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Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Thomas D. Denberg, MD, PhD; Mary Ann Forciea, MD; and Douglas K. Owens, MD, MS, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians* Description: The American College of Physicians developed this
and patient preferences (Grade: strong recommendation; moderate-
guideline to present the available evidence on the pharmacologic
management of the acute, continuation, and maintenance phases
Recommendation 2: The American College of Physicians recom-
of major depressive disorder; dysthymia; subsyndromal depression;
mends that clinicians assess patient status, therapeutic response,
and accompanying symptoms, such as anxiety, insomnia, or neuro-
and adverse effects of antidepressant therapy on a regular basis
vegetative symptoms, by using second-generation antidepressants.
beginning within 1 to 2 weeks of initiation of therapy (Grade:
Methods: Published literature on this topic was identified by using
strong recommendation; moderate-quality evidence).
MEDLINE, EMBASE, PsychLit, the Cochrane Central Register of
Recommendation 3: The American College of Physicians recom-
Controlled Trials, and International Pharmaceutical Abstracts from
mends that clinicians modify treatment if the patient does not have
1980 to April 2007. Searches were limited to English-language
an adequate response to pharmacotherapy within 6 to 8 weeks
studies in adults older than 19 years of age. Keywords for search
of the initiation of therapy for major depressive disorder (Grade:
included terms for depressive disorders and 12 specific second-
strong recommendation; moderate-quality evidence).
generation antidepressants—bupropion, citalopram, duloxetine, es-citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, par-
Recommendation 4: The American College of Physicians recom-
oxetine, sertraline, trazodone, and venlafaxine—and their specific
mends that clinicians continue treatment for 4 to 9 months after a
trade names. This guideline grades the evidence and recommenda-
satisfactory response in patients with a first episode of major de-pressive disorder. For patients who have had 2 or more episodes of
tions by using the American College of Physicians clinical practice
depression, an even longer duration of therapy may be beneficial
(Grade: strong recommendation; moderate-quality evidence). Recommendation 1: The American College of Physicians recom- mends that when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation Ann Intern Med. 2008;149:725-733. www.annals.org
antidepressants on the basis of adverse effect profiles, cost,
For author affiliations, see end of text. Depressive disorders are serious disabling illnesses that guideline is limited to pharmacotherapy with second-
affect 16% of adults in the United States during their
generation antidepressants (selective serotonin reuptake in-
lifetime (1). The economic burden of depressive disorders
hibitors [SSRIs], serotonin norepinephrine reuptake inhib-
is estimated to be $83.1 billion. Depressive disorders in-
itors [SNRIs], and selective serotonin norepinephrine
clude major depressive disorder (MDD); dysthymia; and
reuptake inhibitors [SSNRIs]). First-generation antidepres-
subsyndromal depression, including minor depression. The course of depression can be characterized by 3 phases (Fig- ure). Relapse is defined as the return of depressive symp-
toms during the acute or continuation phases and is there-fore considered part of the same depressive episode,
whereas recurrence is defined as the return of depressive
Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
symptoms during the maintenance phase and is considered
Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-56
Web-Only
Various treatment approaches can be used to manage
depression, such as pharmacotherapy, psychotherapy, and
cognitive behavioral therapy. However, the scope of this
* This paper, written by Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Thomas D. Denberg, MD, PhD; Mary Ann Forciea, MD; and Douglas K. Owens, MD, MS, wasdeveloped for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Douglas K. Owens, MD, MS (Chair); Donald E. Casey Jr., MD, MPH,MBA; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Mary Ann Forciea, MD; Robert H. Hopkins Jr., MD; William Rodriguez-Cintron, MD; and Paul Shekelle, MD, PhD. Approved by the ACP Board of Regents on 13 July 2008.
