Asakura M, Tsukamoto T
Yakubutsu Seishin Kodo. 1985 Dec;5(4):303-19.
A characteristic feature of antidepressant therapy is the lag phase in onset of clinical efficacy. This applies to both typical tricyclics agents and atypical antidepressants, mianserin or maprotiline. Attempts to delineate the molecular mechanisms of action of antidepressants on the basis of acute studies are limited value, and increasing attention is being focused on resultant adaptive changes stemming from their chronic treatment. The drug-induced adaptive modification can occur both pre-and postsynaptically. Regarding presynaptic sites, adaptation in the synthesis and release of norepinephrine (NE) and presynaptic alpha2-receptors and dopamine autoreceptors occur. However, the changes cannot be regarded as being primarily responsible for the therapeutic action of antidepressants. Chronic antidepressant treatments affect also post-synaptic aminergic systems eliciting a reduction of beta-adrenoceptors and in the sensitivity of NE-stimulated adenylate cyclase (NE-AC), and a decrease of 5HT2-receptors. The postsynaptic changes are more pertinent to the mechanisms of action of the drug. However, these properties can not extend to all atypical antidepressants. Fluoxetine, trazodone, alprazolam or MIA fails to alter beta-receptor density or the NE-AC sensitivity, and electroconvulsive therapy produces an increases in 5HT2 sites. More recently, new experiments demonstrate 1) a biomolecular linkage between 5HT and NE neuronal systems at the level of beta-receptors; 2) an acceleration of beta-receptor reduction with combined administration of antidepressants and alpha 2-receptor antagonists; 3) an existence of imipramine-like substance (endocoid) in the brain and a reduction of [3H]imipramine binding sites after chronic treatment with imipramine. While the end result downstream may be the same clinical efficacy, the initial biochemical steps leading to this goal may not be identical for all forms of antidepressants. It is expected that the new approaches can lead to the finding a common mechanism of action to all form of antidepressants.
抗抑郁治疗的一个显著特征是临床疗效起效存在延迟期。这适用于典型的三环类药物以及非典型抗抑郁药，如米安色林或马普替林。基于急性研究来阐明抗抑郁药作用的分子机制价值有限，人们越来越关注其长期治疗所导致的适应性变化。药物诱导的适应性改变可发生在突触前和突触后部位。关于突触前部位，去甲肾上腺素（NE）的合成与释放、突触前α2受体和多巴胺自身受体都会发生适应性变化。然而，这些变化不能被视为抗抑郁药治疗作用的主要原因。长期抗抑郁治疗也会影响突触后胺能系统，导致β肾上腺素能受体减少以及NE刺激的腺苷酸环化酶（NE-AC）敏感性降低，5HT2受体减少。突触后的这些变化与药物的作用机制更为相关。然而，这些特性并不适用于所有非典型抗抑郁药。氟西汀、曲唑酮、阿普唑仑或米氮平不会改变β受体密度或NE-AC敏感性，并电休克治疗会使5HT2位点增加。最近，新的实验表明：1）5HT和NE神经元系统在β受体水平存在生物分子联系；2）联合使用抗抑郁药和α2受体拮抗剂可加速β受体减少；3）大脑中存在类似丙咪嗪的物质（内源性物质）以及长期使用丙咪嗪后[3H]丙咪嗪结合位点减少。虽然最终的下游结果可能是相同的临床疗效，但导致这一目标的初始生化步骤可能并非所有形式的抗抑郁药都相同。预计新方法能够找到所有形式抗抑郁药共同的作用机制。
