Lewis Alan S, van Schalkwyk Gerrit I, Bloch Michael H
Department of Psychiatry, Yale University, 34 Park Street, 3rd Floor, Research, New Haven, CT 06508, United States.
Yale Child Study Center, 230 S. Frontage Road, New Haven, CT 06520, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 3;75:45-53. doi: 10.1016/j.pnpbp.2017.01.001. Epub 2017 Jan 5.
Cognitive dysfunction in schizophrenia (SCZ) and Alzheimer's disease (AD) is a major driver of functional disability but is largely unresponsive to current therapeutics. Animal models of cognitive dysfunction relevant to both disorders suggest the α7 nicotinic acetylcholine receptor (nAChR) may be a promising drug development target, with multiple clinical trials subsequently testing this hypothesis in individuals with SCZ and AD. However, the translational value of rodent cognitive tasks for predicting the overall efficacy of this therapeutic target in clinical trials is unknown. To compare effect sizes between rodent and human studies, we searched PubMed and the Cochrane Library for all randomized, placebo-controlled trials of compounds with pharmacological activity at the α7 nAChR for treatment of cognitive dysfunction in SCZ and AD and identified 18 studies comprising 2670 subjects treated with eight different compounds acting as full or partial agonists. Cognitive outcomes were standardized, and random-effects meta-analyses revealed no statistically significant effects of α7 nAChR agonists on overall cognition or any of eight cognitive subdomains when all doses were included (Range of all cognitive outcomes: Cohen's d=-0.077 to 0.12, negative favoring drug). In contrast, analysis of 29 rodent studies testing the same α7 agonists revealed large effect sizes in multiple commonly used preclinical behavioral tests of cognition (Range: d=-1.18 to - 0.73). Our results suggest that targeting the α7 nAChR with agonists is not a robust treatment for cognitive dysfunction in SCZ or AD and necessitate a better understanding of the translational gap for therapeutics targeting the α7 nAChR.
精神分裂症（SCZ）和阿尔茨海默病（AD）中的认知功能障碍是功能残疾的主要驱动因素，但目前的治疗方法对此大多无效。与这两种疾病相关的认知功能障碍动物模型表明，α7烟碱型乙酰胆碱受体（nAChR）可能是一个有前景的药物开发靶点，随后有多项临床试验在SCZ和AD患者中检验了这一假设。然而，啮齿动物认知任务在预测该治疗靶点在临床试验中的总体疗效方面的转化价值尚不清楚。为了比较啮齿动物和人类研究之间的效应大小，我们在PubMed和Cochrane图书馆中搜索了所有针对α7 nAChR具有药理活性的化合物治疗SCZ和AD认知功能障碍的随机、安慰剂对照试验，确定了18项研究，包括2670名受试者，他们接受了8种不同化合物的治疗，这些化合物作为完全或部分激动剂。对认知结果进行了标准化处理，随机效应荟萃分析显示，当纳入所有剂量时，α7 nAChR激动剂对总体认知或八个认知子领域中的任何一个均无统计学显著影响（所有认知结果的范围：Cohen's d=-0.077至0.12，负值表示药物无效）。相比之下，对29项测试相同α7激动剂的啮齿动物研究的分析显示，在多个常用的临床前认知行为测试中效应大小较大（范围：d=-1.18至-0.73）。我们的结果表明，用激动剂靶向α７nAChR并非治疗SCZ或AD认知功能障碍的有效方法，因此有必要更好地理解靶向α7 nAChR治疗方法的转化差距。