2008 American College of Physicians 725
Clinical Guidelines Using Second-Generation Antidepressants to Treat Depressive Disorders
Two persons independently reviewed abstracts and rel-
Figure. Phases of treatment of major depression.
evant full-text articles; studies were excluded if both re-viewers agreed that they did not meet eligibility criteria. Remission Recovery
Disagreements were resolved by a third reviewer. The re-
Recurrence
viewers used head-to-head trials when available; however,
“Normalcy” Progression to Disorder
no head-to-head evidence was available for many drug
Response
comparisons. The review included placebo-controlled trials
Symptoms
for indirect comparisons in the absence of head-to-head
Severity
trials. For adverse events, the reviewers included data from
Syndrome
observational studies with 100 or more participants andfollow-up of 12 or more weeks. Treatment Phases Continuation Maintenance
Major depressive disorder is a clinical syndrome lasting
(6–12 weeks) (4–9 months) (1 or more
at least 2 weeks during which the patient experiences either
depressed mood or anhedonia plus at least 5 of the follow-
ing symptoms: depressed mood most of the day, nearlyevery day; markedly diminished interest or pleasure in
Reproduced with permission from Physicians Postgraduate Press (KupferDJ. Long-term treatment of depression. J Clin Psychiatry. 1991;52
most activities most of the day; significant weight loss or
gain or appetite disturbance; insomnia or hypersomnia;psychomotor agitation or retardation; inappropriate guilt;diminished ability to think or concentrate or indecisive-
sants (tricyclic antidepressants and monoamine oxidase in-
ness; or recurring thoughts of death, including suicidal ide-
hibitors) are less commonly used than second-generation
ation. Dysthymia is defined as a chronic depressive disor-
antidepressants, which have similar efficacy to and lower
der that is characterized by depressed mood on most days
toxicity in overdose than first-generation antidepressants.
for at least 2 years (3). Subsyndromal depression (also
The goal of this guideline is to present the available
called minor depression) is a mood disturbance of at least 2
evidence on the pharmacologic management of the acute,
weeks’ duration with fewer symptoms of depression than
continuation, and maintenance phases of MDD; dysthy-
MDD (3). Melancholia is defined as a depressive subtype
mia; and accompanying symptoms, such as anxiety, insom-
that is a severe form of MDD and has the essential feature
nia, or neurovegetative symptoms. The target audience
of the loss of interest or pleasure in all, or almost all, ac-
for this guideline is all clinicians, and the target population
tivities or a lack of reactivity to usually pleasurable stimuli.
is all patients with depressive disorders. These recommen-
Other characteristic physical symptoms, including early
dations are based on the systematic evidence review by
morning awakening, marked psychomotor retardation or
Gartlehner and colleagues (2) and the Agency for Health-
agitation, and significant anorexia or weight loss, are also
care Research and Quality–sponsored RTI International–
University of North Carolina Evidence-based Practice
This guideline rates the evidence and recommenda-
tions by using a slightly modified version of the GRADE(Grading of Recommendations, Assessment, Development,
and Evaluation) system (Table 1).
The reviewers searched MEDLINE, EMBASE, Psych-
Lit, the Cochrane Central Register of Controlled Trials,and International Pharmaceutical Abstracts from 1980 toApril 2007. In addition, the reviewers manually searched
Table 1. The American College of Physicians Guideline
reference lists of pertinent review articles and letters to the
Grading System*
editor and used the Center for Drug Evaluation and Re-search database (up to September 2007) to identify unpub-
Quality of Evidence Strength of Recommendation
lished research submitted to the U.S. Food and Drug Ad-
Benefits Clearly Outweigh Benefits Finely
ministration. The Medical Subject Heading terms and
Risks and Burden OR Risks Balanced with and Burden Clearly Risks and Burden
keywords included for literature search involved combining
Outweigh Benefits
depressive disorders with 12 specific second-generation anti-
depressants (bupropion, citalopram, duloxetine, escitalo-
pram, fluoxetine, fluvoxamine, mirtazapine, nefazodone,
paroxetine, sertraline, trazodone, and venlafaxine) and
their specific trade names. The criteria for electronic search
included adults 19 years of age or older, human, and English-
language articles. This guideline is based on evidence de-
* Adopted from the classification developed by the GRADE (Grading of Recom-
mendations, Assessment, Development, and Evaluation) workgroup. 726 18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 www.annals.org
Using Second-Generation Antidepressants to Treat Depressive Disorders Clinical Guidelines
The objective of this guideline is to synthesize the ev-
paring citalopram with escitalopram showed benefits from
idence for the following key questions.
escitalopram (relative benefit, 1.14 [95% CI, 1.04 to
Key question 1: For adults with MDD or dysthymia,
1.26]). However, the clinical significance of this finding
do commonly used medications for depression differ in
was doubtful when the results were pooled on the Mont-
efficacy or effectiveness in treating depressive symptoms?
gomery-Asberg Depression Rating Scale.
