Theory of active antidepressants: A nonsynaptic approach to the treatment of depression
Theory of active antidepressants: A nonsynaptic approach to the treatment of depression
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DOI：
10.1016/j.neuint.2007.04.006
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发表时间：
2008-01-01
影响因子：
4.2
通讯作者：
Kiss, Janos P.
中科院分区：
文献类型：
--
作者：
Kiss, Janos P.
尽管抑郁症是主要的神经精神疾病之一，但任何药物的治疗成功率约为60%，这意味着大约40%的患者对初始治疗没有反应。本综述的主要目的是为目前使用的抗抑郁药的相对无效性提供可能的解释，并提出一种新的作用机制，这可能会提高临床治疗的成功率。根据单胺理论，抑郁症中最重要的神经化学过程是单胺能神经传递的损害以及随之而来的去甲肾上腺素和/或血清素的细胞外浓度的降低。由于绝大多数单胺能静脉曲张不产生突触接触，但能够将递质直接释放到突触外空间，因此单胺能神经传递本质上主要是非突触的。因此，抑郁症可以被视为一种疾病，它是（至少部分）在非突触相互作用受损的基础上发展起来的，有效的治疗必须改善神经系统中的这种非常规通讯。目前使用的抗抑郁药（再摄取抑制剂、负反馈抑制剂、单胺氧化酶抑制剂）只有在单胺能细胞电活跃的情况下才能增加细胞外空间的单胺水平，并且如果没有动作电位诱导的囊泡胞吐作用，这些化合物是无效的。有人提出，选择性和适度诱导载体介导的NA和5-HT释放可能是治疗抑郁症的更好的治疗方法，因为这种新型抗抑郁药，即所谓的“活性抗抑郁药”，具有独立于单胺能细胞电活动的作用机制，因此可以更有效地增强单胺的突触外浓度，从而增强非突触通讯。 (C) 2007 Elsevier Ltd. 保留所有权利。
Although depression is one of the major neuropsychiatric disorders, the success rate of medication for any drug is about 60%, which means that approximately 40% of the patients does not respond to the initial treatment. The major aim of this review is to provide a possible explanation for the relative inefficacy of currently used antidepressants and to propose a novel mechanism of action, which might improve the success rate of clinical treatment. According to the monoamine theory the most important neurochemical process in depression is the impairment of monoaminergic neurotransmission and the concomitant decrease of extracellular concentration of noradrenaline and/or serotonin. Since the vast majority of monoaminergic varicosities makes no synaptic contact but is able to release transmitters directly into the extrasynaptic space, the monoaminergic neurotransmission is predominantly nonsynaptic in nature. Depression can be regarded, therefore, as a disease, which is developed (at least in part) on the basis of the impairment of nonsynaptic interactions and the effective treatment has to improve this non-conventional communication in the nervous system. The currently used antidepressants (reuptake inhibitors, negative feedback inhibitors, monoamino oxidase inhibitors) can increase the monoamine levels in the extracellular space only if the monoaminergic cells are electrically active and without an action potential-induced vesicular exocytosis these compounds are ineffective. It is proposed that a selective and moderate induction of the carrier-mediated release of NA and 5-HT might be a better therapeutic approach to the treatment of depression, since this new class of antidepressants, the so-called 'active antidepressants' have a mechanism of action, which is independent from the electrical activity of monoaminergic cells, therefore the extrasynaptic concentration of monoamines and thereby the nonsynaptic communication can be enhanced more efficiently. (C) 2007 Elsevier Ltd. All rights reserved.