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

Richard A. Hansen, PhD; Gerald Gartlehner, MD, MPH; Kathleen N. Lohr, PhD; Bradley N. Gaynes, MD, MPH; and Timothy S. Carey, MD, MPH
[+] Article and Author 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@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.


Ann Intern Med. 2005;143(6):415-426. doi:10.7326/0003-4819-143-6-200509200-00006
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We found 820 unduplicated citations. Manual review of the reference lists of pertinent review articles produced another 74 articles. Although 6 pharmaceutical companies submitted dossiers, no included studies stemmed from the dossiers. Therefore, 894 citations were included in our database (Appendix Figure), available www.annals.org

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Figures

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Figure 1.
Meta-analysis of fluoxetine compared with paroxetine.

The numbers on each side of the 95% CI are the number of responders over the total number of participants who were randomly allocated to receive that drug. The total number of responders does not always match because of postrandomization exclusions or use of observed cases analysis. *Trial sponsored by or authors affiliated with GlaxoSmithKline (Philadelphia, Pennsylvania) or SmithKline Beecham (Research Triangle Park, North Carolina), the manufacturer of paroxetine. †Trial sponsored by or authors affiliated with Eli Lilly (Indianapolis, Indiana), the manufacturer of fluoxetine. ‡Funding source not reported.

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Figure 2.
Meta-analysis of fluoxetine compared with sertraline.

The numbers on each side of the 95% CI are the number of responders over the total number of participants who were randomly allocated to receive that drug. The total number of responders does not always match because of postrandomization exclusions or use of observed cases analysis. *Trial sponsored by or authors affiliated with Pfizer, Inc. (New York, New York), the manufacturer of sertraline. †Trial sponsored by or authors affiliated with Eli Lilly (Indianapolis, Indiana), the manufacturer of fluoxetine.

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Figure 3.
Meta-analysis of fluoxetine compared with venlafaxine.

The numbers on each side of the 95% CI are the number of responders over the total number of participants who were randomly allocated to receive that drug. The total number of responders does not always match because of postrandomization exclusions or use of observed cases analysis. All trials were sponsored by or had authors affiliated with Wyeth-Ayerst (Madison, New Jersey), the manufacturer of venlafaxine.

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Appendix Figure.
Flow diagram of the systematic review.

SSRI = selective serotonin reuptake inhibitor.

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Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

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Newer Antidepressants and Risk of Bleeding
Posted on September 22, 2005
Prasanta Padhan
JIPMER,PONDICHERRY,INDIA.605006.
Conflict of Interest: None Declared

Dear Editor,

In the treatment of major depression,newer antidepressants are very effective and improve quality of life in these patients.These drugs act primarily by inhibiting serotonin reuptake and recently an increase in incidence gastointestinal bleeding and bleeding from other sites have been reported in patients taking these agents.This could be due to inhibition of platelet activation by serotonin.Risk of bleeding is further increased if patient is already on antiplatelet drugs.Although none of the patients in this study had bleeding as an adverse effect,care should be taken regarding history of bleeding disorder and use of antiplatelet drugs before prescribing newer antidepressants.

Conflict of Interest:

None declared

DIFFERENCES BETWEEN SECOND-GENERATION ANTIDEPRESSANTS?
Posted on October 11, 2005
Emmanuelle Corruble
Paris XI University, Bicetre Universitary Hospital, Assistance Publique - Hôpitaux de Paris, France
Conflict of Interest: None Declared

Based on published studies, Hansen and colleagues (1) recently stated that second"“generation antidepressants do not differ from one another in the treatment of major depression. We believe, however, that in terms of both efficacy and side effects, there are indeed significant differences, and that these differences could be seen if greater consideration could be given to the following points: populations studied, length of the studies and drug dosages.

Regarding the populations studied, Hansen considered only primary care patients. Many studies have shown that antidepressant efficacy is more pronounced in those studies which included in-patients with severe depression (2).

On the question of the length of the studies, Hansen took into consideration only those studies which lasted three months or longer. But in some short-term studies, for example 4 to 8 weeks, differences between the antidepressants were found (2,3,4).

We would also like to point out that the published studies examined did not give sufficient attention to the extent to which the antidepressant dosage can affect efficacy and side effects. Only 7 of the 50 studies reviewed by Hansen (14%) are fixed-dose studies; the remaining are flexible-dose studies, which are less informative for drug comparisons. Differences were observable among fixed-dose studies of second-generation drugs (2,3,5).

In conclusion, in the interest of providing the best possible treatment for those suffering from major depression, we argue for better knowledge of differences between antidepressants. As pharmaceutical companies have up until now only provided inconclusive data in this area, we recommend that future studies comparing various antidepressants be sponsored by public health research funds.

References 1. Hansen RA, Gartlehner G, Lohr KN , Gaynes BN, Carey TS. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med. 2005;143:415-26.

2. Khan A, Kolts RL, Thase ME, Krishnan KRG, Brown WA. Research Design features and patient characteristics associated with the outcome of antidepressant clinical trials. Am J Psychiatry. 2004;161:2045-49.

3. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-41.

4. Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol. 2005;20:131-7. 5. Corruble E, Guelfi JD Antidepressants and major depression: relationship between efficacy and dosage in the therapeutic range ? Acta Psychiatr Scand. 2000;101:343-8.

Conflict of Interest:

None declared

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