Key question 2a: For adults with a depressive syn-
drome, do antidepressants differ in their efficacy or effec-
Effectiveness for Acute Phase
tiveness for maintaining response or remission (preventing
The reviewers gathered evidence from 3 studies that
evaluated effectiveness of different SSRIs (9 –11) and
Key question 2b: For adults receiving antidepressant
found no significant differences among them for the treat-
treatment for a depressive syndrome that has not re-
sponded (acute phase), has relapsed (continuation phase),or has recurred (maintenance phase), do alternative anti-
Quality of Life
depressants differ in their efficacy or effectiveness?
Evidence from 18 fair-quality efficacy trials that eval-
Key question 3: Do second-generation medications
uated quality of life or functional capacity as secondary
used to treat depression differ in their efficacy or effective-
outcomes showed no differences among second-generation
ness for treating accompanying symptoms, such as anxiety,
antidepressants (4, 11–27). Two fair-quality effectiveness
trials showed that fluoxetine, paroxetine, and sertraline
Key question 4: How do the efficacy, effectiveness, or
similarly improved health-related quality of life (work, so-
harms of treatment with antidepressants for a depressive
cial and physical functioning, concentration and memory,
syndrome differ for the following subpopulations: elderly
or very elderly patients; other demographic groups, definedby age, race or ethnicity, or sex; and patients with medical
Speed of Response for Acute Phase
comorbid conditions, such as ischemic heart disease or
Evidence from 7 fair-quality studies showed that mir-
tazapine had a statistically significantly faster onset of ac-
Key question 5: For adults with a depressive syn-
tion than that of citalopram, fluoxetine, paroxetine, or ser-
drome, do commonly used antidepressants differ in safety,
traline (19, 25, 27–32). However, after 4 weeks, most
adverse events, or adherence? Adverse effects of interest
response rates were similar. Also, the response rates of mir-
include but are not limited to nausea; diarrhea; headache;
tazapine and venlafaxine did not differ (18).
tremor; daytime sedation; decreased libido; failure toachieve orgasm; nervousness; insomnia; and more severe
Response to a Second Agent in Treatment-Resistant MDD
Studies showed that 38% of patients did not achieve a
treatment response during 6 to 12 weeks of treatment with
Treatment of MDD
second-generation antidepressants and 54% did not
Efficacy for Acute Phase
achieve remission. One large good-quality study, STAR*D
The reviewers gathered evidence from 80 head-to-head
(Sequenced Treatment Alternatives to Relieve Depression)
RCTs of good to fair quality that offered direct evidence
(33), provided the best evidence for assessing alternative
for 36 of the possible 66 comparisons among second-
medications (sustained-release bupropion, sertraline, and
generation antidepressants (2). The trials compared SSRIs
extended-release venlafaxine) in patients whose initial ther-
with other SSRIs (citalopram, escitalopram, fluoxetine, flu-
apy failed; it showed that 1 in 4 patients became symptom-
voxamine, paroxetine, sertraline); SSRIs (citalopram, es-
free after switching medications and found no difference
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline,
among the 3 drugs. However, 2 small studies (34, 35)
venlafaxine) with SSNRIs (duloxetine) and SNRIs (mir-
showed greater response rates with venlafaxine than with
tazapine, venlafaxine); and SSRIs (citalopram, escitalo-
other second-generation antidepressants.
pram, fluoxetine, fluvoxamine, paroxetine, sertraline, par-oxetine), SNRIs (mirtazapine, venlafaxine), SSNRIs
Maintenance of Response or Remission
(duloxetine), and other second-generation antidepressants
Four fair-quality trials (36 – 40) demonstrated no sub-
(bupropion, nefazodone) with other second-generation anti-
stantial difference between fluoxetine and sertraline, flu-
depressants (bupropion, nefazodone, trazodone).
