Pharmaceutica Products, L.P., Johnson
Pharmaceuticals, Neuronetics, Inc., Organon BioSci- & Johnson P.R.D., Meade-Johnson, Medtronic, Neuro-
ences, Somaxon, and Supernus Pharmaceuticals, Inc. He netics, Otsuka Pharmaceuticals, Parke-Davis Pharmaceuti-
cals, Inc., Pfizer, Inc., Sepracor, Shire Development, Solvay competing interests. The Independent Review Panel re-
Pharmaceuticals, VantagePoint, and Wyeth-Ayerst Labo- viewed this guideline to assess potential biases and found
ratories. He received research support from the Agency for no evidence of influence from the industry and other re-
Healthcare Research and Quality, Corcept Therapeutics, lationships of the Work Group disclosed above. The
Inc., Cyberonics, Inc., Merck, National Alliance for Re- Steering Committee on Practice Guidelines also reviewed
search in Schizophrenia and Depression, National Insti- this guideline and found no evidence of influence from
tute of Mental Health, National Institute on Drug Abuse, these relationships. The development process for this
Novartis, Pharmacia & Upjohn, Predix Pharmaceuticals guideline, including the roles of the Work Group, Inde-
(Epix), Solvay Pharmaceuticals, Inc., and Targacept. pendent Review Panel, Steering Committee, APA Assem-
Dr. Van Rhoads reports no competing interests. bly, and APA Board of Trustees is described in Overview
The Independent Review Panel, including Drs. Reus, of Guideline Development Process on p. 9.
DePaulo, Fawcett, Schneck, and Silbersweig, report no
AMERICAN PSYCHIATRIC ASSOCIATION
STEERING COMMITTEE ON PRACTICE GUIDELINES
John S. McIntyre, M.D., Chair (19992009), Consultant (20092010)
Joel Yager, M.D., Vice-Chair (20082009), Chair (20092010)
Daniel J. Anzia, M.D.
Thomas J. Craig, M.D., M.P.H.
Molly T. Finnerty, M.D.
Bradley R. Johnson, M.D.
Francis G. Lu, M.D.
James E. Nininger, M.D., Vice-Chair (20092010)
Barbara Schneidman, M.D.
Paul Summergrad, M.D.
Sherwyn M. Woods, M.D., Ph.D.
Michael J. Vergare, M.D.
M. Justin Coffey, M.D. (fellow)
Kristen Ochoa, M.D. (fellow)
Jeremy Wilkinson, M.D. (fellow)
Sheila Hafter Gray, M.D. (liaison)
STAFF
Robert Kunkle, M.A., Director, Practice Guidelines Project
Robert M. Plovnick, M.D., M.S., Director, Dept. of Quality Improvement and Psychiatric Services
Darrel A. Regier, M.D., M.P.H., Director, Division of Research
MEDICAL EDITOR
Laura J. Fochtmann, M.D.
CONTENTS
STATEMENT OF INTENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ACKNOWLEDGMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 9
dynamic psychotherapy in individuals with major depres- all, amphetamine, amphetamines, dextroamphetamine,
sive disorder, the Work Group gave this treatment a level atomoxetine, electroconvulsive, vagal nerve stimulation,
III rating, i.e., may be recommended on the basis of in- vagus nerve stimulation, VNS, rTMS, rapid transcranial
dividual circumstances. The Steering Committee gave a magnetic, repetitive transcranial magnetic stimulation,
level II rating, recommended with moderate clinical confi- magnetic stimulation, deep brain stimulation, psychother-
dence, based on the long history of clinical experience apy, psychotherapeutic, psychotherapies, behavior therapy,
with psychodynamic psychotherapy as well as findings behaviour therapy, cognitive therapy, cognitive behavior
from several studies of patients who had depressive symp- therapy, cognitive behavioral analysis system, cognitive be-
toms but not major depressive disorder per se. havioral therapy, cognitive behaviour therapy, cognitive
Relevant updates to the literature were identified through behavioural therapy, psychoanalytic, interpersonal therapy,
a MEDLINE literature search for articles published since interpersonal psychotherapy, group therapy, family ther-
the second edition of the guideline, published in 2000. For apy, marital therapy, couples therapy, psychoanalysis, psy-
this edition of the guideline, literature was identified chodynamic, aversive therapy, desensitization, exposure
through a computerized search of MEDLINE, using Pub- therapy, relaxation techniques, or progressive muscle relax-
Med, for the period from January 1999 to December 2006. ation. This yielded 13,506 abstracts, which were screened
Using the MeSH headings depression or depressive disor- for relevance with a very modest threshold for inclusion,
der, as well as the key words major depression, major de- then reviewed by the Work Group.
pressive disorder, neurotic depression, neurotic depressive, The Psychoanalytic Electronic Publishing database
dysthymia, dysthymic, dysthymic disorder, endogenous de- (http://www.p-e-p.org) was also searched using the terms
pression, endogenous depressive, melancholia, melan- major depression or major depressive. This search yielded
cholic, psychotic depression, atypical depression, seasonal 112 references. The Cochrane databases were also searched
depression, postpartum depression, postpartum depressive for the key word depression, and 168 meta-analyses were
symptoms, unipolar depression, unipolar depressive, or identified. Additional, less formal, literature searches were
pseudodementia yielded 39,157 citations. An additional conducted by APA staff and individual Work Group mem-
8,272 citations were identified by using the key words de- bers and included references through May 2009. Sources
pression or depressive in combination with the MeSH of funding were considered when the Work Group re-
headings affective disorders or psychotic or the key words viewed the literature.
psychosis, psychotic, catatonic, catatonia, mood disorder, The broad scope of this guideline and the substantial
mood disorders, affective disorder, or affective disorders. evidence base resulted in some practical tradeoffs. One
These citations were limited to English language articles such tradeoff worth highlighting is the decision to build
on human treatments using the MeSH headings central upon literature reviews of the first and second editions of
nervous system stimulants, hypnotics and sedatives, anti- the guideline, rather than re-do them. This decision is ac-
convulsants, tranquilizing agents, electric stimulation ther- knowledged to have resulted in an emphasis of study in
apy, electroconvulsive therapy, psychotherapy, antidepres- this guideline on newer treatments, because the majority
sive agents, and monoamine oxidase inhibitors or the key of studies about older treatments, including tricyclic anti-
words antidepressant, antidepressants, antidepressive, anti- depressants and monoamine oxidase inhibitors, were pub-
depressive agents, antidepressive agents, second genera- lished in decades prior to 1999. Readers are advised that
tion, antidepressive agents tricyclic, antidepressive agents, the reviews of this older literature are described in the
tricyclic, fluoxetine, citalopram, escitalopram, paroxetine, previous editions of the guideline. The Work Group for
sertraline, venlafaxine, duloxetine, mirtazapine, nefazo- this edition considered the previous editions during their
done, trazodone, imipramine, desipramine, nortriptyline, evidence review, but for practical reasons, that effort is less
protriptyline, doxepin, trimipramine, amitriptyline, phe- well documented than the groups analysis of the newer
nelzine, tranylcypromine, isocarboxazid, moclobemide, literature. The treatment recommendations of this guide-
antipsychotic agents, testosterone, thyroid, tri iodothyro- line, however, were developed to reflect the complete ev-
nine, thyroxine, omega 3, s adenosyl methionine, s adenosyl- idence base.
methionine, St. Johns wort, hypericum, selegiline, anti- This document represents a synthesis of current scien-
convulsant, anticonvulsants, antipsychotic, antipsychotic tific knowledge and rational clinical practice regarding
agent, antianxiety, anti anxiety, benzodiazepine, benzodiaz- the treatment of patients with major depressive disorder.
epines, zolpidem, sedative, sedatives, hypnotic, hypnotics, It strives to be as free as possible of bias toward any theo-
zaleplon, eszopiclone, valproate, valproic acid, divalproex, retical approach to treatment. In order for the reader to
carbamazepine, oxcarbazepine, gabapentin, topiramate, appreciate the evidence base behind the guideline recom-
lamotrigine, lithium, modafinil, methylphenidate, Adder- mendations and the weight that should be given to each
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 11
recommendation, the summary of treatment recommen- To share feedback on this or other published APA
dations is keyed according to the level of confidence with practice guidelines, a form is available at http://mx.psych.
which each recommendation is made. Each rating of clin- org/survey/reviewform.cfm.
ical confidence considers the strength of the available ev-
idence. When evidence from randomized controlled trials
and meta-analyses is limited, the level of confidence may OFF-LABEL USE OF
also incorporate other clinical trials and case reports as well
as clinical consensus with regard to a particular clinical
MEDICATIONS
decision. In the listing of cited references, each reference Medications discussed in this practice guideline may not
is followed by a letter code in brackets that indicates the have an indication from the U.S. Food and Drug Admin-
nature of the supporting evidence. istration for the disorder or condition for which they are
recommended. Off-label use of medications by individual
physicians is permitted and common. Decisions about off-
GUIDE TO USING THIS label use can be guided by the evidence provided in the
PRACTICE GUIDELINE APA practice guideline, other scientific literature, and clin-
ical experience.
The Practice Guideline for the Treatment of Patients With Ma-
jor Depressive Disorder, Third Edition, consists of three parts
(Parts A, B, and C) and many sections, not all of which will INTRODUCTION
be equally useful for all readers. The following guide is
designed to help readers find the sections that will be most This guideline summarizes the specific approaches to
useful to them. treatment of individuals with major depressive disorder. It
Part A, Treatment Recommendations, is published presupposes that the psychiatrist has diagnosed major de-
as a supplement to the American Journal of Psychiatry and pressive disorder, according to the criteria defined in
contains general and specific treatment recommenda- DSM-IV-TR, in an adult patient and has evaluated the
tions. Section I summarizes the key recommendations of patient to identify general medical conditions that may
the guideline and codes each recommendation according contribute to the disease process (e.g., hypothyroidism,
to the degree of clinical confidence with which the recom- pancreatic carcinoma) or complicate its treatment (e.g.,
mendation is made. Section II is a guide to the formula- cardiac disorders). The treatment recommendations that
tion and implementation of a treatment plan for the follow may also have some relevance for patients who
individual patient. Section III, Specific Clinical Features have depressive symptoms on the basis of other syn-
Influencing the Treatment Plan, discusses a range of clin- dromes, such as dysthymic disorder. Because many pa-
ical considerations that could alter the general recommen- tients have co-occurring psychiatric disorders, including
dations discussed in Section I. substance use disorders, the psychiatrist should also con-
Part B, Background Information and Review of Avail- sider applicable treatment guidelines for these diagnoses.
able Evidence, and Part C, Future Research Needs, are When patients experience depressive symptoms in the
not included in the American Journal of Psychiatry sup- context of another disorder and do not meet the diagnos-
plement but are provided with Part A in the complete guide- tic criteria for major depressive disorder, the APA practice
line, which is available in print format from American guideline pertaining to the primary diagnosis should be
Psychiatric Publishing, Inc., and online through the Ameri- consulted. For patients found to have depressive symp-
can Psychiatric Association (http://www.psychiatryonline. toms within the context of bipolar disorder, the psychiatrist
com). Part B provides an overview of major depressive should refer to APAs Practice Guideline for the Treatment of
disorder, including general information on natural history, Patients With Bipolar Disorder (2). Recommendations on
course, and epidemiology. It also provides a structured the treatment of depressive disorders in children and ad-
review and synthesis of the evidence that underlies the olescents can be found in the American Academy of Child
recommendations made in Part A. Part C draws from the and Adolescent Psychiatrys Practice Parameter for the As-
previous sections and summarizes areas for which more sessment and Treatment of Children and Adolescents With
research data are needed to guide clinical decisions. Depressive Disorders (3).
Part A
TREATMENT RECOMMENDATIONS
I. EXECUTIVE SUMMARY
A. CODING SYSTEM chiatric history, including identification of past symptoms
of mania, hypomania, or mixed episodes and responses to
Each recommendation is identified as falling into one of previous treatments; a general medical history; a personal
three categories of endorsement, indicated by a bracketed history including information about psychological develop-
Roman numeral following the statement. The three cate- ment and responses to life transitions and major life events;
gories represent varying levels of clinical confidence: a social, occupational, and family history (including mood
disorders and suicide); review of the patients prescribed
[I] Recommended with substantial clinical confidence and over-the-counter medications; a review of systems; a
[II] Recommended with moderate clinical confidence mental status examination; a physical examination; and ap-
[III] May be recommended on the basis of individual cir- propriate diagnostic tests as indicated to rule out possible
cumstances general medical causes of depressive symptoms [I]. Assess-
ment of substance use should evaluate past and current use
B. SUMMARY OF RECOMMENDATIONS of illicit drugs and other substances that may trigger or ex-
acerbate depressive symptoms [I].
1. Psychiatric management
Psychiatric management consists of a broad array of inter- c. Evaluate the safety of the patient
ventions and activities that psychiatrists should initiate A careful and ongoing evaluation of suicide risk is neces-
and continue to provide to patients with major depressive sary for all patients with major depressive disorder [I].
disorder through all phases of treatment [I]. Such an assessment includes specific inquiry about sui-
a. Establish and maintain a therapeutic alliance cidal thoughts, intent, plans, means, and behaviors; iden-
In establishing and maintaining a therapeutic alliance, it is tification of specific psychiatric symptoms (e.g., psychosis,
important to collaborate with the patient in decision mak- severe anxiety, substance use) or general medical condi-
ing and attend to the patients preferences and concerns tions that may increase the likelihood of acting on suicidal
about treatment [I]. Management of the therapeutic alli- ideas; assessment of past and, particularly, recent suicidal
ance should include awareness of transference and counter- behavior; delineation of current stressors and potential
transference issues, even if these are not directly addressed protective factors (e.g., positive reasons for living, strong
in treatment [II]. Severe or persistent problems of poor al- social support); and identification of any family history of
liance or nonadherence to treatment may be caused by the suicide or mental illness [I]. In addition to assessing sui-
depressive symptoms themselves or may represent psy- cide risk per se, it is important to assess the patients level
chological conflicts or psychopathology for which psycho- of self-care, hydration, and nutrition, each of which can be
therapy should be considered [II]. compromised by severe depressive symptoms [I]. As part
of the assessment process, impulsivity and potential for
b. Complete the psychiatric assessment risk to others should also be evaluated, including any his-
Patients should receive a thorough diagnostic assessment in tory of violence or violent or homicidal ideas, plans, or in-
order to establish the diagnosis of major depressive disor- tentions [I]. An evaluation of the impact of the depression
der, identify other psychiatric or general medical conditions on the patients ability to care for dependents is an impor-
that may require attention, and develop a comprehensive tant component of the safety evaluation [I]. The patients
plan for treatment [I]. This evaluation generally includes a risk of harm to him- or herself and to others should also be
history of the present illness and current symptoms; a psy- monitored as treatment proceeds [I].
13
14 APA PRACTICE GUIDELINES
d. Establish the appropriate setting for treatment uation has been done [I], either by the psychiatrist or by
The psychiatrist should determine the least restrictive another health care professional. Extensive or specialized
setting for treatment that will be most likely not only to testing for general medical causes of depressive symptoms
address the patients safety, but also to promote improve- may be conducted based on individual characteristics of
ment in the patients condition [I]. The determination of the patient [III].
an appropriate setting for treatment should include con-
sideration of the patients symptom severity, co-occurring g. Monitor the patients psychiatric status
psychiatric or general medical conditions, available support The patients response to treatment should be carefully
system, and level of functioning [I]. The determination of a monitored [I]. Continued monitoring of co-occurring
treatment setting should also include consideration of the psychiatric and/or medical conditions is also essential to
patients ability to adequately care for him- or herself, to developing and refining a treatment plan for an individual
provide reliable feedback to the psychiatrist, and to coop- patient [I].
erate with treatment of the major depressive disorder [I]. h. Integrate measurements into psychiatric management
Measures such as hospitalization should be considered for Tailoring the treatment plan to match the needs of the
patients who pose a serious threat of harm to themselves particular patient requires a careful and systematic assess-
or others [I]. Patients who refuse inpatient treatment can ment of the type, frequency, and magnitude of psychiatric
be hospitalized involuntarily if their condition meets the symptoms as well as ongoing determination of the thera-
criteria of the local jurisdiction for involuntary admission peutic benefits and side effects of treatment [I]. Such assess-
[I]. Admission to a hospital or, if available, an intensive day ments can be facilitated by integrating clinician- and/or
program, may also be indicated for severely ill patients who patient-administered rating scale measurements into ini-
lack adequate social support outside of a hospital setting, tial and ongoing evaluation [II].
who have complicating psychiatric or general medical
conditions, or who have not responded adequately to out- i. Enhance treatment adherence
patient treatment [I]. The optimal treatment setting and The psychiatrist should assess and acknowledge potential
the patients likelihood of benefit from a different level of barriers to treatment adherence (e.g., lack of motivation
care should be reevaluated on an ongoing basis through- or excessive pessimism due to depression; side effects of
out the course of treatment [I]. treatment; problems in the therapeutic relationship; lo-
gistical, economic, or cultural barriers to treatment) and
e. Evaluate functional impairment and quality of life collaborate with the patient (and if possible, the family) to
Major depressive disorder can alter functioning in numer- minimize the impact of these potential barriers [I]. In addi-
ous spheres of life including work, school, family, social tion, the psychiatrist should encourage patients to articu-
relationships, leisure activities, or maintenance of health late any fears or concerns about treatment or its side effects
and hygiene. The psychiatrist should evaluate the patients [I]. Patients should be given a realistic notion of what can
activity in each of these domains and determine the pres- be expected during the different phases of treatment, in-
ence, type, severity, and chronicity of any dysfunction [I]. cluding the likely time course of symptom response and
In developing a treatment plan, interventions should be the importance of adherence for successful treatment and
aimed at maximizing the patients level of functioning as prophylaxis [I].
well as helping the patient to set specific goals appropriate
to his or her functional impairments and symptom sever- j. Provide education to the patient and the family
ity [I]. Education about the symptoms and treatment of major
depressive disorder should be provided in language that is
f. Coordinate the patients care with other clinicians readily understandable to the patient [I]. With the pa-
Many patients with major depressive disorder will be eval- tients permission, family members and others involved in
uated by or receive treatment from other health care pro- the patients day-to-day life may also benefit from educa-
fessionals in addition to the psychiatrist. If more than one tion about the illness, its effects on functioning (including
clinician is involved in providing the care, all treating cli- family and other interpersonal relationships), and its treat-
nicians should have sufficient ongoing contact with the ment [I]. Common misperceptions about antidepressants
patient and with each other to ensure that care is coordi- (e.g., they are addictive) should be clarified [I]. In addition,
nated, relevant information is available to guide treatment education about major depressive disorder should address
decisions, and treatments are synchronized [I]. the need for a full acute course of treatment, the risk of re-
In ruling out general medical causes of depressive symp- lapse, the early recognition of recurrent symptoms, and the
toms, it is important to ensure that a general medical eval- need to seek treatment as early as possible to reduce the risk
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 15
of complications or a full-blown episode of major depres- to patients who do not respond to other treatments [I],
sion [I]. Patients should also be told about the need to given the necessity for dietary restrictions with these med-
taper antidepressants, rather than discontinuing them ications and the potential for deleterious drug-drug inter-
precipitously, to minimize the risk of withdrawal symp- actions. In patients who prefer complementary and alter-
toms or symptom recurrence [I]. Patient education also native therapies, S-adenosyl methionine (SAMe) [III] or
includes general promotion of healthy behaviors such as St. Johns wort [III] might be considered, although evidence
exercise, good sleep hygiene, good nutrition, and decreased for their efficacy is modest at best, and careful attention to
use of tobacco, alcohol, and other potentially deleterious drug-drug interactions is needed with St. Johns wort [I].
substances [I]. Educational tools such as books, pamphlets, Once an antidepressant medication has been initiated,
and trusted web sites can augment the face-to-face educa- the rate at which it is titrated to a full therapeutic dose
tion provided by the clinician [I]. should depend upon the patients age, the treatment set-
ting, and the presence of co-occurring illnesses, concom-
2. Acute phase itant pharmacotherapy, or medication side effects [I].
During the acute phase of treatment, patients should be
a. Choice of an initial treatment modality carefully and systematically monitored on a regular basis
Treatment in the acute phase should be aimed at inducing to assess their response to pharmacotherapy, identify the
remission of the major depressive episode and achieving a emergence of side effects (e.g., gastrointestinal symptoms,
full return to the patients baseline level of functioning [I]. sedation, insomnia, activation, changes in weight, and car-
Acute phase treatment may include pharmacotherapy, de- diovascular, neurological, anticholinergic, or sexual side ef-
pression-focused psychotherapy, the combination of med- fects), and assess patient safety [I]. The frequency of patient
ications and psychotherapy, or other somatic therapies monitoring should be determined based upon the patients
such as electroconvulsive therapy (ECT), transcranial mag- symptom severity (including suicidal ideas), co-occurring
netic stimulation (TMS), or light therapy, as described in the disorders (including general medical conditions), coopera-
sections that follow. Selection of an initial treatment mo- tion with treatment, availability of social supports, and the
dality should be influenced by clinical features (e.g., se- frequency and severity of side effects with the chosen treat-
verity of symptoms, presence of co-occurring disorders ment [II]. If antidepressant side effects do occur, an initial
or psychosocial stressors) as well as other factors (e.g., pa- strategy is to lower the dose of the antidepressant or to
tient preference, prior treatment experiences) [I]. Any change to an antidepressant that is not associated with
treatment should be integrated with psychiatric manage- that side effect [I].
ment and any other treatments being provided for other
diagnoses [I]. 2. Other somatic therapies
ECT is recommended as a treatment of choice for pa-
1. Pharmacotherapy tients with severe major depressive disorder that is not re-
An antidepressant medication is recommended as an ini- sponsive to psychotherapeutic and/or pharmacological
tial treatment choice for patients with mild to moderate interventions, particularly in those who have significant
major depressive disorder [I] and definitely should be pro- functional impairment or have not responded to numer-
vided for those with severe major depressive disorder un- ous medication trials [I]. ECT is also recommended for
less ECT is planned [I]. Because the effectiveness of anti- individuals with major depressive disorder who have asso-
depressant medications is generally comparable between ciated psychotic or catatonic features [I], for those with an
classes and within classes of medications, the initial selec- urgent need for response (e.g., patients who are suicidal
tion of an antidepressant medication will largely be based or nutritionally compromised due to refusal of food or flu-
on the anticipated side effects, the safety or tolerability of ids) [I], and for those who prefer ECT or have had a pre-
these side effects for the individual patient, pharmacolog- vious positive response to ECT [II].
ical properties of the medication (e.g., half-life, actions on Bright light therapy might be used to treat seasonal af-
cytochrome P450 enzymes, other drug interactions), and ad- fective disorder as well as nonseasonal depression [III].
ditional factors such as medication response in prior epi-
sodes, cost, and patient preference [I]. For most patients, a 3. Psychotherapy
selective serotonin reuptake inhibitor (SSRI), serotonin Use of a depression-focused psychotherapy alone is rec-
norepinephrine reuptake inhibitor (SNRI), mirtazapine, ommended as an initial treatment choice for patients with
or bupropion is optimal [I]. In general, the use of nonselec- mild to moderate major depressive disorder [I], with clin-
tive monoamine oxidase inhibitors (MAOIs) (e.g., phenel- ical evidence supporting the use of cognitive-behavioral
zine, tranylcypromine, isocarboxazid) should be restricted therapy (CBT) [I], interpersonal psychotherapy [I], psy-
16 APA PRACTICE GUIDELINES
chodynamic therapy [II], and problem-solving therapy psychotherapy tends to be a bit more gradual than that
[III] in individual [I] and in group [III] formats. Factors from medication, but no treatment should continue un-
that may suggest the use of psychotherapeutic interven- modified if there has been no symptomatic improvement
tions include the presence of significant psychosocial after 1 month [I]. Generally, 48 weeks of treatment are
stressors, intrapsychic conflict, interpersonal difficulties, needed before concluding that a patient is partially respon-
a co-occurring axis II disorder, treatment availability, or sive or unresponsive to a specific intervention [II].
most importantpatient preference [II]. In women who
are pregnant, wish to become pregnant, or are breast- c. Strategies to address nonresponse
feeding, a depression-focused psychotherapy alone is rec- For individuals who have not responded fully to treat-
ommended [II] and depending on the severity of symptoms, ment, the acute phase of treatment should not be con-
should be considered as an initial option [I]. Consider- cluded prematurely [I], as an incomplete response to
ations in the choice of a specific type of psychotherapy in- treatment is often associated with poor functional out-
clude the goals of treatment (in addition to resolving major comes. If at least a moderate improvement in symptoms
depressive symptoms), prior positive response to a specific is not observed within 48 weeks of treatment initiation,
type of psychotherapy, patient preference, and the avail- the diagnosis should be reappraised, side effects assessed,
ability of clinicians skilled in the specific psychotherapeu- complicating co-occurring conditions and psychosocial
tic approach [II]. As with patients who are receiving phar- factors reviewed, and the treatment plan adjusted [I]. It is
macotherapy, patients receiving psychotherapy should be also important to assess the quality of the therapeutic al-
carefully and systematically monitored on a regular basis to liance and treatment adherence [I]. For patients in psy-
assess their response to treatment and assess patient safety chotherapy, additional factors to be assessed include the
[I]. When determining the frequency of psychotherapy frequency of sessions and whether the specific approach
sessions for an individual patient, the psychiatrist should to psychotherapy is adequately addressing the patients
consider multiple factors, including the specific type and needs [I]. If medications are prescribed, the psychiatrist
goals of psychotherapy, symptom severity (including sui- should determine whether pharmacokinetic [I] or phar-
cidal ideas), co-occurring disorders, cooperation with treat- macodynamic [III] factors suggest a need to adjust med-
ment, availability of social supports, and the frequency of ication doses. With some TCAs, a drug blood level can
visits necessary to create and maintain a therapeutic rela- help determine if additional dose adjustments are re-
tionship, ensure treatment adherence, and monitor and ad- quired [I].
dress depressive symptoms and suicide risk [II]. Marital and After an additional 48 weeks of treatment, if the pa-
family problems are common in the course of major de- tient continues to show minimal or no improvement in
pressive disorder, and such problems should be identified symptoms, the psychiatrist should conduct another thor-
and addressed, using marital or family therapy when indi- ough review of possible contributory factors and make ad-
cated [II]. ditional changes in the treatment plan [I]. Consultation
should also be considered [II].
4. Psychotherapy plus antidepressant medication A number of strategies are available when a change in
The combination of psychotherapy and antidepressant the treatment plan seems necessary. For patients treated
medication may be used as an initial treatment for patients with an antidepressant, optimizing the medication dose is
with moderate to severe major depressive disorder [I]. In a reasonable first step if the side effect burden is tolerable
addition, combining psychotherapy and medication may and the upper limit of a medication dose has not been
be a useful initial treatment even in milder cases for pa- reached [II]. Particularly for those who have shown mini-
tients with psychosocial or interpersonal problems, intra- mal improvement or experienced significant medication
psychic conflict, or co-occurring Axis II disorder [II]. In side effects, other options include augmenting the antide-
general, when choosing an antidepressant or psychother- pressant with a depression-focused psychotherapy [I] or
apeutic approach for combination treatment, the same is- with other agents [II] or changing to another non-MAOI
sues should be considered as when selecting a medication antidepressant [I]. Patients may be changed to an antide-
or psychotherapy for use alone [I]. pressant from the same pharmacological class (e.g., from
one SSRI to another SSRI) or to one from a different class
b. Assessing the adequacy of treatment response (e.g., from an SSRI to a tricyclic antidepressant [TCA]) [II].
