DA' NONTOLERANCE' TO NEUROLEPTIC; SUBTYPING SCHIZOPHRENI

从动物文献中，我们知道长期精神抑制剂治疗 减弱了急性治疗中所见的升高的多巴胺活性， 这种现象通常被称为“宽容”。 然而，审查 对精神分裂症患者的纵向研究， 多巴胺的主要代谢产物高香草酸（HVA）的慢性 抗精神病药治疗，提示两种代谢反应模式。 的 第一种模式有时以HVA急性增加为特征，但 其次是更普遍的HVA水平逐渐下降， 或低于预处理值的范围。 第二种模式最好 其特征在于在慢性疾病期间持续增加HVA的产生， 治疗 此外，第一种模式通常与良好的 临床结果，而第二种模式具有较差的结果。 同时，也有证据表明， 精神分裂症患者的多巴胺能功能 因此，据报道， 各种肾上腺素能激动剂和拮抗剂的治疗效果， 高效血清素的抗多巴胺能副作用 抗抑郁药和氯氮平的疗效表明， 多巴胺能参与精神分裂症的病理生理学， 以及调节多巴胺能活性。 我们假设精神分裂症患者的子样本 用慢性精神抑制剂降低患者的多巴胺活性 处理（即，非耐受性）表明一个 提供长回路反馈抑制的内部调节系统， 可能包括非多巴胺能神经递质系统，如血清素。 耐受性/非耐受性范例可以确定生物化学上的 具有β-肾上腺素能异常的同质患者亚组 活动 我们将确定一个亚组的患者谁表现出'不耐受' 稳态血浆水平的氟哌啶醇治疗 通过测量CSF和血浆HVA。 我们会比较这些病人 与那些表现出预期的“容忍”模式的人相比， 临床反应，以及一些外周和中枢指标， 肾上腺素能活性。 我们将比较血小板5-HT 2受体， 血小板5-HT含量、内分泌（催乳素）、代谢（血浆 HVA）和对芬氟拉明的行为反应。

From the animal literature, we know that chronic neuroleptic treatment attenuates the heightened dopamine activity seen with acute treatment, a phenomenon usually described as 'tolerance'. However, a review of longitudinal studies in schizophrenic patients, examining the response of the major dopamine metabolite homovanillic acid (HVA) to chronic neuroleptic treatment, suggests two patterns of metabolic response. The first pattern is sometimes characterized by an acute increase in HVA, but followed more generally by a gradual decrease of the HVA level to within or below the range of the pretreatment value. The second pattern is best characterized by continued heightened production of HVA during chronic treatment. Further, the first pattern is usually associated with a good clinical outcome, while the second pattern with a poor outcome. Concomitantly, there is also evidence to suggest an abnormality in serotonergic functioning in schizophrenic patients. Thus, the reported therapeutic effects of various serotonergic agonists and antagonists, the antidopaminergic side effects of high potency serotonergic antidepressants, and the efficacy of clozapine indicate a significant serotonergic involvement both in the pathophysiology of schizophrenia as well as the modulation of dopaminergic activity. We hypothesize that the inability of a subsample of schizophrenic patients to reduce their dopamine activity with chronic neuroleptic treatment (i.e., nontolerance) indicates the dysfunctioning of an internal regulatory system providing long loop feedback inhibition that may include nondopaminergic neurotransmitter systems such as serotonin. The tolerance/nontolerance paradigm may identify a biochemically homogeneous subgroup of patients who have abnormalities in serotonergic activity. We will identify a subgroup of patients who demonstrate 'nontolerance' to treatment with steady state plasma levels of haloperidol for four weeks by measuring CSF and plasma HVA. We will compare these patients with those that show the expected 'tolerance' pattern, on differences in clinical response, and several peripheral and central measures of serotonergic activity. We will compare platelet 5-HT2 receptors, platelet 5-HT content, and the endocrine (prolactin), metabolic (plasma HVA), and behavioral response to fenfluramine.