Horacek Jiri, Bubenikova-Valesova Vera, Kopecek Milan, Palenicek Tomas, Dockery Colleen, Mohr Pavel, Höschl Cyril
Prague Psychiatric Centre, Prague, Czech Republic.
CNS Drugs. 2006;20(5):389-409. doi: 10.2165/00023210-200620050-00004.
Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained. This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophrenia.When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D(2) receptors seems to be crucial to balancing efficacy and adverse effects - transient D(2) receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D(2) receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D(2) receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D(2) receptors. Balancing presynaptic and postsynaptic D(2) receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D(2) receptors. Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D(2) and serotonin 5-HT(2A) receptor antagonism (e.g. by olanzapine and risperidone), partial D(2) receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors. In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia.
非典型抗精神病药物极大地改善了精神分裂症的治疗。迄今为止，这些药物有效性和不良反应背后的机制尚未得到充分解释。本文总结了非典型抗精神病药物在精神分裂症神经生物学方面的假设作用机制。在考虑精神分裂症的治疗模式时，多巴胺受体阻断和调节的作用仍然占主导地位。多巴胺D(2)受体的最佳占有率似乎对于平衡疗效和不良反应至关重要——短暂的D(2)受体拮抗作用（如喹硫平和氯氮平所达到的）足以获得抗精神病效果，而永久性的D(2)受体拮抗作用（如传统抗精神病药物所引起的）会增加锥体外系症状等不良反应的风险。阿立哌唑诱导的部分D(2)受体激动作用提供了维持D(2)受体最佳阻断和功能的可能性。平衡突触前和突触后D(2)受体拮抗作用（如氨磺必利所诱导的）是另一种机制，它可以通过增加纹状体内内源性多巴胺的释放来防止D(2)受体的过度阻断。5-羟色胺能调节与纹状体多巴胺释放的有益增加有关。对精神分裂症阴性和认知症状的影响与前额叶皮质中的多巴胺释放有关；这可以通过D(2)和5-羟色胺5-HT(2A)受体联合拮抗作用（如奥氮平和利培酮）、部分D(2)受体拮抗作用或抑制性多巴胺自身受体的优先阻断来调节。在精神分裂症的神经发育脱节假说背景下，非典型抗精神病药物（与传统抗精神病药物不同）不仅在纹状体，而且在其他脑区如前额叶皮质和海马体中诱导神经元可塑性和突触重塑。这种机制可能使谷氨酸能功能障碍和结构异常正常化，并影响精神分裂症的核心病理生理底物。
