Tropisetron with Risperidone for Schizophrenia

描述（由申请人提供）：精神分裂症患者的高吸烟率、吸烟对认知的改善以及戒烟对认知的恶化提示吸烟可能改善认知缺陷或药物副作用。这些认知缺陷的表现之一是听觉门控，它测量的是对第二种听觉刺激的抑制。它在精神分裂症中减少，并与注意力和知觉障碍的损害有关。这种抑制过程与7烟碱乙酰胆碱受体（7nAChR）有关，该受体可作为精神分裂症药物治疗的靶点。我们假设α -7烟碱受体激动剂托吡司琼与非典型抗精神病药利培酮一起使用可能改善精神分裂症患者的认知和知觉障碍及症状。这项为期12周的双盲、随机、安慰剂对照试验在200名居住在北京的首发精神分裂症患者的基础上添加托哌司琼（10mg）或安慰剂至6mg利培酮。六个具体目标评估托司司琼是否可以：改善认知缺陷的评估矩阵，2。缓解负面精神病症状；减少利培酮的副作用；逆转P50抑制的异常，如果存在，5。在P50抑制正常化的患者中改善认知障碍，6。减少吸烟的精神分裂症患者的尼古丁使用（吸烟），这是一个有计划的分层，一半吸烟者和一半不吸烟者。我们的初步数据支持托司司琼在使精神分裂症P50异常正常化方面的功效，我们正在进一步评估其改善认知功能的最佳剂量。我们正在申请托司司琼的IND，它有可能通过制造商（诺华制药有限公司）在美国上市。最后，我们已经验证了在北京使用的中国神经心理评估工具，我们之前在北京成功进行了大型药物治疗试验。

DESCRIPTION (provided by applicant): The high rate of smoking in schizophrenia, the improvement in cognition with tobacco use and the deterioration in cognition with tobacco withdrawal suggests that smoking may improve cognitive deficits or medication side effects. One manifestation of these cognitive deficits is auditory sensory gating, which measures suppression the evoked response to the second of two auditory stimuli. It is diminished in schizophrenia and is associated with impairment in attention and perceptual disturbances. This inhibitory process is associated with the 7 nicotinic acetylcholine receptor (7nAChR), which can be a target for pharmacotherapy in schizophrenia. We hypothesize that the alpha-7 nicotinic receptor agonist tropisetron may improve cognitive and perceptual disturbances and symptoms in schizophrenia when added on to the atypical neuroleptic risperidone. This 12-week, double-blind, randomized, placebo-controlled trial adds tropisetron (10 mg) or placebo on to 6 mg risperidone in 200 first-episode Chinese schizophrenics living in Beijing. Six Specific Aims assess whether tropisetron can: 1. ameliorate cognitive deficits as assessed by the MATRICS, 2. alleviate negative psychotic symptoms, 3. reduce the side effects of risperidone, 4. reverse the abnormality in P50 inhibition, when present, 5. improve cognitive impairments in the same patients who normalize P50 inhibition, 6. reduce nicotine use (tobacco smoking) among those schizophrenics who smoke, which is a planned stratification with half smokers and half non-smokers. Our Preliminary Data support the efficacy of tropisetron in normalizing the P50 abnormality of schizophrenia, and we are further evaluating its optimal dosing for improvement in cognitive functioning. We have an IND pending for tropisetron, and it is potentially available in the United States through the manufacturer (NabovanD, Novartis Pharmaceuticals Ltd.) Finally, we have validated Chinese neuropsychological assessment tools to use in Beijing, where we have had previous success in conducting large pharmacotherapy trials.