Silver Henry, Chertkow Yael, Weinreb Orly, Danovich Lena, Youdim Moussa
Molecular Neuropsychiatry Unit, Brain Behavior Laboratory, Shaar Menashe Mental Health Center, and Technion-Faculty of Medicine, Haifa 32000, Israel.
Neurotherapeutics. 2009 Jan;6(1):86-93. doi: 10.1016/j.nurt.2008.10.034.
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.
许多患有重度精神疾病的患者对单一疗法反应不佳，需要加用其他药物。迄今为止，尚无客观的指南来决定哪种联合用药可能有效，用药选择基于以往的临床经验以及反复试验。即使联合用药有效，其增效作用背后的生化机制仍不明确。了解这种协同作用的机制可能为选择药物组合以及研发更有效的药物提供合理依据。在精神分裂症中，阴性症状对抗精神病药物反应较差，但在加用选择性5-羟色胺再摄取抑制剂（SSRI）后可能会有所改善。这种增效作用无法通过将各药物的药理作用简单相加来解释。我们提出，对SSRI增效作用的研究可作为了解临床有效药物协同作用生化机制的一个窗口。在一系列研究中，我们确定了联合用药具有不同于每种单一药物的独特生化效应，并提出其中一些效应参与介导临床疗效。在此，我们回顾部分研究结果，并提出其作用机制涉及对GABA系统的区域选择性调节。有证据表明，SSRI与抗精神病药物的联合用药可能是研究精神分裂症治疗有效协同药物相互作用的一个有用范例。尽管目前范围有限，但关于SSRI与抗精神病药物协同作用的可明确分子靶点的研究结果为未来研究提供了新方向，并为药物研发提供了新的生物分子靶点。