In assessing the adequacy of a therapeutic intervention, it For patients who have not responded to trials of SSRIs, a
is important to establish that treatment has been adminis- trial of an SNRI may be helpful [II]. Augmentation of an-
tered for a sufficient duration and at a sufficient frequency or, tidepressant medications can utilize another non-MAOI
in the case of medication, dose [I]. Onset of benefit from antidepressant [II], generally from a different pharmaco-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 17
logical class, or a non-antidepressant medication such as Patients who respond to an acute course of ECT should
lithium [II], thyroid hormone [II], or a second-generation receive continuation pharmacotherapy [I], with the best
antipsychotic [II]. Additional strategies with less evidence evidence available for the combination of lithium and
for efficacy include augmentation using an anticonvulsant nortriptyline. Alternatively, patients who have responded
[III], omega-3 fatty acids [III], folate [III], or a psychostim- to an acute course of ECT may be given continuation ECT,
ulant medication [III], including modafinil [III]. If anxiety particularly if medication or psychotherapy has been inef-
or insomnia are prominent features, consideration can be fective in maintaining remission [II].
given to anxiolytic and sedative-hypnotic medications
[III], including buspirone, benzodiazepines, and selective 4. Maintenance phase
-aminobutyric acid (GABA) agonist hypnotics (e.g., zol- In order to reduce the risk of a recurrent depressive epi-
pidem, eszopiclone). For patients whose symptoms have sode, patients who have had three or more prior major de-
not responded adequately to medication, ECT remains the pressive episodes or who have chronic major depressive
most effective form of therapy and should be considered disorder should proceed to the maintenance phase of treat-
[I]. In patients capable of adhering to dietary and medica- ment after completing the continuation phase [I]. Mainte-
tion restrictions, an additional option is changing to a non- nance therapy should also be considered for patients with
selective MAOI [II] after allowing sufficient time between additional risk factors for recurrence, such as the presence
medications to avoid deleterious interactions [I]. Transder- of residual symptoms, ongoing psychosocial stressors, early
mal selegiline, a relatively selective MAO B inhibitor with age at onset, and family history of mood disorders [II]. Ad-
fewer dietary and medication restrictions, or transcranial ditional considerations that may play a role in the decision
magnetic stimulation could also be considered [II]. Vagus to use maintenance therapy include patient preference, the
nerve stimulation (VNS) may be an additional option for type of treatment received, the presence of side effects dur-
individuals who have not responded to at least four ade- ing continuation therapy, the probability of recurrence, the
quate trials of antidepressant treatment, including ECT frequency and severity of prior depressive episodes (includ-
[III]. ing factors such as psychosis or suicide risk), the persistence
For patients treated with psychotherapy, consideration of depressive symptoms after recovery, and the presence of
should be given to increasing the intensity of treatment co-occurring disorders [II]. Such factors also contribute to
or changing the type of therapy [II]. If psychotherapy is decisions about the duration of the maintenance phase [II].
used alone, the possible need for medications in addition For many patients, particularly for those with chronic and
to or in lieu of psychotherapy should be assessed [I]. Pa- recurrent major depressive disorder or co-occurring medi-
tients who have a history of poor treatment adherence or cal and/or psychiatric disorders, some form of maintenance
incomplete response to adequate trials of single treat- treatment will be required indefinitely [I].
ment modalities may benefit from combined treatment During the maintenance phase, an antidepressant med-
with medication and a depression-focused psychotherapy ication that produced symptom remission during the acute
[II]. phase and maintained remission during the continuation
phase should be continued at a full therapeutic dose [II]. If
3. Continuation phase a depression-focused psychotherapy has been used during
During the continuation phase of treatment, the patient the acute and continuation phases of treatment, mainte-
should be carefully monitored for signs of possible relapse nance treatment should be considered, with a reduced
[I]. Systematic assessment of symptoms, side effects, ad- frequency of sessions [II]. For patients whose depressive
herence, and functional status is essential [I] and may be episodes have not previously responded to acute or con-
facilitated through the use of clinician- and/or patient- tinuation treatment with medications or a depression-
administered rating scales [II]. To reduce the risk of re- focused psychotherapy but who have shown a response to
lapse, patients who have been treated successfully with ECT, maintenance ECT may be considered [III]. Main-
antidepressant medications in the acute phase should con- tenance treatment with VNS is also appropriate for indi-
tinue treatment with these agents for 49 months [I]. In viduals whose symptoms have responded to this treatment
general, the dose used in the acute phase should be used modality [III].
in the continuation phase [II]. To prevent a relapse of Due to the risk of recurrence, patients should be mon-
depression in the continuation phase, depression-focused itored systematically and at regular intervals during the
psychotherapy is recommended [I], with the best evidence maintenance phase [I]. Use of standardized measurement
available for CBT. aids in the early detection of recurrent symptoms [II].
18 APA PRACTICE GUIDELINES
5. Discontinuation of treatment sis, turning to reduce risks of decubitus ulcers, and passive
When pharmacotherapy is being discontinued, it is best range of motion to reduce risk of contractures [I]. If anti-
to taper the medication over the course of at least several psychotic medication is needed, it is important to monitor
weeks [I]. To minimize the likelihood of discontinuation for signs of neuroleptic malignant syndrome, to which pa-
symptoms, patients should be advised not to stop medi- tients with catatonia may have a heightened sensitivity
cations abruptly and to take medications with them when [II].
they travel or are away from home [I]. A slow taper or When patients with a major depressive disorder also
temporary change to a longer half-life antidepressant may have a co-occurring psychiatric illness, the clinician should
reduce the risk of discontinuation syndrome [II] when dis- address each disorder as part of the treatment plan [I]. Ben-
continuing antidepressants or reducing antidepressant zodiazepines may be used adjunctively in individuals with
doses. Before the discontinuation of active treatment, pa- major depressive disorder and co-occurring anxiety [II], al-
tients should be informed of the potential for a depressive though these agents do not treat depressive symptoms, and
relapse and a plan should be established for seeking treat- careful selection and monitoring is needed in individuals
ment in the event of recurrent symptoms [I]. After discon- with co-occurring substance use disorders [I].
tinuation of medications, patients should continue to be In patients who smoke, bupropion [I] or nortriptyline
monitored over the next several months and should receive [II] may be options to simultaneously treat depression and
another course of adequate acute phase treatment if symp- assist with smoking cessation. When possible, a period of
toms recur [I]. substance abstinence can help determine whether the de-
For patients receiving psychotherapy, it is important to pressive episode is related to substance intoxication or
raise the issue of treatment discontinuation well in ad- withdrawal [II]. Factors that suggest a need for antide-
vance of the final session [I], although the exact process by pressant treatment soon after cessation of substance use
which this occurs will vary with the type of therapy. include a family history of major depressive disorder and
a history of major depressive disorder preceding the on-
6. Clinical factors influencing treatment set of the substance use disorder or during periods of so-
briety [II].
a. Psychiatric factors For patients who have a personality disorder as well as
For suicidal patients, psychiatrists should consider an in- major depressive disorder, psychiatrists should institute
creased intensity of treatment, including hospitalization treatment for the major depressive disorder [I] and con-
when warranted [I] and/or combined treatment with sider psychotherapeutic and adjunctive pharmacothera-
pharmacotherapy and psychotherapy [II]. Factors to con- peutic treatment for personality disorder symptoms [II].
sider in determining the nature and intensity of treatment
include (but are not limited to) the nature of the doctor- b. Demographic and psychosocial factors
patient alliance, the availability and adequacy of social sup- Several aspects of assessment and treatment differ be-
ports, access to and lethality of suicide means, the presence tween women and men. Because the symptoms of some
of a co-occurring substance use disorder, and past and fam- women may fluctuate with gonadal hormone levels, the
ily history of suicidal behavior [I]. evaluation should include a detailed assessment of mood
For patients who exhibit psychotic symptoms during changes across the reproductive life history (e.g., men-
an episode of major depressive disorder, treatment should struation, pregnancy, birth control including oral contra-
include a combination of antipsychotic and antidepressant ception use, abortions, menopause) [I]. When prescribing
medications or ECT [I]. When patients exhibit cognitive medications to women who are taking oral contraceptives,
dysfunction during a major depressive episode, they may the potential effects of drug-drug interactions must be
have an increased likelihood of future dementia, making it considered [I]. For women in the perimenopausal period,
important to assess cognition in a systematic fashion over SSRI and SNRI antidepressants are useful in ameliorating
the course of treatment [I]. depression as well as in reducing somatic symptoms such
Catatonic features that occur as part of a major depres- as hot flashes [II]. Both men and women who are taking an-
sive episode should be treated with a benzodiazepine [I] or tidepressants should be asked whether sexual side effects
barbiturate [II], typically in conjunction with an antidepres- are occurring with these medications [I]. Men for whom
sant [II]. If catatonic symptoms persist, ECT is recom- trazodone is prescribed should be warned of the risk of
mended [I]. To reduce the likelihood of general medical priapism [I].
complications, patients with catatonia may also require The treatment of major depressive disorder in women
supportive medical interventions, such as hydration, nu- who are pregnant or planning to become pregnant re-
tritional support, prophylaxis against deep vein thrombo- quires a careful consideration of the benefits and risks of
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 19
available treatment options for the patient and the fetus [I]. Issues relating to the family situation and family his-
For women who are currently receiving treatment for de- tory, including mood disorders and suicide, can also affect
pression, a pregnancy should be planned, whenever pos- treatment planning and are an important element of the
sible, in consultation with the treating psychiatrist, who initial evaluation [I]. A family history of bipolar disorder
may wish to consult with a specialist in perinatal psychia- or acute psychosis suggests a need for increased attention
try [I]. In women who are pregnant, planning to become to possible signs of bipolar illness in the patient (e.g., with
pregnant, or breast-feeding, depression-focused psycho- antidepressant treatment) [I]. A family history of recur-
therapy alone is recommended [II] and should always be rent major depressive disorder increases the likelihood of
considered as an initial option, particularly for mild to recurrent episodes in the patient and supports a need for
moderate depression, for patients who prefer psycho- maintenance treatment [II]. Family history of a response
therapy, or for those with a prior positive response to to a particular antidepressant may sometimes help in
psychotherapy [I]. Antidepressant medication should be choosing a specific antidepressant for the patient [III]. Be-
considered for pregnant women who have moderate to cause problems within the family may become an ongoing
severe major depressive disorder as well as for those who stressor that hampers the patients response to treatment,
are in remission from major depressive disorder, are re- and because depression in a family is a major stress in it-
ceiving maintenance medication, and are deemed to be at self, such factors should be identified and strong consid-
high risk for a recurrence if the medication is discontin- eration given to educating the family about the nature of
ued [II]. When antidepressants are prescribed to a pregnant the illness, enlisting the familys support, and providing
woman, changes in pharmacokinetics during pregnancy family therapy, when indicated [II].
may require adjustments in medication doses [I]. Electro- For patients who have experienced a recent bereave-
convulsive therapy may be considered for the treatment of ment, psychotherapy or antidepressant treatment should
depression during pregnancy in patients who have psy- be used when the reaction to a loss is particularly pro-
chotic or catatonic features, whose symptoms are severe longed or accompanied by significant psychopathology
or have not responded to medications, or who prefer treat- and functional impairment [I]. Support groups may be
ment with ECT [II]. When a woman decides to nurse, the helpful for some bereaved individuals [III].
potential benefits of antidepressant medications for the
mother should be balanced against the potential risks to c. Co-occurring general medical conditions
the newborn from receiving antidepressant in the mothers In patients with major depressive disorder, it is important
milk [I]. For women who are depressed during the post- to recognize and address the potential interplay between
partum period, it is important to evaluate for the presence major depressive disorder and any co-occurring general
of suicidal ideas, homicidal ideas, and psychotic symp- medical conditions [I]. Communication with other clini-
toms [I]. The evaluation should also assess parenting skills cians who are providing treatment for general medical
for the newborn and for other children in the patients conditions is recommended [I]. The clinical assessment
care [I]. should include identifying any potential interactions be-
In individuals with late-life depression, identification tween medications used to treat depression and those used
of co-occurring general medical conditions is essential, as to treat general medical conditions [I]. Assessment of pain
these disorders may mimic depression or affect choice or is also important as it can contribute to and co-occur with
dosing of medications [I]. Older individuals may also be depression [I]. In addition, the psychiatrist should con-
particularly sensitive to medication side effects (e.g., sider the effects of prescribed psychotropic medications
hypotension, anticholinergic effects) and require adjust- on the patients general medical conditions, as well as the
ment of medication doses for hepatic or renal dysfunction effects of interventions for such disorders on the patients
[I]. In other respects, treatment for depression should par- psychiatric condition [I].
allel that used in younger age groups [I]. In patients with preexisting hypertension or cardiac
The assessment and treatment of major depressive dis- conditions, treatment with specific antidepressant agents
order should consider the impact of language barriers, as may suggest a need for monitoring of vital signs or car-
well as cultural variables that may influence symptom pre- diac rhythm (e.g., electrocardiogram [ECG] with TCA
sentation, treatment preferences, and the degree to which treatment; heart rate and blood pressure assessment with
psychiatric illness is stigmatized [I]. When antidepres- SNRIs and TCAs) [I]. When using antidepressant medi-
sants are prescribed, the psychiatrist should recognize cations with anticholinergic side effects, it is important
that ethnic groups may differ in their metabolism and re- to consider the potential for increases in heart rate in in-
sponse to medications [II]. dividuals with cardiac disease, worsening cognition in indi-
20 APA PRACTICE GUIDELINES
viduals with dementia, development of bladder outlet sion, particularly those who present with daytime sleepi-
obstruction in men with prostatic hypertrophy, and precip- ness, fatigue, or treatment-resistant symptoms [II]. In pa-
itation or worsening of narrow angle glaucoma [I]. Some tients with known sleep apnea, treatment choice should
antidepressant drugs (e.g., bupropion, clomipramine, consider the sedative side effects of medication, with mini-
maprotiline) reduce the seizure threshold and should be mally sedating options chosen whenever possible [I]. Given
used with caution in individuals with preexisting seizure dis- the significant numbers of individuals with unrecognized
orders [II]. In individuals with Parkinsons disease, the human immunodeficiency virus (HIV) infection and the
choice of an antidepressant should consider that seroton- availability of effective treatment, consideration should be
ergic agents may worsen symptoms of the disease [II], given to HIV risk assessment and screening [I]. For pa-
that bupropion has potential dopamine agonist effects tients with HIV infection who are receiving antiretroviral
(benefitting symptoms of Parkinsons disease but poten- therapy, the potential for drug-drug interactions needs to be
tially worsening psychosis) [II], and that selegiline has an- assessed before initiating any psychotropic medications [I].
tiparkinsonian and antidepressant effects but may interact Patients who are being treated with antiretroviral medi-
with L-dopa and with other antidepressant agents [I]. In cations should be cautioned about drug-drug interactions
treating the depressive syndrome that commonly occurs with St. Johns wort that can reduce the effectiveness of
following a stroke, consideration should be given to the HIV treatments [I]. In patients with hepatitis C infection,
potential for interactions between antidepressants and interferon can exacerbate depressive symptoms, making
anticoagulating (including antiplatelet) medications [I]. it important to monitor patients carefully for worsening
Given the health risks associated with obesity and the ten- depressive symptoms during the course of interferon
dency of some antidepressant medications to contribute to treatment [I]. Because tamoxifen requires active 2D6 en-
weight gain, longitudinal monitoring of weight (either by zyme function to be clinically efficacious, patients who
direct measurement or patient report) is recommended receive tamoxifen for breast cancer or other indications
[I], as well as calculation of body mass index (BMI) [II]. If should generally be treated with an antidepressant (e.g.,
significant increases are noted in the patients weight or citalopram, escitalopram, venlafaxine, desvenlafaxine)
BMI, the clinician and patient should discuss potential ap- that has minimal effect on metabolism through the cyto-
proaches to weight control such as diet, exercise, change in chrome P450 2D6 isoenzyme [I]. When depression oc-
medication, nutrition consultation, or collaboration with curs in the context of chronic pain, SNRIs and TCAs may
the patients primary care physician [I]. In patients who be preferable to other antidepressive agents [II]. When
have undergone bariatric surgery to treat obesity, adjust- ECT is used to treat major depressive disorder in an in-
ment of medication formulations or doses may be re- dividual with a co-occurring general medical condition,
quired because of altered medication absorption [I]. For the evaluation should identify conditions that could re-
diabetic patients, it is useful to collaborate with the pa- quire modifications in ECT technique (e.g., cardiac con-
tients primary care physician in monitoring diabetic con- ditions, hypertension, central nervous system lesions) [I];
trol when initiating antidepressant therapy or making these should be addressed insofar as possible and dis-
significant dosing adjustments [II]. Clinicians should be cussed with the patient as part of the informed consent
alert to the possibility of sleep apnea in patients with depres- process [I].
1. Establish and maintain a therapeutic alliance whether a diagnosis of major depressive disorder is war-
A psychiatric assessment begins with establishing thera- ranted and to identify the presence of other psychiatric or
peutic rapport and developing an alliance with the patient, general medical conditions. The general principles and
regardless of the treatment modalities ultimately selected. components of a complete psychiatric evaluation have been
The alliance itself may be the primary active therapeutic outlined in APAs Practice Guideline for Psychiatric Evalua-
agent even for patients who receive monotherapy with tion of Adults, Second Edition (8). The evaluation includes a
medication (4). To establish and maintain a therapeutic al- history of the present illness and current symptoms, in-
liance, it is important for the psychiatrist to be sensitive to cluding vegetative symptoms and symptoms of mania or
the patients concerns. By virtue of their depressed state, psychosis, as well as a psychiatric history that particularly
patients often view themselves in a negative light. They notes current treatments, responses to previous treat-
may feel unworthy of help, embarrassed or ashamed of ments, past hospitalizations or suicide attempts, and the
having an illness, guilty about placing burdens on family presence of co-occurring psychiatric disorders. Assessing
members or the clinician, and distant or alienated from the severity of the specific symptoms of depression may
others. Individuals may also have a negative view of prior be aided by the use of standardized clinician- or patient-
treatment experiences or have misconceptions about psy- administered rating scales such as those described in Sec-
chiatric treatment, which can color the therapeutic rela- tion II.A.8.
tionship. Such issues require open discussion to educate Many individuals with depression attempt to alleviate
the patient about the goals and framework of treatment symptoms through the use of alternative or complemen-
and to provide an empathic and trusting environment in tary treatments, over-the-counter or prescription medica-
which the patient feels comfortable expressing his or her tions or dietary regimens, or through use of caffeine,
self-doubts, fears, and other concerns. Cultural and reli- tobacco, alcohol, or other substances, which may precip-
gious factors may influence the patients view of the depres- itate or exacerbate depressive symptoms. Consequently,
sive illness, his or her receptiveness to psychiatric treatment, each of these factors should be carefully assessed. The per-
and his or her preference of treatment modalities (57). sonal history will include an assessment of psychological
Establishing a therapeutic alliance with a clinician of a dif- development; a sexual history, including history of sexual
ferent background may present additional challenges for abuse or assault; identification of early life trauma, includ-
some patients. Management of the therapeutic alliance ing physical, sexual, or emotional abuse or neglect; deter-
should also include awareness of transference and counter- mination of responses to life transitions, major life events,
transference issues, even if these are not directly addressed or significant traumas; a social history; and an occupational
in treatment. history, including history of military service. Co-occur-
Because patients frequently have strong preferences ring general medical conditions are common and can in-
about treatment options, the psychiatrist should identify fluence the diagnosis of major depressive disorder as well
the patients wishes for treatment and collaborate with the as choices of treatment. Thus, a general medical history is
patient in choosing among effective treatments. In addi- essential, along with a review of the patients current med-
tion, treatment adherence can be enhanced by the delivery ications; a review of systems, including assessment for
of patient-centered care and by a strong treatment alli- pain; and any indicated diagnostic tests or physical exam-
ance with the psychiatrist. Severe or persistent problems inations. The latter may be done by the psychiatrist or by
of poor alliance or nonadherence to treatment may be another physician or medically trained clinician. A mental
caused by the depressive symptoms themselves. They may status examination is crucial in identifying signs of depres-
also represent psychological conflicts or a psychopatho- sion, associated psychosis, cognitive deficits, and factors
logical condition for which psychotherapy should be con- influencing suicide risk (e.g., suicidal ideas, anxiety), as
sidered. well as in identifying co-occurring psychiatric disorders.
If possible and appropriate, the family should be in- Because major depressive disorder is associated with func-
cluded in discussions about the patients illness and plans tional impairment, the presence, type, and severity of the
for treatment. When family members are involved, they dysfunction should be evaluated. Impairments can include
can also be encouraged to play a helpful role in improving deficits in interpersonal relationships and family func-
the patients adherence to treatment and supporting the tioning, work performance, maintenance of health and
therapeutic alliance. hygiene, and deficits in quality of life. Whenever feasible,
assessment should also include input from family members
2. Complete the psychiatric assessment in order to determine the impact of the patients condition
Patients with symptoms of depression should receive a on his or her family. Family members and significant oth-
thorough biopsychosocial assessment, both to determine ers can also report key elements of the patients history or
22 APA PRACTICE GUIDELINES
recent status that the patient may minimize or be unable unless depressive symptoms are still present 2 months
to recall or report accurately. In addition, family function- after the loss, are particularly severe, or are uncharacter-
ing may affect the outcome of the patients depressive ill- istic of or unrelated to bereavement, such as persistent
ness (9, 10). suicidal ideation or morbid preoccupation with worthless-
A family history is also important to obtain and in- ness or guilt (16). Following a stressor, depressive symp-
volves the collection of the family pedigree including par- toms that do not reach sufficient number or severity to be
ents, grandparents, and number and sex of siblings and classified as a major depressive episode may be better de-
children. For patients with children at home, information scribed as an adjustment disorder. Despite the possible
on their symptom state may be useful because of the high presence of antecedent stressors, psychiatrists should not
possibility of psychiatric problems in the offspring of a de- dismiss potentially disabling depressive symptoms as nor-
pressed parent (11, 12). Such problems may require inter- mal, thereby depriving patients of needed therapeutic at-
vention or may be an added stressor for the patient. The tention.
family history includes history of depression or other mood A thorough assessment of depression also includes the
disorders, substance use disorders, psychosis, suicide, and evaluation of psychotic symptoms. Major depressive dis-
unusual behaviors in the patients relatives along with any order may be associated with mood-congruent and mood-
associated impairments. Because family history is a potent incongruent hallucinations and delusions. Depressed pa-
and consistent risk factor for mental disorders, formulat- tients may not initially present with psychotic symptoms,
ing diagnosis and treatment decisions for the patient can and patients may wish to hide shaming or distressing
be aided by knowing the age of onset and severity of psy- thoughts. Therefore, psychiatrists should carefully query
chiatric symptoms in the patients family, as well as relatives patients about such symptoms in order to provide appro-
psychiatric treatment history, especially the tolerability priate treatments for them (see Section III.A.2.a). Identify-
and effectiveness of those treatments. ing the presence of atypical, melancholic, or catatonic
In establishing a diagnosis of major depressive disorder features of depression is also important, as such features
as part of the initial assessment, other differential diag- may influence the choice of treatments (see Sections
nostic possibilities are important to consider. An initial III.A.2.b, III.A.2.c, and III.A.2.d). Considering that major
consideration in the differential diagnosis is mood disorder depressive episodes are common in the course of bipolar I
due to a general medical condition. Specific medical condi- disorder and that recurrent major depressive episodes are
tions that are important to consider and that may be associ- characteristic of bipolar II disorder (17), it is important to
ated with a major depressive episode include neurological consider bipolar disorders as part of the differential diagno-
conditions (e.g., stroke, Parkinsons disease, dementia, sis of major depressive disorder. This distinction is especially
multiple sclerosis), thyroid disorders, metabolic conditions important because the treatments for bipolar disorders of-
(e.g., hypercalcemia), malignancy, and infectious diseases ten differ from those for major depressive disorder.
(1315). Depressive symptoms that would otherwise be All patients who present for treatment for a major de-
diagnosable as major depressive disorder are diagnosed pressive episode should be screened for a past history of
instead as a mood disorder due to a general medical con- manic or hypomanic episodes and for past adverse reac-
dition if the mood disturbance is judged to be the direct tions to antidepressants that might be consistent with a
physiological consequence of a specific general medical con- switch into hypomania or mania. Screening instruments
dition. Similarly, medications used to treat general medical for manic and hypomanic episodes include the Mood Dis-
conditions may induce depressive syndromes. Such medi- orders Questionnaire (18) and the Screening Assessment
cations include transplant anti-rejection agents, chemo- of DepressionPolarity, which includes three easily ad-
therapy agents, interferon, steroids, some antibiotics, and ministered dichotomous questions (19). However, since
others. Depression caused by medications is classified in patients are often unaware of prior hypomanic or manic
the DSM-IV-TR as other (or unknown) substance- episodes, even when questioned carefully, collateral
induced mood disorder (DSM-IV-TR code 292.84) (16). sources of information, such as family members living
Psychosocial stressors and other antecedent events, with the patient, may be crucial in uncovering such epi-
and their possible contribution to the generation of de- sodes. Clinical assessment should also include whether or
pressive symptoms, should be explored in the course of a not the patient is experiencing a mixed episode, which is
psychiatric assessment. Depressive symptoms are a com- characterized by symptoms of both a major depressive ep-
mon response to psychosocial stressors, particularly be- isode and a manic episode that occur nearly every day for
reavement. Symptoms characteristic of a major depressive at least 1 week.
episode may arise after a significant loss; however, the di- It is also important to consider the frequency and chro-
agnosis of major depressive disorder is generally not given nicity of prior episodes of major depressive disorder.
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 23
Chronic forms of depressionsuch as dysthymic disorder, TABLE 1. Factors to Consider in Assessing Suicide Risk
double depression (dysthymic disorder and major de-
Lifetime history, nature, seriousness, and number of
pressive disorder), and major depressive disorder with the
previous attempts and aborted attempts
chronic specifierare all depressions with a duration of
Presence, history, and lethality of suicidal ideation,
at least 2 years. In clinical studies, chronic depression has a
intent, or plans
lower response rate than nonchronic depression, but be-
cause the placebo-response rate is also lower, the relative Access to means for suicide and the lethality of those
clinical benefit is comparable. The onset of benefit in means, such as access to a firearm
chronic depression appears more gradual than in nonchro- Presence of hopelessness, psychic pain, decreased
nic depression. However, despite a smaller response rate self-esteem, narcissistic vulnerability
and slower response, it is important to recognize that Presence of severe anxiety, panic attacks, agitation,
chronic depression is not treatment refractory (20). Un- impulsivity
fortunately, however, in many patients, chronic depression Presence and history of aggression and violence
remains undiagnosed or, if diagnosed, undertreated (21). Nature of cognition, such as loss of executive function,
The presence of a family history of a mood disorder thought constriction (tunnel vision), polarized
should also be determined. Family histories of major de- thinking, closed-mindedness, poor coping and
pressive disorder and bipolar disorder are common in problem-solving skills
those with major depressive disorder, but a family history
Presence of psychotic symptoms, such as command
of bipolar disorder may indicate increased risk of bipolar
hallucinations or poor reality testing
disorder in the patient. A family history of suicide is rele-
vant in determining a patients suicide risk (22) and may Presence of alcohol or other substance use
also signal the presence of an unrecognized mood disor- Presence of major psychiatric disorders, such as major
der in a relative. depressive disorder, bipolar disorder, schizophrenia,
anorexia nervosa, alcohol use disorder, other substance
use disorders, cluster B personality disorders
3. Evaluate the safety of the patient
Recent psychiatric hospitalization
Addressing safety concerns may take precedence over es-
tablishing a full differential diagnosis or completing the Presence of disabling medical illness, especially with
psychiatric assessment. Because of the increased rates of poor prognosis, such as chronic pain, brain and spinal
suicide in depressed patients (2224), a thorough and on- cord injury, malignant neoplasm, HIV or acquired
going evaluation of the patients suicide risk is essential. immunodeficiency syndrome (AIDS), Huntingtons
Some components of an evaluation for suicidal risk are disease, chronic hemodialysis-treated renal failure,
summarized in Table 1. The psychiatrist should evaluate chronic obstructive pulmonary disease
the presence of suicidal ideation and behaviors, the extent Demographic features, such as age, race, marital status,
to which the patient has made plans for or begun to prepare sexual orientation
for suicide, the availability and lethality of the means for Presence of acute or chronic psychosocial stressors, which
suicide, and the degree to which the patient intends to act may include actual or perceived interpersonal losses,
on suicidal plans. A complete assessment also includes clin- financial difficulties or changes in socioeconomic status,
ical factors that may increase the likelihood of a patients family discord, domestic partner violence, and past or
acting on suicidal ideation, including a history of prior sui- current sexual or physical abuse or neglect
cide attempts and the presence of psychotic symptoms, se- Absence of psychosocial support, such as poor
vere anxiety, panic attacks, impulsivity, and substance use. relationships with family, unemployment, living alone,
Patients should also be asked about a family history of sui- unstable or poor therapeutic relationship, recent loss
cide and recent exposure to suicide or suicide attempts by of a relationship
others. A suicide risk assessment should be individualized History of childhood traumas, particularly sexual and
to the particular circumstances of the patient by including physical abuse
an evaluation of the patients strengths, motivation to seek
Family history of or recent exposure to suicide
help, social support systems, and physical health.
Absence of protective factors, such as children in the
Despite the best efforts of the psychiatrist, some pa-
home, sense of responsibility to family, pregnancy,
tients may engage in self-harm (22). Even with careful as-
life satisfaction, cultural beliefs, or religiosity
sessments of suicide risk, the ability to predict suicidal
behavior is poor, with many false positives (i.e., patients Source: Adapted from APAs Practice Guideline for the Assessment
who appear more likely to make attempts or die by suicide and Treatment of Patients With Suicidal Behaviors (22).
24 APA PRACTICE GUIDELINES
but who do not) as well as false negatives (i.e., patients self and to others is another significant determinant of
who appear less likely to make attempts or die by suicide treatment setting. Decisions about treatment setting
but who do). The assessment of suicide risk is complicated should also include consideration of the patients ability to
by the fact that suicidal individuals often conceal their adequately care for him- or herself, provide reliable feed-
thoughts and plans or act impulsively on short-lived sui- back to the psychiatrist, and cooperate with treatment of
cidal thoughts, making their response to direct questions the major depressive disorder.
an unreliable predictor of dangerousness to self. For this Patients with suicidal or homicidal ideation, intention,
reason, in addition to using direct questioning, the psychi- or plans require close monitoring. For those at significant
atrist should also obtain information through observation risk, measures such as hospitalization should be consid-
and collateral history whenever possible (22, 25). ered; hospitalization is usually indicated for patients who
The risk of suicide should also be monitored as treat- are considered to pose a serious threat of harm to them-
ment proceeds, since variations in depressive symptoms selves or others. Patients who refuse can be hospitalized
may be associated with fluctuations in suicide risk. In involuntarily if their condition meets the criteria of the lo-
youth and young adults, increases in suicidal thoughts and cal jurisdiction for involuntary admission. Severely ill pa-
attempts have been reported early in the course of treat- tients who lack or reject adequate social support outside of
ment with antidepressants, although no increases in mor- a hospital setting should be considered for admission to a
tality rates were seen in clinical trials (26). Family members hospital or intensive day program, if available. In addition,
can provide information that increases the likelihood of patients who also have complicating psychiatric or general
early detection of harmful behaviors. It is also useful to medical conditions or who have not responded adequately
convey the expectation that family members will call the to outpatient treatment may need to be hospitalized.
psychiatrist if concerns for safety emerge (27). For informa- The optimal treatment setting and the patients like-
tion about how suicidal ideation or behaviors affect the treat- lihood of benefit from a different level of care should be
ment plan, see Section III.A.1.a. reevaluated on an ongoing basis throughout the course of
Although the greatest risk surrounding depression in- treatment. Unfortunately, the spectrum of treatment set-
volves the patients health, a rare but also potentially di- tings available to patients is often limited by lack of avail-
sastrous outcome of depression is violence toward others, ability of options in the geographic setting, lack of ability
including homicide (28, 29). Psychosis, substance abuse, to pay for care, and/or limitations imposed by third party
impulsivity, and a history of aggression increase this risk payers.
