ATYPICAL ANTIPSYCHOTICS AND P50 GATING IN SCHIZOPHRENIA

描述(改编自申请者的摘要)：这是一项竞争 精神分裂症患者P50听觉感觉门控的研究进展 精神分裂症患者在处理听觉感觉方面存在缺陷 信息。这可以用P50听觉诱发电位来证明。 范例。在这个范例中，精神分裂症患者未能减少 两个紧密配对的听觉咔哒声刺激中第二个的幅度。在……里面 相比之下，正常对照组则会降低对 第二个声音，与第一个声音相比。因此，精神分裂症患者，在 与正常对照组相比，有功能缺陷的 抑制性神经通路，也就是说，它们不能控制传入刺激。 多种常规抗精神病药物的治疗未能使这一点恢复正常 精神分裂症患者的P50听觉门控缺陷。通过以下方式治疗 氯氮平是一种典型的非典型抗精神病药物，已使P50正常化 10例精神分裂症患者的听觉门控治疗。这 部分难治性患者的P50听觉门控正常化 已经持续了两年之久。相比之下，治疗类似数量的 服用利培酮的患者没有使P50听觉门控正常化 相似的一组患者。调查员假设，虽然两人 非典型抗精神病药物有很高的5-HT2/D2阻滞率，只有氯氮平 阻断5-HT3受体。初步数据显示奥氮平， 这也阻断了5-HT3受体，增强了P50听觉门控 精神分裂症患者的非亲属，恩丹西酮，一个纯粹的 5-HT3受体拮抗剂。调查员的具体目标是评估 阻断5-HT3受体的非典型抗精神病药物是否也能增强 P50听觉感觉门控。调查员将研究4组 患者：氯氮平治疗25例，氯氮平治疗25例 利培酮，25例奥氮平治疗患者，25例精神分裂症患者 氟哌啶醇联合恩丹西酮治疗后随访观察 他们接受了两年的治疗。如果是多巴胺能 通过阻断5-HT3受体来阻断 治疗效果，那么除利培酮外，所有三种治疗方法都应该 使这些患者的P50门控正常化。调查员还将研究 其他非典型抗精神病药物上市时。在以前的 研究表明，α-7尼古丁受体介导P50 听觉感觉门控。5-HT3受体在动物体内的阻断释放 海马体中这些部位的乙酰胆碱。这些都是很快的 脱敏。尼古丁短暂地增强了精神分裂症患者的P50门控，但 这种效果很快就会消失。如果氯氮平对P50门控的影响是 主要通过α-7尼古丁受体，然后口服治疗 在氯氮平治疗中，尼古丁不应显示P50门控的增强 病人。口服尼古丁是否增强氯氮平治疗的P50门控 患者，这表明氯氮平的作用不仅仅是通过 α-7尼古丁受体。调查员将研究25名受试者 双盲安慰剂交叉设计。这些研究将增加新的 对氯氮平和相关抗精神病药物如何产生的问题的洞察 增强了治疗效果。

DESCRIPTION (Adapted from applicant's abstract): This is a competing renewal of studies of P50 auditory sensory gating in schizophrenia. Schizophrenic patients have a deficit in processing auditory sensory information. This can be demonstrated using a P50 auditory evoked potential paradigm. In this paradigm, a schizophrenic patient fails to decrease the amplitude of the second of two closely paired auditory click stimuli. In contrast, normal controls decrease the amplitude of the response to the second sound, compared to the first. Thus, schizophrenic patients, in comparison to normal controls have a deficit in the functioning of inhibitory neuronal pathways, i.e., they fail to gate incoming stimuli. Treatment with multiple conventional neuroleptics failed to normalize this P50 auditory gating deficit in schizophrenic patients. Treatment with clozapine, a prototypical atypical antipsychotic agent, has normalized P50 auditory gating in 10 neuroleptic-resistant schizophrenic patients. This normalization of P50 auditory gating in some treatment-resistant patients has lasted up to two years. In contrast, treatment of a similar number of patients with risperidone, did not normalize P50 auditory gating in a similar group of patients. The investigator hypothesized that although both atypical antipsychotics had high 5-HT2/D2 blocking ratios, only clozapine blocks the 5-HT3 receptor. Preliminary data indicates that olanzapine, which also blocks the 5-HT3 receptor, enhances P50 auditory gating in nongating relatives of schizophrenic patients, as does ondansetron, a pure 5-HT3 receptor antagonist. The investigator's specific aims are to assess whether atypical antipsychotics that block the 5-HT3 receptor also enhance P50 auditory sensory gating. The investigator will study 4 groups of patients: 25 patients treated with clozapine, 25 patients treated with risperidone, 25 patients treated with olanzapine, and 25 schizophrenic patients treated with haloperidol and ondansetron in combination and follow them for two years of treatment. If it is the combination of dopaminergic blockade with blockade of the 5-HT3 receptor that is responsible for the therapeutic effect, then all three treatments, except risperidone should normalize P50 gating in these patients. The investigator will also study other atypical antipsychotics as they become available. In previous research, he has documented that the alpha-7 nicotinic receptor mediates P50 auditory sensory gating. Blockade of the 5-HT3 receptor in animals releases acetylcholine at these sites in the hippocampus. These are rapidly desensitizing. Nicotine briefly enhances P50 gating in schizophrenics, but the effect is rapidly lost. If clozapine's effect on P50 gating is primarily through the alpha-7 nicotinic receptor, then treatment with oral nicotine should not show an enhancement of P50 gating in clozapine-treated patients. If oral nicotine enhances P50 gating in clozapine-treated patients, this suggests that the clozapine effect is not mediated solely by the alpha-7 nicotinic receptor. The investigator will study 25 subjects in a double-blind placebo crossover design. These studies would add new insight to the question of how clozapine and related neuroleptics produce enhanced therapeutic effects.