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精神安定药，对于治疗更有效 与以前可用的典型抗精神病药相比，精神分裂症具有耐药性 不太可能引起锥体外系副作用。 它不寻常 治疗特性与广谱药理学特性相匹配。 这种临床和药理作用的结合使其成为一种有用的药物。 用于研究与抗-反应有关的生化因素的探针 精神药物。 然而，尽管其具有潜在的临床和研究潜力 但其使用存在两个问题：剧毒、毒性大。 昂贵的。这些问题表明反应的预测因素可能是 价值。 我们小组和其他人的初步调查结果表明 预处理（不含精神安定药）血浆和脑脊液 (CSF) 生物胺及其代谢物的测量可能具有以下价值： 预测对氯氮平的反应；我们小组的初步调查结果和 其他人还认为，在治疗期间，这些措施的改变可能会 与非典型和典型抗精神病药物的临床反应相关。 利用 6 周的药物清除期，我们建议进行 l2 周的双倍治疗 非典型精神安定药氯氮平 (CLOZ) 和典型药物的盲法研究 抗精神病药物氯丙嗪（CPZ）治疗 90 名难治性精神分裂症患者 患者（以获得 48 名最终样本）。 该研究将利用血浆 和 CSF 测量生物胺及其代谢物，以实现 以下具体目标： (l) 确认和扩展初步调查结果 表明治疗前血浆中高香草酸 (HVA) 和 可能是去甲肾上腺素 (NE)，以及 CSF HVA 与 CSF 5- 的比率 羟基吲哚乙酸 (5HIAA)，预测 CLOZ 的临床反应； （2a 2b）确认并扩展我们的初步调查结果表明 HVA 和 3-甲氧基-4-羟基-苯基乙二醇的血浆水平降低 (MHPG) 在 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 血浆和脑脊液中生物胺及其代谢物的测量 对 CLOZ 治疗的临床反应； (3a) 确认并延长我们的 关于 CWZ 治疗对血浆水平影响的初步发现 HVA、MHPG、多巴胺 (DA) 和 NE；并探讨其比较效果 对这些物质进行 CPZ 处理； (3b) 探讨比较效果 CWZ 和 CPZ 关于 DA、NE、HVA、MHPG、5HIAA 和 HVA/5HIAA 的 CSF 测量； (4) 探讨临床症状与疾病之间的关系 治疗结束时血浆和脑脊液中生物胺和代谢物的测量 药物洗脱期。