voxamine and sertraline, duloxetine and paroxetine, and
The results of individual studies showed no significant
trazodone and venlafaxine for maintaining response or re-
differences between SSRIs or between SSRIs and SNRIs,
mission of MDD. A meta-analysis (41) of 31 randomized
SSNRIs, or other second-generation antidepressants. Some
trials supports the continuation of antidepressant therapy
evidence from meta-analyses showed statistically significant
differences between treatments; however, the effect sizes
In summary, when treating acute-phase MDD, the
were small and the results were probably not clinically sig-
second-generation antidepressants did not significantly dif-
nificant. For example, evidence from 5 studies (4 – 8) com-
fer in efficacy, effectiveness, or quality of life. Mirtazapine
www.annals.org
18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 727
Clinical Guidelines Using Second-Generation Antidepressants to Treat Depressive Disorders
had a significantly faster onset of action. Almost 38% of
Treatment of Symptom Clusters in Patients with
patients did not achieve a treatment response during 6 to
Accompanying Depression
12 weeks of treatment with second-generation antidepres-
The reviewers evaluated the comparative effectiveness
sants and 54% did not achieve remission. Second-genera-
of second-generation antidepressants for treatment of
tion antidepressants did not differ in the rate of achieving
symptom clusters associated with depression. Treatment of Depression in Patients with Accompanying
Evidence from 10 fair-quality head-to-head trials (19,
Symptom Clusters
23, 42, 43, 46, 47, 54 –57) showed no difference in the
The evidence review evaluated the comparative effec-
efficacy of antidepressant medications (fluoxetine, parox-
tiveness of second-generation antidepressants for treatment
etine, and sertraline; sertraline and bupropion; sertraline
of depression associated with symptom clusters, such as
and venlafaxine; citalopram and mirtazapine; and parox-
etine and nefazodone) for treatment of anxiety associatedwith MDD.
Evidence from 6 fair-quality head-to-head trials com-
Insomnia
paring fluoxetine or paroxetine with sertraline, sertraline
Research showed an improvement in sleep scores for
with bupropion, and sertraline with venlafaxine showed
escitalopram over citalopram (58), nefazodone over fluox-
similar antidepressive efficacy for patients with MDD and
etine (49), and trazodone over fluoxetine (13) and ven-
anxiety symptoms (23, 42– 47). One fair-quality trial
lafaxine (36). However, 5 fair-quality head-to-head trials
showed a statistically significantly better response and re-
(13, 25, 36, 48, 49) and a pooled analysis of 3 RCTs (58)
mission rate for venlafaxine than for fluoxetine (42).
provide limited evidence about comparative effectiveness ofantidepressants on insomnia in patients with depression. Insomnia
Limited evidence (48, 49) showed similar efficacy
among fluoxetine, nefazodone, paroxetine, and sertraline for
In 3 fair-quality head-to-head trials (39, 59, 60) and 1
treating depression in patients with accompanying insomnia.
poor-quality trial (61), pain relief did not significantly dif-fer between duloxetine and paroxetine in patients with MDD. Melancholia
Evidence from 2 fair-quality head-to-head trials (44,
Somatization
50) and 1 poor-quality head-to-head study (51) showed
One fair-quality study showed no differences among
that sertraline had a greater response rate than fluoxetine
fluoxetine, paroxetine, and sertraline in improving somati-
and that venlafaxine was better than fluoxetine; however,
small sample sizes and high attrition decrease confidence in
In summary, when treating symptom clusters in pa-
tients with accompanying depression, second-generationantidepressants did not differ in efficacy in treating accom-
panying anxiety, pain, and somatization. Limited evidence
Two studies showed that duloxetine (52) and parox-
suggests that some agents may be more effective in treating
etine (53) had the same response rate compared with pla-
Treatment of Depression in Selected Patient Populations
No studies compared efficacy, effectiveness, and harms
Psychomotor Changes
of second-generation antidepressants among subgroups
Evidence from 1 fair-quality head-to-head trial showed
and the general population for treatment of depressive syn-
that fluoxetine and sertraline had similar antidepressive ef-
dromes. However, numerous studies conducted subgroup
ficacy in patients with psychomotor retardation but sertra-
analyses or used subgroups as study populations.
line had better efficacy in patients with psychomotor agi-tation (44). However, these results should be interpreted
with caution because of the small number and size of the
Evidence from head-to-head trials (10, 17, 26, 31, 62–
70), meta-analyses (71, 72), and placebo-controlled trials
In summary, when treating depression in patients with
(73–79) showed no differences in efficacy of second-
accompanying symptom clusters, second-generation anti-
generation antidepressants in elderly (65 to 80 years of
depressants did not differ in efficacy in treating accompa-
age), very elderly (Ͼ80 years of age), or younger patients.