(3032). Psychiatrists accordingly should assess not only
suicidal risk but also history of violence, homicidal ide- 5. Evaluate functional impairment and quality of life
ation, and plans of violence toward others. Additional as- The assessment of a patient with major depressive disorder
sessment may be necessary under specific circumstances. includes a determination of the severity and chronicity of
For example, it is important to assess the impact of pa- symptoms. Even mild depression can impair function and
rental depression (including peripartum depression) on threaten life and the quality of life. In the extreme, de-
children in the home, with specific attention given to the pressed people may be totally unable to function socially
parents vulnerability to neglect or harm the children (33). or occupationally or even to feed and clothe themselves
Whenever suicidal or violent ideas are expressed or sus- and maintain minimal personal hygiene. Severely depressed
pected, careful documentation of the decision-making pro- patients may be immobilized to the point of being bedrid-
cess is essential. In addition, patients who exhibit suicidal den, with associated medical complications.
or violent ideas or intent require close monitoring. The psychiatrist should address impairments in func-
tioning and help the patient to set specific goals appropriate
4. Establish the appropriate setting for treatment to his or her functional impairments and symptom severity.
Treatment settings for patients with major depressive dis- This will likely involve helping the patient to establish in-
order include a continuum of possible levels of care, from termediate, pragmatic steps in the course of recovery. For
involuntary hospitalizations to partial hospital programs, example, the psychiatrist may help patients who are having
skilled nursing homes, and in-home care. In general, pa- difficulty meeting commitments to develop a reasonable
tients should be treated in the least restrictive setting that plan to fulfill their obligations (e.g., work, family obliga-
is most likely to prove safe and effective. The psychiatrist tions), potentially by making alternative arrangements.
should choose an appropriate site of treatment after eval- The psychiatrist may advise other patients not to make ma-
uating the patients clinical condition, including symptom jor life changes while in the midst of a major depressive
severity, co-occurring conditions, level of functioning, and episode. Impairments in the patients overall quality of life
available support system. The estimated degree of risk to should also be assessed, which can be done by asking pa-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 25
tients what bothers them the most about their depression ordination of the overall treatment plan is essential and is
and determining how their current activities and enjoy- enhanced by clear role definitions, plans for the manage-
ment of life have been altered by their depressive symp- ment of crises or relapses, and regular communication
toms. The overall goals of treatment of major depressive among the clinicians who are involved in the treatment.
disorder should focus on alleviating functional impair- Psychiatrists may at times serve as consultants to ongo-
ments and improving quality of life in addition to achieving ing treatment of depression by other prescribers. Health
symptom resolution and episode remission. care professionals other than psychiatrists may prescribe
antidepressant medication for their patients for a variety of
6. Coordinate the patients care with other clinicians reasons, including convenience, financial reasons, stigma,
The psychiatrist should assure that a comprehensive assess- and access to care issues (37). Primary care doctors, obste-
ment of general medical conditions is performed in order tricians, and physicians of other disciplines may screen for
to identify factors that may precipitate or exacerbate de- depression and initiate treatment for patients. In fact, at
pressive symptoms. He or she may initiate the medical least one-fourth of patients presenting to primary care set-
evaluations or coordinate care with other appropriate clini- tings may have major depressive disorder, and 70%80%
cians. In some situations, review of medical records provided of antidepressants are prescribed by a primary care physician
by the patient will suffice. In other situations, particularly or medical subspecialist (38, 39). Regardless of whether the
when medical treatment is indicated, the psychiatrist should, psychiatrist is acting as a consultant or transferring ongo-
with the patients permission, arrange for collaborative care ing care to another clinician (e.g., with transition from an
with other clinicians. Such collaboration may incorporate inpatient to outpatient setting), communication and coor-
discussion of prescribed medication, including dose changes dination of treatment are essential. Optimal communi-
and possible drug interactions as well as necessary diagnos- cation with other health care professionals can improve
tic procedures and medical monitoring, which may include overall treatment by assuring that medical conditions and
laboratory measures and ECG (34). psychosocial issues are appropriately addressed. Good com-
In treating the patients depressive illness, a multifaceted munication also decreases the risk that patients will receive
approach is typically required that may include provision inconsistent information about treatment options and risks
of depression-focused psychotherapy, pharmacotherapy, and benefits. Furthermore, communication among clini-
ECT, or other therapeutic approaches. Under some cir- cians improves vigilance against relapse, side effects, and risk
cumstances, all aspects of treatment will be administered to self or others.
by one psychiatrist, and this model of care may improve
integration of treatment components (35) or reduce over- 7. Monitor the patients psychiatric status
all treatment cost (36). In other situations, treatment may As treatment progresses, different features and symptoms
require the coordinated effort of several clinicians. This of the patients illness may emerge or subside. The psychi-
decision is frequently influenced by the clinicians ex- atrist should carefully and systematically monitor changes
pertise in providing the indicated therapeutic modality, in the patients psychiatric status, including major depres-
economic factors, availability of treatment, and by the pa- sive disorder symptoms, as well as symptoms of other po-
tients preferences. When this treatment model is used, tential co-occurring conditions (Table 2). Monitoring the
one team member must assume the primary overall re- patients status for the emergence of or changes in destruc-
sponsibility for the patients care. This individual serves as tive impulses toward self or others is especially crucial; ad-
the coordinator of the treatment plan, advocates for the ditional measures such as hospitalization or more intensive
appropriate level of care, oversees the family involvement, treatment should be considered for patients found to be at
makes decisions regarding which potential treatment mo- higher risk. In addition, the patient should be monitored
dalities are useful and which should be discontinued, helps for treatment-emergent side effects, some of which may be
assess the effects of medications, and monitors the pa- difficult to distinguish from symptoms of the underlying
tients safety. Because of the diversity and depth of medical depressive disorder or co-occurring medical conditions.
knowledge and expertise required for this oversight func- Significant changes in a patients psychiatric status or the
tion, a psychiatrist is generally optimal for this role, al- emergence of new symptoms may warrant a diagnostic re-
though this staffing pattern may not be possible in some evaluation of the patient. For example, patients who note
health care settings. If the treatment is split, the psychia- worsening irritability, increased difficulty sleeping, racing
trist who is providing the psychiatric management and the thoughts, growing impulsivity, euphoria, or rapid shifts in
medication treatment should meet with the patient fre- mood should be monitored more closely and may warrant
quently enough to monitor his or her care. Ongoing co- re-evaluation and consideration of a possible bipolar dis-
26 APA PRACTICE GUIDELINES
order diagnosis. Often family members or caregivers notice TABLE 2. Items to Monitor Throughout Treatment
changes in the status of the patient first and are therefore
Symptomatic status, including functional status, and
able to provide valuable input to the psychiatrist.
quality of life
Degree of danger to self and others
8. Integrate measurements into psychiatric management
Signs of switch to mania
The integration of measurement tools into psychiatric man-
agement, which has been referred to as measurement-based Other mental disorders, including alcohol and other
care, may enhance the quality of care and improve clinical substance use disorders
outcomes (40). Clinician-rated and/or self-rated scales can General medical conditions
help determine the trajectory of disease course and effects Response to treatment
of treatment. Many such scales are available in several ver- Side effects of treatment
sions that vary by number of items. Self-rated scales are con- Adherence to treatment plan
venient to use but require review, interpretation, and discus-
sion with the patient. In research studies, commonly used
tools include the Inventory of Depressive Symptoms (IDS), Although the use of rating scales is not yet common
which is available in clinician-rated and self-rated versions practice in clinical settings, in part due to pragmatic con-
(http://www.ids-qids.org/), the clinician-rated Hamilton cerns (51), the use of such scales can be valuable in mon-
Rating Scale for Depression (HAM-D) (http://healthnet. itoring symptoms and treatment progress. In addition,
umassmed.edu/mhealth/HAMD.pdf) (41, 42), the clinician- electronic monitoring is becoming more feasible, as elec-
rated Montgomery Asberg Depression Rating Scale tronic health records are more commonly utilized and
(MADRS) (http://www.cnsforum.com/streamfile.aspx?file patients and psychiatrists have increased access to techno-
name=MADRS.pdfandpath=pdf) (43), and the self-rated 9- logical tools that can help monitor and record symptoms.
item Patient Health Questionnaire (PHQ-9) (http://www. Baseline data and information about treatment-emergent
depression-primarycare.org/clinicians/toolkits/materials/ changes can be collected systematically from the patient
forms/phq9/) (44, 45). The Beck Depression Inventory and electronically transmitted via telephone or the Inter-
(BDI, BDI-II) is another commonly used, copyrighted, 21- net. In addition to providing secure electronic capture of
question multiple-choice self-rated instrument (46). patient data, computerized decision support systems can
Systematic measurement of side effects can also assist in be useful in implementing evidence-based treatment for
the provision of treatment. Several self-report rating scales major depressive disorder (52).
have been developed for assessing side effects of antidepres-
sant treatment and are available in English and Spanish ver- 9. Enhance treatment adherence
sions (http://www.edc.pitt.edu/stard/public/ assessment_ For treatment to be successful, it is essential to support the
forms.html). The Frequency, Intensity, and Burden of Side patients adherence to all details of the regimen by provid-
Effects Rating Scale (FIBSER), which has also been re- ing education about the illness and its treatment, maintain-
ferred to as the Frequency and Intensity of Side Effects ing a strong therapeutic alliance, mobilizing family and
Rating/Global Rating of Side Effect Burden, uses three other supports (including eliciting questions and clarifying
global Likert scale ratings to assess side effects experienced common misconceptions), evaluating factors affecting ad-
over the preceding week (47, 48). The Patient Rated Inven- herence, and addressing barriers to adherence as they arise.
tory of Side Effects (PRISE) is a 9-item scale that asks pa- Major depressive disorder is often a chronic or recurrent
tients about the presence of side effects in eight organ system condition that requires patients to participate actively in
domains, as well as about other side effects (47, 48). A cli- and adhere to treatment plans for long periods, despite the
nician-administered scale, the Toronto Side Effects Scale, fact that side effects or requirements of treatments may be
that focuses on antidepressant medication side effects is burdensome. Patients may have strong preferences for mo-
also available (http://ww1.cpa-apc.org:8080/publications/ dality of treatment or medication choice, particularly if
archives/cjp/2002/march/orAntidepressantsAppendix.asp) they or a family member have had past experience with the
(49). The Udvalg for Kliniske Undersgelser (UKU) side treatment or medication. When feasible, factoring in these
effect rating scale (50) (available at http:/ /www.cnsforum. preferences may improve adherence to treatment. During
com/streamfile.aspx?filename=UKU. pdfandpath=pdf) is the acute phase, patients with major depressive disorder
often used in research studies and may offer clinicians ad- may be poorly motivated, unduly pessimistic about their
ditional questions that could be asked about side effects, chances of recovery with treatment, suffering from deficits
but it is likely to be too detailed for routine clinical use. in memory, or poorly caring for themselves. During the
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 27
maintenance phase, euthymic patients may undervalue the (http://www.helpingpatients.org), and from Rx Assist
benefits of and focus on the burdens of treatment. The psy- (http://www.rxassist.org).
chiatrist should recognize these possibilities, emphasize the
importance of adherence for successful treatment and pro- 10. Provide education to the patient and the family
phylaxis, and encourage the patient to articulate any con- Education concerning major depressive disorder and its
cerns regarding adherence (e.g., side effects, costs of treat- treatments should be provided to all patients. Education is
ment, scheduling conflicts, lack of transportation or child an essential element of obtaining informed consent to
care). Patient and family attitudes about depression and its treatment. Whenever possible, education should also be
treatment can also influence adherence. Family members provided to involved family members and significant oth-
can play an important role in promoting optimism about ers, although generally the patients consent is required
treatment, assisting patients with adherence and providing before such information can be shared. Specific topics to
the psychiatrist with input on side effects or other treat- discuss may include that major depressive disorder is a
ment-related concerns that may influence adherence. medical illness and that effective treatments are both nec-
Some aspects of adherence will vary with the type of essary and available. This information may be especially
treatment being used. For example, patients in psychother- important for patients who attribute their illness to a
apy may experience increased anxiety as they confront fear- moral defect, or for family members who are convinced
ful or difficult topics. This anxiety, in turn, may decrease that there is nothing wrong with the patient. Education
adherence to psychotherapy, and patients may begin to ar- regarding available treatment options will help patients
rive late to or miss therapy sessions. In patients who are make informed decisions, anticipate side effects, and ad-
beginning treatment with a medication, common side ef- here to treatments. Patients with depression can become
fects of medication options should be discussed. Patients easily discouraged in treatment, especially if there is less
should be involved in treatment decisions and encouraged than a full initial response. The psychiatrist should en-
to convey input on side effects that they consider reason- courage and educate patients to distinguish between the
able or unbearable. Side effects such as weight gain, cog- hopelessness that is a symptom of depression and the rel-
nitive dulling, sexual side effects, sedation or fatigue, and atively hopeful actual prognosis. In addition, for patients
agitation may represent different burdens to different in- treated with antidepressant medication or ECT, psychia-
dividuals. Emphasizing the following specific topics im- trists may choose to discuss a predictable progression of
proves adherence: 1) explaining when and how often to treatment effects: first, side effects may emerge, then neu-
take the medicine; 2) suggesting reminder systems, such rovegetative symptoms remit, and finally mood improves.
as pill boxes, alarms, etc.; 3) discussing the need to take Often significant others notice symptomatic improve-
medication for at least 24 weeks before beneficial effects ment before the patient does.
may be noticed; 4) emphasizing the need to take medica- Given the chronic, episodic nature of major depressive
tion even after feeling better; 5) reviewing the need to disorder, exacerbations are common. Patients, as well as
consult with the psychiatrist before discontinuing medi- their families, if appropriate, should be instructed about
cation; 6) giving the patient an opportunity to express his the significant risk of relapse. They should be educated
or her understanding of the medication, hearing his or her to identify early signs and symptoms of new episodes and
concerns, and correcting any misconceptions, and 7) ex- the stressors that may precede them. Patients should also
plaining what to do if problems or questions arise (53). be instructed to seek adequate treatment as early in the
Behavioral tailoring, which involves developing an indi- course of the new episode as possible to decrease the like-
vidualized approach to incorporating medication into the lihood of a full-blown exacerbation or complications.
daily routine and can also include simplifying the medica- Patient and family education also includes general pro-
tion regimen, has demonstrated efficacy for individuals motion of healthy behaviors such as good sleep hygiene
with schizophrenia and may also be applicable to individuals and decreased use of caffeine, tobacco, alcohol, and other
with other psychiatric illnesses (54). Adherence may also potentially deleterious substances. For most individuals,
be improved by minimizing the cost and complexity of exercise carries benefits for overall health. Data generally
medication regimens. Most antidepressant medications support at least a modest improvement in mood symp-
are available in generic forms, which are generally less toms for patients with major depressive disorder who en-
costly. For individuals who cannot afford needed medi- gage in aerobic exercise (5561) or resistance training
cations, some pharmaceutical companies offer patient as- (62, 63). Regular exercise may also reduce the prevalence
sistance programs. Information on such programs is of depressive symptoms in the general population, with
available from pharmaceutical company Web sites, from specific benefit found in older adults (64, 65) and individ-
the Web site of the Partnership for Prescription Assistance uals with co-occurring medical problems (57, 66).
28 APA PRACTICE GUIDELINES
Modality
Pharmacotherapy in
Combination With
Depression-Focused Depression-Focused Electroconvulsive
Severity of Illness Pharmacotherapy Psychotherapy Psychotherapy Therapy
Mild to Moderate Yes Yes May be useful for Yes, for certain
patients with psycho- patients
social or interpersonal
problems, intrapsy-
chic conflict, or
co-occurring Axis II
disorder
Severe Without Yes No Yes Yes
Psychotic Features
Severe With Yes, provide both No Yes, provide both Yes
Psychotic Features antidepressant and antidepressant and
antipsychotic antipsychotic
medication medication
FIGURE 1. Recommended Modalities for Acute Phase Treatment of Major Depressive Disorder
a
TABLE 4. Cytochrome P450 Enzyme Metabolism of Antidepressive Agents
1A2 2B6 2C9 2C19 2D6 3A4
Amitriptyline + + ++ ++ ++ +
Bupropion + ++ + +
b
Hydroxybupropion ++
Citalopram ++ + ++
Desipramine + ++
Desvenlafaxine +
Duloxetine ++ ++
Escitalopram ++ + +
Fluoxetine + + ++ + ++ +
b
Norfluoxetine +++
Imipramine ++ + ++ ++ ++
Maprotiline + ++
Mirtazapine ++ + ++ +
b
8-Hydroxymirtazapine ++ ++
Mirtazapine-N-oxideb ++
Nortriptyline + + ++ +
Paroxetine ++
Protriptyline ++
Selegiline + ++ + +
Sertraline ++ + ++ + +
Venlafaxine + + ++ +
b
O-Norvenlafaxine ++
Sources: (82, 83). The extent to which each medication is a substrate for a specific enzyme is indicated as follows: +++ = exclusive sub-
strate, ++ = major substrate, + = minor substrate.
a
Information about drug metabolism and drug-drug interactions is constantly evolving. The information in this table can serve as a
guide; however, the reader is encouraged to access regularly updated online sources of drug-drug interactions.
b
Active metabolite of parent compound.
In choosing an antidepressant medication, many psy- or purging. In older adults and others with malnutrition,
chiatrists also consider the family history of response to autonomic disorders (e.g., diabetic neuropathy, Parkin-
particular medications; however, the impact of this factor sons disease), or low blood pressure, TCAs may exacer-
on the likelihood of the patients response to these medi- bate hypotension and orthostasis, resulting in syncope or
cations is unclear. Nevertheless, the medication experiences falls. Selective serotonin reuptake inhibitors and SNRIs
of others close to the patient do influence the patients be- may be inappropriate for patients who are experiencing
lief about particular medications and pharmacotherapy in sexual dysfunction. Patients who are receiving tamoxifen
general. for breast cancer or other indications should generally be
The presence of co-occurring psychiatric or general treated with an antidepressant (e.g., citalopram, escitalo-
medical conditions can be a significant factor influencing pram, venlafaxine, desvenlafaxine) that has minimal effect
the choice of an antidepressant medication. For example, on metabolism through the cytochrome P450 2D6 isoen-
TCAs are generally not optimal in patients with cardiovas- zyme, because reduced metabolism of tamoxifen through
cular conditions, cardiac conduction defects, closed angle CYP 2D6 is likely to be associated with lower levels of
glaucoma, urinary retention, significant prostatic hyper- tamoxifens active metabolite (7679) with the possibility of
trophy, or eating disorders with significant malnutrition poorer patient outcomes (80, 81).
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 31
a
TABLE 5. Cytochrome P450 Enzyme Inhibition by Antidepressive Agents
1A2 2A6 2B6 2C8 2C9 2C19 2D6 2E1 3A4
Amitriptyline + + +
Bupropion +++
Citalopram + + + +
b ++ ++ ++ + ++
Desipramine
Desvenlafaxine +
Duloxetine ++
Escitalopram ++
Fluoxetine ++ ++ ++ + ++ +++ +
c
Norfluoxetine + ++ + ++ +
Imipramine + + + +
Mirtazapine + +
d ++ + + ++
Nortriptyline
Paroxetine + +++ + + +++ +
Selegiline + + + + + + +
Sertraline + ++ + + ++ ++ ++
c
Desmethylsertraline + + + +
Venlafaxine + + +
Sources: (82, 83). The extent to which each medication is a substrate for a specific enzyme is indicated as follows: +++ = strong inhib-
itor, ++ = moderate inhibitor, + = weak inhibitor.
a
Information about drug metabolism and drug-drug interactions is constantly evolving. The information in this table can serve as a
guide; however, the reader is encouraged to access regularly updated online sources of drug-drug interactions.
b
Also a metabolite of imipramine. cActive metabolite of parent compound. dAlso a metabolite of amitriptyline.
Because of the need for dietary restrictions and the po- even when anxiety symptoms are considered (85, 8790).
tential for serious side effects and drug interactions, use of Although a few analyses suggest small advantages of
MAOIs is generally limited to patients who do not re- SNRIs over SSRIs in rates of remission (91), a preponder-
spond to other treatments. MAOIs may be particularly ance of the data finds no significant evidence of the supe-
effective for patients with major depressive disorder with riority of any other class or agents over SSRIs (84, 89, 90,
atypical features, although many psychiatrists prefer to 9295). One meta-analysis suggests a slight superiority of
prescribe SSRIs for such patients because of SSRIs greater escitalopram compared with other SSRIs and venlafaxine
safety and tolerability and more favorable adverse effect (93), and another found significantly greater efficacy for
profile. escitalopram, sertraline, venlafaxine, and mirtazapine as
compared with duloxetine, fluoxetine, fluvoxamine, and
a. Efficacy of antidepressant medications paroxetine (96), but other studies show no differences in
1. Selective serotonin reuptake inhibitors efficacy among individual SSRIs (84, 9395, 97, 98).
Selective serotonin reuptake inhibitors currently available
include fluoxetine, sertraline, paroxetine, fluvoxamine, 2. Serotonin norepinephrine reuptake inhibitors
citalopram, and escitalopram. A large body of literature The serotonin norepinephrine reuptake inhibitors currently
supports the superiority of SSRIs compared with placebo available are venlafaxine, desvenlafaxine (the principal
in the treatment of major depressive disorder. In more metabolite of venlafaxine), and duloxetine. An immediate-
than 10 systematic reviews and meta-analyses, the effec- release form of venlafaxine is available, but most clinicians
tiveness of SSRIs has been compared with that of other an- prefer the extended-release formulation because it is ap-
tidepressant medications, mainly TCAs. The SSRIs have proved for once-daily dosing and may be less often asso-
demonstrated comparable efficacy to the TCAs (8488), ciated with reported withdrawal symptoms.
32 APA PRACTICE GUIDELINES
Each of these medications is efficacious (i.e., superior for this indication, reduces desire for nicotine, and dou-
to placebo in controlled studies and meta-analyses) (95, bles rates of smoking cessation (109, 110). Patients typi-
99), and venlafaxine (75150 mg/day) and duloxetine cally experience minimal weight gain or even weight loss
(60 mg/day) showed comparable efficacy in a pair of trials on bupropion (111), and for this reason it may be an ap-
(100). For venlafaxine and perhaps desvenlafaxine, clini- propriate antidepressant for patients who are overweight
cally significant norepinephrine reuptake inhibition may or obese.
not be achieved for the average patient at lower therapeu- Mirtazapine is thought to work through noradrenergic
tic doses, although desvenlafaxine has a much greater and serotonergic mechanisms, although this tetracyclic
bioavailability, resulting in a lower effective dose. In indi- compound is not a reuptake inhibitor (112). Mirtazapine
vidual studies, venlafaxine and duloxetine are generally as has comparable efficacy to SSRIs (113).
effective as SSRIs (see the meta-analyses of Nemeroff et Trazodone is the oldest medication from this group
al. [101] and Thase et al. [102] for tabulated summaries of that is still in wide use. Although trazodone is an effective
individual study results from the more than 40 relevant antidepressant, relative to placebo (105, 114, 115), in con-
randomized controlled trials). Results of comparative temporary practice it is much more likely to be used in
studies of desvenlafaxine are not known at this time. Rel- lower doses as a sedative-hypnotic than as an antidepres-
ative to SSRIs, some analyses of pooled data sets have sug- sant. Despite widespread use of trazodone as a hypnotic,
gested a small advantage for SNRIs (91), which might few data support its use for this indication.
afford clinically modest benefits for patients with more se- Nefazodone has an analogous structure to trazodone but
vere depression (102) or for patients who have not re- somewhat different pharmacological properties. In com-
sponded to prior trials of SSRIs (103). However, other parative trials versus SSRIs, nefazodone showed compa-
meta-analyses have shown equivalent efficacy for SSRIs rable efficacy and overall tolerability (116).
and SNRIs (95), whereas some have shown superiority of
individual medications but no clearcut medication class 4. Tricyclic antidepressants
effects (96). Relative to TCAs, venlafaxines efficacy is Tricyclic antidepressants (amitriptyline, nortriptyline,
comparable (91, 104, 105), whereas the more recently in- protriptyline, imipramine, desipramine, doxepin, and tri-
troduced duloxetine and desvenlafaxine have not been mipramine) are effective treatments for major depressive
systematically compared with TCAs. disorder and have comparable efficacy to other classes of
antidepressants, including SSRIs, SNRIs, and MAOIs
3. Other antidepressant medications (85, 105). The efficacy of subclasses of tricyclics (e.g., sec-
A number of other antidepressant medications differ struc- ondary amines or tertiary amines) appears to be compara-
turally or in their pharmacological action from medications ble. TCAs may be particularly effective in certain
in the categories just described and are included here. populations, such as in hospitalized patients (117, 118).
Although bupropion is classified as a norepinephrine Conventional wisdom is that this advantage is explained
and dopamine reuptake inhibitor, the latter effect is rela- by the superiority of TCAs (versus SSRIs) among the subset
tively weak, and its mechanism of action remains unclear of patients with melancholia or more severe depression,
(106). There are three formulations of bupropion: im- because such a specific advantage has not been consis-
mediate release, sustained release, and extended release. tently documented in studies of less severely ill outpa-
Bupropion is distinct from most antidepressants in not tients (85, 105, 118).
having an indication for the treatment of any primary
anxiety disorder, and it may be less well tolerated than 5. Monoamine oxidase inhibitors
other antidepressants among patients with significant MAOIs currently used as antidepressants include phenel-
anxiety. In addition, a meta-analysis showed that SSRIs zine, tranylcypromine, isocarboxazid, moclobemide, and
were modestly superior to bupropion for a subset of pa- the transdermally delivered formulation of selegiline.
tients with major depressive disorder and anxiety (107). MAOIs have comparable efficacy to other antidepres-
For individuals with low to moderate levels of anxiety, the sants for outpatients with major depressive disorder and
same meta-analysis showed that the efficacy of bupropion may be appropriate for patients with major depressive dis-
in treating major depressive disorder was roughly com- order who have not responded to safer and more easily
parable to that of the SSRIs (107). Results of another used treatments (119, 120). In fact, the role of MAOIs in
meta-analysis suggested that bupropion may be more likely major depressive disorder is now almost exclusively re-
to improve symptoms of fatigue and sleepiness than at served for patients who have not responded to at least sev-
least some of the SSRIs (108). Bupropion may be a good eral other pharmacotherapies. Studies have demonstrated
choice for patients who have a goal of quitting smoking as the effectiveness of MAOIs in patients who have not re-
it has U.S. Food and Drug Administration (FDA) approval sponded to other antidepressant medications, particularly
34 APA PRACTICE GUIDELINES
TCAs (119). However, the effectiveness of MAOIs rela- (e.g., SSRI, SNRI, TCA) and substitute an MAOI, toxic
tive to other strategies for treatment-resistant patients in interactions can best be avoided by allowing at least a 2-week
contemporary practice remains unclear, particularly for washout period between medication trials (Table 8). The
patients who have not responded to multiple sequential long half-life of the SSRI fluoxetine and its metabolites
trials with SSRIs and SNRIs (121). necessitates a 5- to 6-week washout period or longer be-
MAOIs have been shown to be particularly effective in fore the use of an MAOI. Additional information about
treating depressed patients with atypical features, so psy- serotonin syndrome with specific medication classes can
chiatrists should consider using these medications for pa- be found in Sections II.B.2.b.1.g. and II.B.2.b.5.b.
tients with symptoms such as reactive moods, reverse neu- Because knowledge of potential drug-drug interactions
rovegetative symptoms, and sensitivity to rejection (119, is frequently changing, it is useful to consult a frequently
120, 122). There do not appear to be any significant differ- updated drug information database before selecting an
ences in efficacy among the older MAOIs (119), although antidepressant in a patient taking other medications.
there are important individual differences in responsive-
ness, and these medications are not interchangeable. 1. Selective serotonin reuptake inhibitors
There are no comparative studies of the newer transder- SSRIs have comparable tolerability overall, but the spe-
mal (skin patch) formulation of selegiline; its efficacy has cific medications differ somewhat in their side effect pro-
only been established relative to placebo (123125), and files, which may guide selection of an agent for an
clinical experience is limited. individual patient. Pharmacokinetic issues, including half-
life and effect on the CYP-450 enzyme system, are addi-
b. Side effects of antidepressant medications tional considerations in the choice of an SSRI.
The severity of side effects from antidepressant medica-
tions in clinical trials has been assessed both through the a. Gastrointestinal
frequency of reported side effects and through the fre- SSRIs commonly cause nausea, vomiting, and diarrhea
quency of treatment dropout. The likelihood of different (98). These adverse events are generally dose dependent
side effects varies among classes of antidepressant medi- and tend to dissipate over the first few weeks of treatment.
cations, among subclasses, and among individual agents. In some patients, however, diarrhea persists.
In addition, most newer antidepressants are better toler- b. Activation/insomnia
ated than TCAs (8488, 97, 117, 126) and safer in over- SSRIs sometimes precipitate or exacerbate restlessness, ag-
dose (127, 128). itation, and sleep disturbancesside effects that often
When side effects occur during treatment with an an- attenuate with time. Anxiety may be minimized by intro-
tidepressant, an initial strategy is to lower the dose of the ducing the agent at a low dose. Akathisia has also been re-
antidepressant or to change to an antidepressant that is ported in patients taking SSRIs (129) and may contribute
not associated with that side effect. As an example, bupro- to reported restlessness or activation. If akathisia does oc-
pion can be used if patients encounter sexual side effects cur, a beta-blocker or benzodiazepine can be tried to re-
with an SSRI medication. When lowering the dose or dis- duce symptoms. Insomnia can be treated by using sleep
continuing the medication is not effective, additional strat- hygiene techniques or CBT as a first approach or by add-
egies may be considered. These additional strategies are ing a sedative-hypnotic medication or trazodone. Some
described in Table 7, which also lists prominent and clin- have found melatonin to be helpful in treating SSRI-
ically relevant side effects associated with particular med- induced insomnia.
ication classes.
