All antipsychotics bind to the dopamine D2 receptor. An “optimal” level of D2 receptor blockade with antipsychotics is thought to ameliorate the positive symptoms of schizophrenia. However, persistent D2 receptor blockade is associated with a deteriorating clinical response in a subset of patients. Interestingly, antipsychotics with a weaker D2 receptor binding profile appear somewhat superior in this respect. This evidence challenges the hypothesis that D2 receptor blockade is the sole mechanism of antipsychotic efficacy and points to consistent inter-individual responses to antipsychotic treatment.

Here, we hypothesize that clinically effective doses of antipsychotics would lead to the formation of a D2 receptor “reserve” that is likely composed of presynaptic dopamine D2 autoreceptors. The majority of the remaining postsynaptic dopamine receptors are instead occupied by antipsychotics. Endogenous dopamine would then mainly interact with this D2 autoreceptor reserve, thereby reducing the presynaptic synthesis and release of dopamine and resulting in an indirect antipsychotic effect. This new proposal reconciles conceptual and empirical gaps encountered when clinical outcomes are compared to the pharmacology of antipsychotics.

所有抗精神病药均与多巴胺D2受体结合。抗精神病药对D2受体的“最佳”阻断被认为可改善精神分裂症的阳性症状。然而，持续的D2受体阻滞与一部分患者的临床反应恶化有关。有趣的是，在这方面，具有较弱的D2受体结合特性的抗精神病药似乎有些优越。该证据挑战了D2受体阻滞是抗精神病药功效的唯一机制这一假说，并指出了个体间对抗精神病药治疗的一致反应。

在这里，我们假设抗精神病药的临床有效剂量将导致D2受体“储备”的形成，该储备可能由突触前多巴胺D2自身受体组成。相反，大多数剩余的突触后多巴胺受体被抗精神病药占据。然后，内源性多巴胺将主要与该D2自身受体储备相互作用，从而减少突触前的合成和多巴胺的释放，并导致间接的抗精神病作用。当将临床结果与抗精神病药的药理学进行比较时，这项新建议弥补了在概念和经验上的差距。