Kapur Shitij, Mamo David
Schizophrenia Program, CAMH, Toronto, ON, Canada.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1081-90. doi: 10.1016/j.pnpbp.2003.09.004.
A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a "one-size-fits-all polypharmacy-in-a-pill" approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology.
抗精神病药物的历史回顾表明，虽然氯丙嗪和利血平的治疗效果几乎是同时被发现并积极研究的，但随后的药物开发仅限于作用于突触后受体的药物，而非调节多巴胺释放的药物。非典型抗精神病药物的基本特性是它们在不产生锥体外系副作用（EPS）或催乳素升高的情况下产生抗精神病作用的能力。多巴胺D2受体的调节对于抗精神病药物的作用仍然是必要且充分的，对D2受体的亲和力是区分典型和非典型药物特征的最重要单一因素。大多数抗精神病药物，包括非典型抗精神病药物，其治疗效果显示出D2受体占有率的剂量依赖性阈值，尽管不同药物的精确阈值不同。一些非典型抗精神病药物似乎未达到EPS和催乳素升高的阈值，这可能解释了它们的非典型性质。为了将抗精神病药物的生物学理论与其心理效应联系起来，提出了一种假说，即精神病是一种刺激和想法异常突显的状态，而抗精神病药物通过调节中脑边缘多巴胺系统，减弱这些症状的突显度。因此，抗精神病药物并非消除精神病：它们为症状的缓解提供了神经化学平台。未来的抗精神病药物可能需要摒弃“一种适用于所有人的复方药丸”方法，以治疗精神分裂症的所有不同方面。至少在理论上，一种更好的方法是针对精神分裂症的不同维度（例如阳性、阴性、认知和情感）开发特定的治疗方法，这些方法可以灵活使用并根据患者呈现的精神病理学进行滴定。
