Gerald Gartlehner, MD, MPH; Bradley N. Gaynes, MD, MPH; Richard A. Hansen, PhD, RPh; Patricia Thieda, MA; Angela DeVeaugh-Geiss, MS; Erin E. Krebs, MD, MPH; Charity G. Moore, PhD, MSPH; Laura Morgan, MA; Kathleen N. Lohr, PhD
Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.
Acknowledgment: The authors thank Timothy S. Carey, MD, MPH, and Stacey Williams, MA, from the University of North Carolina at Chapel Hill, and also Linda Lux, MPA, and Loraine Monroe of RTI International.
Grant Support: By a contract from the Agency for Healthcare Research and Quality to the RTI InternationalUniversity of North Carolina Evidence-based Practice Center (contract no. 290-02-0016).
Potential Financial Conflicts of Interest:Employment: A. DeVeaugh-Geiss (GlaxoSmithKline). Consultancies: B.N. Gaynes (Pfizer, Wyeth-Ayerst, Shire Pharmaceutical). Honoraria: B.N. Gaynes (GlaxoSmithKline). Stock ownership or options (other than mutual funds): A. DeVeaugh-Geiss (GlaxoSmithKline). Expert testimony: B.N. Gaynes (Phillips Lytle). Grants received: B.N. Gaynes (Agency for Healthcare Research and Quality, National Institute of Mental Health, Bristol-Myers Squibb, Novartis, Pfizer, Robert Wood Johnson Foundation, M-3 Corporation), R.A. Hansen (GlaxoSmithKline). Grants pending: B.N. Gaynes (National Institute of Mental Health, Agency for Healthcare Research and Quality).
Requests for Single Reprints: Gerald Gartlehner, MD, MPH, Danube University, Karl Dorrek-Strae, 3500 Krems, Austria; e-mail, email@example.com.
Current Author Addresses: Dr. Gartlehner: Danube University, Karl Dorrek-Strae, 3500 Krems, Austria.
Dr. Gaynes: Department of Psychiatry, Campus Box 7160, University of North Carolina, Chapel Hill, NC 27599.
Dr. Hansen: University of North Carolina, School of Pharmacy, Campus Box 7360, Chapel Hill, NC 27599.
Ms. Thieda and Ms. Morgan: University of North Carolina, Sheps Center for Health Services Research, 725 Martin Luther King Jr. Boulevard, Chapel Hill, NC 27599.
Ms. DeVeaugh-Geiss: University of North Carolina, Department of Epidemiology, Campus Box 7435, Chapel Hill, NC 27599.
Dr. Krebs: Roudebush Veterans Affairs Medical Center, 1481 West 10th Street, Indianapolis, IN 46202.
Dr. Moore: Center for Research on Health Care Data, University of Pittsburgh, 200 Meyran Avenue, Suite 300, Pittsburgh, PA 15213.
Dr. Lohr: RTI International, PO Box 12194, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194.
Second-generation antidepressants dominate the management of major depressive disorder, dysthymia, and subsyndromal depression. Evidence on the comparative benefits and harms is still accruing.
To compare the benefits and harms of second-generation antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine) for the treatment of depressive disorders in adults.
MEDLINE, EMBASE, PsychLit, Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007, limited to English-language articles. Reference lists of pertinent review articles were manually searched and the Center for Drug Evaluation and Research database was explored to identify unpublished research.
Abstracts and full-text articles were independently reviewed by 2 persons. Six previous good- or fair-quality systematic reviews or meta-analyses were included, as were 155 good- or fair-quality double-blind, placebo-controlled, or head-to-head randomized, controlled trials of at least 6 weeks' duration. For harms, 35 observational studies with at least 100 participants and follow-up of at least 12 weeks were also included.
Using a standard protocol, investigators abstracted data on study design and quality-related details, funding, settings, patients, and outcomes.
If data were sufficient, meta-analyses of head-to-head trials were conducted to determine the relative benefit of response to treatment and the weighted mean differences on specific depression rating scales. If sufficient evidence was not available, adjusted indirect comparisons were conducted by using meta-regressions and network meta-analyses. Second-generation antidepressants did not substantially differ in efficacy or effectiveness for the treatment of major depressive disorder on the basis of 203 studies; however, the incidence of specific adverse events and the onset of action differed. The evidence is insufficient to draw conclusions about the comparative efficacy, effectiveness, or harms of these agents for the treatment of dysthymia and subsyndromal depression.
