Mallinckrodt Craig H, Meyers Adam L, Prakash Apurva, Faries Douglas E, Detke Michael J
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
Psychopharmacol Bull. 2007;40(2):101-14.
Previous experience with antidepressant studies highlight the difficulties in discriminating an effective drug from placebo. In hopes of improving signal detection, three easy-to-implement methodologies were employed during the development of a recently approved antidepressant.
Results from alternative and traditional methods could be compared directly because most studies employed both methods. This database included 11 double-blind, placebo-controlled trials (some with multiple dose arms and/or active comparators) yielding 22 treatment arms of antidepressants at or above the minimally effective dose noted in their U.S. labels.
Results agreed with the previous evidence showing that the performance of a likelihood-based, mixed-effects model repeated measures (MMRM) analysis was superior to that of analysis of covariance with missing values imputed using the last observation carried forward (LOCF) approach; MMRM correctly identified drug as superior to placebo in 14/22 (63.6%) comparisons versus 11/22 (50.0%) for LOCF. In agreement with previous studies, use of subscales of the Hamilton Depression Rating scale (HAMD) improved signal detection compared to the HAMD total score. Using MMRM with HAMD subscales correctly identified drug as superior to placebo in up to 17/22 (77.3%) comparisons. Excluding double-blind, placebo lead-in responders did not increase the frequency of correctly identifying drug-versus-placebo differences.
The 22 drug-versus-placebo comparisons in this report offer a small amount of evidence and therefore may not be convincing on their own, although results do agree with previous research. Researchers may be able to take advantage of these easy-to-implement methods while we wait for further improvements in other areas.
以往抗抑郁药研究的经验凸显了区分有效药物与安慰剂的困难。为了提高信号检测能力，在一种最近获批的抗抑郁药的研发过程中采用了三种易于实施的方法。
由于大多数研究同时采用了替代方法和传统方法，因此可以直接比较这两种方法的结果。该数据库包括11项双盲、安慰剂对照试验（有些试验有多个剂量组和/或活性对照），产生了22个抗抑郁药治疗组，其剂量达到或高于美国药品标签中注明的最低有效剂量。
结果与先前的证据一致，表明基于似然性的混合效应模型重复测量（MMRM）分析的性能优于采用末次观察结转（LOCF）方法对缺失值进行估算的协方差分析；在22次比较中，MMRM正确识别出药物优于安慰剂的有14次（63.6%），而LOCF为11次（50.0%）。与先前的研究一致，与汉密尔顿抑郁量表（HAMD）总分相比，使用HAMD分量表可提高信号检测能力。使用MMRM和HAMD分量表在多达17/22次（77.3%）的比较中正确识别出药物优于安慰剂。排除双盲、安慰剂导入期有反应者并没有增加正确识别药物与安慰剂差异的频率。
本报告中的22次药物与安慰剂比较提供的证据较少，因此仅凭这些结果可能不具说服力，尽管结果与先前的研究一致。在我们等待其他领域进一步改进的同时，研究人员或许能够利用这些易于实施的方法。
