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Effectiveness of Antidepressants: An Evidence Myth Constructed From a Thousand Randomized Trials?

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Effectiveness of Antidepressants: An Evidence Myth Constructed From a Thousand Randomized Trials?

John P A Ioannidis. Philos Ethics Humanit Med.

Abstract

Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval). However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second meta-analysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted reporting of results has built and nourished a seemingly evidence-based myth on antidepressant effectiveness and how higher evidence standards, with very large long-term trials and careful prospective meta-analyses of individual-level data may reach closer to the truth and clinically useful evidence.

Figures

Figure 1
Figure 1
Anticipated mean and range of average effect size (ES) for trials in countries where a drug is approved, when the true average effectiveness is ES = 0.20 and the standard deviation (SD) of the estimated ES across trials is 0.20, 0.40, and 0.60. Trials are assumed to be of similar size and similar weight in the calculations. Forty approval packages with 5 trials each have been simulated in each of the three settings and the data show the ES in the successful packages (those where the average ES is at least 0.20).

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