Adjusted indirect comparisons have methodological limitations and cannot conclusively rule out differences in efficacy.
Current evidence does not warrant the choice of one second-generation antidepressant over another on the basis of differences in efficacy and effectiveness. Other differences with respect to onset of action and adverse events may be relevant for the choice of a medication.
Table 1. Second-Generation Antidepressants Approved for Use in the United States
Appendix Table 1. Characteristics of Studies with Poor Internal Validity
Study flow diagram.
The number of included articles differs from the number of included studies because some studies have multiple publications.
Appendix Table 2. Comparative Efficacy and Effectiveness Studies on Therapy for Major Depressive Disorder
Appendix Table 3. Comparative Efficacy and Effectiveness Studies on Therapy for Dysthymia
Appendix Table 4. Comparative Efficacy and Effectiveness Studies on Therapy for Subsyndromal Depressive Disorders
Appendix Table 5. Comparative Efficacy and Effectiveness Studies on Maintaining Remission and Preventing Relapse
Appendix Table 6. Comparative Efficacy and Effectiveness Studies on Therapy for Recurrent and Treatment-Resistant Depression
Appendix Table 7. Placebo-Controlled Studies of Relapse and Recurrence
Appendix Table 8. Comparative Efficacy and Effectiveness Studies of Treatment in Adults with Major Depressive Disorder and Accompanying Symptoms
Appendix Table 9. Studies of Comparative Risk for Harms in Adults with Major Depressive Disorder
Appendix Table 10. Comparative Efficacy and Effectiveness Studies in Subgroups
Appendix Table 11. Randomized, Placebo-Controlled Trials Included for Indirect Comparisons
Table 2. Summary of Findings on General Effectiveness
Table 3. Summary of Findings on Adverse Events: Comparative Risk for Harms
Table 4. Summary of Findings on Effectiveness in Subgroups
Relative benefit of response comparing selective serotonin reuptake inhibitors (SSRIs) with other SSRIs
All estimates are based on network meta-analyses except for those marked with an asterisk or a dagger.
* Based on meta-analysis of head-to-head trials.
Based on indirect comparisons with meta-regression.
Relative benefit of response comparing selective serotonin reuptake inhibitors (SSRIs) with selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) and SSRIs with serotonin and norepinephrine reuptake inhibitors (SNRIs
Relative benefit of response comparing selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other second-generation antidepressants (ADs) with other second-generation ADs.
All estimates are based on network meta-analyses except for those marked with an asterisk.* Based on meta-analysis of head-to-head trials.
Table 5. Main Differences in Specific Adverse Events
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Thomas E. Finucane
Johns Hopkins School of Medicine
December 5, 2008
Comparative Benefits and Harms of Second-Generation Antidepressants
Dr. Gartlehner and colleague's Background Paper on the comparative benefits and harms of second-generation antidepressants (SGAs) finds "no substantial differences in efficacy among these drugs," but notes that "other differences" may be relevant in choosing a drug (1). They also note that 69% of the studies were supported by the pharmaceutical industry, and for 21% of the studies, source of funding could not be determined. Drug company funding has a strong impact on the published literature. Companies naturally tend to seek publication of results favorable to their products (2).
Seven fair quality studies are cited, all showing that mirtazapine leads to higher weight gain than other SGAs; not shown is that all seven studies are sponsored by mirtazapine's vendor, Organon, and that three of the seven have at least one author who is a drug company employee. Without any good evidence, a market niche for mirtazapine has been created: depressed patients who are losing weight.
Writers of systematic reviews must decide how to weigh vendor-sponsored evidence, especially when most or all of the available evidence is vendor-sponsored. Here is a modest suggestion. In bibliographies, why not make the first initial of the first author scarlet if the paper is sponsored by the vendor? This would make it easy to see where the influence of industry might be suspected.
1. Gartlehner G, Gaynes BN, Hansen RA, Thieda P, DeVeaugh-Geiss A, Krebs EE, Moore CG, et al. Comparative benefits and harms of second-generation antidepressants: Background paper for the American College of Physicians. Ann Intern Med. 2008; 149: 734-750.
2. Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: A review of publication and presentation. PLoS Med 2008; 5(11): e217: 0001-10.
Gartlehner G, Gaynes BN, Hansen RA, et al. Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians. Ann Intern Med. 2008;149:734–750. doi: 10.7326/0003-4819-149-10-200811180-00008
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Published: Ann Intern Med. 2008;149(10):734-750.
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