nying anxiety, insomnia, and pain. However, limited evi-dence suggests that sertraline had better efficacy for
managing melancholia and psychomotor agitation. Also,
Second-generation antidepressants were equally effec-
venlafaxine may be superior to fluoxetine for treating anxiety. 728 18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 www.annals.org
Using Second-Generation Antidepressants to Treat Depressive Disorders Clinical Guidelines
Race or Ethnicity Other Severe Adverse Events. Evidence evaluating ad-
One poor-quality trial showed no differences in effi-
verse events, such as seizures, cardiovascular risks (increases
in systolic or diastolic blood pressure and pulse or heartrate), hyponatremia, hepatotoxicity, or the serotonin syn-
Comorbid Conditions
drome, is scarce but should be kept in mind when patients
No studies directly compared the effect of second-
are being treated with a second-generation antidepressant.
generation antidepressants on depressed patients with co-
Weak evidence indicates that bupropion may be associated
morbid conditions versus the general population. In 1
with an increased risk for seizures, venlafaxine may be as-
poor-quality head-to-head trial (83), fluoxetine, parox-
sociated with an increased risk for cardiovascular events,
etine, and sertraline differed in efficacy or tolerability.
and nefazodone may be associated with an increased risk
In summary, second-generation antidepressants did
not differ in efficacy among subgroups and special popula-
In summary, most of the second-generation anti-
tions categorized according to age, sex, race or ethnicity, or
depressants had similar adverse effects. The most com-
monly reported adverse events were constipation, diarrhea,
Risk for Harms and Adverse Events
dizziness, headache, insomnia, nausea, sexual adverse
The reviewers gathered evidence from 80 head-to-head
events, and somnolence. Nausea and vomiting were the
efficacy studies and 42 additional studies (see Gartlehner
most common reasons for discontinuation in efficacy stud-
and colleagues’ (2) Appendix Table 9, available at www
ies. Paroxetine was associated with an increased risk for
.annals.org) (2). The methods used to assess adverse events
sexual dysfunction. Selective serotonin reuptake inhibitors
varied greatly, and few studies used objective scales.
resulted in an increased risk for nonfatal suicide attempts. Treatment of Dysthymia Adverse Events Profile
One good-quality (16) and 4 fair-quality placebo-
The most commonly reported adverse events included
controlled trials (22, 24, 96 –99) showed mixed evidence
constipation, diarrhea, dizziness, headache, insomnia, nau-
on the efficacy and effectiveness of fluoxetine, paroxetine,
sea, sexual adverse events, and somnolence. Nausea and
and sertraline for the treatment of dysthymia.
vomiting were the most common reasons for discontinua-tion in efficacy studies. Most of the second-generationantidepressants had similar adverse events, with some dif-
ferences in the incidence of specific adverse events: Ven-
The available evidence does not support clinically sig-
lafaxine had a higher incidence of nausea and vomiting
nificant differences in efficacy, effectiveness, or quality
than other SSRIs; sertraline had a higher rate of diarrhea
of life among SSRIs, SNRIs, SSNRIs, or other second-
than bupropion, citalopram, fluoxetine, fluvoxamine, mir-
generation antidepressants for the treatment of acute-phase
tazapine, nefazodone, paroxetine, or venlafaxine; mirtazap-
MDD. However, mirtazapine had a faster onset of action
ine and paroxetine resulted in higher weight gain than ser-
than fluoxetine, paroxetine, or sertraline. Also, 38% of the
traline, trazodone, or venlafaxine; and trazodone was
patients did not achieve a treatment response during 6 to
associated with a higher incidence of somnolence than bu-
12 weeks of treatment with second-generation antidepres-
propion, fluoxetine, mirtazapine, paroxetine, or venlafaxine.
sants, and 54% did not achieve remission.