Serotonin syndrome, as the name implies, is presumed c. Sexual side effects
to result from high levels of serotonin in the brain. Although Although loss of erectile or ejaculatory function in men
it can occur with administration of one or more seroto- and loss of libido and anorgasmia in both sexes may be
nergic medications, it is most severe when an MAOI is complications of virtually any antidepressant medication,
coadministered with another serotonergic medication. these side effects appear to be more common with SSRIs.
Consequently, great care must be taken when changing The psychiatrist should ascertain whether the reported sex-
patients from another antidepressant medication to an ual dysfunction is a result of the antidepressant medication,
MAOI and from an MAOI to other antidepressant medi- the underlying major depressive disorder, a co-occurring
cations because of the persistent effects of discontinued medical disorder, a disturbance in a relationship, or a need
medications. A washout period is essential before and after for education about sexual functioning. If sexual dysfunc-
using an MAOI. If the psychiatrist chooses to discontinue tion is determined to be a side effect of the antidepressant
a monoamine-uptake-blocking antidepressant medication medication, a number of strategies are available, including
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 35
Cardiovascular
Arrhythmias TCAs Avoid in patients with cardiac instability or ischemia.
Attend to interactions with anti-arrhythmics.
Hypertension SNRIs, bupropion Monitor blood pressure. Keep dose as low as possible.
Add antihypertensive.
Hypertensive crisis MAOIs Seek emergency treatment. If hypertension is severe,
intravenous antihypertensive agents (e.g., labetalol,
sodium nitroprusside) may be required.
Increase in cholesterol Mirtazapine Add a statin.
Orthostatic hypotension TCAs, trazodone, nefazodone, Add fludrocortisone. Add salt to diet.
MAOIs
Anticholinergic
Constipation TCAs Encourage adequate hydration. Add bulk laxative.
Delirium TCAs Evaluate for other possible contributors to delirium.
Dry mouth TCAs, SNRIs, bupropion Suggest use of sugarless gum or candy.
Urinary hesitancy TCAs Add bethanechol.
Visual changes TCAs Add pilocarpine eye drops.
Neurologic
Headaches SSRIs, SNRIs, bupropion Assess for other etiologies (e.g., caffeinism, bruxism,
migraine, tension headache).
Myoclonus TCAs, MAOIs Add clonazepam.
Seizures Bupropion, TCAs, amoxapine Assess for other etiologies, and add anticonvulsant
medication, if clinically indicated.
Sexual
Arousal, erectile TCAs, SSRIs, SNRIs Add sildenafil, tadalafil, buspirone, or bupropion.
dysfunction
Orgasm dysfunction TCAs, SSRIs, venlafaxine, Add sildenafil, tadalafil, buspirone, or bupropion.
desvenlafaxine, MAOIs
Priapism Trazodone Obtain emergency urological evaluation.
Other
Activation SSRIs, SNRIs, bupropion Administer in the morning.
Akathisia SSRIs, SNRIs Add a beta-blocker or benzodiazepine.
Bruxism SSRIs Obtain dental consultation, if clinically indicated
Diaphoresis TCAs, some SSRIs, SNRIs Add an 1-adrenergic antagonist (e.g., terazosin), central
2-adrenergic agonist (e.g., clonidine), or
anticholinergic agent (e.g., benztropine).
Fall risk TCAs, SSRIs Monitor blood pressure for evidence of hypotension or
orthostasis; assess for sedation, blurred vision, or
confusion; modify environment to reduce risk.
Gastrointestinal (GI) SSRIs Identify whether concomitant medications may affect
bleeding clotting.
(continued)
36 APA PRACTICE GUIDELINES
Other (continued)
Hepatotoxicity Nefazodone Provide education about and monitor for clinical
evidence of hepatic dysfunction. Obtain hepatic
function tests, if clinically indicated.
Insomnia SSRIs, SNRIs, bupropion Use morning dosing. Add a sedative-hypnotic at
bedtime. Add melatonin. Provide CBT or education in
sleep hygiene.
Nausea, vomiting SSRIs, SNRIs, bupropion Administer after food or in divided doses.
Osteopenia SSRIs If clinically indicated, obtain bone density monitoring
and add specific treatment to reduce bone loss (e.g.,
calcium and vitamin D supplements, bisphosphonates,
selective estrogen receptor agents).
Sedation TCAs, trazodone, nefazodone, Use bedtime dosing. Add modafinil or methylphenidate.
mirtazapine
Severe serotonin syndrome MAOIs Obtain emergency evaluation. Consider admission to a
critical care unit.
Weight gain SSRIs, mirtazapine, TCAs, Encourage exercise. Obtain input from dietician. If
MAOIs changing antidepressants, consider a secondary amine
(if a TCA is required) or other antidepressant with
fewer weight issues (e.g., bupropion).
a
Initial approaches to treatment-emergent side effects include decreasing or discontinuing the medication and changing to another
antidepressant with a different side effect profile. Treatments included here are additional measures.
may no longer be needed, although such interventions (e.g., paroxetine, fluoxetine) are administered concomi-
have not been found to alter fall risk, per se (152). Inquir- tantly with tamoxifen, the metabolism of tamoxifen to its
ing about a history of falls in the past year and assessing for active metabolite is reduced (7679), resulting in a poten-
abnormalities in gait and balance can also help in identi- tial decrease in its efficacy in preventing breast cancer re-
fying patients at particular risk for falling (153). lapse (80, 81). Interaction with other drugs was higher for
fluoxetine, fluvoxamine, and paroxetine than for sertra-
f. Effects on weight
line, citalopram, and escitalopram (98, 160, 161).
Weight gain, at times substantial, occurs in some patients
As described above, there can be a potentially lethal in-
taking SSRIs (154). Patients who take paroxetine have a
teraction between SSRIs and MAOIs: the serotonin syn-
higher incidence of weight gain than those who take other
drome. At least five half-lives should elapse between the
SSRIs (98, 155). Fluoxetine causes an initial reduction in
time an SSRI is stopped and an MAOI is started; for flu-
weight, which tends to normalize with continued treatment
oxetine discontinuation, this means waiting approximately
(156).
56 weeks before starting an MAOI; for discontinuation of
g. Serotonin syndrome other SSRIs, approximately 2 weeks should pass before
Use of SSRIs has been associated with the rare develop- starting an MAOI (162). A 2-week waiting period has been
ment of a syndrome caused by an excess of central nervous suggested after discontinuing an MAOI before starting an
system serotonergic activity. Features of serotonin syn- SSRI or another MAOI (Table 8).
drome include abdominal pain, diarrhea, flushing, sweat-
ing, hyperthermia, lethargy, mental status changes, tremor i. Discontinuation syndrome
and myoclonus, rhabdomyolysis, renal failure, cardiovas- Selective serotonin reuptake inhibitors generally should
cular shock, and possibly death (157). Although serotonin not be abruptly discontinued after extended therapy and,
syndrome can occur rarely with the use of SSRIs alone, it is whenever possible, should be tapered over several weeks
usually associated with the simultaneous use of multiple to minimize discontinuation-emergent symptoms. Clini-
serotonergic agents and is most severe when SSRIs are given cal experience and a few controlled studies suggest that
together with MAOIs. Consequently, when an SSRI is be- among the SSRIs, discontinuation-emergent symptoms
ing changed to an MAOI or vice versa, particular attention are more likely with paroxetine than sertraline, citalo-
must be give to the duration of time between treatments pram, or escitalopram and least likely to occur with fluox-
(Section II.B.2.b) to avoid precipitating a potentially lethal etine (due to the long elimination half-life of its primary
serotonin syndrome. Serotonin syndrome has also been re- metabolite, norfluoxetine) (163, 164). Discontinuation-
ported when SSRIs are used in combination with tramadol, emergent symptoms include both flu-like experiences
high-dose triptans, or the antibiotic linezolid, which also such as nausea, headache, light-headedness, chills, and body
has some ability to inhibit MAO (158, 159). aches, and neurological symptoms such as paresthesias,
insomnia, and electric shock-like phenomena. These
h. Drug interactions symptoms typically resolve without specific treatment
The potential for drug-drug interactions differs signifi- over 12 weeks. However, some patients do experience
cantly across the SSRIs. Selective serotonin reuptake in- more protracted discontinuation syndromes, particularly
hibitors have variable effects on hepatic microsomal those treated with paroxetine, and may require a slower
enzymes and therefore cause both increases and decreases downward titration regimen. Another strategy is to change
in the blood levels of other medications. For example, to a brief course of fluoxetine, e.g., 10 mg for 12 weeks,
when SSRIs that strongly inhibit the CYP 2D6 isoenzyme and then taper and discontinue the fluoxetine (165).
38 APA PRACTICE GUIDELINES
2. Serotonin norepinephrine reuptake inhibitors cautiously in patients with psychotic disorders. Other
The most common side effects of the SNRIs (venlafaxine, side effects with bupropion include agitation, jitteriness,
desvenlafaxine, and duloxetine) are similar to those seen mild cognitive dysfunction, insomnia, and gastrointesti-
with SSRIs, including nausea and vomiting, sexual dys- nal upset.
function, and activation; like the side effects seen with
b. Mirtazapine
SSRIs, those with SNRIs can attenuate with continued
The most common side effects of mirtazapine include dry
use. The SNRIs also are more likely to be associated with
mouth, sedation, and weight gain. For this reason, mir-
side effects that reflect noradrenergic activity, including
tazapine is often given at night and may be chosen for de-
increased pulse rate, dilated pupils, dry mouth, excessive
pressed patients with initial insomnia and weight loss.
sweating, and constipation. Although all three SNRIs carry
Although these side effects tend to occur early in the
the warning of increased blood pressure, this risk is greater
treatment course and may attenuate with continued use,
during therapy with venlafaxine at doses above 150 mg/day
the weight gain associated with mirtazapine is greater than
(166) than with duloxetine at doses of 60120 mg/day
that with other non-TCA, non-MAOI antidepressants (95)
(167) or desvenlafaxine at doses of 50100 mg/day (168).
and may make it a less attractive choice for some pa-
Because this blood pressure increase is dose-related, SNRI-
tients. Mirtazapine increases serum cholesterol levels in
induced hypertension may respond to dose reduction. In
some patients (171). Although several patients treated
the absence of a reduction in hypertension, a different an-
with mirtazapine were observed to have agranulocytosis
tidepressant medication may be considered. Alternatively,
in early studies, subsequent clinical experience has not con-
in a patient with well-controlled depressive symptoms, it
firmed an elevated risk (172).
may be preferable to add an antihypertensive agent rather
than risk a depressive relapse or recurrence with medica- c. Trazodone
tion tapering. As with the SSRIs, abrupt discontinuation The most common side effect with trazodone is sedation.
of SNRIs should be avoided whenever possible. Discon- Because the sedation associated with trazodone is greater
tinuation symptoms, which are sometimes protracted, are than that with other non-TCA, non-MAOI antidepres-
more likely to occur with venlafaxine (and, by implication, sants (95), this can be an advantage in patients with initial
desvenlafaxine) than duloxetine (100) and may necessitate a insomnia (173). Trazodone can also cause cardiovascular
slower downward titration regimen or change to fluoxet- side effects, including orthostasis, particularly among el-
ine. As described above (Section II.B.2.b), there can be a derly patients or those with preexisting heart disease. Use
potentially lethal interaction between SNRIs and MAOIs: of trazodone has also been associated with life-threat-
the serotonin syndrome. ening ventricular arrhythmias in several case reports
(173). Trazodone also can cause sexual side effects, in-
3. Other antidepressant medications
cluding erectile dysfunction in men; in rare instances, pri-
a. Bupropion apism occurs, which might require surgical correction
Bupropion differs from other modern antidepressants by (174, 175).
its lack of direct effects on serotonergic neurotransmission
and, as a consequence, a virtual lack of sexual side effects d. Nefazodone
(169). Neurologic side effects with bupropion include head- Side effects with nefazodone include dry mouth, nausea,
aches, tremors, and seizures (106). The risk of seizures is constipation, orthostasis, and visual alterations (176). Se-
minimized by avoiding high doses (e.g., using no more dation is also common and may necessitate a gradual
than 450 mg/day), avoiding rapid titration, using divided titration of nefazodone. However, in patients with insom-
dosing schedules for the immediate-release and sustained- nia, the sedating properties of nefazodone can be helpful
release formulations, and avoiding use of bupropion in pa- in improving sleep (177). There appears to be a low inci-
tients with risk factors for seizures. Bupropion should also dence of treatment-emergent sexual dysfunction (178,
not be used in patients who have had anorexia nervosa or 179) with nefazodone and, unlike trazodone, it has not
bulimia nervosa because of elevated risk of seizures (170). been associated with priapism. Nefazodone has also been
The risk of seizures may also be increased by the con- associated with rare but potentially fatal liver failure (180,
comitant use of inhibitors of CYP 2B6 (e.g., desipramine, 181), which has limited its use in recent years. Drug-drug
sertraline, paroxetine, fluoxetine) due to the resulting in- interactions can also be problematic as nefazodone in-
crease in bupropion blood levels. Bupropion has been as- hibits hepatic microsomal enzymes and can raise levels of
sociated with a low risk of psychotic symptoms, including concurrently administered medications such as certain
delusions and hallucinations. It should therefore be used antihistamines, benzodiazepines, and digoxin.
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 39
bothersome to the patient, the agent may be continued 5. Monoamine oxidase inhibitors
without a change in dose. If the myoclonus is problem-
atic and the blood level is within the recommended range, a. Hypertensive crises
the patient may be treated with clonazepam at a dose of A hypertensive crisis can occur when a patient taking an
0.25 mg t.i.d. Alternatively, the antidepressant medication MAOI ingests large amounts of tyramine or other vasoac-
may be changed. In overdoses, TCAs can cause seizures. tive amines in foods or medications (202). This reaction is
Some vulnerable patients may experience seizures even characterized by the acute onset of severe headache, nau-
on therapeutic doses of a TCAespecially clomipramine sea, neck stiffness, palpitations, profuse perspiration, and
and maprotiline (197). Amoxapine, a dibenzoxazepine- confusion and can possibly lead to stroke and death (119).
derivative tricyclic antidepressant, also produces seizures Dietary restrictions include avoiding foods such as aged
in overdose and has active metabolites that block dopam- cheeses or meats, fermented products, yeast extracts, fava
ine receptors, conferring a risk of extrapyramidal side ef- or broad beans, red wine, draft beers, and overripe or
fects and tardive dyskinesia (198). spoiled foods (202, 203). A number of medications includ-
ing norepinephrine reuptake blocking drugs (e.g., SNRIs,
f. Falls
TCAs), sympathomimetic vasoconstrictive agents, and over-
Use of TCAs has been associated with an increased risk of
the-counter decongestants can also produce a hyperten-
falls in a number of studies and meta-analyses, and the rel-
sive crisis when used in combination with MAOIs (202,
ative risk of falling appears comparable to that with SSRI
204). Individuals with asthma who receive MAOIs should
treatment (141, 144, 145). Although systematic reviews
be cautioned regarding interactions with sympathomimetic
show a relatively minor effect of orthostatic hypotension on
bronchodilators, although other antiasthma agents ap-
fall risk, TCAs may contribute to orthostasis and falls in in-
pear to be safe. Stimulants may be added to MAOIs, but
dividual patients (153). If orthostatic hypotension is prom-
only with caution and in selected individuals with treatment-
inent or associated with gait or balance problems, it may
resistant symptoms (205, 206).
require further evaluation and treatment to minimize the
At low doses (6 mg/24 hours), selegiline differs from
likelihood of falls (199). Other aspects of fall risk with
the older MAOIs in selectively blocking MAO B. In addi-
TCAs are similar to those that have already been described
tion, the transdermal delivery of selegiline bypasses en-
for patients treated with SSRIs (Section II.B.2.b.1.e). Other
zyme inhibition in the gut and first-pass metabolism in the
causes of falls include bradycardia, cardiac arrhythmia, a
liver. As a result, a low-tyramine diet is not needed when
seizure, or ataxia.
selegiline is prescribed at the minimum therapeutic dose.
g. Medication interactions However, few safety data are available at higher doses at
A number of medications that inhibit, induce, or are me- which selegiline becomes nonselective and inhibits both
tabolized by hepatic microsomal enzymes can interact MAO A and MAO B. Consequently, a low-tyramine diet is
with TCAs (200). For example, medications that induce needed when doses of 9 mg/24 hours and higher are pre-
CYP 3A4 such as carbamazepine or barbiturates will cause scribed as with other MAOIs (207, 208). Moclobemide,
a decrease in serum levels of TCAs. Drugs such as the an- which is available in Canada but not the United States, dif-
tipsychotic medication perphenazine or SSRIs such as flu- fers from the above MAOIs in binding reversibly to MAO
oxetine or paroxetine can inhibit metabolism via CYP and makes dietary restrictions unnecessary with moclobe-
2D6, resulting in a reduced clearance and increased levels mide. The potential for drug-drug interactions with sele-
of TCAs. Tricyclic antidepressants can also alter the phar- giline and moclobemide has not been fully studied, but
macokinetics or pharmacodynamics of other medications; caution suggests that the same drug interactions should be
for example, TCAs can cause a lowering of valproate lev- considered as when prescribing the older, nonselective, ir-
els and reduce the activity of clonidine. Therefore, adjust- reversible MAOIs.
ments in medication doses may be necessary when TCAs Although some clinicians continue to recommend that
are administered concomitantly with other drugs for which patients carry nifedipine as a self-administered antidote
there is an interaction. The ability to obtain meaningful an- (e.g., 10 mg by mouth at the first sign of a hypertensive
tidepressant blood levels to guide dosing is an advantage crisis [209]), this practice has not been approved by the
with several of the TCAs (e.g., nortriptyline, amitripty- FDA, and there are concerns about both the safety and
line, desipramine, imipramine) (201). Potentially danger- efficacy of this strategy, which can produce dangerous
ous interactions, including hypertensive crises and seroto- hypotension (210). Definitive treatment of hypertensive
nin syndrome, can develop when TCAs are administered crises usually involves intravenous administration of an
with MAOIs (see Sections II.B.2.b and II.B.2.b.5.b), nore- antihypertensive agent (e.g., labetalol, sodium nitroprus-
pinephrine, or epinephrine. side) in an emergency department setting.
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 41
Titration of the dose to full therapeutic doses generally (201, 232, 233). When such medications are given, obtain-
can be accomplished over the initial week(s) of treatment ing blood drug levels can be particularly informative when
but may vary depending on the development of side effects, patients have not responded to treatment with an adequate
the patients age, and the presence of co-occurring medical dose of antidepressant medication for an adequate dura-
and psychiatric conditions. In general, patients who are tion; when patients are particularly vulnerable to the toxic
older, are medically compromised, or have decreased abil- effects of a medication and require the lowest possible
ity to metabolize and clear antidepressant medications will effective dose; when there are concerns about patient ad-
require lower doses. In such patients, reduction of initial herence; and when there is concern that drug-drug inter-
and therapeutic doses to 50% of usual adult doses is often actions are adversely affecting antidepressant medication
recommended, and dose escalations should be made at a levels. In time, genetic testing may help guide selection or
slower rate than for younger and healthier adults. Doses dosing of antidepressants, but data are currently insufficient
will also be affected by the side effect profile of medications to justify the cost of such tests (229).
and the patients ability to tolerate these side effects. Med- Some antidepressant medications, especially TCAs,
ication doses should also be tailored to individual patients can cause significant morbidity and mortality in overdose
depending on the potential for pharmacokinetic alterations (190, 191). Ingestion of a 10-day supply of a tricyclic agent
and drug-drug interactions. administered at a dose of 200 mg/day is often lethal. Early
Patients who have started taking an antidepressant on in treatment, it is prudent to dispense only small quan-
medication should be carefully and systematically moni- tities of such antidepressant medications and keep in mind
tored to assess their response to treatment, the emergence the possibility that patients can hoard medications over
of side effects, their clinical condition, safety, and adher- time. Alternatively, in patients who are suicidal, it may be
ence to treatment. Use of clinician- and patient-rated preferable to employ agents that are safer in overdose
scales can facilitate such assessments (see Section II.A.8). such as the SSRIs, bupropion, or mirtazapine.
Factors to consider when determining the frequency of
treatment visits include the severity of illness, the patients 3. Other somatic therapies
cooperation with treatment, the availability of social sup-
ports, the presence of co-occurring general medical ill- a. Electroconvulsive therapy
nesses, and the progression of symptom change. Visits Electroconvulsive therapy has the highest rates of response
should also be frequent enough to monitor and address and remission of any form of antidepressant treatment, with
suicide risk and to actively promote treatment adherence, 70%90% of those treated showing improvement (234
since attrition from treatment continues to be a major 236). Although the remission rate with ECT appears to be
hurdle in maximizing outcomes. Patients in clinical trials lower when it is used in community settings than when it is
appear to benefit from monitoring once a week or more. used in clinical trials (237), the proportion of patients with
This frequency of monitoring enhances adherence rates major depressive disorder who respond to ECT is still
and likely helps patients avoid the demoralization that greater than the proportion who respond to antidepressant
may occur before the onset of beneficial effects (216). In medication. In addition, ECT has been associated with sig-
the recently completed STAR*D (Sequenced Treatment nificant improvements in health-related quality of life (238).
Alternatives to Relieve Depression) trial, up to six visits Consequently, ECT should be considered for patients with
were recommended during the first 12 weeks (acute phase) severe major depressive disorder that is not responsive to
of measurement-based treatment at each of the four treat- psychotherapeutic and/or pharmacological interventions,
ment steps (40). In clinical practice, the frequency of particularly those with significant functional impairment
monitoring during the acute phase of pharmacotherapy who have not responded to numerous medication trials
may vary and can be as often as multiple times per week in (239). Electroconvulsive therapy may be particularly bene-
more complex circumstances. The method of monitoring ficial and can be considered as a first-line treatment option
(e.g., face-to-face visits, telephone contact, or contact with for severe major depressive disorder when it is coupled with
another clinician knowledgeable about the patient) may psychotic features (240, 241), catatonia (239, 242), suicide
vary depending on the clinical context and the treatment risk (243), or food refusal leading to nutritional compro-
modality. mise, as well as in other situations when a particularly rapid
Although for most patients, monitoring of antidepres- antidepressant response is required (240), such as with se-
sant blood levels is not necessary, it may be useful for those verely ill inpatients (239). Electroconvulsive therapy is also
taking TCAs. For some medications, particularly nortrip- indicated as a first-line treatment for patients who have pre-
tyline, amitriptyline, desipramine, and imipramine, blood viously shown a positive response to this treatment modality
drug levels correlate with both efficacy and side effects or who prefer it (239).
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 43
1. Side effects of electroconvulsive therapy and any specifically indicated laboratory, radiologic, or
Electroconvulsive therapy is a very safe treatment, and imaging studies) to define factors that may influence the
there are no absolute contraindications to its use (239). risk of ECT, and an anesthesia evaluation to identify and
Risks of morbidity and mortality, in general, do not exceed address the nature and extent of anesthetic risk and the
those associated with anesthesia alone (239, 244, 245). need for modification of medications or anesthetic tech-
However, the presence of some medical conditions may nique (239). This evaluation should include a summary of
necessitate modifications in anesthesia or ECT adminis- treatment indications, treatment risks, and a suggestion of
tration. any indicated additional evaluative procedures, alterations
Electroconvulsive therapy may have cardiovascular side in treatment, or modifications in ECT technique (239). In
effects, mediated by changes in the autonomic nervous assessing indications for caution (e.g., recent myocardial
system with the initial stimulus and subsequent seizure infarction, cardiac arrhythmias, intracranial space-occu-
activity (239). More specifically, ECT typically causes a pying lesions), the relative risks and benefits should be
transient rise in heart rate and blood pressure, with asso- carefully weighed in collaboration with an anesthesiolo-
ciated increases in cardiac workload and intracranial pres- gist, a general medical physician, and other specialists, as
sure. These effects can be managed by optimizing blood necessary. Once completed, the pre-ECT evaluation will
pressure control prior to ECT and administering anti- serve as the basis for a specific, individualized discussion
hypertensive agents (e.g., short-acting beta-blockers or of the risks and benefits of ECT relative to other thera-
calcium channel blockers) at the time of ECT (239). Ar- peutic options as part of the informed consent process.
rhythmias, which are usually transient, can also occur in With the patients permission, it is helpful to educate the
conjunction with ECT and can be managed with usual patients family about ECT and involve them in discus-
antiarrhythmic therapies if they do not resolve spontane- sions relating to consent.
ously (239). An additional aspect of decision-making prior to ECT
Electroconvulsive therapy can also be associated with relates to the use of psychotropic medications during the
cognitive effects, the most common of which is a period of ECT course. There is growing use of ECT combined with
confusion following the ECT and associated anesthesia antidepressant medication. Although data supporting this
that generally lasts between 30 and 60 minutes (246). practice are still few, it does not appear to increase side ef-
Electroconvulsive therapy also is associated with antero- fects and may augment response (259, 260). An additional
grade amnesia, which typically resolves soon after the last goal of combination treatment is to minimize the risk of
ECT treatment (247). Some degree of retrograde amne- relapse between the end of the ECT course and the attain-
sia, particularly for recent memories, may continue for a ment of full antidepressant effectiveness. Antipsychotic
longer period of time after the end of the ECT course medications are typically continued during the ECT
(247) but is less pronounced for autobiographical memo- course (239, 261), although most data on this practice come
ries than for impersonal memories (248). These cognitive from studies of patients with schizophrenia who are re-
effects of ECT are related to electrode placement, stimulus ceiving ECT. The safety of combining lithium and ECT
dosage, age, and premorbid cognitive status (249253). has been questioned, although there are conflicting data
Retrograde amnesia also improves over time, typically re- (239, 262). Medications that have anticonvulsant proper-
solving within 6 months (248, 252), although some patients ties are often discontinued or given at decreased doses
report incomplete recovery of memories, particularly for during the ECT course to minimize effects on seizure in-
events around the time of the treatment (247, 254). Rarely, duction (239, 261). With benzodiazepines, there is some
patients report more pervasive and persistent cognitive evidence that concurrent use may diminish ECT effective-
disruption, the basis of which is uncertain (252, 255). For ness, particularly when right unilateral electrode place-
many individuals, however, subjective memory (256) and ment is used (263).
quality of life (238) is improved following ECT with the Electroconvulsive therapy may be administered either
resolution of the major depressive episode and its associ- unilaterally or bilaterally (using a bitemporal or bifrontal
ated deficits in memory or executive functioning (257, electrode placement). Compared with patients who re-
258). ceive bilateral treatment, most patients who receive right
unilateral electrode placement with low stimulus intensi-
2. Implementation of electroconvulsive therapy ties experience fewer cognitive effects but less therapeutic
The evaluation preceding ECT consists of a psychiatric benefit (253). Stimuli of higher intensity (i.e., 500% above
history and examination to verify that ECT is indicated, a seizure threshold) are associated with antidepressant ef-
general medical evaluation (including medical history and fects more comparable to those seen with bilateral elec-
physical examination with cognitive assessment, vital signs, trode placements, although such stimulus intensities are
44 APA PRACTICE GUIDELINES
not always achievable with existing ECT devices (264). Re- ment paradigms complicates the interpretation of re-
gardless of what electrode placement is chosen, stimulus search findings, these meta-analyses also support the use
dosing should be individualized and stimulus parameters of high-frequency TMS over the left dorsolateral pre-
adjusted to induce an adequate generalized seizure, which frontal cortex. Lesser degrees of treatment resistance may
is typically at least 20 seconds or greater in motor duration be associated with a better acute response to TMS (274).
and 30 seconds in EEG duration (239). Failure to induce In comparison with ECT, TMS has been found in ran-
an adequate seizure should be followed immediately by domized studies to be either less effective than ECT (275)
restimulation at higher energies until an adequate seizure or comparable in efficacy to ECT (276278), but in the
is elicited. latter studies TMS was more effective and ECT was less
Electroconvulsive therapy is typically administered effective than is typically seen in clinical trials. A fewer
23 times/week; less frequent administration has been as- number of studies have compared cognitive effects of
sociated with less cognitive impairment but also a longer TMS and ECT. One randomized trial found no signifi-
lag in the onset of action (265). In clinical practice, the cant difference between TMS and non-dominant uni-
need for ECT to be administered at this frequency could lateral ECT on performance on neuropsychological tests
produce logistical barriers for some patients who would at 2 and at 4 weeks of treatment (276), although a small
either require hospitalization or transportation after ECT open-label trial reported a greater degree of memory dif-
sessions. The acute course of ECT treatment typically ficulties with ECT than with TMS shortly after the treat-
consists of six to 12 treatments and generally does not ex- ment course (279).
ceed 20 treatments (239, 266). It is important that treat- Across all studies, TMS was well tolerated and was asso-
ment continue until symptoms have remitted or clearly ciated with low rates of treatment dropout (270, 280).
reached a plateau, since relapse rates appear to be greater Transient scalp discomfort and headaches were the most
and overall prognosis worse if ECT is discontinued pre- commonly reported side effects (280).
maturely (237). Use of a formal rating scale may be help- In clinical practice, the need for daily TMS could pro-
ful in assessing symptom response as well as the cognitive duce logistical barriers for some patients.
side effects of treatment, permitting adjustments in the
treatment parameters or frequency (239, 267). c. Vagus nerve stimulation
For more detail on the administration of ECT, see APAs Vagus nerve stimulation is approved for use in patients
The Practice of Electroconvulsive Therapy: Recommendations with treatment-resistant depression on the basis of its po-
for Treatment, Training, and Privileging (A Task Force Report tential benefit with long-term treatment. There is no in-
of the American Psychiatric Association) (239). dication for the use of VNS in acute phase treatment of
depression, as data showed no evidence for acute efficacy
b. Transcranial magnetic stimulation (281, 282). Further information on the use of VNS as an
Transcranial magnetic stimulation (TMS) uses a specifically adjunct to other antidepressive treatments is provided in
designed magnetic coil that is placed in contact with the Section II.B.7.c.
head to generate rapidly alternating magnetic-resonance-
imaging-strength magnetic fields and produce electrical 4. Psychotherapy
stimulation of superficial cortical neurons. Based on the There has been considerable research on time-limited
results of a multisite randomized sham-controlled clinical psychotherapies for major depressive disorder, although
trial of high-frequency TMS over the left dorsolateral the number of studies is smaller than for pharmacothera-
prefrontal cortex (268), TMS was cleared by the FDA in pies. Most research has focused on individual, in-person,
2008 for use in individuals with major depressive disorder outpatient treatment, in part based on the needs and con-
who have not had a satisfactory response to at least one straints of research methods. However, research has also
antidepressant trial in the current episode of illness. How- begun to explore psychotherapies in differing formats,
ever, another large randomized sham-controlled trial of including groups, over the telephone, and with computer
TMS added to antidepressant pharmacotherapy showed assistance.
no significant benefit of left dorsolateral prefrontal cortex When psychotherapy is part of the treatment plan, it
TMS (269). In comparisons of actual TMS versus sham must be integrated with psychiatric management (Section
TMS, most (270272) but not all (273) recent meta-anal- II.A) and any other treatments (e.g., pharmacotherapy) that
yses have found relatively small to moderate benefits of are being provided. Clinical considerations and other
TMS in terms of clinical response. Although the primary patient factors should be considered in determining the
studies used in these meta-analyses are highly overlapping nature and intensity of psychotherapy. Typically psycho-
and the variability in TMS stimulus parameters and treat- therapy is given in an ambulatory setting, although some
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 45
psychotherapies might benefit depressed inpatients, given type of psychotherapy and/or addition or change to med-
adequate lengths of stay and courses of treatment (283 ication if psychotherapy for major depressive disorder has
285). Like pharmacotherapy, the effectiveness of psycho- not resulted in significant improvement in 48 weeks.
therapy will vary with the skill and training of the therapist.
