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
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articles were manually searched and the Center for Drug Evaluation and Research database was explored to identify unpublished research.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.
Appendix Table 1.
The number of included articles differs from the number of included studies because some studies have multiple publications.
Appendix Table 2.
Appendix Table 3.
Appendix Table 4.
Appendix Table 5.
Appendix Table 6.
Appendix Table 7.
Appendix Table 8.
Appendix Table 9.
Appendix Table 10.
Appendix Table 11.
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.
All estimates are based on network meta-analyses except for those marked with an asterisk.* Based on meta-analysis of head-to-head trials.
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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, Thieda P, DeVeaugh-Geiss A, Krebs EE, 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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