CLOZAPINE RESPONSE AND BIOGENIC AMINES IN SCHIZOPHRENIA

精神分裂症中氯氮平的反应和生物胺

• 批准号: 2033956
• 负责人: ALAN I GREEN
• 金额: $ 77.37万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2033956
• 关键词: 3 methoxy 4 hydroxyphenylethyleneglycol; abnormal involuntary movement; antipsychotic agents; blood chemistry; cerebrospinal fluid; chlorpromazine; clinical trials; clozapine; dopamine; dosage; extrapyramidal disorder; homovanillate; human subject; human therapy evaluation; hydroxyindoleacetate; longitudinal human study; mental disorder chemotherapy; neurochemistry; neurotransmitter metabolism; norepinephrine; pharmacokinetics; psychological tests; psychopharmacology; schizophrenia; serotonin

Clozapine, an atypical neuroleptic, is more effective for treatment- resistant schizophrenia than typical neuroleptics previously available and is less likely to cause extrapyramidal side effects. Its unusual therapeutic profile is matched by a broad-spectrum pharmacologic profile. This combination of clinical and pharmacological effects makes it a useful probe for studying biochemical factors involved in the response to anti- psychotic drugs. However, despite its potential clinical and research value, there are two problems with its use: it is highly toxic and very expensive. These problems suggest that a predictor of response could be of value. Preliminary findings from our group and others have revealed that pretreatment (neuroleptic-free) plasma and cerebrospinal fluid (CSF) measures of biogenic amines and their metabolites may be of value in predicting response to clozapine; preliminary findings from our group and others also suggest that, during treatment, changes in these measures may be correlates of clinical response to atypical and typical neuroleptics. Utilizing a 6 week drug-washout period, we propose to do a l2 week double- blind study of the atypical neuroleptic clozapine (CLOZ) and the typical neuroleptic chlorpromazine (CPZ) in 90 treatment-refractory schizophrenic patients (to obtain a final sample of 48). The study will utilize plasma and CSF measures of biogenic amines and their metabolites to achieve the following specific aims: (l) To confirm and extend preliminary findings suggesting that pretreatment plasma levels of homovanillic acid (HVA) and possibly norepinephrine (NE), as well as the ratio of CSF HVA to CSF 5- hydroxy-indoleacetic acid (5HIAA), predict clinical response to CLOZ; (2a and 2b) to confirm and extend our preliminary findings suggesting that decreases in plasma levels of HVA and 3-methoxy-4-hydroxy-phenylglycol (MHPG) during treatment with CLOZ correlate with clinical response to CLOZ; (2c and 2d) to explore the relationships between patterns of changes in plasma and CSF measures of biogenic amines and their metabolites and clinical response to CLOZ treatment; (3a) to confirm and extend our preliminary findings on the effects of CWZ treatment on plasma levels of HVA, MHPG, dopamine (DA) and NE; and to explore the comparative effect of CPZ treatment on these substances; (3b) to explore the Comparative effects of CWZ and CPZ on CSF measures of DA, NE, HVA, MHPG, 5HIAA and HVA/5HIAA; and (4) to explore the relationships between clinical symptomatology and plasma and CSF measures of biogenic amines and metabolites at the end of the drug-washout period.

氯氮平是一种非典型的神经疗法，对治疗更有效 - 耐药性精神分裂症比以前可用的典型神经疗法 不太可能引起锥体外副作用。 它不寻常 治疗特征与广谱药理学特征相匹配。 临床和药理作用的这种结合使其成为有用的 研究参与反应的生化因素 精神药物。 但是，尽管具有潜在的临床和研究 价值，其使用有两个问题：它是剧毒剧毒，非常非常 昂贵的。这些问题表明响应的预测因子可能是 价值。 我们小组和其他人的初步发现表明 预处理（无神经摄影）血浆和脑脊液（CSF） 生物胺及其代谢产物的测量在 预测对氯氮平的反应；我们小组的初步发现以及 其他人还建议，在治疗期间，这些措施的变化可能 与非典型和典型的神经疗法的临床反应有关。 利用为期6周的毒品洗涤期，我们建议做一个L2周的双人 非典型神经肽氯氮平（CLOZ）和典型的盲目研究 90种治疗精神分裂症患者中的神经诱变的氯丙烷（CPZ） 患者（获得最终样本为48）。 该研究将利用血浆 和CSF的生物胺及其代谢产物的测量 以下特定目的：（l）确认和扩展初步发现 表明同型酸（HVA）和 可能是去甲肾上腺素（NE），以及CSF HVA与CSF 5-的比率 羟基 - 印度甲酸（5HIAA），预测对CLOZ的临床反应； （2a 和2b）确认和扩展我们的初步发现，表明 血浆HVA和3-甲氧基-4-羟基 - 苯基乙二醇的血浆水平降低 （MHPG）在用CLOZ治疗期间与临床反应相关 克洛兹； （2C和2D）探索变化模式之间的关系 在血浆和CSF的生物胺及其代谢产物的测量中 对CLOZ治疗的临床反应； （3a）确认并扩展我们的 对CWZ处理对等离子体水平的影响的初步发现 HVA，MHPG，多巴胺（DA）和NE；并探讨 CPZ对这些物质进行治疗； （3b）探索比较效果 CWZ和CPZ在CSF的DA，NE，HVA，MHPG，5HIAA和HVA/5HIAA的CSF测量中； （4）探索临床症状和 生物胺和代谢物的血浆和CSF测量结束时 吸毒期。