Patient factors, such as the nature and duration of depres- a. Specific psychotherapies
sive symptoms, beliefs and attitudes toward psychotherapy, 1. Cognitive and behavioral therapies
and early life experiences (e.g., history of trauma) also affect In the treatment of depressed patients, psychotherapies
treatment response to psychotherapy. Psychotherapy is that focus primarily on aspects of cognitive patterns and
particularly useful in addressing the psychosocial stressors those that emphasize behavioral techniques can be used
and psychological factors that have an impact on the devel- alone, but are generally used in combination. Cognitive-
opment or maintenance of depressive symptoms. behavioral therapy combines cognitive psychotherapy
Cognitive-behavioral therapy, interpersonal psycho- with behavioral therapy and maintains that irrational
therapy (IPT), and behavioral psychotherapies (e.g., be- beliefs and distorted attitudes toward the self, the environ-
havioral activation) have demonstrated acute efficacy in ment, and the future perpetuate depressive affects and
treating major depressive disorder. There is less evidence compromise functioning. The goal of CBT is to reduce
for other psychotherapies. However, one meta-analysis depressive symptoms by challenging and reversing these
found no large differences in long-term efficacy between beliefs and attitudes and encouraging patients to change
any of the major psychotherapies, including dynamic psy- their maladaptive preconceptions and behaviors in real
chotherapy, for mild and moderate depression (286). In life (298).
terms of longer term outcomes, psychotherapy is generally Cognitive-behavioral therapy is an effective treatment
found to have more prolonged effects than pharmacother- for major depressive disorder. In meta-analyses, CBT has
apy after cessation of active treatment. In particular, IPT generally surpassed control conditions in efficacy and has
and CBT have shown lasting benefits in maintaining remis- had equal efficacy compared with other empirically sup-
sion (287289). These time-limited treatments are essen- ported psychotherapies (i.e., IPT and behavior therapy)
tially equipotent with antidepressant medications for (299). Studies comparing the effectiveness of CBT with
outpatients with mild to moderate acute depression but pharmacotherapy, however, are methodologically challeng-
probably should be used in conjunction with medication ing to conduct, and results are inconsistent (296, 300).
for severe or melancholic major depressive disorder. Some Also unclear is whether CBT is less effective for patients
research has suggested patient and illness characteristics with more severe depressive symptoms.
that might predict differential benefits of CBT over IPT, Behavior therapy for major depressive disorder is based
and vice versa, for patients with major depressive disorder on theoretical models drawn from behavior theory (301)
(e.g., see reference 290), but such preliminary findings re- and social learning theory (302). Behavioral activation is a
quire replication. newly articulated behavioral intervention with some pos-
Cognitive-behavioral therapy and IPT appear less ef- itive preliminary results that merit further study (288,
fective than pharmacotherapy for chronic depression, at 303). Specific behavior therapy techniques include ac-
least as acute monotherapy (291296). Nonetheless, in tivity scheduling (304, 305), self-control therapy (306),
patients who respond to medication, psychotherapy may social skills training (307), and problem solving (308). Be-
foster the development of social skills and confidence af- havior therapy involves graded homework, scheduling of
ter years of depression-related impairments (297). enjoyable activities, and minimizing unpleasant activities
Psychotherapy carries its own side effects. A psycho- (309). Behavior therapy has demonstrated efficacy, at times
therapy that requires considerable time or patience may superior to cognitive therapy, in treating major depressive
be poorly tolerated. The work of psychotherapy itself may disorder (310).
generate anxiety or other strong feelings, which may be
difficult for patients to manage. An indirect measure of 2. Interpersonal psychotherapy
the relative side effects and tolerability of psychotherapy The focus of IPT is on current life changes, including
can be obtained from the dropout rates in clinical trials; losses, role disputes and role transitions, social isolation,
however, many other factors can also affect these rates deficits in social skills, and other interpersonal factors that
(e.g., other burdens of the research trial, specific features may interact with the development of the depressive
of the clinical management provided, logistical barriers in episode (311, 312). In IPT the goal is to intervene by iden-
attending appointments). Depending on what can reason- tifying the current trigger of the depressive episode, facil-
ably be expected with the given type of psychotherapy, the itating mourning in the case of bereavement, promoting
psychiatrist should consider a change in the intensity or recognition of related affects, resolving role disputes and
46 APA PRACTICE GUIDELINES
role transitions, and building social skills to improve rela- ing the psychological basis of the presenting symptoms or
tionships and to acquire needed social supports. In IPT, on a selected underlying conflict. Sometimes a goal of psy-
major depressive disorder is defined as a medical illness, chodynamic psychotherapy, brief or extended, may be to
and the illness, rather than the patient, is blamed for the help the patient accept or adhere to necessary pharmaco-
symptoms. Interpersonal psychotherapys medical model therapy (331).
makes it highly compatible with pharmacotherapy in Although psychodynamic psychotherapy is often used
combined treatment. in clinical practice, its efficacy in the acute phase of major
Interpersonal psychotherapy is an efficacious treat- depressive disorder remains less well studied in controlled
ment for major depressive disorder (296, 313). Studies trials than the efficacy in this phase of some other forms of
have shown efficacy of this treatment in depressed pri- psychotherapy. This research is reviewed in Part B, Sec-
mary care patients and patients with more severe depres- tion V.B.3.
sion (311). The efficacy of IPT has been demonstrated for
adolescents, pregnant and postpartum women, and geri- 4. Problem-solving therapy
atric patients (311). Interpersonal psychotherapy can also Problem-solving therapy is a manual-guided, brief treat-
be used as a monthly maintenance therapy to prevent ment lasting six to 12 sessions. This therapy, often admin-
relapse (289, 314, 315). Some studies have also suggested istered by nurses or social workers, has been used to
possible subgroups in whom IPT may show differential prevent depression in elderly and/or medically ill patients,
efficacy, specifically among HIV-positive patients (316) and it has also been used to treat patients with relatively
and patients who have co-occurring obsessive personality mild depressive symptoms. The approach combines ele-
traits and who are single and not living with others (317). ments of cognitive therapy (addressing negative assess-
Furthermore, for patients with severe life events, IPT may ments of situations) and IPT (focal problem solving). Some
have advantages over therapies that do not focus on such studies have reported modest improvement in patients
events directly. with mild depressive symptoms. Although problem solv-
ing therapy has had limited testing for patients with major
3. Psychodynamic psychotherapy depressive disorder, it may have a role in targeted patient
The term psychodynamic psychotherapy encompasses a populations with mild depression (332335).
range of brief to long-term psychotherapeutic interven-
tions (318320). These interventions derive from psycho- 5. Marital therapy and family therapy
dynamic theories about the etiology of psychological Marital and family problems are common in the course of
vulnerability, personality development, and symptom for- mood disorders, and comprehensive treatment often de-
mation as shaped by development and conflict occurring mands assessing and addressing these problems. Marital
during the life cycle from earliest childhood forward (321 and family problems may be the consequence of major de-
325). Some of these theories focus on conflicts related to pressive disorder but may also increase vulnerability to
guilt, shame, interpersonal relationships, the management developing major depressive disorder or retard recovery
of anxiety, and repressed or unacceptable impulses. Others from it (336339). A number of marital and family ther-
address developmental psychological deficits produced by apies have been shown to be effective in the treatment
inadequacies or problems in the relationship between the of depression. Techniques include behavioral approaches
child and emotional caretakers, resulting in problems of (338), problem-focused approaches (340), and strategic
self-esteem, sense of psychological cohesiveness, and emo- marital therapy (341, 342). Family therapy has also been
tional self-regulation (323, 326330). found to be helpful in the treatment of more severe forms
Psychodynamic psychotherapy may be brief but usu- of depression in conjunction with medications and hospi-
ally has a longer duration than other psychotherapies, and talization (343).
its aims extend beyond immediate symptom relief. These
goals are to modify underlying psychological conflicts and 6. Group therapy
deficits, which increase the patients vulnerability to depres- Group psychotherapy is widely practiced, but research on
sive affect and the development of major depressive disor- its application to major depressive disorder is limited.
der. Psychodynamic psychotherapy is therefore broader Specific types having some data to support their efficacy
than most other psychotherapies, encompassing both cur- include CBT (344347) and IPT (348351). Meta-analyses
rent and past problems in interpersonal relationships, of the relative effectiveness of psychotherapeutic approaches
self-esteem, and developmental conflicts associated with conducted in group format versus individual format have
anxiety, guilt, or shame. Time-limited, structured psycho- not involved patients with rigorously defined major depres-
dynamic psychotherapy may focus more on understand- sive disorder (352355).
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 47
On the basis of a very limited controlled study, support- addition, patients with chronic, treatment-resistant de-
ive group therapy has been suggested to have utility in the pression may require long-term treatment.
treatment of major depressive disorder. In a study of de- The optimal frequency of psychotherapy has not been
pressed outpatients, a mutual support group and group rigorously studied in controlled trials. The psychiatrist
CBT were found to be equally effective in reducing de- should consider multiple factors when determining the
pressive symptoms (346). In a study of HIV-positive pa- frequency for individual patients, including the specific
tients with mild to moderate major depressive disorder, type and goals of the psychotherapy, the frequency neces-
structured supportive group therapy plus placebo yielded sary to create and maintain a therapeutic relationship, the
similar decreases in depressive symptoms to structured frequency of visits required to ensure treatment adher-
group therapy plus fluoxetine (356). Individuals experienc- ence, and the frequency necessary to monitor and address
ing stressors such as bereavement or chronic illness may suicide risk and other safety concerns. Time-limited brief
benefit from contact with others facing similar challenges. psychotherapies may mobilize many depressed patients to
Medication maintenance support groups may also of- more rapid improvement. The severity of illness, the pa-
fer benefits, although data from controlled trials for pa- tients cooperation with treatment, availability of social
tients with major depressive disorder are lacking. Such supports, cost, geographic accessibility, and presence of
groups inform the patient and family members about co-occurring general medical problems may also influ-
prognosis and medication issues, providing a psychoedu- ence visit frequency. The frequency of outpatient visits
cational forum that contextualizes a chronic mental illness during the acute phase is generally weekly but may vary
in a medical model. based on these factors. Some experienced clinicians find
The efficacy of self-help groups led by lay members that sessions are needed at least twice weekly, at least ini-
(357) in the treatment of major depressive disorder has tially, for patients with moderate to severe depression.
not been well studied. However, one investigation of Regardless of the type of depression-focused psycho-
group therapies found that a higher proportion of de- therapy that is selected, the clinician should carefully and
pressed outpatients had remission following treatment in systematically monitor the patients response to treatment,
groups led by professionals than had remission following which can be facilitated by the use of clinician- and patient-
participation in groups led by nonprofessionals (346). rated scales at regular intervals (see Section II.A.8). If 48
Further study is needed on the possibility that self-help weeks of treatment do not yield at least moderate im-
groups may serve a useful role in enhancing the support provement (20% diminution in symptoms), the clinician
network and self-esteem of participating patients with should thoroughly review and reappraise the treatment
major depressive disorder and their families. plan.
Overall, group therapy has some evidence to support
its use as well as the potential advantage of lowered cost, c. Combining psychotherapy and medication
inasmuch as one or two therapists can treat a larger num- Several meta-analyses of studies of the combination of
ber of patients simultaneously. This advantage needs to be psychotherapy and pharmacotherapy for patients with
weighed against the difficulties in assembling the group, major depressive disorder have documented a modest ad-
the lesser intensity of focus patients receive relative to in- vantage for the combination as compared with one or the
dividual psychotherapy, and potentially adverse effects other modality alone (359361). Particularly large addi-
from interactions with other group members. tive effects have been observed in individual studies of pa-
tients with chronic depression (362), patients with severe
b. Implementation recurrent depression (359), and hospitalized patients
It can be useful to establish an expected duration of psy- (285). Combined treatment might therefore be consid-
chotherapy at the start of treatment. Communicating this ered a treatment of first choice for patients with major de-
expectation may help mobilize the patient and focus treat- pressive disorder with more severe, chronic, or complex
ment goals, yet there are few data available on the optimal presentations. Combining family therapy with pharmaco-
duration of specific depression-focused psychotherapies. therapy has also been found to improve posthospital care
In many trials, CBT and IPT have been delivered in ap- for depressed patients (343).
proximately 1216 weekly sessions. In a subanalysis of one Dual treatment combines the unique advantages of each
clinical trial, CBT delivered in 16 weeks was more effec- therapeutic modality: while pharmacotherapy may provide
tive than CBT delivered in 8 weeks for those with severe earlier symptomatic relief, psychotherapy yields broader
major depressive disorder (358). Moreover, evidence sug- and longer lasting improvement (363). Psychotherapy can
gests benefit from monthly continuation phase treatment also be used to address issues that arise during pharmaco-
with IPT in reducing the probability of relapse (314). In therapy, such as decreased adherence. However, the advan-
48 APA PRACTICE GUIDELINES
comparable benefits of electroacupuncture and amitripty- TABLE 9. Potential Reasons for Treatment Nonresponse
line (404), and another small randomized trial in depressed
Inaccurate diagnosis
women showed benefits of acupuncture relative to a sham
Unaddressed co-occurring medical or psychiatric
control (405). However, a subsequent larger study did not
disorders, including substance use disorders
replicate these results (406), and a recent meta-analysis
concluded that acupuncture was not associated with any Inappropriate selection of therapeutic modalities
benefits in treating major depression in terms of response Inadequate dose of medication or frequency of
or remission rates (407). Assuming needles are properly psychotherapy
sterilized, there do not appear to be substantial risks of Pharmacokinetic/pharmacodynamic factors affecting
acupuncture treatment. However, based on current evi- medication action
dence, acupuncture is not recommended in the treatment Inadequate duration of treatment
of major depressive disorder. Nonadherence to treatment
Persistent or poorly tolerated side effects
6. Assessing response and adequacy of treatment Complicating psychosocial and psychological factors
The goal of acute phase treatment for major depressive dis- Inadequately trained therapist or poor fit between
order, insofar as possible, is to achieve remission and a re- patient and therapist
turn to full functioning and quality of life. Remission is
defined as at least 3 weeks of the absence of both sad mood
and reduced interest and no more than three remaining For pharmacotherapy, determination of the adequacy of
symptoms of the major depressive episode (408). However, treatment requires ensuring that antidepressant medica-
it is not uncommon for patients to have substantial but in- tions have been used for an adequate dose and duration.
complete symptom reduction or improvement in function- This can be assessed using standardized measurement in-
ing during acute phase treatment. A number of studies have struments (414). Generally, adequate treatment with an
provided compelling evidence that even mild residual antidepressant medication for at least 46 weeks is neces-
symptoms at the end of a depressive episode are associated sary before concluding that a patient is not responsive or
with significant psychosocial disability, compared with as- only partially responsive to a particular medication (218,
ymptomatic remission (409); a more than three times faster 221). For patients with no improvement in symptoms
relapse to a subsequent major depressive episode (410); and during the initial weeks of treatment, treatment should be
in first-episode patients, a more chronic future course (410 reevaluated and possibly changed. Furthermore, there is
412). The presence of mild residual symptoms has been little evidence to support extending antidepressant medi-
shown to be an even stronger predictor of a subsequent re- cation trials beyond 6 weeks in patients who have shown
turn to a major depressive episode than a prior history of no response. Patients with chronic forms of depression or
multiple episodes of major depressive disorder (410). For with co-occurring Axis I disorders or general medical
this reason, it is important not to conclude the acute phase conditions may require a longer duration of acute phase
of treatment prematurely for partially responsive patients. treatment before concluding that a different treatment
Throughout treatment, both the patients response and the strategy is indicated (224).
adequacy of treatment must be vigilantly and systematically For psychotherapy, treatment should be reassessed if
monitored. Use of structured measures of depression there has not been meaningful improvement after a few
symptom severity, side effects, treatment adherence, and months, depending on what can reasonably be expected for
functional status can facilitate identification of patients who the given type of psychotherapy. Patients should be reas-
have not had a complete response to treatment (40, 44). sessed every 34 months to ensure adequate improvement.
If a patient is found to have an incomplete treatment Regardless of treatment modality, lack of improvement
response, the treatment itself should be evaluated. Medi- over time warrants reconsideration of interventions, given
cations must be thoughtfully selected and given at an ad- the large number of available treatment options.
equate dose and for an adequate duration. Similarly,
psychotherapy must be well chosen for the patient, skill- 7. Strategies to address incomplete response
fully executed, and conducted over an appropriate period The psychiatrist should consider a change in treatment
of time with an adequate frequency of visits. In addition to for patients who have not fully responded to an adequate
being caused by inadequate treatment, poor response may acute phase treatment over a sufficient time, generally
result from multiple other factors (413) that are enumer- 48 weeks. The treatment plan can be revised by imple-
ated in Table 9. menting one of several therapeutic options, including op-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 51
Response
timizing the initial treatment, changing to a different treatment options should be considered, including ECT
treatment, and combining treatments. These options are and a consultation from an expert in mood disorders. De-
outlined in Figure 2 and described in more detail below. spite optimal treatment, some patients may continue to
Following any change in treatment, the patient should have chronic depressive symptoms. For these patients, the
continue to be closely monitored. If there is not at least a psychiatrist should add a disease management component
moderate improvement in major depressive disorder to the overall treatment plan. This component involves
symptoms after an additional 48 weeks of treatment, the setting realistic expectations, improving functioning, and
psychiatrist should conduct another thorough review. This developing self-management skills (415, 416).
reappraisal should include the following: verifying the pa-
tients diagnosis and adherence; uncovering and address- a. Maximizing initial treatments
ing clinical factors that may be preventing improvement, For patients who have not fully responded to treatment
such as the presence of co-occurring general medical con- for depression, an initial strategy is to optimize the inten-
ditions or psychiatric conditions (e.g., alcohol or substance sity of psychotherapy or maximize the dose of medication,
abuse); evaluating for potential drug-drug interactions; especially if the upper limit of the antidepressant dose has
obtaining collateral information from those involved with not been reached. Decisions about pharmacotherapy will
the patient; and uncovering and addressing psychosocial, involve a balancing of efficacy, side effects, and medica-
psychological, and personality factors that may be imped- tion adherence. Dose escalation and management of side
ing recovery (Table 9). If no new information is uncovered effects at critical decision points are essential in order to
to explain the patients lack of adequate response, other avoid premature discontinuation of the chosen antide-
52 APA PRACTICE GUIDELINES
pressant medication and to maximize the dose and dura- or changing to a depression-focused psychotherapy should
tion of the antidepressant therapy (40, 218). also be considered for patients with major depressive dis-
Because of pharmacokinetic and pharmacodynamic order who do not respond fully to medication treatment.
differences among individuals, some patients may require Other strategies for patients who do not respond ade-
doses higher than those approved by the FDA to achieve quately to pharmacotherapy include changing to an
adequate blood levels of a medication and receive thera- MAOI after allowing sufficient time between medications
peutic benefits. Patients who have had their dose in- to avoid hazardous interactions (see Table 8). Transcranial
creased should be monitored for increased severity of side magnetic stimulation could also be an option, as it appears
effects; dose increases should be considered only for pa- to be safe and well tolerated (270, 280). In addition, it has
tients who do not have significant or intolerable side ef- shown small to moderate benefits in most (268, 270272)
fects while taking the medication. Frequent follow-up but not all (269, 273) clinical trials and recent meta-anal-
contact (either in person or via the phone) may be neces- yses. Recent randomized trials suggest that quetiapine
sary to address symptoms, side effects, and patient adher- monotherapy also produces a greater reduction in depres-
ence in order to personalize treatment to the specific sive symptoms than placebo (423, 424), with comparable
clinical needs of the patient. When available and clinically efficacy to duloxetine (424), although the potential side ef-
meaningful, therapeutic ranges for blood levels of antide- fects of second-generation antipsychotic treatment need
pressant medications are useful in optimizing medication to be taken into consideration. ECT remains the most ef-
dosing (201, 232, 233). fective therapy for patients with treatment-resistant symp-
Individual differences are common in the time to re- toms (239, 425), although results of clinical trials differ
sponse and the tolerability of treatments. For patients who on whether patients with medication-resistant symptoms
have shown a partial response to treatment, particularly have responses to ECT that are comparable to those of
those with features of personality disorders and prominent patients without documented medication resistance (426
psychosocial stressors, extending the antidepressant med- 428).
ication trial (e.g., by 48 weeks) may allow up to one-third
of patients to respond more fully (417419). c. Augmenting and combining treatments
In patients who are receiving psychotherapy, similar Pharmacotherapy can be combined with a depression-
principles apply in terms of monitoring and adjusting focused psychotherapy, both as an initial treatment plan,
treatment in the context of nonresponse or difficulty tol- and as a strategy to address nonresponse to treatment in
erating psychotherapy (331). Factors to be considered in- one modality or the other. See Section II.B.4.c above for
clude the frequency of sessions, the type of psychotherapy further information about combining pharmacotherapy
being used, the quality of the therapeutic alliance, and the and psychotherapy.
possible need for medications in lieu of or in addition to Antidepressant medications can be augmented with an-
psychotherapy. Whereas increasing the frequency of ther- other non-MAOI antidepressant or with other, nonanti-
apy sessions is a reasonable approach to nonresponse, this depressant agents. The addition of a second non-MAOI
approach is based on clinical wisdom and has not been antidepressant may be helpful, particularly for patients
systematically studied. who have had a partial response to antidepressant mono-
therapy (429). One option is to add a second non-MAOI
b. Changing to other treatments antidepressant medication from a different pharmacolog-
Changing to a different non-MAOI antidepressant medi- ical class, taking care to avoid drug-drug interactions. An-
cation is a common strategy for patients with treatment- other option is to add an adjunctive, nonantidepressant
resistant major depressive disorder, especially those who medicationsuch as lithium, thyroid hormone, an anti-
have not shown at least partial response to the initial med- convulsant, a psychostimulant, or a second-generation
ication regimen. Although there are no specific patient (atypical) antipsychotic. More information about these
characteristics that predict which medication to choose strategies is given later in this section.
(420), results from STAR*D suggest that changing to a Some limited evidence and clinical experience support
second-step treatment results in additional remission rates the addition of bupropion to an SSRI. This combination
of about 25%, and further changes are associated with con- is generally well tolerated, although bupropion, a moder-
tinued remission, albeit at lower rates (about 13%14%). ately potent inhibitor of CYP 2D6, increases blood levels
Treatment can be changed to a non-MAOI antidepressant of some SSRIs (430). In one study, combined treatment
medication from the same pharmacological class (e.g., with bupropion and an SSRI resulted in better outcomes
from one SSRI to another SSRI) or to one from a different than either therapy alone (431). Another commonly used
class (e.g., from an SSRI to a TCA) (369, 421422). Adding strategy is the combination of mirtazapine and an SSRI or
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 53
venlafaxine. Generally, mirtazapine 1530 mg at bedtime not all (456) clinical trials. Risperidone augmentation, in
is added to the incompletely effective antidepressant and doses of up to 3 mg daily (457, 458) also appears to improve
titrated up to 45 mg/day on the basis of response and tol- the response to antidepressant agents. In most of these trials,
erability (432). the onset of the effect of second-generation antipsychotic
For patients with pronounced anxiety or persistent augmentation has been rapid, although the magnitude of
insomnia not adequately relieved by an SSRI or SNRI, ad- the advantage relative to placebo has been relatively mod-
junctive use of anxiolytic and sedative-hypnotic medica- est. In the only two trials to utilize active comparison
tions is common (433, 434). These include benzodiazepines groups, the combination of olanzapine and fluoxetine was
such as clonazepam (435) and selective GABA agonists such not significantly more effective at study endpoint than con-
as zolpidem (436) and eszopiclone (437). Buspirone has also tinued therapy with nortriptyline (450) or venlafaxine (451).
been used adjunctively in anxious individuals (429). Al- Naturalistic follow-up data also suggest that long-term
though adjunctive therapy of anxiety or insomnia can has- weight gain can be problematic for many patients receiving
ten symptomatic relief, there is no evidence of sustained second-generation antipsychotic augmentation therapy,
benefit, and some patients have difficulty stopping the anx- particularly with the olanzapine-fluoxetine combination
iolytic or hypnotic medication (438, 439). (459). In addition, a recent meta-analysis suggests that the
Lithium, thyroid hormone, and stimulants are some- rate at which SGA augmentation is discontinued is nearly
times combined with antidepressants to augment re- four-fold greater than study discontinuation among sub-
sponse. Lithium is the most extensively studied of these jects randomly assigned to placebo (448). When compared
adjuncts (440443) and may also reduce the long-term with other strategies for antidepressant nonresponders, aug-
risk of suicide (444). The interval before full response to mentation with a second-generation antipsychotic carries
adjunctive lithium is said to be in the range of several days disadvantages: the high cost of many agents, the significant
to 6 weeks. The blood level required to enhance the ef- risk of weight gain and other metabolic complications (e.g.,
fects of antidepressants still has not been confirmed. If ef- dyslipidemia, hypertriglyceridemia, glucose dysregulation,
fective and well tolerated, lithium should be continued at diabetes mellitus), and potential risk of hyperprolactine-
least for the duration of acute treatment and perhaps be- mia, tardive dyskinesia, neuroleptic malignant syndrome,
yond the acute phase for purposes of relapse prevention. and QTc prolongation. Thus, the advantages and disadvan-
Thyroid hormone supplementation, even in euthyroid tages of antipsychotic medications should be considered
patients, may increase the effectiveness of antidepressant when choosing this augmentation strategy. In addition,
medication treatment, whether used as an augmentation when augmentation with a second-generation antipsychotic
agent (445, 446) or in combination with an antidepressant is effective, it is uncertain how long augmentation therapy
from the outset of therapy (447). The dose typically used should be maintained.
for this purpose is 25 mcg/day of triiodothyronine, in- Many clinicians find that augmentation of antidepres-
creased to 50 mcg/day if the response is inadequate after sants with low doses of stimulants such as methylphenidate
about a week. The duration of treatment required has not or dextroamphetamine may help ameliorate otherwise
been well studied. suboptimally responsive depression (460462), although
Second-generation antipsychotic medications may in- not all clinical trials have shown benefits from this strat-
crease the rates of response or remission of depressive egy (463). More recently, the novel compound modafinil
symptoms in patients who typically have not responded to has shown modest benefit when combined with SSRIs, re-
more than two medication trials (448), even when psy- lated to specific effects on residual symptoms such as fa-
chotic symptoms are not present. Generally, in clinical tigue and hypersomnolence (464467). Although there
practice, lower doses are used for antidepressant augmen- are no clear guidelines regarding the length of time stim-
tation than for treatment of psychosis. For example, the ulants or modafinil should be coadministered, in one ex-
combination of olanzapine and fluoxetine has been exten- tension study the effects of modafinil were maintained across
sively studied (449452) and is typically initiated with 6 mg 12 weeks of additional therapy (468). Physicians prescrib-
of olanzapine and 25 mg of fluoxetine daily and titrated up- ing modafinil for this off-label use should become familiar
ward as tolerated to a maximum of 18 mg of olanzapine and with rare but dangerous cutaneous reactions to it, includ-
75 mg of fluoxetine daily. Aripiprazole has received FDA ing reported instances of Stevens-Johnson syndrome,
approval for augmentation of antidepressive agents and is toxic epidermal necrolysis, drug rash with eosinophilia
typically initiated at 2.55 mg/day and titrated upward as and systemic symptoms (469), and cytochrome P450 in-
tolerated to a maximum of 30 mg/day (453). With quetia- teractions. Modafinil can also induce CYP 3A4 and render
pine, doses of 25 to 400 mg/day have been used, with ben- contraceptive medications and other medications metab-
efits for depressive symptoms found in some (454, 455) but olized through this route ineffective.
54 APA PRACTICE GUIDELINES
Although their use in this context has not been exten- toms that have not responded to repeated trials of antide-
sively evaluated, anticonvulsants such as carbamazepine, pressant treatment.
valproic acid, and lamotrigine may offer some benefit in
the treatment of medication-resistant major depressive
C. CONTINUATION PHASE
disorder (121, 429, 470473).
