Gerald Gartlehner, MD, MPH; Richard A. Hansen, PhD, RPh; Laura C. Morgan, MA; Kylie Thaler, MD, MPH; Linda Lux, MPA; Megan Van Noord, MSIS; Ursula Mager, PhD, MPH; Patricia Thieda, MA; Bradley N. Gaynes, MD, MPH; Tania Wilkins, MSc; Michaela Strobelberger, MA; Stacey Lloyd, MPH; Ursula Reichenpfader, MD, MPH; Kathleen N. Lohr, PhD
Second-generation antidepressants dominate the management of major depressive disorder (MDD), but evidence on the comparative benefits and harms of these agents is contradictory.
To compare the benefits and harms of second-generation antidepressants for treating MDD in adults.
English-language studies from PubMed, Embase, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to August 2011 and reference lists of pertinent review articles and gray literature.
2 independent reviewers identified randomized trials of at least 6 weeks' duration to evaluate efficacy and observational studies with at least 1000 participants to assess harm.
Reviewers abstracted data about study design and conduct, participants, and interventions and outcomes and rated study quality. A senior reviewer checked and confirmed extracted data and quality ratings.
Meta-analyses and mixed-treatment comparisons of response to treatment and weighted mean differences were conducted on specific scales to rate depression. On the basis of 234 studies, no clinically relevant differences in efficacy or effectiveness were detected for the treatment of acute, continuation, and maintenance phases of MDD. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of health-related quality of life.
Most trials were conducted in highly selected populations. Publication bias might affect the estimates of some comparisons. Mixed-treatment comparisons cannot conclusively exclude differences in efficacy. Evidence within subgroups was limited.
Current evidence does not warrant recommending a particular second-generation antidepressant on the basis of differences in efficacy. Differences in onset of action and adverse events may be considered when choosing a medication.
Agency for Healthcare Research and Quality.
Multiple second-generation antidepressants with different pharmacologic actions are available for treating major depressive disorder in adults.
This comparative effectiveness review of 234 studies found no clinically important differences in treatment response among second-generation antidepressants. Differences among agents did exist in onset of action, dosing regimens, and adverse effects.
Most studies were efficacy trials conducted in selected populations.
Possible side effects, convenience of dosing regimens, and costs may best guide the choice of a second-generation antidepressant for treating major depression in adults, because these agents probably have similar efficacy.
* The number of included articles differs from the number of included studies because some studies have multiple publications.
h-h = head-to-head; MA = meta-analysis; MTC = mixed-treatment comparison.
* The first number indicates the number of trials comparing 2 drugs; the second indicates the number of additional studies used to perform MTCs.
h-h = head-to-head; MA = meta-analysis; MTC = mixed-treatment comparison; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = serotonin reuptake inhibitor.
* The first number indicates the number of trials directly comparing 2 drugs; the second indicates the number of additional studies used to perform MTCs.
MTC = mixed-treatment comparison; SSRI = selective serotonin reuptake inhibitor.
MTC = mixed-treatment comparison; SNRI = serotonin and norepinephrine reuptake inhibitor.
Appendix Table 1.
Appendix Table 2.
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David, Straton, Psychiatrist
Mermaid Waters Therapy Clinic, Gold Coast, Qld, Australia
April 16, 2012
Uncertainty and meta-analyses
This paper follows an earlier meta-analysis by the same team. (1). The first paper compared fluvoxamine to other antidepressants, showing the other drug favored on every one of eleven (11/11) comparisons.
The present 'Updated Meta-analysis' also compares fluvoxamine to other antidepressants but, surprisingly, shows fluvoxamine favored in eleven out of twelve (11/12) comparisons.
I have put the graphics from each paper side-by-side here to illustrate the change.
One possible explanation for the difference might have been new research that was available to the second review but not the first. The sampling time of the first paper was 1980 to April 2007, and of the second was 1980 to August 2011. There was only one new paper on fluvoxamine in the references (2).
It found no significant differences between fluvoxamine and any other antidepressants in terms of efficacy and tolerability.
It is surprising that such a neutrally worded paper should lift fluvoxamine from being a 11/11 loser to a 11/12 winner.
It seems that the wide confidence intervals in the studies on fluvoxamine mean that changes in the point estimates should be taken with a pinch of salt.
Another possibility might have been a change in the statistical method used in the two papers.
As a clinician trying to practice evidence-based medicine, I have learned to be sceptical about the claims made by pharmaceutical reps and their hand-picked industry-funded research. I am also cautious about conclusions that can be drawn from the 'real-world' studies such as STAR*D, because of the small numbers in the later steps.
Instead, I have been tending to trust the meta-analyses of the sort that the MANGA study group (Meta-Analysis of New Generation Antidepressants) has been producing. But the wild swings apparent in cases such as this make me wary of trusting these as well.
I used to be uncertain, but now I'm not so sure!
References. 1) Gartlehner G, Gaynes B, Hansen R. Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians. Ann Intern Med. 2008;149:734-750 Full-text
2) IM Omori, N Watanabe, A Nakagawa. Efficacy, tolerability and side-effect profile of fluvoxamine for major depression: meta-analysis. J Psychopharmacol, July 2009; vol. 23, 5: pp. 539-550
Gartlehner G, Hansen RA, Morgan LC, et al. Comparative Benefits and Harms of Second-Generation Antidepressants for Treating Major Depressive Disorder: An Updated Meta-analysis. Ann Intern Med. 2011;155:772–785. doi: 10.7326/0003-4819-155-11-201112060-00009
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Published: Ann Intern Med. 2011;155(11):772-785.
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