Ioannidis John P A
Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and the Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece.
Philos Ethics Humanit Med. 2008 May 27;3:14. doi: 10.1186/1747-5341-3-14.
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 "Negative" trials were either left unpublished or were distorted to present "positive" results.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.
抗抑郁药，尤其是新型抗抑郁药，是全球处方量最大的药物之一，年销售额达数十亿美元。这些药物进入市场之前似乎都经过了严格的监管控制。针对抗抑郁药已经开展了一千多项随机试验。统计学上的显著疗效已得到反复证实，医学文献中充斥着数百项“阳性”试验（包括批准前和批准后）。然而，最近的两项荟萃分析对这种情况提出了质疑。第一项荟萃分析使用了提交给美国食品药品监督管理局（FDA）以批准12种抗抑郁药物的数据。虽然这些试验中只有一半具有形式上显著的有效性，但发表的报告几乎无一例外地声称有显著结果。“阴性”试验要么未发表，要么被歪曲以呈现“阳性”结果。基于FDA数据，这些药物的平均疗效很小，而发表的文献表明疗效更大。第二项荟萃分析同样使用了提交给FDA的数据，研究了治疗效果与抑郁症基线严重程度之间的关系。药物与安慰剂的差异随着基线严重程度的增加而增大，只有在极少数患有严重重度抑郁症的患者群体中，这种差异才大到具有临床意义。在严重重度抑郁症中，抗抑郁药并没有变得更有效，只是安慰剂失去了效果。这些数据表明，抗抑郁药的效果可能比其广泛宣传的要差。短期益处很小，而益处与危害的长期平衡尚未得到充分研究。我将讨论如何通过使用许多临床结果无关紧要的小型随机试验、对统计学显著性的不当解释、操纵性的研究设计、有偏差的研究人群选择、短期随访以及对结果的选择性和歪曲性报告，构建并助长了一个关于抗抑郁药有效性的看似基于证据的神话，以及如何通过更高的证据标准，即进行非常大型的长期试验并对个体水平的数据进行仔细的前瞻性荟萃分析，可能更接近真相并获得临床有用的证据。