A rarely used strategy is the combined use of a TCA or Continuation phase pharmacotherapy is strongly recom-
trazodone and an MAOI (474, 475). The combination of a mended following successful acute phase antidepressant
TCA and an MAOI has been used for more than three therapy, with a recommended duration of continuation
decades for treatment of some of the most treatment- therapy of approximately 49 months (assuming good and
resistant depressive disorders; however, the risk of drug- consistent control of depression symptoms). The goal of
drug interactions necessitates careful monitoring (119). continuation treatment is to prevent relapse (i.e., the re-
Of particular concern with these combinations is the sero- emergence of significant depressive symptoms or dys-
tonin syndrome, characterized by delirium, hyperthermia, function) in the vulnerable period immediately following
hyperreflexia, myoclonus, and, rarely, death (see Section remission (i.e., a complete alleviation of symptoms) (408,
II.B.2.b.5.b). Use of an MAOI in combination with a 410, 411). The possibility of relapse should be carefully
TCA and related antidepressants should probably not be monitored during the continuation phase as this is when
considered until other pharmacological strategies for pa- risk of relapse is highest (483). Within the first 6 months
tients with treatment-resistant illness have been exhausted; following recovery from a major depressive episode, re-
psychiatrists and patients choosing to use the combina- lapse of depressive symptoms is common, with the propor-
tion of an MAOI and a TCA should be well acquainted tion of patients with relapse ranging from 20% of patients
with the potential hazards and carefully weigh the relative in mixed samples (484487) to as many as 85% of severely
risks and benefits of such a strategy. depressed inpatients receiving treatment with ECT (234,
Vagus nerve stimulation was approved for use in pa- 488, 489). These studies also show that relapse rates are
tients whose symptoms have not responded to at least greater if antidepressant treatment (including ECT) is
four adequate trials of antidepressant medications and/or discontinued or reduced in dose or intensity following re-
ECT. Acute benefits were not observed in the sham- covery (234, 489, 490). There is evidence that patients
controlled portion of the VNS trial (282). When com- who do not completely recover during acute treatment
pared with a parallel treatment-as-usual arm, the long- have a significantly higher risk of relapse (and a greater
term (12 year) open-label extension showed small (476, need for continuation treatment) than those who have no
477) but persistent (478) improvements in symptoms with residual symptoms (227, 491, 492). Similarly, patients
VNS that could be clinically significant for some patients. who have not fully achieved remission with psychother-
Other open-label studies have also shown some benefit apy are at greater risk of relapse in the near term (364,
when VNS is used simultaneously with pharmacotherapy 365, 367, 493, 494). To reduce the risk of relapse during
(479481). the continuation phase, treatment should generally con-
As with any surgical device implantation, there is a tinue at the same dose, intensity, and frequency that were
small risk of postsurgical infection (482). A majority of in- effective during the acute phase. Although the number of
dividuals experience hoarseness or voice alteration during randomized controlled trials of antidepressant medica-
stimulation, and coughing, dyspnea, and neck discomfort tions in the continuation phase is limited, the available
are common (281, 481) but generally are tolerable to pa- data indicate that patients treated for a first episode of un-
tients (282, 479). Patients also need to be informed of the complicated major depressive disorder who exhibit a sat-
implications of having an implanted VNS device for fu- isfactory response to an antidepressant medication should
ture medical care (482). For example, with a VNS device continue to receive a full therapeutic dose of that agent for
in place, brain MRI requires the use of a special send- at least 49 months after achieving full remission (105,
receive coil. The VNS device may affect the operation of 225, 495).
other implanted devices such as cardiac pacemakers or Published studies for the continuation phase with older
defibrillators and other procedures such as diathermy, and TCAs as well as newer medications have consistently
whole body or radiofrequency receive-only MRI are con- shown efficacy of these medications in preventing relapse,
traindicated. VNS is also contraindicated in the presence compared with placebo. Lithium has also been shown to
of bilateral or left cervical vagotomy. have efficacy in preventing relapse (496).
Relative to other antidepressive treatments, the role of Cognitive-behavioral therapy may prevent relapse of
VNS remains a subject of debate. However, it could be depression when used as augmentation to medication
considered as an option for patients with substantial symp- treatment. It may also bestow an enduring, protective ben-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 55
efit that reduces the risk of relapse after the treatment has termine whether any specific precipitants are contributing
ended (363). Cognitive group therapy helps to prevent re- to the relapse of depression. For example, the onset or
lapse and recurrence for patients in remission after a ma- worsening of psychosocial stressors, substance use disor-
jor depressive episode (497). Mindfulness-based cognitive ders, or general medical conditions can contribute to in-
therapy is a variant of cognitive therapy that encourages creased depressive symptoms. In addition, decreased
patients to pay attention to their thoughts and feelings in treatment adherence or reductions in medication blood
the moment and to accept them rather than judging or levels (e.g., due to drug-drug interactions or increased cig-
trying to change or disprove them. Among patients with arette use) can also prompt a depressive relapse.
remitted depression, mindfulness-based cognitive ther-
apy groups may reduce risk of relapse for patients who
D. MAINTENANCE PHASE
have already experienced three or more episodes (498).
Such benefits for CBT (and potentially, for other psycho- Patients with chronic and/or recurrent major depressive
therapies) would offer an advantage over pharmacother- disorder who complete the continuation phase without
apy, which works only as long as the patient continues the relapse proceed to the maintenance phase of treatment, in
antidepressant medication. which the goal is to protect susceptible patients against re-
Continuation therapy is also essential in reducing re- currence of subsequent depression.
lapse risk after an acute course of ECT (239). Although Patients who have had three or more prior major de-
relapse occurs for many patients regardless of continua- pressive episodes should receive maintenance treatment.
tion strategy (234, 488, 489), remission of symptoms fol- Within the first 6 months following recovery from a ma-
lowing successful treatment with ECT may be maintained jor depressive episode, 20% of patients will experience a
with either pharmacotherapy or continuation ECT (234). recurrence (484). Between 50% and 85% of patients will
Research shows that continuation ECT is comparable in have at least one lifetime recurrence, usually within 2 or 3
efficacy to the combination of nortriptyline and lithium years (502), although there is little consistency in the time
(234) and that the latter combination is superior to to recurrence for any individual patient (484). Patients
nortriptyline alone in preventing relapse (489). Although who have had a prior major depressive episode also have a
there is limited information regarding prognostic factors, high risk of experiencing subsequent affective episodes
relapse may be less likely among patients with melan- other than another major depressive episode, such as a
cholic depression who receive continuation ECT after re- manic, hypomanic, or dysthymic episode (503). The num-
mission with acute ECT than among those who receive ber of lifetime major depressive episodes is significantly
continuation pharmacotherapy after remission with acute associated with the probability of recurrence, such that the
ECT (499). risk of recurrence increases by 16% with each successive
Given the significant risk of relapse during the contin- episode (484).
uation phase of treatment, it is essential to assess depres- Maintenance therapy should be considered more
sive symptoms, functional status, and quality of life in a strongly for patients with additional risk factors for recur-
systematic fashion, which can be facilitated by the use of rence, such as the presence of residual symptoms, ongoing
periodic, standardized measurements. It is often helpful psychosocial stressors, family history of mood disorders,
for patients and families to identify particular signs (e.g., and the severity of prior episodes (504) (see Table 10). Ad-
lack of engagement in specific activities that are usually en- ditional considerations that may play a role in the decision
joyed, specific signal symptoms or patterns of thought) to use maintenance therapy include patient preference,
that are typical of their earlier depressive episodes and may the presence of side effects during continuation therapy,
suggest the beginnings of a depressive relapse. Further- and the severity of prior depressive episodes, including
more, any sign of symptom persistence, exacerbation, or factors such as psychosis or suicide risk. Due to the risk of
reemergence or of increased psychosocial dysfunction recurrence and the importance of early detection of recur-
during the continuation period should be viewed as a har- rent symptoms, patients should be monitored periodically
binger of possible relapse. and in a systematic fashion during the maintenance phase;
If a relapse does occur during the continuation phase, a such assessments can be facilitated by the use of standard-
return to the acute phase of treatment is required. An initial ized rating scales, as described in Section II.A.8.
step is often to increase the dose of medication (500) or, In general, the treatment that was effective in the acute
with continuation ECT, to increase the frequency of and continuation phases should be used in the maintenance
treatment (501). For patients receiving psychotherapy, an phase.
increased frequency of sessions or a shift in the psycho- Among the therapeutic options available for mainte-
therapeutic focus may be needed. It is also essential to de- nance treatment, antidepressant medications have received
56 APA PRACTICE GUIDELINES
TABLE 10. Risk Factors for Recurrence of Major Depressive less, several studies have shown that acute psychotherapies
Disorder for major depressive disorder also have maintenance ben-
efits. For example, even once-monthly maintenance IPT
Persistence of subthreshold depressive symptoms
has been shown to forestall relapse in patients at high risk
Prior history of multiple episodes of major depressive for relapse (289, 314, 315, 513). Most of these studies have
disorder used once-monthly maintenance IPT, but research has
Severity of initial and any subsequent episodes not demonstrated that frequency of sessions affects out-
Earlier age at onset come (289). In one study, maintenance cognitive therapy
Presence of an additional nonaffective psychiatric delivered over 2 years was as effective as maintenance
diagnosis medication for recurrent major depressive disorder (514).
Presence of a chronic general medical disorder Combining psychotherapysuch as CBT, cognitive ther-
apy, or IPTwith pharmacotherapy in the maintenance
Family history of psychiatric illness, particularly mood
phase has also been considered by investigators. Some
disorder
results suggest that the combination of antidepressant
Ongoing psychosocial stressors or impairment
medications plus psychotherapy may be more effective in
Negative cognitive style preventing relapse than treatment with single modalities
Persistent sleep disturbances (314, 365, 506, 515, 516).
For patients receiving treatment with pharmacother-
the most study. There have been more than 30 trials of phar- apy and/or psychotherapy, the frequency of visits during
macotherapy in the maintenance phase, and results have the maintenance phase should be set according to the
generally demonstrated the effectiveness of antidepres- clinical condition and the specific treatments being used.
sant medication for relapse prevention (105, 226, 314, 505 The frequency can range from as low as once every several
507). Many of these trials used TCAs (314, 506), although months for stable patients who require only psychiatric
results of trials involving newer antidepressant medica- management and medication monitoring to as high as
tions have been assessed in a recent meta-analysis (507). once or twice per week for those receiving psychodynamic
Lithium has also been used as maintenance treatment for psychotherapy. For CBT and IPT, maintenance-phase
major depressive disorder (441). Despite this, there is lim- treatments usually involve a decreased frequency of visits
ited information on many of the clinical decisions involving (e.g., once a month). The duration of the maintenance
medication use in the maintenance phase. Even though phase will vary depending on the frequency and severity
lower doses of medication are less likely to produce side of prior major depressive episodes, the tolerability of
effects, results from one study suggest that full doses are treatments, and patient preferences. For many patients,
superior to lower doses in the maintenance phase (508). some form of maintenance treatment may be required in-
Particularly if medications are well-tolerated, it is gener- definitely.
ally advisable to prescribe the same antidepressant medi- Electroconvulsive therapy has also been used in the
cation doses for maintenance therapy that were effective maintenance phase, although evidence for its benefits
in prior phases of treatment. Even with adequate mainte- comes largely from case reports (239). Patients who exhibit
nance treatment, pharmacotherapy is not invariably suc- repeated episodes of moderate or severe major depressive
cessful in preventing relapse and return of symptoms, which disorder despite optimal pharmacological treatment or pa-
still occur in as many as 25% of individuals (509, 510). It is tients who are medically ineligible for such treatment may
unclear whether some relapses during maintenance ther- be maintained with periodic ECT. Although the optimal
apy are loss of therapeutic efficacy, a phenomenon that frequency and duration of maintenance phase ECT treat-
has been referred to as tachyphylaxis, but many such re- ments has not been well studied, maintenance ECT is
lapses appear related to inadequate prophylactic effects often administered monthly; individuals for whom this
of medication (511). When relapses occur, clinicians is insufficient may find treatment at more frequent inter-
typically address them using the same approaches described vals to be beneficial (501).
to treat incomplete responses to treatment, such as in-
creasing the dose of medication, changing to a different
E. DISCONTINUATION OF TREATMENT
medication, or adding another medication or a depression-
focused psychotherapy to augment therapeutic response If maintenance-phase treatment is not indicated, stable
(510, 512). patients may be considered for discontinuation of treat-
There have been fewer investigations of the effective- ment after the continuation phase. The precise timing
ness of psychotherapy in the maintenance phase. Nonethe- and method of discontinuing psychotherapy and pharma-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 57
cotherapy for major depressive disorder have not been have their medications tapered gradually over a longer pe-
systematically studied. riod (518, 519). Another strategy is to change to a brief
The decision to discontinue treatment should be based course of fluoxetine, e.g., 10 mg for 12 weeks, and then
on the same factors considered in the decision to initiate discontinue the fluoxetine (165). The psychiatrist should
maintenance treatment (Table 10), including the probabil- closely monitor patients withdrawing from antidepres-
ity of recurrence, the frequency and severity of past epi- sants and provide reassurance that symptoms are time-
sodes, the persistence of depressive symptoms after limited and can be addressed by more gradual tapering
recovery, the presence of co-occurring disorders, and pa- (see Section II.B.2.b.1.i).
tient preferences. The type of treatment being received How to end psychotherapy is typically dependent on
may also play a role in the decision making. In general, the type of therapy. For time-limited approaches, termi-
psychotherapy has a longer lasting treatment effect and nation is usually broached from the initiation of treatment
carries a lower risk of relapse following discontinuation and periodically revisited, as the therapist-patient dyad
than pharmacotherapy. In terms of timing, patients should notes which session they are in, how many remain, and
be advised not to discontinue medications before holidays, how they have progressed toward defined goals. In dy-
significant events (e.g., weddings), or stressful events. namically oriented psychotherapy, the therapist typically
Patients should be carefully monitored during and im- raises termination as an issue well in advance of the final
mediately after treatment discontinuation to ensure that session, using the opportunity to explore remaining and
remission is stable. The highest risk for a relapse is seen in unresolved issues in transference.
the first 2 months after discontinuation of treatment. Before the discontinuation of active treatment, pa-
Hence, it is important to schedule a follow-up visit during tients should be informed of the potential for a depressive
this period to ensure stability. relapse. Early signs of major depressive disorder should be
When pharmacotherapy is being discontinued, it is reviewed, often with a family member, and a plan estab-
best to taper the medication over the course of at least lished for seeking treatment in the event of recurrent
several weeks. Such tapering allows for the detection of symptoms. Patients should continue to be monitored
recurring symptoms at a time when patients are still par- over the next several months to identify early evidence of
tially treated and therefore more easily returned to full recurrent symptoms. Again, systematic assessment of
therapeutic treatment if needed. In addition, such taper- symptoms, side effects, adherence, and functional status
ing can help minimize the incidence of antidepressant during this period of high vulnerability is strongly rec-
medication discontinuation syndromes, particularly with ommended. If a patient does suffer a recurrence after dis-
paroxetine and venlafaxine (98, 163, 164). Discontinuation continuing medication, treatment should be promptly
syndromes are problematic because their symptoms in- reinitiated. Usually, the previous treatment regimen to
clude disturbances of mood, energy, sleep, and appetite which the patient responded in the acute and continuation
and can therefore be mistaken for or mask signs of relapse phases should be reinitiated (520). Patients who have a re-
(517). Consequently, patients should be advised not to currence following discontinuation of antidepressant
stop medications abruptly and to take medications with therapy should be considered to have experienced another
them when they travel or are away from home. Discontin- major depressive disorder episode and should receive
uation syndromes have been found to be more frequent af- adequate acute-phase treatment followed by continua-
ter discontinuation of medications with shorter half-lives, tion-phase treatment and possibly maintenance-phase
and patients maintained on short-acting agents should treatment.
apy and psychotherapy. In patients at high risk for suicide creased mortality in the study subjects as a result of suicide
and in whom a particularly rapid antidepressant response (531). To alert clinicians to the need for vigilance and
is required, consideration should be given to the use of communication during the initial phase of antidepressant
ECT (239, 243, 521). Patients with major depressive dis- treatment, the FDA has issued a black-box warning per-
order who present to an emergency department with sui- taining to children, adolescents, and young adults that ad-
cidal ideation, or who have made a suicide attempt, should vises of this increase in the risk of suicidal thinking and
be triaged to determine their level of safety and establish behavior; information on the warning is available on the
the appropriate level and setting of care. Upon entrance FDA Web site at http://www.fda.gov/cder/drug/antide-
to the emergency department, they should be searched to pressants/default.htm. In making decisions about treat-
permit removal of potentially dangerous items, such as ment, this awareness of a potential increase in suicidal
weapons and personal belongings that could cause harm thinking and behavior in children, adolescents, and young
(e.g., sharp objects, belts, shoes, medications). Factors to adults must be balanced against the negative effects, in-
consider in determining the nature and intensity of treat- cluding suicide, of untreated depression (532) as well as
ment include (but are not limited to) access to and lethal- the demonstrated benefits of antidepressant treatment
ity of suicide means, past and family history of suicidal (523, 533535). For adults age 65 years or older, a review
behavior, co-occurring substance abuse, the availability of the evidence from clinical trials showed a decrease in
and adequacy of social supports, and the nature of the the risk of suicidal thinking or behaviors with antidepres-
doctor-patient alliance. sant treatment, with no change in risk detected for other
To lower the risk of suicide, the psychiatrist should also adults (age 25 to 64 years) (536).
treat modifiable risk factors, such as anxiety (especially For additional details about the treatment of suicidal
panic attacks), insomnia, agitation, psychotic symptoms, individuals, clinicians are encouraged to consult APAs
and substance abuse (22), in addition to treating the major Practice Guideline for the Assessment and Treatment of Pa-
depressive episode. Among inpatients who died by suicide, tients With Suicidal Behaviors (22).
Busch et al. (522) observed that a great majority were
admitted for indications other than suicidal ideation, and b. Major depressive disorderrelated cognitive dysfunction
anxiety and agitation were common, suggesting that such Cognitive inefficiency and impairment are common fea-
symptoms should be addressed if they are present. Family tures of major depressive disorder. Many depressed patients
members can also play an important role in detecting and report slowed thoughts, poor concentration, distractibility,
preventing suicidal behaviors. When permitted by the pa- and reduced capacity to process information. They also dis-
tient, the psychiatrist should educate those close to the play diminished attention to self-care and to their environ-
patient concerning appropriate interventions and encour- ment. Transient cognitive impairment, especially involving
age communication. attention, concentration, and memory storage and retrieval,
There has been a growing controversy about the risk of are demonstrable through neuropsychological testing (537).
suicidal ideas and behaviors (sometimes referred to as In extreme cases, especially in elderly patients, these deficits
suicidality) after initiation of antidepressant treatment. are so prominent that patients appear to have dementia. For
Although information on such risk continues to evolve, a individuals who exhibit symptoms of a dementia syndrome,
predictive relationship to suicide has never been demon- it is crucial that any underlying depressive disorder be iden-
strated. Clinical experience has long suggested that pa- tified and treated.
tients may develop the energy and capacity to act on self- Among depressed patients, the differential diagnosis of
destructive plans made earlier in the course of their illness cognitive dysfunction includes degenerative dementias
if neurovegetative and psychomotor symptoms respond (such as Alzheimers disease and Picks disease) and revers-
to antidepressant treatment before mood improves. More ible causes (such as vitamin B12 deficiency, folate deficiency,
recently, meta-analyses of data from clinical trials have testosterone deficiency, substance use). Several clinical fea-
shown statistically significant increases in suicidal thoughts tures help distinguish major depressive disorderrelated
or behaviors in individuals age 25 years or younger who cognitive dysfunction from other dementia syndromes.
are treated with antidepressant medication, compared When performing cognitive tasks, depressed patients gen-
with placebo, with an approximately 1.5- to 2.5-fold in- erally exert less effort and report greater incapacity than do
crease in the relative risk (26, 523530). In percentage patients with dementia. The latter, especially in more ad-
terms, it is estimated that one to three of 100 individuals vanced stages, typically do not recognize their cognitive
age 25 years or younger could potentially have an increase failures, since insight is impaired. In contrast, depressed
in suicidal thoughts or behaviors with antidepressant patients may report being unable to think or remember.
treatment (26), although there has been no evidence of in- Patients with major depressive disorderrelated cognitive
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 59
dysfunction lack the signs of cortical dysfunction (i.e., apha- by at least two of the following manifestations: immobil-
sia, apraxia, agnosia) encountered in dementias such as ity, as evidenced by catalepsy or stupor; extreme agitation;
Alzheimers disease (538, 539). Nevertheless, distinguishing extreme negativism; peculiarities of voluntary movement,
dementia from depression-related cognitive dysfunction as evidenced by posturing, stereotyped movements, man-
can be difficult, particularly as the two may coexist. For fur- nerisms, or grimacing; and echolalia or echopraxia (556,
ther discussion of the co-occurrence of dementia and de- 557). The presence of catatonia should prompt a thor-
pression, the reader may also wish to consult APAs Practice ough differential diagnosis as it can also occur in asso-
Guideline for the Treatment of Patients With Alzheimers Dis- ciation with general medical conditions and with several
ease and Other Dementias, Second Edition (539). other psychiatric disorders, including bipolar disorder
The detection of major depressive disorderrelated and schizophrenia (556, 558, 559). Catatonic signs often
cognitive dysfunction alerts the psychiatrist to the need dominate the clinical presentation and may be so severe as
for treatment of the underlying major depressive disorder, to be life-threatening, compelling the consideration of ur-
which should in turn reduce the signs and symptoms of gent somatic treatment. Patients with catatonic features
the cognitive dysfunction. Although initially reversible, may also need supportive medical interventions including
major depressive disorderrelated cognitive dysfunction hydration, nutrition, prophylaxis against deep vein throm-
increasingly appears to be a harbinger of subsequent de- bosis, turning to prevent bed sores, and passive range of
mentia (540, 541). In addition, research suggests that cer- motion to prevent contractures. Intravenous administra-
tain types of executive cognitive dysfunction predict greater tion of a benzodiazepine (e.g., lorazepam, diazepam) or a
disability and limited treatment response in geriatric pa- barbiturate (e.g., amobarbital) may induce rapid relief
tients with depression (542, 543). (242, 553) and can be followed by continued oral admin-
istration for patients who show an initial response. When
2. DSM depressive subtypes such intervention is ineffective, the clinician should con-
sider the urgent use of ECT (239, 242). The efficacy of
a. Psychotic features ECT in catatonia is well documented in the case series
Major depressive disorder is sometimes accompanied by literature (239) and is usually apparent after a few treat-
hallucinations or delusions, which may be congruent or ments. After catatonic manifestations recede, antidepres-
incongruent with the depressed mood. Recognition of sant medication treatments may be needed during acute
psychosis is essential among patients with major depres- and maintenance phases of treatment. In addition to anti-
sive disorder as it is often undetected, resulting in ineffec- depressant medications, ongoing treatment may include
tive treatment (544546). Psychotic features constitute a ECT, lithium, antipsychotics, or a combination of these
risk factor for recurrent major depressive disorder and re- approaches, depending upon the patients condition. Pa-
current psychosis and hence indicate the need for mainte- tients with catatonia may have an increased susceptibility
nance treatment. to neuroleptic malignant syndrome when exposed to an-
Electroconvulsive therapy is highly effective in treating tipsychotic medications (560), and this should be consid-
psychotic depression (241) and can be considered as a ered in planning treatment.
first-line treatment option whenever major depressive
disorder is associated with psychotic features (239, 243, c. Melancholic features
547). Pharmacotherapy can also be used as a first-line Melancholic features describe characteristic somatic
treatment option for major depressive disorder with psy- symptoms, such as the loss of interest or pleasure in all, or
chotic features. Psychotic depression typically responds almost all, activities or a lack of reactivity to usually plea-
better to the combination of an antipsychotic and an an- surable stimuli. Other symptoms include worsened de-
tidepressant medication rather than treatment with either pression in the morning, early morning awakening, and
component alone (547549), although some research has significant anorexia or weight loss, among others (16).
shown comparable responses for antidepressive treatment Major depressive disorder with melancholic features is re-
or antipsychotic treatment alone (550, 551). Lithium aug- sponsive to both pharmacotherapy and ECT. Serotonin
mentation is helpful for some patients who have not re- norepinephrine reuptake inhibitors and TCAs may have
sponded to combined treatment with antidepressant and an advantage over SSRIs for this patient population (561,
antipsychotic medication (262, 552). 562). Psychotherapy may be less appropriate for patients
with melancholia (563), particularly if the symptoms pre-
b. Catatonic features vent engagement with the therapist (e.g., lack of interest
A catatonic syndrome sometimes occurs in the context of in activities). Major depressive disorder with melancholic
major depressive disorder (553556) and is characterized features may also be associated with an added risk of sui-
60 APA PRACTICE GUIDELINES
cide (564) and an increased risk of subsequent recurrence The entire range of treatments for major depressive
despite the use of maintenance pharmacotherapy (509). disorder may be used to treat major depressive disorder
with seasonal pattern, either in combination with or as an
d. Atypical features alternative to light therapy. As a primary treatment, light
Major depressive disorder with atypical features is charac- therapy may be recommended as a 1- to 2-week time-limited
terized by a pattern of marked mood reactivity and at least trial (395), primarily for outpatients with clear seasonal
two additional symptoms, including leaden paralysis, a patterns. For patients with more severe forms of major
long-standing pattern of interpersonal rejection sensitivity, depressive disorder with seasonal pattern, the use of light
significant weight gain or increase in appetite, and hyper- therapy is considered adjunctive to pharmacological in-
somnia (the latter two of which are considered reversed tervention. In terms of specific antidepressive agents, the
vegetative symptoms) (16). The phrase atypical features extended release formulation of bupropion is FDA approved
distinguishes this depressive subtype from the more classi- for use with patients who have major depressive disorder
cal endogenous presentation of depression, but it does with seasonal pattern.
not connote an uncommon or unusual form of depression.
Atypical features are more common in women, are associ-
3. Co-occurring psychiatric disorders
ated with an earlier age at onset of depression and a greater
degree of associated anxiety disorders, and frequently have Co-occurring psychiatric disorders generally complicate
a more chronic, less episodic course, with only partial in- treatment. Patients with major depressive disorder who
terepisode recovery (565, 566). These atypical features are also have other psychiatric disorders have greater symp-
also common in the depressed phase of bipolar I disorder tom severity and are more challenging to treat than pa-
and bipolar II disorder (567, 568), indicating a need for tients with major depressive disorder alone. Yet the
careful screening for manic or hypomanic episodes in pa- presence of co-occurring Axis I or Axis II disorders should
tients who present with atypical depressive symptoms. not lead clinicians to conclude that patients are untreat-
In the treatment of major depressive disorder with able. Furthermore, other Axis I or Axis II disorders may
atypical features, MAOIs have greater efficacy than TCAs masquerade as major depressive disorder or may seem to
(122, 569572). Some data also support the use of SSRIs, co-occur with the depression. In these cases, the other ap-
bupropion, and CBT in this patient population (573 parent disorders evanesce with successful treatment of the
577). Electroconvulsive therapy is also effective in treat- underlying major depressive disorder.
ing patients with atypical features (578). The presence and
a. Dysthymic disorder
severity of specific symptoms as well as safety consider-
ations should help guide the choice of treatment for major Dysthymic disorder is a chronic mood disorder with
depressive disorder with atypical features. For example, if symptoms that fall below the threshold for major depres-
a patient does not wish to, cannot, or appears unlikely to sive disorder. Because of this, it may escape notice and
adhere to the dietary and medication precautions associ- may be inadequately treated. Nonetheless, it can cause
ated with MAOI treatment, the clinician should consider significant suffering and disability. In some patients, both
alternative antidepressant medication or psychotherapy. dysthymic disorder and major depressive disorder (so-
called double depression) may be diagnosed.
e. Seasonal pattern In the treatment of dysthymic disorder and chronic
A seasonal pattern of major depressive disorder is charac- major depressive disorder, there is demonstrated efficacy
terized by a regular temporal relationship between partic- for antidepressant medications, including TCAs, SSRIs,
ular periods of the year and the onset and remission of other newer agents, and MAOIs. Unfortunately, clinical
symptoms, which is not the result of seasonally related trials provide little evidence of the relative efficacies of
psychosocial stressors (e.g., seasonal unemployment, sig- particular agents (105, 579). In general, pharmacotherapy
nificant anniversaries). The most common presentation of dysthymic disorder resembles that for episodes of
in the northern hemisphere is the regular appearance of major depressive disorder; responses to antidepressant
symptoms between early October and late November and medications by patients with dysthymic and chronic
regular remission from mid-February to mid-April. Epi- major depressive disorders have been comparable to the
sodes of major depressive disorder with seasonal pattern responses by patients with major depressive disorder
frequently have atypical features such as hypersomnia and episodes (580). In double depression, antidepressant
overeating. Some of these patients experience manic or medication can reverse not only the acute major depres-
hypomanic episodes as well; hence, it is important to di- sive episode but also the co-occurring dysthymic disorder
agnose bipolar disorder when appropriate. (581).
