Efficacy and Safety of Second-Generation Antidepressants in the Treatment of Major Depressive Disorder

20 September 2005 | Volume 143 Issue 6 | Pages 415-426

Background: Reviews have compared the efficacy and tolerability of newer second-generation antidepressants with those of placebo or older treatments, but comparative evidence for use of second-generation antidepressants to treat major depressive disorder has not been evaluated.

Purpose: To systematically evaluate comparative data on the efficacy, effectiveness, and tolerability of commonly prescribed second-generation antidepressants (selective serotonin reuptake inhibitors, bupropion, duloxetine, mirtazapine, and venlafaxine) in the treatment of major depressive disorder.

Data Sources: MEDLINE, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through February 2005 for reviews; randomized, controlled trials; meta-analyses; and observational studies.

Study Selection: The authors reviewed 46 head-to-head randomized, controlled trials comparing one second-generation antidepressant with another. Twenty-four observational studies and placebo-controlled trials were also included for assessment of safety and tolerability.

Data Extraction: Two researchers independently reviewed titles and abstracts. Trained reviewers abstracted data from each study and assigned an initial quality rating. A second reviewer verified the data extraction and quality rating.

Data Synthesis: According to fair to good evidence, the second-generation antidepressants that were compared had only minimal differences in efficacy, and 88% of comparative efficacy studies reported no statistically significant difference in any outcome measure at the end of the study. One effectiveness trial rated good and 2 effectiveness trials rated fair reported no statistically significant differences in primary outcome measures for compared drugs. Meta-analyses showed a modest but statistically significant additional treatment effect for sertraline and venlafaxine compared with fluoxetine. About 96% of comparative trials were sponsored by or had at least 1 author affiliated with a pharmaceutical company; the remaining trials did not report funding sources. Adverse event profiles differed among drugs; however, the degree and quality of adverse event assessment varied and only 13% of trials used a standardized scale to assess adverse events.

Limitations: Quantitative analyses could not be done for many drug comparisons because the quantity and quality of the evidence were inadequate. Most published evidence was from trials sponsored by pharmaceutical companies, and publication bias may have occurred.

Conclusions: Overall, second-generation antidepressants probably do not differ substantially for treatment of major depressive disorder. Choosing the agent that is most appropriate for a given patient is difficult.

Editors' Notes Context The relative benefits and harms of newer, second-generation antidepressants are sometimes confusing. Contribution In this review of 46 head-to-head randomized trials, the authors generally found no major differences in the numbers of adults with major depression who responded to second-generation antidepressants, such as selective serotonin reuptake inhibitors, bupropion, duloxetine, mirtazapine, and venlafaxine. The overall incidence of adverse events appeared similar across drugs, although types of adverse events varied. Cautions Trials were funded by industry and had variable quality and follow-up duration. Implications Second-generation antidepressants generally have similar benefits but different possible harms for adults with major depression. —The Editors

 

Author and Article Information

From University of North Carolina, Chapel Hill, North Carolina.

Acknowledgments: The authors thank Laura Morgan for support with study retrieval; Leah Randolph for her contribution to study coordination and reference management; and Leila Kahwati, Heather Himburg, and Melissa Butler for assistance with data abstraction. In addition, they thank Mark Helfand (Center for Evidence-based Policy at the Oregon Health and Science University) and other peer reviewers, who provided constructive comments on earlier versions of the article.

Grant Support: Funding for this research was provided to the Cecil G. Sheps Center for Health Services Research through a subcontract with the Center for Evidence-Based Policy, Oregon Health and Science University. Dr. Gaynes was supported in part by a National Institute of Mental Health K23 Career Development Award (MH01951-03); he has also received grant and research support from the Robert Wood Johnson Foundation and the Agency for Healthcare Research and Quality.

Potential Financial Conflicts of Interest: Consultancies: B.N. Gaynes (Pfizer, Inc., Wyeth-Ayerst); Honoraria: B.N. Gaynes (GlaxoSmithKline); Grants received: B.N. Gaynes (Pfizer, Inc., Ovation Pharmaceuticals).

Requests for Single Reprints: Richard A. Hansen, PhD, Division of Pharmaceutical Policy and Evaluative Sciences, University of North Carolina at Chapel Hill, Room 205M, Beard Hall, Campus Box 7360, Chapel Hill, NC 27599; e-mail, rahansen{at}unc.edu.

Current Author Addresses: Dr. Hansen: Division of Pharmaceutical Policy and Evaluative Sciences, University of North Carolina at Chapel Hill, Room 205M, Beard Hall, Campus Box 7360, Chapel Hill, NC 27599.

Drs. Gartlehner and Carey: Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, 725 Airport Road, Campus Box 7590, Chapel Hill, NC 27599.

Dr. Lohr: Department of Health Policy and Administration, School of Public Health, University of North Carolina at Chapel Hill, McGavran-Greenberg, Campus Box 7411, Chapel Hill, NC 27599.

Dr. Gaynes: Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, 240 Med School Wing C, Campus Box 7160, Chapel Hill, NC 27599.

Author Contributions: Conception and design: R.A. Hansen, G. Gartlehner, B.N. Gaynes.

Analysis and interpretation of the data: R.A. Hansen, G. Gartlehner, B.N. Gaynes.

Drafting of the article: R.A. Hansen, K.N. Lohr, B.N. Gaynes.

Critical revision of the article for important intellectual content: R.A. Hansen, G. Gartlehner, K.N. Lohr, B.N. Gaynes, T.S. Carey.

Final approval of the article: R.A. Hansen, K.N. Lohr, B.N. Gaynes.

Provision of study materials or patients: R.A. Hansen, G. Gartlehner.

Statistical expertise: R.A. Hansen, B.N. Gaynes.

Obtaining of funding: B.N. Gaynes, T.S. Carey.

Administrative, technical, or logistic support: G. Gartlehner, T.S. Carey.

Collection and assembly of data: R.A. Hansen, G. Gartlehner, B.N. Gaynes, T.S. Carey.

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