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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
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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
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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 Physicians apy to treat patients with acute major depression, they select recommends that clinicians modify treatment if the patient second-generation antidepressants on the basis of adverse effect does not have an adequate response to pharmacotherapy profiles, cost, and patient preferences (Grade: strong recom- within 6 to 8 weeks of the initiation of therapy for major mendation; 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 Physicians Trials Reviewing the Comparative Efficacy and Effectiveness
recommends that clinicians continue treatment for 4 to 9 of Treating Major Depressive Disorder
months after a satisfactory response in patients with a firstepisode of major depressive disorder. For patients who have Duration of
Dosage, mg/d
had 2 or more episodes of depression, an even longer duration Therapy, 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
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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- tration; 2001. Accessed at www.fda.gov/cder/foi/nda/2002/21-323.pdf _Lexapro_Statr.pdf on 3 October 2008.
7. Lepola UM, Loft H, Reines EH. Escitalopram (10-20 mg/day) is effective and
well tolerated in a placebo-controlled study in depression in primary care. Int
Clin Psychopharmacol. 2003;18:211-7. [PMID: 12817155]
8. Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized,
rations and dosages of treatments used in the trials that double-blind study of the efficacy of escitalopram versus citalopram in outpatient reviewed the comparative efficacy and effectiveness of sec- treatment of major depressive disorder. Int Clin Psychopharmacol. 2005; ond-generation antidepressants for treating recurrent and 9. Ekselius L, von Knorring L, Eberhard G. A double-blind multicenter trial
comparing sertraline and citalopram in patients with major depression treated in
general practice. Int Clin Psychopharmacol. 1997;12:323-31. [PMID: 9547134]
From the American College of Physicians and the University of Penn- 10. Kroenke K, West SL, Swindle R, Gilsenan A, Eckert GJ, Dolor R, et al.
sylvania, Philadelphia, Pennsylvania; University of Colorado, Aurora, Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a Colorado; and Veterans Affairs Palo Alto Health Care System and Stan- randomized trial. JAMA. 2001;286:2947-55. [PMID: 11743835] ford University, Stanford, California.
11. Sechter D, Troy S, Paternetti S, Boyer P. A double-blind comparison of
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patients. Eur Psychiatry. 1999;14:41-8. [PMID: 10572324] all patients and all clinical situations. Thus, they are not intended to 12. Aberg-Wistedt A, Agren H, Ekselius L, Bengtsson F, Akerblad AC. Sertra-
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oxetine versus trazodone: efficacy and activating-sedating effects. J Clin Psychia-
Disclaimer: The authors of this article are responsible for its contents,
including any clinical or treatment recommendations. No statement in 14. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalo-
this article should be construed as an official position of the Agency for pram and venlafaxine extended release in the treatment of major depressive dis- Healthcare Research and Quality or the U.S. Department of Health and order. J Clin Psychiatry. 2004;65:1190-6. [PMID: 15367045] 15. Boyer P, Danion JM, Bisserbe JC, Hotton JM, Troy S. Clinical and eco-
nomic comparison of sertraline and fluoxetine in the treatment of depression. A
Grant Support: Financial support for the development of this guideline
6-month double-blind study in a primary-care setting in France. Pharmacoeco- comes exclusively from the American College of Physicians’ operating 16. Devanand DP, Nobler MS, Cheng J, Turret N, Pelton GH, Roose SP,
et al. Randomized, double-blind, placebo-controlled trial of fluoxetine treatment
for elderly patients with dysthymic disorder. Am J Geriatr Psychiatry. 2005;13:
Potential Financial Conflicts of Interest: Grants received: V. Snow
(Atlantic Philanthropies, Novo Nordisk, Boehringer Ingelheim, Centers 17. Finkel SI, Richter EM, Clary CM, Batzar E. Comparative efficacy of sertra-
for Disease Control and Prevention, Sanofi Pasteur, Endo). Any conflict line vs. fluoxetine in patients age 70 or over with major depression. Am J Geriatr of interest of the group members was declared, discussed, and resolved.
Psychiatry. 1999;7:221-7. [PMID: 10438693]
18. Guelfi JD, Ansseau M, Timmerman L, Kørsgaard S. Mirtazapine-Venlafax-
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, Amer-
ine Study Group. Mirtazapine versus venlafaxine in hospitalized severely de-
ican College of Physicians, 190 N. Independence Mall West, Philadel- pressed patients with melancholic features. J Clin Psychopharmacol. 2001;21: phia, PA 19106; e-mail, aqaseem@acponline.org.
425-31. [PMID: 11476127]
19. Leinonen E, Skarstein J, Behnke K, Agren H, Helsdingen JT. Efficacy and
tolerability of mirtazapine versus citalopram: a double-blind, randomized study in
Current author addresses are available at www.annals.org.
patients with major depressive disorder. Nordic Antidepressant Study Group. Int
Clin Psychopharmacol. 1999;14:329-37. [PMID: 10565799]
20. McPartlin G, Reynolds A, Anderson C, Casoy J. A comparison of once-daily
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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.
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Source: http://www.themgo.com/content/ACPDepressionGuideline.pdf