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 61
Patients with dysthymic disorder, as well as patients sessive-compulsive disorder may appear as a co-occurring
with chronic and severe major depressive disorder, typi- condition in some patients with major depressive disor-
cally have a better response to the combination of phar- der. Clomipramine and SSRIs have demonstrated efficacy
macotherapy and psychotherapy than to either alone in managing obsessive-compulsive symptoms in addition
(294, 295), although results of combined treatment stud- to treating depression (593595).
ies have been mixed and complicated by methodological
problems (582). c. Dementia
Patients with dementia are predisposed to depression, and
b. Anxiety disorders the psychiatrist should therefore screen for depression in
As a group, anxiety disorders are the most commonly oc- this population, although this is sometimes challenging
curring psychiatric disorders in patients with major de- (539). One screening tool is the Cornell Scale for Depres-
pressive disorder (583). A 2005 epidemiological study sion in Dementia, which incorporates self-report with
found that among individuals with major depressive dis- caregiver and clinician ratings of depressive symptoms
order, 62% also met the criteria for generalized anxiety (596). Treatment of major depressive disorder in the cog-
disorder, 52% for social phobia, 50% for posttraumatic nitively impaired patient requires careful supervision and
stress disorder (PTSD), 48% for panic disorder, 43% for monitoring of the patients pharmacotherapy; this may
specific phobia, and 42% for obsessive-compulsive disor- entail education of home health aides, nursing home staff,
der (584). In addition, agitation and anxiety, including and others. Antidepressants are likely to be efficacious in
panic attacks, are frequent co-occurring symptoms of treatment of depressive symptoms, but they do not im-
major depressive disorder. The appearance of anxiety and prove cognition, and data on antidepressant use in pa-
agitation in patients in a major depressive episode, particu- tients with dementia are limited (597599). Individuals
larly when accompanied by racing or ruminative thoughts, with dementia are particularly susceptible to the adverse
should alert the clinician to the possibility of a mixed effects of muscarinic blockade on memory and attention.
mood state of a bipolar spectrum disorder (585). Therefore, individuals with dementia generally do best
In studies of major depressive disorder with a co- when given antidepressant medications with the lowest
occurring anxiety disorder, both depressive symptoms and possible degree of anticholinergic effect, e.g., bupropion,
anxiety symptoms respond to antidepressant medication fluoxetine, sertraline, trazodone, and, of the tricyclic
treatment (586). However, TCAs and SSRIs may initially agents, desipramine or nortriptyline (600). Alternatively,
worsen rather than alleviate anxiety symptoms, including some patients do well when given stimulants in small
panic attacks; patients should be so advised, and these doses. Electroconvulsive therapy is also effective in major
medications should be introduced at low doses and slowly depressive disorder superimposed on dementia. It should
increased when treating such patients. Adjunctive anti- be used if medications are associated with an excessive risk
panic agents, such as benzodiazepines, may be necessary of adverse effects, are not tolerated, or if immediate reso-
as well. Selective serotonin reuptake inhibitors are bene- lution of the major depressive disorder episode is medi-
ficial for patients with co-occurring depression and social cally indicated (such as when it interferes with the
anxiety disorder (587) and co-occurring depression and patients acceptance of food). In individuals with demen-
PTSD (588). Bupropion is comparable to SSRIs in the tia, ECT treatment may be associated with a transient
treatment of patients with major depressive disorder and worsening of the patients cognitive status (239, 601, 602).
low to moderate levels of anxiety (82), but studies vary as APAs Practice Guideline for the Treatment of Patients With
to whether bupropion is (589) or is not (590) effective in Alzheimers Disease and Other Dementias, Second Edition
the treatment of panic disorder. Because benzodiazepines (539) contains more information about the treatment of
are not antidepressants and carry their own adverse effects depression and dementia.
and toxicity, including abuse and dependence, benzodiaz-
epines should not be the primary pharmacological agents d. Substance use disorders
for patients with major depressive disorder who have co- Major depressive disorder frequently occurs with alcohol
occurring anxiety symptoms. These agents may be used or other substance abuse or dependence. Therefore, the
adjunctively with other antidepressive treatments, how- psychiatrist should obtain a detailed history of the pa-
ever (591). Psychotherapies such as CBT, behavioral ther- tients substance use. With the patients permission, family
apy, and IPT may also be used to treat anxiety symptoms members, friends, or co-workers can be collateral sources
in the context of major depressive disorder (591, 592). of information. If the evaluation reveals a substance use
Obsessive-compulsive symptoms are also common in disorder, this should be addressed in treatment. A patient
patients with major depressive episodes. In addition, ob- with major depressive disorder who has a co-occurring
62 APA PRACTICE GUIDELINES
substance use disorder is more likely to require hospital- depressive disorder should generally be the initial target;
ization, more likely to attempt suicide, and less likely to if evidence of a personality disorder persists when the de-
adhere to treatment than a patient with major depressive pressive symptoms have resolved, psychotherapeutic and
disorder of similar severity uncomplicated by substance adjunctive pharmacotherapeutic approaches may be help-
use (603608). ful (610615). Patients with virtually any personality dis-
Detoxifying patients before initiating antidepressant order exhibit a less satisfactory antidepressant medication
medication therapy is advisable when possible (110). An- treatment response, in terms of both social functioning
tidepressants may be used to treat depressive symptoms and residual major depressive disorder symptoms, than do
following initiation of abstinence if symptoms do not im- individuals without personality disorders (616). Personal-
prove over time. It is difficult to identify patients who should ity disorders tend to interfere with treatment adherence
begin a regimen of antidepressant medication therapy and development of a psychotherapeutic relationship. Fur-
soon after initiation of abstinence, because depressive thermore, many personality disorders increase the risk of
symptoms may have been induced by intoxication and/or episodes and increase time to remission of major depres-
withdrawal of the substance. A family history of major de- sive disorder (617, 618). Patients with various personality
pressive disorder, a history of major depressive disorder disorders also showed high rates of new-onset major de-
preceding alcohol or other substance abuse, or a history of pressive episodes in a large prospective study (619) and were
major depressive disorder during periods of sobriety raises at higher risk of attempting suicide than patients without
the likelihood that the patient might benefit from antide- a co-occurring personality disorder (620).
pressant medication, which may then be started early in Axis II diagnoses should be made with caution during a
treatment. Comparing the temporal pattern of symptoms major depressive episode, as depressive symptoms may ex-
with the periods of use and abstinence of the substance aggerate or mimic personality traits. Treatment of the de-
may help to clarify the patients diagnosis. Repeated, lon- pressive disorder for these patients can cause the apparent
gitudinal psychiatric assessments may be necessary to dis- personality disorder symptoms to remit or greatly dimin-
tinguish substance-induced depressive disorder from co- ish. Depressed patients may believe that their current
occurring major depressive disorder, particularly because symptoms have been present from early life, when in fact
some individuals with substance use disorders reduce they only began with the current episode. Such misper-
their substance consumption once they achieve remission ceptions often hinder accurate diagnosis. Some Cluster C
of a co-occurring major depressive disorder. personality disorders (e.g., avoidant, dependent, obses-
Co-occurring substance use, especially with stimulant sive-compulsive) may reflect the residual impact of recurrent
drugs, raises the risk of deleterious interactions with MAOIs, depressive symptoms and may remit with maintenance
although few such events have been reported (609). Ben- therapy (621).
zodiazepines and other sedative-hypnotics carry the po- Patients with borderline personality disorder have a
tential for abuse or dependence and should rarely be particularly high rate of major depressive disorder: 20%
prescribed to patients with co-occurring substance use in a community sample (622) and 50% in clinical samples
disorders, except as part of a brief detoxification regimen. (623). About 10%15% of patients with major depressive
Hepatic dysfunction and hepatic enzyme induction fre- disorder have co-occurring borderline personality disor-
quently complicate pharmacotherapy of patients with al- der (624), and the percentage increases significantly in
coholism and other substance abuse. These conditions hospital and partial hospital samples. Patients with bor-
may require careful monitoring of blood levels (as appro- derline personality disorder often exhibit mood lability,
priate for the medication), therapeutic effects, and side ef- rejection sensitivity, inappropriate intense anger, and de-
fects to avoid the opposing risks of either psychotropic pressive mood crashes. These symptoms are also com-
medication intoxication or underdosing. mon in patients with depression, particularly with atypical
For individuals with nicotine dependence who wish to features, complicating the diagnosis of these disorders.
stop smoking, bupropion and nortriptyline treatment in- Antidepressants are in general less effective in treating de-
crease smoking cessation rates by about twofold (109) and pressive episodes in patients with major depressive disor-
would be useful to consider when selecting a specific an- der and borderline personality disorder (625629), with
tidepressive agent (110). an overall response rate to all therapies of 20% (630).
For patients with major depressive disorder and border-
e. Personality disorders line personality disorder, the personality disorder must
For patients who exhibit symptoms of both major depres- also be addressed in treatment. Symptoms of both dis-
sive disorder and a personality disorder, psychiatrists orders can initially be treated with an SSRI or SNRI. Be-
should consider appropriate treatment for each. Major havioral impulsivity and dyscontrol can also be treated
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 63
with low-dose antipsychotics, lithium, and some antiepi- important relationship or life role. This is particularly
leptic medications. Monoamine oxidase inhibitors, al- true in initial episodes of depression, with psychosocial
though efficacious, are not recommended due to the risk of stressors being less associated with the onset of recurrent
serious side effects and the difficulties with adherence to episodes (632). Lower socioeconomic status, nonmarried
dietary restrictions. Psychotherapeutic approaches such as status, unemployment, urbanization, and violent trauma
dialectical behavioral therapy and psychodynamic psy- seem to increase the risk of developing major depressive
chotherapy have been useful in treatment of borderline disorder, whereas religious belief may decrease it (633
personality disorder as well. In patients with borderline 635). Among those exposed to trauma, the prevalence of
personality disorder particular attention must be paid to major depressive disorder seems to be higher among per-
the maintenance of therapeutic rapport, which is frequently sons who develop PTSD than among those who do not
disrupted, and to the risk of self-harm and suicide, which (636). A recent meta-analysis underlined that among ref-
occurs in 8%10% of such individuals. More information ugees, PTSD was diagnosed in one of 10 and one in 20 had
about the treatment of borderline personality disorder can major depressive disorder (637).
be found in APAs Practice Guideline for Treatment of Patients Marital discord has been identified as a potent risk factor
With Borderline Personality Disorder (610). in women for the development of depression (638, 639).
Problems in the family setting may become an ongoing
f. Eating disorders stressor that hampers the patients response to treatment.
Eating disorders are also common in patients with major Ambivalent, abusive, rejecting, or highly dependent family
depressive disorder (631). Selective serotonin reuptake relationships may predispose an individual to major depres-
inhibitors are the best studied medications for treatment sive disorder. The psychiatrist should screen for such fac-
of eating disorders, with fluoxetine having the most evi- tors and consider family therapy, as indicated, for these
dence for the effective treatment of bulimia nervosa (170). patients. Family therapy may be conducted in conjunction
Antidepressants may be less effective in patients who are with individual and pharmacological therapies. Even for in-
severely underweight or malnourished, and normalizing stances in which there is no apparent family dysfunction, it
weight should take priority in these patients. Although is important to provide the family with education about the
SSRIs and psychotherapy are widely used for patients nature of the illness and to enlist the familys support and
with anorexia nervosa, the evidence base on which these cooperation with the treatment.
practices rest is modest. Patients with chronic anorexia The psychiatrist may choose to treat a major depressive
nervosa have in general been less responsive to formal episode with an antidepressant, even if a major stressor
psychotherapy. On the other hand, evidence strongly sup- preceded the episode. Nonetheless, attention to the rela-
ports the use of CBT in the treatment of bulimia nervosa. tionship of both prior and concurrent life events to the
Other therapies (e.g., IPT, group therapies, family ther- onset, exacerbation, or maintenance of major depressive
apy) and medications such as SSRIs have also been studied disorder symptoms is an important aspect of the overall
and have demonstrated effectiveness for this disorder. treatment approach and may enhance the therapeutic al-
Bupropion should be avoided in individuals with eating liance, help to prevent relapse, and guide the current
disorders due to the increased risk of seizures in these pa- treatment. A close relationship between a life stressor and
tients. Electroconvulsive therapy has not generally been major depressive disorder suggests the potential utility of
useful in treating eating disorder symptoms. Although a psychotherapeutic intervention coupled, as indicated,
there are few data to guide treatment of co-occurring ma- with somatic treatment.
jor depressive disorder and eating disorders, it is reason-
able to optimize treatment of both disorders based on 2. Bereavement
these and other considerations. More information about Bereavement is a particularly severe stressor that can trig-
the treatment of eating disorders can be found in APAs ger a major depressive episode. However, grief, the natural
Practice Guideline for the Treatment of Patients With Eating response to bereavement, resembles depression, and this
Disorders, Third Edition (170). sometimes causes confusion. Psychiatrists treating be-
reaved individuals should differentiate symptoms of normal
B. DEMOGRAPHIC AND PSYCHOSOCIAL acute grief, complicated grief, and major depressive disor-
der, as each of these disorders requires a unique manage-
VARIABLES
ment plan. Normal grief should be treated with support
1. Major psychosocial stressors and psychoeducation about symptoms and the course of
Major depressive disorder may follow a substantial ad- mourning; complicated grief requires a targeted psycho-
verse life event, especially one that involves the loss of an therapy, with or without concomitant medication (535,
64 APA PRACTICE GUIDELINES
640); and major depressive disorder should be treated with ferent cultures express depressive symptoms differently,
medication and/or depression-focused psychotherapy. particularly somatic and psychomotor symptoms (657).
Acute grief is the universal reaction to loss of a loved Specific cultural variables may also influence the assess-
one, and it is a highly dysphoric and disruptive state (641). ment of major depressive disorder symptoms. For exam-
Acute grief is characterized by prominent yearning and ple, in some cultures, depressive symptoms may be more
longing for the person who died, recurrent pangs of sad- likely to be attributed to physical diseases (658). In addi-
ness and other painful emotions, preoccupation with tion, language barriers can impede accurate psychiatric
thoughts and memories of the person who died, and rela- diagnosis and effective treatment (659), and, even when
tive lack of interest in other activities and people. Despite speaking the same language, individuals of different cul-
the similarity with depression, only about 20% of be- tures may use different psychological terms to describe
reaved people meet the criteria for major depressive dis- their symptoms (6, 7). In addition, the importance of in-
order. Successful mourning leads to resolution of acute dividual experience should not be underestimated in the
grief over a period of about 6 months. Integrated grief re- therapeutic relationship (660). The assessment and treat-
mains as a permanent state in which there is ongoing sad- ment process can also be influenced by religious beliefs
ness about the loss often accompanied by ongoing feelings (5). Individuals with high levels of religious involvement
of yearning for the person who died. However, when the may have diminished rates of major depressive disorder
death is accepted, and grief integrated, the person is again (661, 662).
interested in his or her own life and other people. Differences in the utilization of psychiatric services by
Complicated grief is a recently recognized syndrome in some cultural and ethnic groups have been well docu-
which symptoms of acute grief are prolonged, associated mented. Relative to Caucasians, African Americans and
with intense and persistent yearning and longing for the Latinos appear less likely to receive treatment for mood
deceased person, and complicated by guilty or angry ru- disorders (663665).
minations related to the death and/or avoidance behavior. Several studies have underscored the lower frequency
Studies of individuals bereaved by the attacks of Septem- of use of antidepressant drugs (and more specifically,
ber, 11, 2001, have demonstrated that complicated grief is SSRIs) (648, 666669), ECT (670), and psychotherapy
a distinct condition from either major depressive disorder (671, 672) in minority groups, compared with Caucasians. If
or PTSD (642, 643). It is important to note that treatment treatment for depression is initiated, African Americans are
for depression is not effective in relieving symptoms of disproportionately more likely to receive pharmacother-
complicated grief (640). apy (672), to drop out of treatment (673), and to develop
Although DSM-IV-TR excludes the diagnosis of major chronic symptoms (674) than are Caucasian patients.
depressive disorder during the first 2 months following These differences in mental health service use by minority
bereavement, major depressive disorder in the wake of be- populations appear to have a number of potential causes.
reavement can impede the course of mourning. Bereave- Cultures and ethnicities may differ in the degree to which
ment-related depression responds to antidepressant psychiatric illness is stigmatized (675) and in the prefer-
medication and should be treated; otherwise it is likely to ences of individuals for treatment (676678). For exam-
become chronic and impairing (644). There is no indica- ple, studies have found that Hispanic individuals were
tion that depression in the context of bereavement differs more likely to prefer counseling than whites, whereas Af-
from other major depressive episodes, and data indicate rican Americans varied across studies in their relative
that chronicity of bereavement-related depression over preference for counseling rather than pharmacotherapy
13 months is similar to chronicity of depression in other (6, 679). Service use by minority populations is more af-
contexts (644). fected by financial constraints (including those related to
insurance) and social barriers (e.g., stigma) than the use of
3. Culture and ethnicity comparable services by Caucasians (664, 680, 681). In ad-
An appreciation of cultural and ethnic variables is impor- dition, pharmacological factors may play a role in patient
tant to the accurate diagnosis of major depressive disorder preferences and adherence, as ethnic groups may differ in
and in the selection and conduct of psychotherapy and their relative rates of metabolism (682684) and side ef-
pharmacotherapy (645647). Although major depressive fects and response to antidepressant medications (685
disorder is seen across cultural and ethnic groups, and the 688).
age at onset, gender differences, and prevalence of co-oc-
curring conditions are similar across cultures, the actual 4. Older age
incidence and prevalence of depression vary (648656). The combined prevalence of major depression, dysthymic
Furthermore, some evidence suggests that patients of dif- disorder, and minor depression in individuals over age
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 65
60 years has been reported to be as high as 25%, and ma- coexist, especially in elderly patients (696, 699). This eval-
jor depressive disorder has been reported to be present in uation should include a systematic review of the patients
14%42% of nursing home residents (689). Elderly pa- medications. Some medications have been reported to in-
tients typically display more vegetative signs and cogni- duce depressive symptoms (e.g., beta-blockers), although
tive disturbance but report less subjective dysphoria than they may simply be producing lethargy and fatigue that
younger patients. Major depressive disorder may conse- mimic depression (700, 701). Consequently, the psychia-
quently be misattributed to physical illness, dementia, or trist must carefully assess whether a given medication is
the aging process itself. For older adults with chronic contributing to depressive symptoms before prematurely
illness or physical disability, including those expected to altering what may be a valuable treatment. Patients un-
remain in a long-term care facility, depression may be er- dergoing their first major depressive episode in old age
roneously regarded as expected or inevitable, and therefore should be assessed for an undiagnosed neurological or
untreatable (690). As a result, it is common for major de- other general medical disorder that may be responsible
pressive disorder to be undiagnosed and untreated among for the depressive symptoms. Similarly, frequently co-
older adults. occurring symptoms of major depressive disorder, such as
As in all depressed individuals, a suicide risk assessment lassitude or pain, may mimic symptoms of a general med-
is an essential element of the evaluation process in older ical condition. Pain in older adults, especially from ortho-
individuals. Although older adults constitute only 13% of pedic sources, may contribute significantly to the presence
the U.S. population, they account for 19% of all suicides, of depression in this population (702).
with elderly white men having the highest rates of com- Once the patient has been thoroughly assessed, the
pleted suicides (691). This increase in suicide risk with ag- treatment considerations for depressed geriatric patients
ing in some demographic groups should be taken into are essentially the same as for younger patients. A meta-
consideration when estimating suicide risk and develop- analysis has shown that SSRIs; TCAs; and cognitive-
ing a plan to reduce such risk. behavioral, behavioral, and psychodynamic therapies are
Several general medical conditions common among all superior to placebo in the acute treatment for depres-
older adults are risk factors for depression. In addition, sion in subjects older than age 55 years (703708). In ad-
the presence of depression often exacerbates the course of dition, treatments for depression have been shown to be
the co-occurring medical condition and is a risk factor for effective in nursing home populations (709, 710), as well
poor outcomes. For example, elderly patients who are de- as in inpatient and traditional outpatient settings of care.
pressed and recovering from hip fractures have poorer However, compared with younger individuals, older pa-
functional outcomes from rehabilitative care and are less tients may be more likely to experience relapses and less
likely to return to full ambulation, compared with older likely to achieve a full response to treatment with antide-
adults with hip fractures who are not depressed (692 pressant medications (711714). In contrast, ECT is not
694). There is also frequent co-occurrence of major de- only effective as a treatment for depression among older
pressive disorder and cardiovascular disease; 25% or more individuals, but those over age 65 years actually have bet-
of those with cardiovascular disease also have major de- ter response rates than younger patients (715). Consid-
pressive disorder, and co-occurring depression increases eration should also be given to combined treatment with
the morbidity and mortality of cardiovascular illness pharmacotherapy and psychotherapy, as evidence for the
(695697). The term vascular depression has been used to efficacy of stand-alone psychotherapy, such as CBT, is
describe depression occurring in late life in patients with weak (716). Although the role of stimulants for antide-
clinical evidence of cerebrovascular disease (698), al- pressant monotherapy is very limited, these compounds
though at this time it has not been established as a unique have some role in apathetic major depressive disorder in
subtype of depression. In addition, major depressive dis- elderly patients with complicating general medical condi-
order is a complication of cerebral infarction (see Section tions. Late-life depression associated with vascular disease
III.C.3). There is also a high prevalence of major depres- has also been found to respond well to treatment with an-
sive disorder among patients with dementia, and mood tidepressants (717) and, in one unreplicated study, to
symptoms may precede cognitive symptoms and diagno- TMS (718). Furthermore, in a recent randomized con-
sis of dementia (see Section III.A.3.C). trolled trial, administering escitalopram prophylactically
Just as patients with medical conditions should be to patients who had experienced a stroke resulted in
screened for depression, patients exhibiting symptoms of lower rates of depression at 12 months (334). Psychoso-
depression should be thoroughly evaluated for the pres- cial factors are also frequent contributors to depression
ence of co-occurring medical conditions, as major depres- among older adults and should be addressed as part of the
sive disorder and general medical illnesses frequently treatment plan (719, 720).
66 APA PRACTICE GUIDELINES
There are several considerations in prescribing medi- A body of systematic evidence suggests a particular
cations for elderly patients. As with any patient, the psychi- value for various forms of collaborative or team-based
atrist should attempt to use as few medications as possible, care for elderly patients. Such care combines, for example,
and this is especially important given the complexity and specialty mental health consultation/intervention with
multiplicity of issues in elderly patients. It is often useful primary care management or community-based outreach
to use medications that address several issues at once, such and monitoring of care (732, 733). Older adults with de-
as choosing mirtazapine for a depressed, elderly patient with pression can benefit from integration of mental health
weight loss and insomnia. Elderly patients typically require services in the setting where they typically receive their
a lower oral dose than younger patients to yield a partic- general medical care. It has been shown that support for
ular blood level, and they tolerate a given blood level less algorithm-driven depression care processes within the
well. Nevertheless, the blood levels at which antidepres- primary care outpatient practice can lead to increased
sant medications are maximally effective for elderly pa- treatment adherence and improved clinical outcomes, in-
tients appear to be the same as those for younger patients cluding a reduction in mortality (734).
(721, 722). Dose regimens should be adjusted for age-
related metabolic changes, with close attention paid to 5. Gender
hepatic and renal metabolic function. For patients who As part of the diagnostic assessment of a woman with ma-
are receiving other medications, careful attention should jor depressive disorder, there should be a detailed inquiry
be paid to potential drug interactions (160, 161, 723725) regarding reproductive life history and mood symptoms
(Tables 4 and 5). associated with reproductive life events, such as menses,
Elderly patients are particularly prone to orthostatic use of oral contraceptive agents, peripartum, infertility,
hypotension and cholinergic blockade; for this reason, menopause, and pregnancy loss due to abortions, miscar-
SSRIs, SNRIs, and other antidepressants should be con- riages, and perinatal losses. Although associations be-
sidered over MAOIs or TCAs. Among the TCAs, de- tween reproductive factors and major depressive disorder
sipramine and nortriptyline should be considered over are neither widespread nor consistent, some women may
amitriptyline, imipramine, and doxepin, due to increas- be particularly vulnerable to fluctuations in gonadal hor-
ing sensitivity to side effects and toxicity with advancing mone levels (735). The perimenopausal transition has
age. Treatment with SSRIs causes the syndrome of in- been identified as a high-risk period for new-onset major
appropriate antidiuretic hormone secretion (SIADH) at a depressive disorder, with high variability of sex hormones
higher rate in elderly patients than in younger patients (726, as a risk factor (736, 737). Women in the perimenopausal
727). Patients taking SSRIs have a three times greater risk transition may benefit from the use of serotonergic anti-
of developing SIADH than patients taking other antide- depressants, for mood and also for somatic symptoms such
pressants, with the greatest risk among elderly patients as hot flashes (738).
(728). Since women are often caretakers in families, psycho-
For maintenance treatment, one study has shown that social stresses such as caring for an ill husband, child, or
antidepressant medication (nortriptyline) and IPT are ef- parent must be carefully assessed. Treating depressed
fective for elderly patients with recurrent major depres- mothers is associated with improved prognosis for their
sive disorder (315), yet a trend toward superior response children as well (739). Maternal remission from depression
was observed for combined pharmacotherapy and IPT, was associated after 3 months with significantly decreased
compared with pharmacotherapy alone. Another study diagnoses and symptoms in their children, compared with
demonstrated that paroxetine (but not monthly psycho- children of mothers whose depression had not remitted.
therapy) was effective as maintenance therapy for elderly Thus, treating depressed mothers may crucially benefit
patients (729). For older patients with particularly se- both the patients and their children.
vere or treatment-resistant depressive illness, addition of The patients gender also factors into other treatment
maintenance ECT to nortriptyline appears to improve considerations for major depressive disorder. For exam-
treatment outcome (730). Among elderly patients who ple, the risks of certain adverse effects from treatments
have had prior depression, the risk of developing another may also differ by gender. When prescribing trazodone to
episode of major depressive disorder is substantially in- men, it is important to provide education about the risk of
creased in those who develop or report sleep disturbance priapism (174). Older men typically have prostatic hyper-
(731). Sleep disturbances may function as independent trophy, making them particularly sensitive to anticho-
predictors of depression and are not simply prodromal de- linergic effects of some antidepressants on the bladder
pressive symptoms. outlet. While both men and women may experience de-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 67
creased libido or anorgasmia while taking SSRIs, men eration of the high prevalence of both unplanned pregnancy
may also experience ejaculatory dysfunction (740). Some and major depressive disorder in women, the risks and
women who are taking birth control pills require higher benefits of antidepressants and untreated maternal de-
doses of TCA medications because of the induction of the pression during pregnancy should be discussed with all fe-
hepatic enzymes responsible for medication metabolism. male patients who have reproductive potential. Whenever
Similarly, medications that induce hepatic enzymes, such possible, a pregnancy should be planned in consultation
as anticonvulsants used as adjunctive treatment, reduce with a treating psychiatrist, who may wish to consult with
the effectiveness of contraceptives. a specialist in perinatal psychiatry. For women who are
pregnant or planning to become pregnant, decisions
6. Pregnancy and postpartum about treatment for depression require weighing multiple
Major depressive disorder during pregnancy and postpar- benefits and risks for the woman as well as for the fetus.
tum presents unique treatment considerations. During Making such decisions may require several discussions
these periods, approximately 10% to 15% of perinatal and will generally involve discussions with the patients
women will experience major depressive disorder, which partner as well as her obstetrician.
is at least as common as rates reported for women in non- Antidepressant medications carry some reported risks
reproductive states (741, 742). Evaluation and communi- in pregnancy (see below), but so does untreated depres-
cation of risks and benefits of antidepressants during sion. Suicide risk, marital discord, the inability to engage
pregnancy and breast-feeding is challenging and must in- in appropriate obstetrical care, and difficulty caring for
clude the risks of untreated maternal mood disorder, the other children must also be considered. There are also se-
limited body of research that informs safety of antidepres- rious and well-characterized risks to the fetus of exposure
sants, and the general lack of prospective long-term data to maternal major depressive disorder, including the pos-
following antidepressant exposure in utero and through sibility of low birth weight secondary to poor maternal
lactation. weight gain (or frank weight loss) and increased risk of ob-
Depression-focused psychotherapy or other nonmedi- stetrical complications such as premature delivery (748).
cation therapies may be considered first for some women, Antidepressant efficacy has not been determined for
and psychotherapy should be considered as part of the pregnant women, and questions remain as to whether
treatment plan whenever possible. As childbearing is a life medications have equivalent efficacy during pregnancy,
stressor with psychosocial repercussions that may be ame- compared with the nonpregnant state. Some safety data
nable to psychotherapy, psychotherapy may serve to min- are available, but the findings often conflict, making data
imize medication exposure in some women. Although interpretation challenging and difficult to apply to the
there is little controlled research, psychotherapies appear care of individual patients. Nevertheless, antidepressant
efficacious in antenatal and postpartum depression, with medication should be considered and discussed as an op-
IPT being the best studied (743, 744). Therefore, depres- tion with pregnant women who have moderate to severe
sion-focused psychotherapies such as IPT and CBT major depressive disorder.
should be considered in the treatment plan as a first-line For women who are in remission from major depres-
treatment or in combination with medication to minimize sive disorder and receiving maintenance medication
medication exposure, especially if the individual has expe- and/or for women deemed to be at high risk for a recur-
rienced a good response to a particular psychotherapy in rence if the medication is discontinued, the risks of treat-
the past or strongly prefers to avoid medication. ment with medications must also be weighed against the
risks of alternative treatment options and untreated de-
a. Depression during pregnancy pression. Relapse rates for women with a history of major
Psychiatrists should be familiar with the management of depressive disorder are high during pregnancy, especially
major depressive disorder in the context of pregnancy if antidepressants are discontinued (749).
