Stahl S M
Clinical Neuroscience Research Center, San Diego, CA 02122, USA.
J Affect Disord. 1998 Dec;51(3):215-35. doi: 10.1016/s0165-0327(98)00221-3.
Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive-compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.
血清素选择性再摄取抑制剂（SSRIs）目前是所有医学领域中最常被处方的治疗药物之一。它们的治疗作用多种多样，从治疗抑郁症到强迫症、恐慌症、贪食症及其他病症均有疗效。血清素的大量生物底物、受体和途径不仅是介导SSRIs治疗作用的候选因素，也是其副作用的介导因素。具体而言，SSRIs的即时作用大多是副作用，可能由SSRIs的起始作用介导，即血清素转运体的负变构调节。解释这些即时副作用的一个主要假说是，在身体中调节相关生理过程的离散区域，特定血清素受体亚型处的血清素会增加。这些相同离散脑区中突触后受体的脱敏可能解释了对这些相同副作用产生耐受性的原因。SSRIs治疗效果的解释可能在于延迟的神经化学适应。对此作用的一个主要假说是中脑缝际核中树突体血清素1A自身受体的脱敏。解释SSRIs为何具有如此多样治疗作用的假说是，树突体5HT1A自身受体脱敏会增加那些关键脑区以及那些可能介导各种疾病病理生理过程的关键血清素受体亚型处的血清素。了解离散解剖途径中血清素受体亚型的分布情况，可能会增进我们对这些重要药物治疗作用和副作用的理解。
