Mode of action of antidepressant drugs.
Mode of action of antidepressant drugs.
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DOI：
10.1016/0006-2952(78)90226-5
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发表时间：
1978-02
影响因子：
5.8
通讯作者：
F. Sulser;J. Vetulani;P. Mobley
中科院分区：
文献类型：
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作者：
F. Sulser;J. Vetulani;P. Mobley
尽管抗抑郁药物的广泛使用，但其在人体中抗抑郁作用的确切机制仍有待阐明。然而，人们普遍认为，抗抑郁药[三环类抗抑郁药和单胺氧化酶（MAO）抑制剂]的治疗作用至少有一部分可能是突触后受体部位去甲肾上腺素（NE）和/或5-羟色胺（5-HT）可用性增加的结果。临床抗抑郁活性是否与药物增加NE或5-HT利用率的作用更密切相关的问题很难回答，因为MAO抑制剂增加两种单胺的利用率，而三环类抗抑郁药影响两种胺的转运机制或在体内转化为代谢物，与母体药物一起抑制两种系统。而且。一些抗精神病药物也被报道对两种摄取系统都有有效的阻断作用[1，2]。如果5-NT阻断NE摄取的相对程度的差异确实具有临床意义，那么使用更具选择性的抑制剂（如马普替林和尼索西汀）的可用性和对照临床试验（NE吸收的优先抑制剂）和FG 4963 [3]、Lu 10-171 [4]和百忧解（5-HT摄取的优先抑制剂），应该提供一个更明确的答案这个问题。氟西汀是特别令人感兴趣的，因为该药物是5-HT摄取进入特定脑区域的选择性抑制剂，并且其伯胺的N-去甲基化不会改变其抑制5-HT摄取的效力或选择性[S]。而WBlinder rt ul. [6]报道了在一项双盲研究中，与氯丙咪嗪+安慰剂相比，氯丙咪嗪和色氨酸更快地改善了抑郁症，Shopsin et al. [7，S]发现色氨酸羟化酶抑制剂对氯苯丙氨酸逆转了MAO抑制剂和三环类抗抑郁药的抗抑郁作用，色氨酸对三环类抗抑郁药抗抑郁作用的增强作用仍不明确[9，lo]。此外，使用更有选择性的5-HT摄取抑制剂FG 4963的临床研究迄今为止并不令人鼓舞[ll]，使用三环类抗抑郁药i $ rindole和米安色林获得的结果对当前的生物胺假说提出了额外的问题。
Despite the widespread use of antidepressant drugs, ihe precise mechanism of their antidepressant action in man remains to be elucidated. It has been generally accepted, however, that at least part of the therapeutic action of antidepressants drugs [tricychc antidepressants and monoa~ ne oxidase (MAO) inhibitors] may be the consequence of an increased availability of norepinephrine(NE) and/or serotonin (5-HT) at post-synaptic receptor sites. The question of whether the clinical antidepressant activity is more closely related to the effect of the drugs in increasing the availability of NE or of 5-HT is difficult to answer because MAO inhibitors increase the availability of both monoamines, and tricyclic antidepressants affect transport mechanisms of both amines or are in uiuo converted to metabolites which in concert with the parent drug will inhibit both systems. Moreover. some of the antipsychotic agents have also been reported to exert potent blocking effects on both uptake systems [1, 2]. If differences in the relative degree of blocking uptake of NE of 5-NT are indeed of clinical significance, the availability of, and controlled clinical trials with more selective inhibitors, such as maproptiline and nisoxetine (preferential inhibitors of NE uptake) and FG 4963 [3], Lu 10-171 [4] and fluoxetine (preferential inhibitors of 5-HT uptake), should provide a more definite answer to this problem. Fluoxetine is of particular interest because this drug is a selective inhibitor of 5-HT uptake into specific brain regions in oiuo and N-demethylation to its primary amine does not alter either its potency or selectivity toward inhibiting uptake of 5-HT [S]. While WBlinder rt ul.[6] reported a more rapid improvement of depressive symptomatology in a double blind study with chlorimipramine and tryptophan as compared to chlorimipramine+ placebo, and Shopsin et al.[7, S] found that the tryptophan hydroxylase inhibitor pchlorophenylalanine reversed the antidepressant effects of both MAO inhibitors and tricyclic antidepressants, the potentiation by tryptophan of the antidepressant action of tricyclic antidepres~ nts remains equivocal [9, lo]. Moreover, clinical studies with a more selective inhibitor of 5-HT uptake, FG 4963, have so far not been very encouraging [ll], Results obtained with the tricyclic antidepressant i $ rindole and with mianserin raise additional questions about the current biogenic amine hypothesis of