(745). More than 80% of women in the United States will
have children (746), and about half of pregnancies are 1. Risks of antidepressants during pregnancy
unplanned (747). Therefore, pregnanciesincluding un- The impact of the duration and timing of antidepressant
planned pregnanciesare likely to occur during the course exposure during pregnancy requires further study. Wisner
of treatment of major depressive disorder, as it is often a et al. (750) reviewed the risks associated with the use of
chronic and/or recurrent condition that is a major cause antidepressants during pregnancy, and a growing body of
of disability during the reproductive years and dispropor- complicated literature has followed. Overall, risk of ter-
tionately affects women, compared with men. In consid- atogenicity with antidepressants following first trimester
68 APA PRACTICE GUIDELINES
exposure appears to be low, although some rare birth de- cognition, or motor or behavioral development indepen-
fects have been observed to occur at higher rates with use dent of maternal depressed mood during pregnancy and
of specific SSRIs (751, 752). First-trimester paroxetine the childs early life (766, 767).
exposure has been associated with cardiac malformations,
a finding that resulted in changes in FDA labeling for par- 2. Implementation of pharmacotherapy
oxetine from C to D (753); labeling changes have been during pregnancy
made to all SSRI antidepressants with regard to this pos- No controlled trials inform the use of antidepressants
sibility when used during pregnancy. There have been during pregnancy. Dose requirements may change during
conflicting results regarding whether first-trimester par- pregnancy because of changes in volume of distribution,
oxetine exposure and cardiac teratogenicity are associated hepatic metabolism, protein binding, and gastrointestinal
(754, 755). For fluoxetine, one study (756) found a higher absorption. Pharmacokinetic changes in late pregnancy
incidence of three or more minor physical anomalies in may result in lower blood levels, with clinical implica-
infants exposed to fluoxetine than in a control group, and tions, although more study is needed to develop monitor-
fetuses exposed to fluoxetine after 25 weeks gestation had ing and dosing guidelines. The limited data in this area
lower birth weights, which were associated with lower demonstrate that pregnant women metabolize TCAs and
maternal weight gain. Although one case-control study SSRIs more rapidly in late pregnancy (769774).
reported a potential association between late antenatal A number of factors influence antidepressant choice
SSRI use and the rare but serious condition of persistent during pregnancy. If a woman has had a history of a good
pulmonary hypertension in the newborn (PPHN) (757), response to or is already taking a particular antidepres-
two subsequent retrospective chart review studies showed sant, it is logical to consider that antidepressant among
no such association (758, 759). An additional case-control first-line treatments in an effort to minimize the number
study (760) showed a marginally significant increase in the of different medication exposures. Using a single agent is
relative risk of PPHN with SSRI use, but the estimated also preferable to using several medications concomi-
rate of PPHN occurrence was 1.5 per 1,000 births, which tantly. Because paroxetine use is classified as having a higher
is less than the rate of 2.7 per 1,000 births reported by oth- level of risk than other SSRIs, it should not be considered
ers (758) in non-SSRI exposed infants. Therefore, while a first-line treatment when selecting a new antidepressant
many physicians are concerned about the reported associ- for a pregnant patient. Fluoxetine has the longest half-life
ation between SSRIs and PPHN, the preponderance of and is more likely to be demonstrated at high levels in
evidence from published studies on this topic does not newborns after in utero exposure. Sertraline has been
support an association. Use of SSRIs may also be associ- demonstrated to have lower cord blood levels than other
ated with prematurity (761, 762), although untreated de- SSRIs, although the clinical significance of this is un-
pression and stress during pregnancy may also contribute known (775). Although there are few data for bupropion
to the risk of prematurity (748, 763). Some naturalistic and safety in pregnancy, its benefits for smoking cessation
studies and health care utilization studies suggest that may make it especially useful in women who have major
antidepressants are associated with shorter length of ges- depressive disorder and who smoke cigarettes, as tobacco
tation (761, 762), but there have been no randomized stud- is a known teratogen. Given these data, it is recommended
ies of the treatment of antenatal major depressive disorder that consideration be given to using an antidepressant
that would adequately control for untreated maternal de- with some available safety information that has been
pression, antidepressant use, and confounding variables studied in pregnant women. For women who discontinue
related to treatment selection. With late pregnancy anti- medication during pregnancy and are deemed at risk for
depressant use, some but not all studies show a risk of postpartum depression, medication can be restarted fol-
medical complications such as prematurity and a transient lowing delivery.
neonatal withdrawal/adaptation syndrome (761, 764). The Electroconvulsive therapy is also recommended as a
syndrome in the neonate appears to be associated with an- treatment option for major depressive disorder during
tidepressant use in the third trimester, has been reported pregnancy (239). The current literature supports the
in babies exposed in utero to TCAs and SSRIs, and in- safety for mother and fetus, as well as the efficacy of ECT
cludes transient symptoms such as jitteriness, tremor, dif- during pregnancy (239). The psychiatrist should consider
ficulty with feedings, and other symptoms (764). Several ECT for pregnant patients with moderate to severe de-
studies, involving relatively small samples, have examined pression who are unresponsive to or unsuitable for phar-
effects of antidepressant exposure during pregnancy on macotherapy, for pregnant patients with major depressive
subsequent childhood behavior and development and disorder with psychotic features, and for pregnant pa-
found minimal (765) or no (766768) effects on language, tients electing to use this modality as a matter of prefer-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 69
ence after having weighed the relative risks and benefits of ity to provide physically and emotionally appropriate care
ECT and other treatment options. For details on the use for her baby and other children. The psychiatrist should
of ECT during pregnancy, refer to The Practice of Electro- work with the patient to develop a plan to manage this ef-
convulsive Therapy: Recommendations for Treatment, Train- fect, such as enlisting family members to assist with child
ing, and Privileging (A Task Force Report of the American care.
Psychiatric Association) (239). Antidepressants are often prescribed for postpartum de-
pression, according to the same principles delineated for
b. Postpartum depression other types of major depressive disorder, despite a limited
Major depressive disorder with postpartum onset is de- number of controlled studies. Two placebo-controlled tri-
fined in DSM-IV-TR as a major depressive episode with als of SSRIs (fluoxetine and paroxetine) have been pub-
onset within 4 weeks of delivery. However, the occurrence lished for the treatment of postpartum depression, with
and course of major depressive disorder in childbearing fluoxetine appearing more efficacious than placebo and
women is heterogeneous, and definitions of postpartum paroxetine being comparable to placebo on primary out-
depression may evolve with continued research (16, 776). come measures of depressive symptoms (783, 784). Wisner
In major depressive disorder with postpartum onset, anx- et al. (785) did not find a difference in response and remis-
iety symptoms are more prevalent than in major depres- sion rates in a randomized controlled trial of sertraline ver-
sive disorder occurring at other times (777). It is not sus nortriptyline for postpartum major depressive disorder.
uncommon for women with postpartum depression to Open studies of other antidepressants in postpartum
experience obsessions and/or compulsions, and obses- women suggest efficacy, although some studies included
sions may often involve thoughts of harming the baby, only a small number of participants (786). Paroxetine alone
which must be differentiated from postpartum psychosis. and paroxetine plus CBT both produced a significant change
Psychiatrists should provide psychoeducation about ma- from baseline in one study, but there was no placebo-only
jor depressive disorder to pregnant and postpartum group for comparison (787).
women and their families to improve the detection of ma- Patients and clinicians are often concerned about the
jor depressive disorder during pregnancy and the postpar- risks of possible exposure to antidepressants during
tum period. breast-feeding. These risks, however, must be weighed
Several other psychiatric conditions may follow child- against the well-known, and at times profound, risks to
birth (778). The transient 7- to 10-day depressive condi- the woman and her children of untreated postpartum
tion referred to as postpartum blues is by definition too depression. Mothers should be counseled regarding the
mild to meet the criteria for major depressive disorder and relative risks and benefits when making these treatment
does not require medication. In addition to providing re- decisions. Antidepressant medications are considered
assurance, psychiatrists should encourage mothers who compatible with breast-feeding, but long-term data are
experience postpartum blues to increase psychosocial sup- not available regarding risks and benefits. Although there
port and obtain help with the care of the infant. Puerperal have been some suspected case reports of adverse effects
psychosis is a more severe disorder complicating one to in breast-feeding infants exposed to maternal antidepres-
two of 1,000 births. Although postpartum psychosis is sants, most studies show low levels of exposure via breast
rare, women with this disorder may have homicidal im- milk, with the exception of fluoxetine, which appears to
pulses toward the newborn; for this reason, careful assess- have a dose-related risk for detectable levels in infant sera
ment of homicidal as well as suicidal ideation, intention, (788, 789). At this time, there are no studies which have
and plans is important. Postpartum psychosis must always determined a safe amount and duration of antidepres-
be treated as a psychiatric emergency, with hospitalization sant exposure in the fetus and newborn. However, ex-
considered for the safety of the mother and baby (779). posure to antidepressants via breast milk is considered
Many patients who have had episodes of this type ulti- substantially lower than in-utero exposure. Women who
mately prove to have bipolar disorder (780). elect to breast-feed while taking antidepressants should be
The womans parenting skills for both the newborn supported in doing so, given the widely known health
baby and any other children in her care must be carefully benefits (e.g., immune system effects) to infants who are
assessed. Untreated maternal major depressive disorder, breast-fed. Similarly, women who elect to bottle-feed
and specifically postpartum depression, have negative should also be supported in this decision. Some women
consequences for children, with adverse effects on attach- will not accept treatment with antidepressant medication
ment and child development (781, 782). Major depressive while they are breast-feeding. Depression-focused psy-
disorder can seriously interfere with the new mothers abil- chotherapy can be recommended instead.
70 APA PRACTICE GUIDELINES
lower heart rate variability in these patients, compared proaches to preventing depression after stroke, problem-
with nondepressed patients (804). Particularly in patients solving therapy has been best studied, but findings are in-
with a history of major depressive disorder (805), there is consistent (334, 825).
evidence that the depressive symptoms associated with When depression develops after a stroke, it has detri-
cardiac illness respond to antidepressants (717, 806, 807). mental effects on quality of life (823). In addition, the
However, studies in which the attempt has been made to presence of depression 1 month following a stroke has
influence cardiac-related mortality through treatment of been associated with an increase in subsequent mortality
depression have shown mixed results (808811). (828). Use of screening tools such as the PHQ-9 may help
A depressed patient with a history of a cardiac problem to identify depressive episodes after stroke (829), and care
should be monitored for the emergence of cardiac symp- management may improve outcomes once poststroke de-
toms, ECG changes, persistent tachycardia, or orthostatic pression is recognized (830). Psychotherapies have not
blood pressure decrements. Consultation with the pa- been well studied as treatments for poststroke depression;
tients cardiologist before and during antidepressant med- however, a meta-analysis of randomized trials that have
ication treatment may be advisable, especially for patients been conducted did not show efficacy (825). Findings on
who have recently had a myocardial infarction. Increases the therapeutic effects of antidepressants in post-stroke
in heart rate and blood pressure may be associated with depression have been mixed, perhaps due to the substan-
the use of agents with noradrenergic properties such as tial heterogeneity of study populations and designs (831,
SNRIs and stimulants; thus, changes in heart rate and blood 832). Although a meta-analysis did not show any differ-
pressure should be assessed after treatment with these ence in the rate of depressive remission with antidepres-
agents is instituted in patients with coronary artery dis- sant treatments compared with placebo (832), patients
ease, hypertension, or congestive heart failure. Although receiving an antidepressant did show more improvement
TCAs have been used effectively to treat major depressive in depressive symptoms (831, 832) and a greater propor-
disorder in patients with some forms of ischemic heart tion were classified as treatment responders (831). Individ-
disease (812), psychiatrists should take particular care in ual randomized controlled trials have shown therapeutic
using TCAs for patients with a history of ventricular ar- benefits for several SSRIs, including fluoxetine, sertraline,
rhythmia, subclinical sinus node dysfunction, conduction and citalopram (833836), and for the TCA nortriptyline
defects (including asymptomatic conduction defects), pro- (837, 838); however, not all studies have shown benefit for
longed QT intervals, or a recent history of myocardial in- some of these agents (837, 839841). Nevertheless, for in-
farction (184, 185, 813818). Selective serotonin reuptake dividuals with poststroke depressive symptoms, a trial of
inhibitors, SNRIs, and bupropion appear to be safer for antidepressant therapy may be considered, with SSRIs
patients with preexisting cardiac disease; several SSRIs being better tolerated and having fewer contraindications
have been used safely in patients with cardiac disease in in this older and more medically ill population (842, 843).
large clinical trials (807, 809, 810, 819). Electroconvulsive However, in individuals who are receiving concomitant
therapy can also be used safely in individuals with cardiac treatment with anticoagulant (e.g., warfarin) or antiplatelet
disease or arrhythmias, although specialist consultation (e.g., dipyridamole, clopidogrel, aspirin) medications, it is
and modifications in ECT technique or anesthesia may be important to consider the potential for an increased bleed-
indicated (239, 245, 820822). Monamine oxidase inhibi- ing risk due to drug-drug interactions with antidepres-
tors do not adversely affect cardiac conduction, rhythm, sants (844, 845).
or contraction but may induce orthostatic hypotension
and have risks relating to drug-food and drug-drug inter- 4. Parkinsons disease
actions. Major depressive disorder occurs to some degree in 40%
50% of patients with Parkinsons disease. Patients with
3. Stroke Parkinsons disease experience alterations of serotonergic
Depression is observed in approximately one-third to and noradrenergic systems that may induce depression.
one-half of individuals in the weeks to months following a There is no evidence favoring any particular antidepres-
stroke, with a substantial proportion developing major sant medication from the standpoint of therapeutic effi-
depressive disorder (334, 823, 824). Although conclusions cacy and safety for patients with Parkinsons disease
of meta-analyses are mixed (825, 826), some research complicated by major depressive disorder (846). A meta-
suggests that antidepressant treatment immediately fol- analysis of placebo-controlled studies identified a clear
lowing a stroke may reduce rates of depression (334) and benefit for both active treatment and placebo, but it did
possibly mortality (827). Among psychotherapeutic ap- not find differences between them (847). Although SSRIs
72 APA PRACTICE GUIDELINES
can be used, there is some risk of worsening of Parkinsons likely to increase the risk of developing seizures (856
disease symptoms (increases in off time and exacerba- 858). However, blood levels of TCAs may be increased by
tion of tremor) with agents that are primarily serotonergic several antiepileptic drugs, increasing the side-effect bur-
(848). Bupropion, in contrast, exerts a beneficial effect on den of the anticholinergic and other side effects of tricy-
the symptoms of Parkinsons disease in some patients but clics (859).
may also induce psychotic symptoms, perhaps because of Some anticonvulsants appear useful for treatment and
its agonistic action in the dopaminergic system (849). prophylaxis of mood disorders (e.g., carbamazepine, val-
Noradrenergic agents and SNRIs may also be preferable proate, lamotrigine). Thus, in patients with depression and
to SSRIs. Nonselective MAOIs (e.g., tranylcypromine, epilepsy, consideration can be given to concomitant pre-
phenelzine, isocarboxazid) may adversely interact with L- scription of an anticonvulsant (or elevating the dose of an
dopa products (850). Selegiline, also known as L-depre- existing anticonvulsant). Nevertheless, anticonvulsant com-
nyl, is a selective type B MAOI recommended in the treat- pounds may also have a negative effect on mood for some
ment of Parkinsons disease. Selegiline loses its specificity patients (859). For example, barbiturates and possibly vi-
for MAO B in doses greater than 10 mg/day. As a result, it gabatrin have been associated with an increased risk for
may induce serotonin syndrome when given in higher depression (860). In addition, a recent FDA statement noted
doses in conjunction with serotonin-enhancing antide- that increased rates of depression and suicide risk may be
pressant medications. The theoretical benefits of the an- associated with anticonvulsants (861).
timuscarinic effects of some of the tricyclic agents in the
treatment of patients with major depressive disorder with 6. Obesity
Parkinsons disease are offset by the memory impairment Many individuals with major depressive disorder will be
that may result. Amoxapine, an antidepressant medication overweight or obese, given the high prevalence of excess
with dopamine-receptor-blocking properties, should be weight in the general population (862). In addition, rates
avoided for patients who have Parkinsons disease. Lith- of depression may be increased in obese individuals, par-
ium may, in some instances, induce or exacerbate parkin- ticularly among women and in those with a body mass in-
sonian symptoms. Electroconvulsive therapy exerts a dex (BMI) greater than 40 (863). Individuals with obesity
transient beneficial effect on the symptoms of idiopathic resulting from binge eating disorder also have higher rates
Parkinsons disease in many patients (851, 852); however, of depression (170). In the subgroup of patients with atyp-
it might occasionally worsen L-dopa-induced dyskinesias ical depression, increased eating and weight gain are
and induce a transient interictal delirium (853), which ne- symptomatic of the depressive disorder (864). For other
cessitates reductions in doses of dopamine agonist medi- patients, the lack of motivation and energy that occur with
cations (239). depression can make it difficult to maintain an exercise
regimen or nutritional dietary habits. In addition, treat-
5. Epilepsy ment with many antidepressant medications appears to
The prevalence of depression in individuals with epilepsy lead to weight gain (865) and also makes it more difficult
appears to be increased in secondary and tertiary care cen- to lose weight in a structured weight management program
ter samples, although in population-based studies this in- (866).
crease is not well established (854). On the other hand, In treating individuals with major depressive disorder
major depressive disorder significantly increases the risk who are overweight or obese, the effects of treatment on
of unprovoked seizures even after the adjustment of age, weight should be considered in selecting a therapeutic ap-
sex, length of medical follow-up, and medical therapies proach. If pharmacotherapy is used, the selection of an an-
for depression (855). In addition, some antidepressant tidepressant medication should include consideration of
drugs, such as TCAs and bupropion, lower the seizure its relative tendency to contribute to weight gain, which
threshold and have a dose-dependent epileptogenic po- is generally greatest with mirtazapine, TCAs (tertiary
tential. This seizure risk is intermediate for immediate- TCAs more so than secondary TCAs), and MAOIs and
release formulations of bupropion, maprotiline, and less prominent with SSRIs and SNRIs (865). Bupropion is
TCAs (in particular, clomipramine) and low for sustained- generally weight neutral and has been associated with
release formulations of bupropion (17, 197, 856). modest weight reduction when used to treat major de-
Major depressive disorder in patients with seizure dis- pressive disorder in obese adults (867, 868). Longitudinal
orders can usually be safely and effectively managed ac- monitoring of weight, either by direct measurement or
cording to the same principles outlined for patients patient report, can permit monitoring of BMI, as well as
without seizures. In particular, SSRIs and SNRIs are not early intervention if weight gain becomes a problem with
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 73
antidepressant treatment. Patients concerns about weight significant dosing adjustments, it is useful to collaborate
gain may also contribute to poor adherence, and monitor- with the patients primary care physician in monitoring
ing of weight can facilitate such discussions. The impact diabetic control because fluctuations in fasting blood glu-
of weight on medication dosing should also be consid- cose may occur. Some evidence suggests that use of TCAs
ered. In one study, greater relative body weight was asso- may be associated with worsened glycemic control, and
ciated with a lesser likelihood of response to a fixed dose other antidepressants (such as SSRIs) may be preferable to
trial of an antidepressant (869), perhaps suggesting a need TCAs for patients with diabetes (896, 897).
for increases in medication dose with increasing body
weight. 8. Sleep apnea
Psychotherapeutic approaches to treatment avoid the The possible contribution of obstructive sleep apnea (OSA)
potential for medication-induced weight gain and may to depressive symptoms is an important consideration, par-
also have modest benefits in weight management. Cogni- ticularly in patients who are obese, report excessive daytime
tive-behavioral therapy has shown efficacy in the treat- sleepiness, or have treatment-resistant depressive symp-
ment of binge eating disorder (170, 870) and could toms. Symptoms such as fatigue and poor sleep quality can
potentially be used in addressing obesity (871) and medi- occur in sleep apnea as well as in major depressive disorder,
cation-induced weight gain (872). requiring a careful assessment to distinguish whether either
The increasing use of surgical treatments for obesity or both disorders are present. Underrecognition of OSA is
also has implications for the treatment of patients with common, and rates of OSA appear to be increasing with the
major depressive disorder. Depression is common among increasing prevalence of obesity (898). Although the proto-
bariatric surgical candidates and, in and of itself, is not a typical sleep apnea patient is likely to be obese with a his-
contraindication for surgery (873877). Long-term fol- tory of snoring, sleep apnea may still be present even in the
low-up studies show improvements in co-occurring gen- absence of these findings (899). Individuals with OSA or
eral medical conditions (878), as well as decreases in excessive daytime sleepiness appear to have greater rates of
depressive symptoms and improved quality of life with depression than comparison groups (900902), although the
weight loss (879881). However, weight loss after surgery rates of depressive symptoms and major depressive disor-
may be less pronounced in individuals with a lifetime di- der diagnosis fluctuate across studies (903). In addition, ep-
agnosis of major depressive disorder (882) or in those with idemiological findings suggest an increasing likelihood of
severe psychiatric illness that has required hospitalization depression with increasing sleep-related breathing disorder
(883). Close follow up is important following bariatric severity (904). With initiation of continuous positive airway
surgery in order to assess for changes in psychiatric symp- pressure treatment, improvement in OSA symptoms has
toms, assist patients in the psychological and psychosocial been associated with decreased depressive symptoms (905,
adaptation to weight loss, and adjust medication regi- 906), in addition to reductions in OSA-associated health
mens. Particularly following jejunoileal bypass or bilio- risks (898). Consequently, recognition and treatment of
pancreatic diversion, but also following gastric bypass OSA is important among individuals with major depressive
procedures, altered dissolution (884) and absorption of disorder. Identification of OSA is also important to treat-
medication may require adjusting the dose of medication ment planning, as use of sedating medications can exacer-
or changing from a slow-release to an immediate-release bate OSA and worsen daytime sleepiness, with associated
formulation (875). complications (907).
Rates of major depressive disorder are increased among and study design, one-half to two-thirds of depressed in-
individuals with HIV infection, compared with HIV-nega- dividuals will typically note some type of pain (702, 939
tive individuals (913). When treating major depressive dis- 941). Conversely, in primary care settings, individuals
order in patients who also have HIV, antidepressant with pain symptoms are about twice as likely to be de-
medications can be used safely and effectively (914, 915), pressed as those without pain, and the rates of depression
although high placebo response rates and high study attri- are further increased if pain is chronic or involves multiple
tion rates have sometimes confounded interpretation of re- types of pain (940, 942). It is important to note that indi-
search findings (916, 917). When antidepressants are used, viduals with co-occurring pain and depression tend to
SSRIs are better tolerated than TCAs (918, 919). In indi- have worse treatment outcomes and poorer overall func-
viduals who are receiving treatment with antiretroviral tioning than those with either condition alone (940, 942
agents, it is important to check for potential drug-drug in- 944). Consequently, every patient with depression should
teractions when choosing a medication regimen (920). Sig- be assessed for the presence, nature, location, and severity
nificant interactions can also occur if St. Johns wort is taken of pain complaints.
by patients receiving antiretroviral medications. Although Overall, antidepressant treatment has been associated
few studies have been conducted in patients who meet di- with reductions in pain symptoms among individuals with
agnostic criteria for major depressive disorder, individual psychogenic or somatoform pain disorders (945). How-
and group psychotherapies using interpersonal, cognitive- ever, among trials of second-generation antidepressants in
behavioral, and psychoeducational approaches have also individuals with co-occurring pain and depression, dulox-
been associated with reductions in depressive symptoms etine, venlafaxine, and paroxetine seem to be of compara-
among patients with HIV infection (316, 921926). ble but relatively minor benefit (939, 946, 947).
Persons with mental illness also have elevated rates of Neuropathic pain is commonly associated with diabetic
infection with hepatitis C (927), and infection with hepati- peripheral neuropathy but may also have other etiologies
tis C is commonly present in individuals with HIV infec- such as postherpetic neuralgia. For neuropathic pain in
tion (928). Among individuals with hepatitis C, depressive general, evidence-based guidelines recommend the use of
symptoms are common, and many patients fully meet the TCAs or SNRIs (948, 949). Of the antidepressant medica-
criteria for major depressive disorder (929). Treatment of tions, TCAs have been found to be most effective in de-
hepatitis C with interferon appears to be associated with a creasing pain associated with both postherpetic neuralgia
further increase in the risk for depression, although find- (950, 951) and diabetic neuropathy (949, 952) but have no
ings vary depending upon the study population, concomi- apparent effect on HIV-associated neuropathic pain (949).
tant medications (e.g., ribavirin), and the type of interferon Given the greater tolerability of SNRI antidepressants,
used for therapy (930, 931). The increase in depressive these agents may sometimes be chosen before a TCA for a
symptoms with interferon treatment may also be more patient with co-occurring depression and neuropathic pain.
prominent in patients with greater levels of pretreatment In addition, if a TCA is used, therapeutic drug monitoring
depression (932). This suggests a need for careful monitor- may be helpful, given the wide variability of TCA blood
ing if patients with current major depressive disorder are levels across individuals (953).
administered interferon, particularly since many patients Similar effects have been found for the use of antide-
treated with interferon have unrecognized or insufficiently pressants to prevent migraine and tension-type headaches.
treated depression (933). Studies in which antidepressant In patients with and without co-occurring depression,
medications were administered concomitantly with inter- TCAs show greater efficacy than SSRIs (954, 955), but
feron have shown inconsistent prophylactic effects (934, SNRIs also have some evidence for efficacy (956, 957). In
935). However, antidepressant therapy does seem to be ef- individuals with tension-type headaches, addition of stress
fective when used to treat depression that develops in the management therapy may augment the effects of TCA
course of interferon therapy for hepatitis C infection (936, treatment (958).
937). Consequently, major depressive disorder should not Antidepressant treatment is also recommended for in-
be viewed as a contraindication to the treatment of hepatitis dividuals with fibromyalgia, as it is associated with reduc-
C infection, particularly given the severe long-term hepatic tions in pain and often leads to improvements in function,
complications associated with chronic infection (938). with the best evidence available for amitriptyline (959).
Beneficial effects are observed in those with or without
10. Pain syndromes co-occurring major depressive disorder (960962). Al-
Pain syndromes and major depressive disorder frequently though evidence from controlled trials is more limited for
co-occur. Although the reported prevalence of pain nonpharmacological approaches than for antidepressant
among depressed patients varies with cultural differences treatment, education, exercise, and CBT are generally rec-
Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition 75
ommended for the treatment of fibromyalgia in combina- ties so that patients do not receive prescriptions for the
tion with antidepressant medication (963, 964). same medications or have their doses for given medica-
In the context of rheumatoid arthritis, antidepressant tions adjusted by several different prescribing clinicians,
medications also appear to be effective in reducing pain as and to set up a mechanism and plan whereby all prescrib-
well as treating depressive symptoms (965967). Evidence ing clinicians consistently keep one another informed
for psychosocial treatment is less consistent, with mind- about changes in their treatment plans and prescriptions.
fulness meditation and emotion regulation therapy being
associated with reduced pain and enhanced coping in in- 11. Obstructive uropathy
dividuals with rheumatoid arthritis and depression (968), Enlarged prostate size and other causes of bladder outlet
but CBT having mixed results (966, 968). In individuals obstruction are relative contraindications to the use of an-
with co-occurring depression and osteoarthritis, collabo- tidepressant medication compounds with antimuscarinic
rative depression care has been associated with reduced effects. For this reason, tertiary amine TCAs are best
pain severity, improved function, and enhanced quality of avoided in these patients. Benzodiazepines, trazodone,
life in those with low pain scores at baseline but had no ef- and MAOIs may also retard bladder emptying. The anti-
fect when compared with usual treatment in those with depressant medications with the least propensity to do
severe arthritis pain (969, 970). this are SSRIs, SNRIs, and bupropion. If a TCA is chosen,
For individuals with chronic low back pain, there are the secondary amine desipramine is the least likely to
conflicting opinions about the utility of antidepressant cause urinary hesitancy or retention.
medications in reducing pain or improving function, even
in the presence of co-occurring depression (971, 972). 12. Glaucoma
Nevertheless, antidepressant medications may still be in- Medications with anticholinergic potency may precipitate
dicated to treat depression on the basis of individual cir- acute narrow-angle glaucoma in susceptible individuals
cumstances. (i.e., those with shallow anterior chambers) (973). Patients
Since depressed patients with concurrent pain are of- with glaucoma receiving local miotic therapy may be
ten treated by primary care physicians and other medical treated with antidepressant medications, including those
specialists with a variety of potent analgesic medications, possessing anticholinergic properties, provided that their
including narcotics, psychiatrists treating such patients intraocular pressure is monitored during antidepressant
are advised to be in contact with these other physicians medication treatment. Prescription of agents lacking
initially and on a regular ongoing basis as indicated. The anticholinergic activity avoids this risk. Other agents
purposes of such contacts are to review the entire treat- sometimes used in psychiatry, e.g., topiramate and related
ment plan, to assure that all prescribing physicians are sulfa-based medications, may cause acute angle closure
aware of the full extent of pharmacological interventions, glaucoma by ciliary body edema, a different mechanism
to coordinate specific prescribing areas and responsibili- (974).
Appendix
EDUCATIONAL RESOURCES FOR PATIENTS AND FAMILIES
Academy of Cognitive Therapy ConsumerLab.com
http://www.academyofct.org Tests herbal and vitamin products for purity and posts the
results on the Web
California Teratogen Information Service and Clini-
http://www.consumerlab.com
cal Research
Tel: 18005323749 (CA only) Depression After Delivery, Inc.
Tel: (610) 5432131 91 East Somerset Street
http://www.otispregnancy.org Raritan, NJ 08869
Tel: (800) 9444773
http://www.depressionafterdelivery.com
76 APA PRACTICE GUIDELINES
ACKNOWLEDGMENT
Massimiliano Beghi, M.D., assisted with the evidence review for this guideline.
REFERENCES
The following coding system is used to indicate the nature of the supporting evidence in the references:
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groups, both the subjects and the investigators are blind to the assignments.
[A] Randomized clinical trial. Same as above but not double-blind.
[B] Clinical trial. A prospective study in which an intervention is made and the results of that intervention are
tracked longitudinally; study does not meet standards for a randomized clinical trial.
[C] Cohort or longitudinal study. A study in which subjects are prospectively followed over time without any spe-
cific intervention.
[D] Case-control study. A study in which a group of patients and a group of control subjects are identified in the
present and information about them is pursued retrospectively or backward in time.
[E] Review with secondary data analysis. A structured analytic review of existing data, e.g., a meta-analysis or a
decision analysis.
[F] Review. A qualitative review and discussion of previously published literature without a quantitative syn-
thesis of the data.
[G] Other. Textbooks, expert opinion, case reports, and other reports not included above.
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