Movement Disorders Program, Butler Hospital , 345 Blackstone Blvd, Providence, RI 02906 , USA.
Expert Opin Pharmacother. 2013 Oct;14(14):1969-75. doi: 10.1517/14656566.2013.819345.
Parkinson's disease (PD) is a neurobehavioral disorder defined by its motor features. Its treatment is frequently complicated by the presence of psychotic symptoms, most prominently hallucinations and delusions. These cause major distress and are the primary cause for nursing home placement. Current treatment requires either a reduction in medications for mobility or the addition of atypical antipsychotics, none of which are approved in the United States, and which are associated with major potential drawbacks.
Information from extensive personal experience, a Pubmed literature search plus a direct request to Acadia Pharmaceuticals was used for this review. A brief review of the clinical problem and its current state of treatment will be followed by a discussion of pimavanserin and its potential role in treating PD psychosis (PDP). Several observations have implicated serotonin in the physiology of psychotic symptoms. Lysergic acid diethylamide, phencyclidine, and similar drugs that activate 5HT2A serotonin receptors produce psychotic syndromes, and almost all antipsychotic neuroleptics share the property of blocking the 5HT2A receptor as well as the dopamine D2 receptor. The reduced motor side effects of the second-generation antipsychotics have been ascribed to these drugs having greater 5HT2A antagonism than the first generation. Studies in animal models of psychosis have suggested benefits from drugs blocking the 5HT2A receptor alone without the motor side effects seen with D2 receptor antagonism.
Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP.
帕金森病（PD）是一种以运动特征为特征的神经行为障碍。其治疗常常因精神病症状的存在而变得复杂，最突出的是幻觉和妄想。这些症状会造成严重的困扰，也是导致入住疗养院的主要原因。目前的治疗需要减少治疗运动的药物或添加非典型抗精神病药物，这些药物在美国都没有批准，而且存在很大的潜在风险。
本综述使用了来自广泛的个人经验、PubMed 文献搜索以及对 Acadia 制药公司的直接请求的信息。简要回顾了临床问题及其目前的治疗现状，然后讨论了 pimavanserin 及其在治疗帕金森病精神病（PDP）中的潜在作用。有几项观察结果表明，血清素在精神病症状的生理中起作用。麦角酸二乙酰胺、苯环己哌啶和类似的激活 5HT2A 血清素受体的药物会产生精神病综合征，几乎所有的抗精神病神经阻滞剂都具有阻断 5HT2A 受体和多巴胺 D2 受体的特性。第二代抗精神病药物的运动副作用减少归因于这些药物具有比第一代药物更强的 5HT2A 拮抗作用。在精神病动物模型中的研究表明，单独阻断 5HT2A 受体的药物具有益处，而没有与 D2 受体拮抗作用相关的运动副作用。
pimavanserin 是一种 5HT2A 反向激动剂，没有运动副作用，具有与安慰剂相当的显著安全性。它的抗精神病作用和缺乏运动副作用使它成为治疗帕金森病精神病的理想药物，这是一个主要的未满足的需求。一项 PDP 的 III 期试验证明了极好的耐受性和显著的益处。FDA 同意为治疗 PDP 的适应证提交计划中的新药批准（NDA）。
