Stahl Stephen M, Shayegan Darius K
Department of Psychiatry, University of California San Diego, USA.
J Clin Psychiatry. 2003;64 Suppl 19:6-12.
Schizophrenia is a highly complex disorder characterized by a diversity of symptoms, psychotic and nonpsychotic, that most likely arise from heterogeneous neuroanatomical and neurochemical malfunctions. As with all antipsychotic agents, ziprasidone targets the key hypothetical neurochemical disturbance in psychosis-excessive dopamine neurotransmission at dopamine D2 receptors in the mesolimbic pathway of the brain-presumably responsible for the positive symptoms of schizophrenia. Like other atypical antipsychotic agents, ziprasidone is a serotonin-2A (5-HT2A)/dopamine D2 antagonist; however, its in vitro 5-HT2A/D2 receptor affinity ratio is higher than that of the other first-line atypical antipsychotic agents (namely, risperidone, olanzapine, quetiapine, and aripiprazole). Ziprasidone also exhibits potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in human brain tissue, characteristics that predict heightened negative symptom relief, enhanced modulation of mood, cognitive improvement, and reduced motor dysfunction. Ziprasidone has moderate affinity for serotonin and norepinephrine reuptake sites, predicting antidepressant/anxiolytic activity. On the other hand, ziprasidone's low affinity for alpha1-adrenoceptors, as well as histamine H1 and muscarinic M1 receptors, suggests that patients should experience relatively little orthostatic hypotension, sedation, cognitive disturbance, weight gain, or dysregulation of prolactin levels. Efficacy and tolerability data from trials to date indicate that ziprasidone's clinical activity is consistent with its receptor profile.
精神分裂症是一种高度复杂的疾病，其特征是存在多种症状，包括精神病性和非精神病性症状，这些症状很可能源于异质性的神经解剖和神经化学功能障碍。与所有抗精神病药物一样，齐拉西酮针对精神病中关键的假设性神经化学紊乱——大脑中脑边缘通路多巴胺D2受体处多巴胺神经传递过多，这可能是精神分裂症阳性症状的原因。与其他非典型抗精神病药物一样，齐拉西酮是一种5-羟色胺-2A（5-HT2A）/多巴胺D2拮抗剂；然而，其体外5-HT2A/D2受体亲和力比其他一线非典型抗精神病药物（即利培酮、奥氮平、喹硫平和阿立哌唑）更高。齐拉西酮在人脑组织中还与5-HT2C、5-HT1D和5-HT1A受体表现出强相互作用，这些特性预示着能更好地缓解阴性症状、增强情绪调节、改善认知以及减少运动功能障碍。齐拉西酮对5-羟色胺和去甲肾上腺素再摄取位点具有中等亲和力，预示着具有抗抑郁/抗焦虑活性。另一方面，齐拉西酮对α1-肾上腺素能受体以及组胺H1和毒蕈碱M1受体的低亲和力表明，患者出现体位性低血压、镇静、认知障碍、体重增加或催乳素水平失调的情况相对较少。迄今为止的试验中的疗效和耐受性数据表明，齐拉西酮的临床活性与其受体特征相符。
