Clozapine for Cannabis Use Disorder in Schizophrenia

描述(由申请人提供)：大麻使用障碍(CUD)，在精神分裂症(SCZ)患者中比普通人群中常见十倍，使这种严重的精神疾病的病程恶化。由于SCZ发生在1%的人口中，13%到42%的这种疾病患者同时发生CUD，这给社会带来了一个重要的公共卫生问题。不幸的是，大多数可用于治疗SCZ患者的抗精神病药物似乎并没有限制他们的大麻使用。此外，初步数据表明，一种可能会很好地限制这些患者使用大麻的抗精神病药物氯氮平(CLOZ)并未用于此目的；它是为那些精神病治疗耐药的患者保留的。然而，这项提案背后的首要思想是，CLOZ的使用受到了不合理的限制，应该更广泛地适用于SCZ患者，这些患者同时患有CUD，但其精神病不一定对治疗产生抗药性。这一观点得到了我们关于CLOZ效应的初步临床和动物数据的支持，以及我们关于SCZ患者使用大麻的神经生物学模型的支持，该模型为CLOZ的这种效应提供了药理学基础。然而，即使所有的论据都支持CLOZ对SCZ和CUD患者的潜在好处，它的副作用可能会限制其使用，直到一项全面有力的研究证明它有能力减少SCZ患者的大麻使用。这项提议旨在启动这样一项研究。如果像我们假设的那样，这项研究证实并扩展了我们之前关于CLOZ对SCZ和CUD患者的影响的初步数据，它将为扩大CLOZ在这一人群中的使用提供强大的推动力。在这项拟议的研究中，132名同时患有SCZ和CUD的患者将被随机分配到服用CLOZ或利培酮(RISP)的12周疗程中。这项建议的主要具体目的是：(1)检验接受CLOZ治疗的患者与接受RISP治疗的患者相比将减少大麻使用量的假设。子公司AIMS将进一步阐明CLOZ在这一人群中的作用：(2)确定接受CLOZ治疗的患者是否会在(I)精神症状、(Ii)生活质量和(Iii)神经心理功能方面有改善；以及(B)探索与服用RISP的患者相比，服用CLOZ的患者是否会表现出更好的奖赏反应；以及(3)探索COMT Val158 Met基因座具有Val/Val基因的患者在CLOZ治疗期间是否比那些没有Val/Val COMT基因的患者更有可能减少大麻的使用。如果这项研究表明CLOZ将比RISP更多地减少SCZ患者的大麻使用，它将提供必要的证据，开始将临床实践转向在这些患者中使用。鉴于SCZ患者中与CUD相关的发病率增加，这样做可以显著改善这些患者的临床结局。最后，CLOZ在这项研究中的使用也可能反映出它作为治疗SCZ和共生CUD的下一代药物的原型的潜力。

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD), which is up to ten times more common in patients with schizophrenia (SCZ) than in the general population, worsens the course of this severe psychiatric disorder. Since SCZ occurs in 1% of the population, the co-occurrence of CUD in 13% to 42% of people with this disorder presents society with an important public health problem. Unfortunately, most antipsychotics available for treatment of patients with SCZ do not appear to limit their cannabis use. Moreover, the one antipsychotic that preliminary data suggest may well limit cannabis use in these patients, clozapine (CLOZ), is not used for this purpose; it is reserved for patients whose psychosis is treatment resistant. The overarching idea behind this proposal, however, is that CLOZ's use is being unreasonably restricted and should be made more widely available for patients with SCZ who have a co-occurring CUD but whose psychosis is not necessarily treatment resistant. This notion is supported by our preliminary clinical and animal data on the effects of CLOZ, as well as our neurobiological model of the basis of cannabis use in patients with SCZ that provides a pharmacologic rationale for this effect of CLOZ. Even given all the arguments favoring the potential benefits of CLOZ in patients with SCZ and CUD, however, its side effect profile will likely limit its use until a fully powered study demonstrates its ability to decrease cannabis use n patients with SCZ. This proposal aims to launch such a study. If, as we hypothesize, this study confirms and extends our previous preliminary data of the effects of CLOZ in patients with SCZ and CUD, it will provide a strong impetus to expand the use of CLOZ in this population. In the proposed study, 132 patients who are comorbid for both SCZ and CUD will be randomized to a 12 week treatment course with either CLOZ or risperidone (RISP). The primary specific aim of this proposal is: (1) To test the hypothesis that patients treated with CLOZ will have decreased cannabis use as compared to patients treated with RISP. Subsidiary aims will further elucidate the effects of CLOZ in this population: (2) a) To determine whether patients treated with CLOZ will have improvements in (i) psychiatric symptoms; (ii) quality of life; and (iii) neuropsychological functions as compared to those taking RISP; and b) to explore whether patients taking CLOZ will show improved reward responsiveness as compared to those taking RISP; and (3) To explore whether those patients with the val/val genotype at the COMT Val158Met locus are more likely to decrease cannabis use during CLOZ treatment than are those without the val/val COMT genotype. Should this study indicate that CLOZ will lessen cannabis use in patients with SCZ more than RISP, it will provide evidence needed to begin to shift clinical practice toward its use in these patients. Given the increased morbidity associated with CUD in patients with SCZ, doing so could dramatically improve the clinical outcome of these individuals. Lastly, CLOZ's use in this study may also reflect its potential to serve as a prototype of the next generation of medications for treatment of SCZ and co-occurring CUD.