Tropisetron with Risperidone for Schizophrenia

描述(申请人提供)：精神分裂症患者吸烟率高，吸烟后认知能力改善，戒烟后认知能力下降，表明吸烟可能会改善认知缺陷或药物副作用。这些认知缺陷的一个表现是听觉感觉门控，它测量对两个听觉刺激中的第二个的诱发反应的抑制。它在精神分裂症中减弱，并与注意力障碍和知觉障碍有关。这一抑制过程与7烟碱型乙酰胆碱受体(7nAChR)有关，该受体可成为精神分裂症药物治疗的靶点。我们假设，当α-7尼古丁受体激动剂托烷司琼与非典型的抗精神病药利培酮一起使用时，可能会改善精神分裂症的认知和知觉障碍和症状。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中国精神分裂症患者的基础上，在6 mg利培酮的基础上加入托烷司琼(10 Mg)或安慰剂。评估托烷司琼是否可以：1.改善Matrics评估的认知缺陷，2.减轻阴性精神病症状，3.减少利培酮的副作用，4.逆转P50抑制的异常，如果存在，5.改善P50抑制正常化的患者的认知障碍，6.减少吸烟的精神分裂症患者中尼古丁的使用(吸烟)，这是一个有计划的分层，一半吸烟者，一半不吸烟者。我们的初步数据支持托烷司琼在精神分裂症P50异常正常化方面的疗效，我们正在进一步评估其改善认知功能的最佳剂量。我们有一种用于托烷司琼的IND悬而未决，它可能通过制造商(诺华制药有限公司的NabovanD)在美国上市。最后，我们已经验证了中国神经心理学评估工具在北京的使用，我们之前在北京成功地进行了大规模的药物治疗试验。

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.