Development of novel treatments for positive, cognitive, and negative symptoms continue to be a high‐priority area of schizophrenia research and a major unmet clinical need. Given that all randomized controlled trials (RCTs) conducted to date failed with one add‐on medication/mechanism of action, future RCTs with the same approach are not warranted. Even if the field develops a medication for cognition, others are still needed to treat negative and positive symptoms. Therefore, fixing one domain does not completely solve the problem. Also, targeting the cholinergic system, glutamatergic system, and cholinergic plus alpha7 nicotinic and N‐methyl‐D‐aspartate (NMDA) receptors failed independently. Hence, targeting other less important pathophysiological mechanisms/targets is unlikely to be successful. Meta‐analyses of RCTs targeting major pathophysiological mechanisms have found some efficacy signal in schizophrenia; thus, combination treatments with different mechanisms of action may enhance the efficacy signal. The objective of this article is to highlight the importance of conducting RCTs with novel combination treatments in schizophrenia to develop antischizophrenia treatments. Positive RCTs with novel combination treatments that target the alpha7 nicotinic and NMDA receptors simultaneously may lead to a disease‐modifying therapeutic armamentarium in schizophrenia. Novel combination treatments that concurrently improve the three domains of psychopathology and several prognostic and theranostic biomarkers may facilitate therapeutic discovery in schizophrenia.

中文翻译：

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Alpha7 烟碱-N-甲基-D-天冬氨酸假说在治疗精神分裂症及其他疾病中的作用。

开发针对阳性、认知和阴性症状的新疗法仍然是精神分裂症研究的优先领域，也是未满足的主要临床需求。鉴于迄今为止进行的所有随机对照试验 (RCT) 均因一种附加药物/作用机制而失败，因此未来的 RCT 没有必要采用相同的方法。即使该领域开发了一种用于认知的药物，仍然需要其他人来治疗阴性和阳性症状。因此，固定一个域并不能完全解决问题。此外，针对胆碱能系统、谷氨酸能系统和胆碱能加 α7 烟碱和N-甲基-D天冬氨酸 (NMDA) 受体独立失败。因此，针对其他不太重要的病理生理机制/目标不太可能成功。针对主要病理生理机制的随机对照试验的荟萃分析发现了精神分裂症的一些疗效信号；因此，具有不同作用机制的联合治疗可能会增强疗效信号。本文的目的是强调在精神分裂症中进行 RCT 与新型联合治疗以开发抗精神分裂症治疗方法的重要性。同时针对 α7 烟碱和 NMDA 受体的新型联合治疗的阳性随机对照试验可能会导致精神分裂症的疾病改善治疗设备。