Grunder Gerhard, Carlsson Arvid, Wong Dean F
Department of Psychiatry, University of Mainz, Mainz, Germany.
Arch Gen Psychiatry. 2003 Oct;60(10):974-7. doi: 10.1001/archpsyc.60.10.974.
Antagonism of D2-like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80% (striatal) D2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular pharmacologic feature characterizes a new class of atypical antipsychotics that does not match the original concept of a therapeutic occupancy window for antagonist antipsychotics. When not involving pure antagonists, it implies a need to adjust the expected receptor occupancy (measured using positron emission tomography) for the therapeutic window.
对D2样多巴胺受体的拮抗作用是精神药物抗精神病疗效的潜在机制。正电子发射断层扫描研究表明，多巴胺受体拮抗剂的抗精神病作用发生在纹状体D2受体占有率介于60%至80%之间的治疗窗内。锥体外系副作用的发生率在超过80%阈值时会增加。然而，新型非典型抗精神病药物阿立哌唑在临床剂量下可占据高达95%的纹状体D2样多巴胺受体，且阿立哌唑所致锥体外系副作用的发生率并不高于安慰剂。对这一发现最可能的解释是阿立哌唑对D2样多巴胺受体具有微弱的部分激动作用。这一特殊的药理学特性表征了一类新型非典型抗精神病药物，其与拮抗剂抗精神病药物治疗性占有率窗的原始概念并不相符。当不涉及纯拮抗剂时，这意味着需要针对治疗窗调整预期的受体占有率（使用正电子发射断层扫描测量）。
