预防效果还是撤药反应？对提交给美国食品药品监督管理局的抗抑郁药预防复发试验的事件发生时间数据的分析。
Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA.
作者信息
Hengartner Michael P, Plöderl Martin
机构信息
Department of Applied Psychology, Zurich University of Applied Sciences (ZHAW), PO Box 707, Zurich, CH-8037, Switzerland.
Department of Crisis Intervention and Suicide Prevention, University Clinic for Psychiatry, Psychotherapy, and Psychosomatics, Christian Doppler Clinic, Paracelsus Medical University Salzburg, Austria.
出版信息
Ther Adv Psychopharmacol. 2021 Aug 10;11:20451253211032051. doi: 10.1177/20451253211032051. eCollection 2021.
BACKGROUND
Relapse prevention trials build the scientific foundation for recommendation of antidepressant continuation and maintenance therapy. However, the validity of the evidence is disputed and may be biased due to withdrawal confounding.
METHODS
We analysed survival curves from all antidepressant relapse prevention trials submitted to the United States (US) Food and Drug Administration (FDA) between 1987 and 2012 for 13 approved drugs. The main outcome was the percent of the drug effect (placebo-antidepressant difference in relapse events) at any week of the maintenance phase in relation to the total drug effect at the endpoint of the randomised maintenance phase.
RESULTS
Altogether, 14 studies with a mean observation period of 38.9 weeks (Kaplan-Meier estimators) were analysed. At week 3, a mean of 20.6% [95% confidence interval (CI) = 10.9-30.3%] of the total drug effect was achieved. At weeks 6 and 12, the corresponding figures were 50.3% (37.3-63.3%) and 69.0% (55.1-82.8%). No further antidepressant-placebo separation was observed as of week 24 [101.0% of total drug effect (94.6-107.3%)]. This means that censoring relapse events that occurred in the first 3, 6, 12 and 24 weeks would reduce the total drug effect at study endpoint by 20.6%, 50.3%, 69.0% and 101.0%, respectively. Assuming antidepressants had a constant prophylactic effect over 38.9 weeks, we further showed that, around week 6, the antidepressant-placebo separation was about three times larger than expected.
CONCLUSION
The placebo-antidepressant separation was disproportionally large between weeks 3 and 6 of the randomised maintenance phase. The benefits of continuing antidepressants relative to abrupt/rapid discontinuation declined sharply after week 6. This indicates an excess of relapse events in the placebo arms during the early maintenance phase that may be due to withdrawal reactions caused by abrupt/rapid discontinuation of active treatment. If these early relapse events are due to a direct pharmacological effect, then antidepressants' true prophylactic long-term effects are substantially overestimated.
背景
预防复发试验为抗抑郁药持续治疗和维持治疗的推荐奠定了科学基础。然而，证据的有效性存在争议，且可能因撤药混杂因素而产生偏差。
方法
我们分析了1987年至2012年间提交给美国食品药品监督管理局（FDA）的13种获批药物的所有抗抑郁药预防复发试验的生存曲线。主要结局是维持期任何一周的药物效应百分比（复发事件中安慰剂与抗抑郁药的差异）与随机维持期终点时的总药物效应的关系。
结果
共分析了14项研究，平均观察期为38.9周（Kaplan-Meier估计值）。在第3周时，达到了总药物效应的20.6%[95%置信区间（CI）=10.9-30.3%]。在第6周和第12周时，相应数字分别为50.3%（37.3-63.3%）和69.0%（55.1-82.8%）。截至第24周未观察到进一步的抗抑郁药与安慰剂分离[总药物效应的101.0%（94.6-107.3%）]。这意味着审查在前3、6、12和24周发生复发事件将分别使研究终点时的总药物效应降低20.6%、50.3%、69.0%和101.0%。假设抗抑郁药在38.9周内具有恒定的预防效果，我们进一步表明，在第6周左右，抗抑郁药与安慰剂的分离比预期大3倍左右。
结论
在随机维持期的第3周和第6周之间，安慰剂与抗抑郁药的分离不成比例地大。第6周后，继续使用抗抑郁药相对于突然/快速停药的益处急剧下降。这表明在早期维持期安慰剂组的复发事件过多，这可能是由于突然/快速停用活性治疗引起的撤药反应所致。如果这些早期复发事件是由于直接的药理作用，那么抗抑郁药真正的长期预防作用被大大高估了。
Zotero 插件