Lavergne Francis, Jay Thérèse M
Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, INSERM U894, Centre Hospitalier Sainte-Anne Paris, France.
Front Neurosci. 2010 Nov 19;4:192. doi: 10.3389/fnins.2010.00192. eCollection 2010.
From our research and literature search we propose an understanding of the mechanism of action of antidepressants treatments (ADTs) that should lead to increase efficacy and tolerance. We understand that ADTs promote synaptic plasticity and neurogenesis. This promotion is linked with stimulation of dopaminergic receptors. Previous evidence shows that all ADTs (chemical, electroconvulsive therapy, repetitive transcranial magnetic stimulation, sleep deprivation) increase at least one monoamine neurotransmitter serotonin (5-HT), noradrenaline (NA) or dopamine (DA); this article focuses on DA release or turn-over in the frontal cortex. DA increased dopaminergic activation promotes synaptic plasticity with an inverted U shape dose-response curve. Specific interaction between DA and glutamate is mediated by D1 receptor subtypes and Glutamate (NMDA) receptors with neurotrophic factors likely to play a modulatory role. With the understanding that all ADTs have a common, final, DA-ergic stimulation that promotes synaptic plasticity we can predict that (1) AD efficiency is related to the compound strength for inducing DA-ergic stimulation. (2) ADT efficiency presents a therapeutic window that coincides with the inverted U shape DA response curve. (3) ADT delay of action is related to a "synaptogenesis and neurogenesis delay of action." (4) The minimum efficient dose can be found by starting at a low dosage and increasing up to the patient response. (5) An increased tolerance requires a concomitant prescription of a few ADTs, with different or opposite adverse effects, at a very low dose. (6) ADTs could improve all diseases with cognitive impairments and synaptic depression by increasing synaptic plasticity and neurogenesis.
通过我们的研究和文献检索，我们提出了一种对抗抑郁治疗（ADTs）作用机制的理解，这应该会提高疗效和耐受性。我们知道ADTs能促进突触可塑性和神经发生。这种促进与多巴胺能受体的刺激有关。先前的证据表明，所有的ADTs（化学药物、电休克治疗、重复经颅磁刺激、睡眠剥夺）至少会增加一种单胺神经递质，即血清素（5-HT）、去甲肾上腺素（NA）或多巴胺（DA）；本文重点关注额叶皮质中DA的释放或周转率。DA增加的多巴胺能激活以倒U形剂量反应曲线促进突触可塑性。DA与谷氨酸之间的特异性相互作用由D1受体亚型和谷氨酸（NMDA）受体介导，神经营养因子可能起调节作用。基于所有ADTs都有一个共同的、最终的、促进突触可塑性的多巴胺能刺激这一认识，我们可以预测：（1）抗抑郁效率与诱导多巴胺能刺激的化合物强度有关。（2）ADT效率呈现出一个与倒U形DA反应曲线一致的治疗窗口。（3）ADT的起效延迟与“突触发生和神经发生的起效延迟”有关。（4）最低有效剂量可以通过从低剂量开始并逐渐增加至患者出现反应来确定。（5）耐受性增加需要同时开具几种具有不同或相反不良反应的ADTs，且剂量非常低。（6）ADTs可以通过增加突触可塑性和神经发生来改善所有伴有认知障碍和突触抑制的疾病。
