Serretti Alessandro, De Ronchi Diana, Lorenzi Cristina, Berardi Domenico
Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Milan, Italy.
Curr Med Chem. 2004 Feb;11(3):343-58. doi: 10.2174/0929867043456043.
The first compounds showing efficacy in the treatment of schizophrenia and other psychotic disorders was chlorpromazine, an anti-histaminic compound casually observed to possess antipsychotic effects. The discovery of the real mechanism of action of antipsychotic substances dates back to the 1960s, when researchers found that these compounds act as dopamine receptor antagonists. Unfortunately, this type of drugs cannot block the D2 receptors only in the mesolimbic dopaminergic pathway (which mediates their therapeutic effects), because of their non-selective D2 receptor blockage in both the mesolimbic and striatal regions, and the consequent appearance of side effects related to striatal interaction in the same dosage range as is needed for the therapeutical effects. Clozapine, discovered in the early 1970s, seemed to represent the solution to contrast these side effects, as it possesses antipsychotic activity without inducing extrapyramidal disorders in humans or catalepsy in rats; for this reason, it was defined as an "atypical" antipsychotic drug. Later, other beneficial properties, such as improvement of negative symptoms and of cognitive dysfunction and efficacy in neuroleptic-resistant schizophrenia, were included in the definition of "atypical". In recent years, the appearance of new atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone) has opened new ways to therapy. The aim of this paper is to review literature about newer antipsychotics, focusing on their advantages in terms of efficacy and side effect profiles when compared to classical and older atypical antipsychotics, and to evaluate the efficacy of the different new antipsychotics when compared to one another.
第一种显示出对精神分裂症和其他精神障碍有治疗效果的化合物是氯丙嗪，它是一种抗组胺化合物，偶然间被发现具有抗精神病作用。抗精神病药物真正作用机制的发现可追溯到20世纪60年代，当时研究人员发现这些化合物可作为多巴胺受体拮抗剂。不幸的是，这类药物不能仅阻断中脑边缘多巴胺能通路中的D2受体（该通路介导其治疗作用），因为它们会非选择性地阻断中脑边缘和纹状体区域的D2受体，结果在产生治疗效果所需的相同剂量范围内出现与纹状体相互作用相关的副作用。20世纪70年代初发现的氯氮平似乎是解决这些副作用的办法，因为它具有抗精神病活性，且不会在人类中诱发锥体外系疾病或在大鼠中诱发僵住症；因此，它被定义为一种“非典型”抗精神病药物。后来，其他有益特性，如改善阴性症状和认知功能障碍以及对难治性精神分裂症的疗效，也被纳入“非典型”的定义中。近年来，新型非典型抗精神病药物（利培酮、奥氮平、喹硫平、齐拉西酮）的出现为治疗开辟了新途径。本文的目的是综述有关新型抗精神病药物的文献，重点关注它们与经典和老一代非典型抗精神病药物相比在疗效和副作用方面的优势，并评估不同新型抗精神病药物相互比较时的疗效。
