ANTIPSYCHOTIC DRUG-INDUCED DYSKINESIAS

抗精神病药物引起的运动障碍

• 批准号: 2244486
• 负责人: DANIEL E CASEY
• 金额: $ 34.37万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2244486
• 关键词: Ceboidea; MAO inhibitors; Parkinson's disease; SCH 23390; adrenergic agents; antiadrenergic agents; antipsychotic agents; apomorphine; blood chemistry; bromocriptine; cholinesterase inhibitors; chordate locomotion; clozapine; combination chemotherapy; dextroamphetamine; dopamine receptor; dosage; drug administration rate /duration; drug adverse effect; drug tolerance; ethology; extrapyramidal disorder; haloperidol; longitudinal animal study; neuropharmacology; nonhuman therapy evaluation; pergolide; tardive dyskinesia

Neuroleptic drugs are highly efficacious agents in controlling symptoms of schizophrenia and other psychoses, but have undesirable early and late neurological side effects which are poorly understood. Reversible acute extrapyramidal syndromes (EPS) of acute dystonia and parkinsonism occur in up to 95% of patients and are one of the major reasons why schizophrenics discontinue their medication and suffer a psychotic relapse. Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary movements, may develop in 20% of patients (and up to 50% of high risk elderly). Unfortunately, we are not able to predict who is at risk for these side effects. The pathophysiology of acute EPS and TD is believed to involve dopamine (DA) receptor blockade with early EPS due to reduced DA influences and TD due to overactive DA processes. The specific roles of DA receptor subtypes (D1 D2), serotonin and norepinephrine, are minimally understood. Many new compounds which are potentially antipsychotic offer the opportunity to more precisely study the mechanisms of actions of these drugs and to evaluate their potential for improving the antipsychotic efficacy and reducing the neurological side effect risks. Research in a nonhuman primate model with studies that parallel clinical treatment issues in both the short term and long term can provide both practical and heuristic data. The acute EPS studies will evaluate the contribution of specific drugs which affect D1 and D2 receptor subtypes, investigate their interactions, and assess the prevention/aggravation potentials of new antipsychotic drugs with serotonin antagonist properties. Clozapine, a novel antipsychotic drug, will also be evaluated to identify its mechanism of action and potential side effects. The long-term TD studies will examine the effect of continuous and interrupted haloperidol. The central issues are: 1) individual vulnerability, and 2) time course for developing acute EPS, DA receptor hypersensitivity, and TD during these distinct treatment regimes. Behavioral changes will be assessed by perturbations in DA function with DA agonists (apomorphine, amphetamine, bromocriptine, pergolide, and SKF 38393) and antagonists (haloperidol, SCH 23390) before, during, and after haloperidol.

抗精神病药是控制精神分裂症的高效药物 精神分裂症和其他精神病的症状，但有不良症状 早期和晚期的神经系统副作用，效果不佳 明白了。 可逆性急性锥体外系综合征（EPS） 高达 95% 的患者会出现急性肌张力障碍和帕金森病 是精神分裂症患者停止治疗的主要原因之一 药物治疗并遭受精神病复发。 迟发性运动障碍 (TD)，一种潜在的不可逆转的不自主运动综合症， 20% 的患者可能会出现这种情况（高达 50% 的高风险患者可能会出现这种情况） 老年）。 不幸的是，我们无法预测谁面临风险 对于这些副作用。 急性 EPS 和 TD 的病理生理学被认为涉及 由于 DA 减少而导致早期 EPS 受多巴胺 (DA) 受体阻断 由于过度活跃的 DA 过程而产生的影响和 TD。 具体的 DA 受体亚型 (D1 D2)、血清素和 去甲肾上腺素，人们知之甚少。 许多新化合物 是潜在的抗精神病药物，为更多人提供机会 精确研究这些药物的作用机制并 评估其提高抗精神病功效的潜力 并降低神经系统副作用的风险。 研究在一个 非人灵长类动物模型与临床平行研究 短期和长期的治疗问题可以提供 实用数据和启发性数据。 急性 EPS 研究将评估特定的贡献 影响 D1 和 D2 受体亚型的药物，研究其作用 相互作用，并评估预防/加重的潜力 具有血清素拮抗剂特性的新型抗精神病药物。 氯氮平是一种新型抗精神病药物，也将进行评估 确定其作用机制和潜在的副作用。 长期 TD 研究将检验连续和 中断氟哌啶醇。 核心问题是：1）个人 脆弱性，以及 2) 发生急性 EPS、DA 的时间过程 这些不同治疗期间的受体超敏反应和 TD 政权。 行为变化将通过扰动来评估 DA 功能与 DA 激动剂（阿扑吗啡、安非他明、 溴隐亭、培高利特和 SKF 38393) 和拮抗剂 （氟哌啶醇，SCH 23390）在氟哌啶醇之前、期间和之后。