Although the evidence base was limited, second-gen-
Severe Adverse Events
eration antidepressants did not differ in efficacy in patients
Sexual Dysfunction. Bupropion had a significantly
with accompanying symptoms or subgroups based on age,
lower rate of sexual adverse events than fluoxetine or
sex, race or ethnicity, or other comorbid conditions.
sertraline (84 – 88). Paroxetine had higher rates of sexual
The most commonly reported adverse events were
dysfunction than fluoxetine, fluvoxamine, nefazodone, or
constipation, diarrhea, dizziness, headache, insomnia, nau-
sertraline (30, 48, 56, 89). Absolute rates of sexual dys-
sea, sexual side effects, and somnolence. Nausea and vom-
function are probably underreported.
iting were the most common reasons for discontinuation
Suicidality. Studies evaluating the risk for suicidality
in efficacy studies. Although studies evaluating the risk
(suicidal thinking or behavior) in patients showed no
for suicidality (suicidal thinking or behavior) in patients
differences among second-generation antidepressants (90 –
showed no differences between second-generation anti-
94). However, 1 meta-analysis showed that although no
depressants, patients receiving SSRIs had an increased risk
evidence indicated an increase in the risk for suicide with
SSRIs (odds ratio, 0.85 [CI, 0.20 to 3.40]), the risk fornonfatal suicide attempts did increase (odds ratio, 1.57[CI, 0.99 to 2.55]) (91). Another meta-analysis of pub-
FUTURE RESEARCH
lished data (95) showed similar results, with SSRIs associ-
Research using multiple-group or head-to-head trials is
ated with an increased risk for suicide attempts compared
needed to evaluate the efficacy and effectiveness of second-
with placebo (odds ratio, 2.25 [CI, 3.3 to 4.6]).
generation antidepressants for the treatment of dysthymia
www.annals.org
18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 729
Clinical Guidelines Using Second-Generation Antidepressants to Treat Depressive Disorders
and subsyndromal depression. Effectiveness trials with less
rates of sexual dysfunction than fluoxetine, fluvoxamine,
stringent eligibility criteria that include health outcomes,
nefazodone, or sertraline. In addition, SSRIs are associated
long duration of follow-up, and primary care populations
with an increased risk for suicide attempts compared with
would be valuable for determining whether existing differ-
placebo. Physicians and patients should discuss adverse
ences among second-generation antidepressants are clini-
event profiles before selecting a medication.
cally meaningful in real-world settings. A focus on varia-
Recommendation 2: The American College of Physicians
tions in efficacy and effectiveness in subgroups, such as
recommends that clinicians assess patient status, therapeutic re-
very elderly persons, patients with comorbid conditions, or
sponse, and adverse effects of antidepressant therapy on a regular
different sexes, is also needed. More research is urgently
basis beginning within 1 to 2 weeks of initiation of therapy
needed to evaluate the most appropriate duration of anti-
(Grade: strong recommendation; moderate-quality evidence).
depressant treatment for maintaining remission. It is im-
The U.S. Food and Drug Administration advises that
portant to evaluate the effectiveness of combination ther-
all patients receiving antidepressants be closely monitored
apy and whether any second-generation antidepressant is
on a regular basis for increases in suicidal thoughts and
better than another in patients who either did not respond
behaviors (100). Such monitoring should begin 1 to 2 weeks
to or could not tolerate a first-line treatment.
after initiation of therapy. Patients should be monitored forthe emergence of agitation, irritability, or unusual changes in
behavior, because these symptoms can indicate that the de-
ECOMMENDATIONS
pression is getting worse. The risk for suicide attempts is
Recommendation 1: The American College of Physicians
greater during the first 1 to 2 months of treatment. recommends that when clinicians choose pharmacologic ther-Recommendation 3: The American College of Physiciansapy to treat patients with acute major depression, they selectrecommends that clinicians modify treatment if the patientsecond-generation antidepressants on the basis of adverse effectdoes not have an adequate response to pharmacotherapyprofiles, cost, and patient preferences (Grade: strong recom-within 6 to 8 weeks of the initiation of therapy for majormendation; moderate-quality evidence).depressive disorder (Grade: strong recommendation; moderate-
Various approaches, including pharmacotherapy, psy-
chotherapy, and cognitive behavioral therapy, are effective
One of the most important aspects of care is assessing
for treatment of depression. Existing evidence does not
the response to treatment and making necessary changes in
justify the choice of any second-generation antidepressant
therapy if the response is not sufficient after adequate treat-
over another on the basis of greater efficacy and effective-
ment. Clinicians should consider whether addition of other
ness. Efficacy and effectiveness of these agents do not differ
therapeutic modalities may be indicated. The response rate
among subgroups based on age, sex, or race or ethnicity.
