Many patients suffering from major psychiatric disorders do not respond adequately to monotherapy and require additional drugs. To date, there are no objective guidelines for deciding which combination may be effective, and the choice is based on previous clinical experience and on trial and error. Even when combination drugs are effective, the biochemical mechanisms responsible for the value-added effect are unknown. Understanding the mechanism of such synergism may provide a rational basis for choosing drug combinations and for developing more effective drugs. In schizophrenia, negative symptoms respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRI). This augmenting effect cannot be explained by summating the pharmacological effects of the individual drugs. We proposed that the study of SSRI augmentation can serve as a window to understanding the biochemical mechanisms of clinically effective drug synergism. In a series of studies we identified unique biochemical effects of the combination, different from each individual drug, and proposed that some of these are involved in mediating the clinical effect. Here we review some of the findings and propose that the mechanism of action involves regionally selective modulation of the GABA system. The evidence indicates that the SSRI antidepressant-antipsychotic combination may be a useful paradigm for studying therapeutically effective synergistic drug interactions in schizophrenia. Although as yet limited in scope, the findings of definable molecular targets for synergistic SSRI-antipsychotic interaction provide new directions to inform future research and provide novel bio-molecular targets for drug development.

中文翻译：

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多功能药物治疗：从选择性血清素再摄取抑制剂增强阴性症状精神分裂症抗精神病药物的研究中我们可以学到什么？


许多患有严重精神疾病的患者对单一疗法没有充分反应，需要额外的药物。迄今为止，还没有客观的指南来决定哪种组合可能有效，并且选择是基于以前的临床经验和反复试验。即使组合药物有效，产生增值效应的生化机制仍不清楚。了解这种协同作用的机制可以为选择药物组合和开发更有效的药物提供合理的基础。在精神分裂症中，阴性症状对抗精神病药物反应不佳，但当使用选择性血清素再摄取抑制剂（SSRI）增强这些症状时可能会有所改善。这种增强作用不能通过总结各个药物的药理作用来解释。我们提出，SSRI 增强研究可以作为了解临床有效药物协同作用的生化机制的窗口。在一系列研究中，我们确定了该组合与每种药物不同的独特生化作用，并提出其中一些与调节临床效果有关。在这里，我们回顾了一些研究结果，并提出作用机制涉及 GABA 系统的区域选择性调节。证据表明，SSRI 抗抑郁药-抗精神病药组合可能是研究精神分裂症治疗有效的协同药物相互作用的有用范例。尽管范围有限，但 SSRI-抗精神病药协同相互作用的可定义分子靶点的发现为未来的研究提供了新的方向，并为药物开发提供了新的生物分子靶点。