Khan Arif, Fahl Mar Kaysee, Faucett Jim, Khan Schilling Shirin, Brown Walter A
Northwest Clinical Research Center, Bellevue, WA, USA.
Department of Psychiatry, Duke University School of Medicine, Durham, NC, USA.
World Psychiatry. 2017 Jun;16(2):181-192. doi: 10.1002/wps.20421.
More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant-placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r=0.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p=0.42) and the magnitude of antidepressant-placebo differences (10.5% vs. 10.3%, p=0.37) have remained statistically equivalent. Furthermore, the frequency of positive trial arms has gone up in the past 15 years (from 47.8% to 63.8%), but this difference in frequency has not reached statistical significance. Trial design features that were previously associated with a possible lower magnitude of placebo response were not implemented, and their relationship to the magnitude of placebo response could not be replicated. Of the 34 recent trials, two implemented enhanced interview techniques, but both of them were unsuccessful. The results of this study suggest that the relationship between the magnitude of placebo response and the outcome of antidepressant clinical trials is weak at best. These data further indicate that antidepressant-placebo differences are about the same for all of the sixteen antidepressants approved by the FDA in the past thirty years.
十五年多前，人们注意到抗抑郁药物临床试验的失败率很高，且此类负面结果被认为与安慰剂反应程度的增加有关。然而，对于这一现象及其与近期抗抑郁药物临床试验结果的关系存在相当大的争议。为了对此进行调查，我们查阅了美国食品药品监督管理局（FDA）对1987年至2013年间批准的16种抗抑郁药物（85项试验、115个试验组、23109名患者）的审评资料。我们计算了安慰剂和抗抑郁药物反应的程度、抗抑郁药物与安慰剂的差异，以及效应量和成功率，并对这些指标随时间的变化进行了比较。探索性分析研究了试验设计和实施随时间的潜在变化。正如预期的那样，安慰剂反应的程度在过去30年中稳步上升，自2000年以来增加了6.4%（r = 0.46，p < 0.001）。与预期相反，抗抑郁药物反应的程度也出现了类似的增加（6.0%，r = 0.37，p < 0.001）。因此，效应量（0.30对0.29，p = 0.42）以及抗抑郁药物与安慰剂的差异程度（10.5%对10.3%，p = 0.37）在统计学上仍然相当。此外，在过去15年中，阳性试验组的频率有所上升（从47.8%升至63.8%），但这种频率差异未达到统计学显著性。先前与较低安慰剂反应程度可能相关的试验设计特征并未实施，且无法重现它们与安慰剂反应程度的关系。在最近的34项试验中，有两项采用了强化访谈技术，但均未成功。本研究结果表明，安慰剂反应程度与抗抑郁药物临床试验结果之间的关系充其量很微弱。这些数据进一步表明，在过去三十年中，FDA批准的这16种抗抑郁药物的抗抑郁药物与安慰剂的差异大致相同。
