Cannabis & Schizophrenia: fMRI Reward Circuit Biomaker

描述（申请人提供）：大麻使用障碍（CUD）在精神分裂症（SCHIZ）患者中很常见，是导致精神分裂症发病的重要因素。虽然典型的抗精神病药物不能控制这些患者的大麻使用，但我们小组和其他人的初步数据表明，非典型抗精神病药物氯氮平（CLOZ）可能比典型抗精神病药物或“新型”（后CLOZ）抗精神病药物利培酮（RISP）或奥氮平（OLAN）更有效地限制精神分裂症患者的大麻使用。我们正在进行一项NIDA资助的（DA 13196）为期12周的随机临床试验，以进一步评估与RISP或OLAN治疗的患者相比，CLOZ对精神分裂症和合并症CUD患者大麻使用、临床症状/生活质量的影响。这个R21应用程序提出了一个“附加的”功能性核磁共振（fMRI）脑奖励回路的试点研究，以这个“基础”研究。我们之前假设CLOZ（但不是RISP， OLAN或典型的抗精神病药物）将有助于使功能失调的大脑奖励回路正常化，这可能是精神分裂症患者共病大麻使用的基础。在这项“附加”研究中，从“基础”研究中选取24名接受RISP治疗的患者作为子样本，在接受RISP治疗的同时，对大脑奖励回路进行fMRI货币奖励探测。在“基础”研究中，这些患者中的一半将被随机分配到CLOZ，另一半将继续使用RISP进行为期12周的临床试验；在“附加”研究中，所有患者将在12周时重复fMRI奖励回路测试，一组匹配的正常对照也将接受两次测试（在招募时和12周时）。拟议的研究将试图确定CLOZ（与RISP相比）对大脑奖励回路作用的潜在成像生物标志物。本研究的首要假设是，与正常对照相比，接受RISP治疗的患者对大脑奖赏回路探针的反应会出现缺陷，而接受CLOZ治疗的患者会出现这些缺陷。我们还预测，大脑奖赏回路反应的正常化与患者大麻使用的减少之间存在关系。我们希望这项研究能带来一种有效的方法来测试药物，这些药物可能会减少精神分裂症患者的大麻使用。这一点非常重要，因为尽管CLOZ有好处，但它的毒性使许多临床医生不愿使用它。因此，寻找比CLOZ更安全的新药物，可能能够限制精神分裂症患者使用大麻，具有相当大的公共卫生意义。

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD), common in patients with schizophrenia (SCHIZ), contributes greatly to the morbidity of SCHIZ. Although typical antipsychotic medications do not control cannabis use in these patients, preliminary data from our group and others suggest that the atypical antipsychotic drug clozapine (CLOZ) may limit cannabis use in patients with SCHIZ much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotics risperidone (RISP) or olanzapine (OLAN). We are conducting a NIDA funded (DA 13196) 12-week randomized clinical trial to further assess CLOZ effects on cannabis use, clinical symptoms/quality of life in patients with schizophrenia and comorbid CUD, as compared to patients treated with RISP or OLAN. This R21 application proposes an "add-on" functional MRI (fMRI) pilot study of brain reward circuitry to this "base" study. We have previously hypothesized that CLOZ (but not RISP, OLAN or typical antipsychotics) will help normalize dysfunctional brain reward circuits that may underlie comorbid cannabis use in SCHIZ. In this "add-on" study, a sub-sample of 24 RISP treated patients from the "base" study will undergo an fMRI monetary reward probe of brain reward circuit while being treated with RISP. In the "base" study, half of these patients will be randomized to CLOZ and half will remain on RISP for the 12- week clinical trial; in the "add-on" study, all patients will have repeat fMRI reward circuit testing at 12 weeks, and a matched group of normal controls will also be tested, twice (at recruitment and at 12 weeks). The proposed study will attempt to identify a potential imaging biomarker" of the action of CLOZ (as compared to RISP) on brain reward circuits. The overarching hypothesis for this research is that patients treated with RISP will demonstrate deficiencies in response to a brain reward circuit probe compared to normal controls and that these deficiencies will be normalized in patients treated with CLOZ. We also predict that there will be a relationship between the normalization of brain reward circuit response and decrease in cannabis use by patients. We expect this research to lead to an efficient method for testing medications that putatively may decrease cannabis use in SCHIZ. This is of great importance because, despite the benefits of CLOZ, its toxicity discourages many clinicians from using it. Finding new medications, safer than CLOZ, that may be able to limit cannabis use In patients with SCHIZ is thus of considerable public health relevance.