to drug therapy may be as low as 50%. In addition, the
However, differences have been reported among some
evidence is insufficient to determine which patient factors
medications in mild (constipation, diarrhea, dizziness,
can reliably predict response or nonresponse to an individ-
headache, insomnia, nausea, and somnolence) to major
ual drug. Multiple pharmacologic therapies might be re-
(sexual dysfunction and suicidality) adverse effects. Bupro-
quired for patients who do not respond to first- or second-
pion is associated with a lower rate of sexual adverse events
line treatments. Insufficient evidence exists to prefer one
than fluoxetine or sertraline, whereas paroxetine has higher
agent over another as second-line therapy. Table 2 sum- marizes the durations and dosages of treatments used in the trials reviewing the treatment of MDD. Table 2. Durations and Dosages of Treatments Used in the Recommendation 4: The American College of PhysiciansTrials Reviewing the Comparative Efficacy and Effectiveness recommends that clinicians continue treatment for 4 to 9of Treating Major Depressive Disorder months after a satisfactory response in patients with a firstepisode of major depressive disorder. For patients who haveDuration of Dosage, mg/d had 2 or more episodes of depression, an even longer durationTherapy, wk of therapy may be beneficial (Grade: strong recommendation;
Duration of therapy depends on the risk for relapse or
recurrence. Patients who achieve remission with acute-
phase treatment should continue receiving antidepressant
therapy for 4 to 9 months to prevent relapse. No evidence
indicates differences among second-generation antidepres-
sants in preventing relapse (loss of response during contin-
uation-phase treatment) or recurrence (loss of response
during maintenance-phase treatment). Patients who havehad 2 or more episodes may benefit from a longer duration
* Trials reviewing comparative efficacy and effectiveness did not report P values ordid not reach statistical significance.
of therapy (years to lifelong). Table 3 summarizes the du- 730 18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 www.annals.org
Using Second-Generation Antidepressants to Treat Depressive Disorders Clinical Guidelines
Revision. Washington, DC: American Psychiatric Assoc; 2000. Table 3. Durations and Dosages of Treatments Used in the
4. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI Trials Reviewing the Comparative Efficacy and Effectiveness
escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-6. [PMID:12000207]
for Treating Recurrent and Treatment-Resistant Depression
5. Colonna L, Andersen HF, Reines EH. A randomized, double-blind, 24-week study of escitalopram (10 mg/day) versus citalopram (20 mg/day) in primary care Duration of Dosage, mg/d
patients with major depressive disorder. Curr Med Res Opin. 2005;21:1659-68. Therapy, wk
6. FDA Center for Drug Evaluation and Research. Statistical Review of NDA
21-323 (Escitalopram Oxalate). Rockville, MD: U.S. Food and Drug Adminis-
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18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 733 Annals of Internal Medicine Current Author Addresses: Drs. Qaseem and Snow: 190 N. Indepen- dence Mall West, Philadelphia, PA 19106. Dr. Denberg: 12631 East 17th Avenue, B180, Academic Office 1, Au- rora, CO 80045. Dr. Forciea: 3615 Chestnut Street, Philadelphia, PA 19104. Dr. Owens: 117 Encina Commons, Stanford, CA 94305. www.annals.org
18 November 2008 Annals of Internal Medicine Volume 149 • Number 10 W-139
clinical practice James W middleton Grace leong linda mann MBBS, PhD, FAFRM(RACP), is Director, Statewide Spinal Cord Injury Service, and Associate Rehabilitation Specialist, Statewide Spinal Professor, Rehabilitation Studies Unit, Faculty of Medicine, The University of Sydney, New South Specialist, Spinal Cord Injuries Unit, Royal management of spinal cord injury
------------------------------------------------------------------------------------------------------------ The Need for Surgery For many individuals who are morbidly obese, defined as being 100 pounds or more overweight, surgery is the only method that helps to control weight successfully. Most diet plans have proven ineffective. Weight loss surgery promotes weight loss by decreasing foo