Clozapine for Cannabis Use Disorder in Schizophrenia

氯氮平治疗精神分裂症大麻使用障碍

• 批准号: 8373622
• 负责人: ALAN I GREEN
• 金额: $ 97.2万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373622
• 关键词: Adverse effects; Agranulocytosis; Antipsychotic Agents; Brain; Cannabis; Catechols; Clinical; Clinical Data; Clinical Trials; Clozapine; Comorbidity; Cues; Data; Detection; Disease; Dopamine; Double-Blind Method; Drug Formulations; Environment; Finland; Frequencies; General Population; Generic Drugs; Genotype; Goals; Guidelines; Hostility; Individual; Intervention; Investigation; Mediating; Mental disorders; Modeling; Monitor; Morbidity - disease rate; Myocarditis; Neurobiology; Outcome; Patients; Pharmaceutical Preparations; Population; Psychotic Disorders; Public Health; Publishing; Quality of life; Randomized; Recommendation; Reporting; Resistance; Rewards; Risperidone; Sample Size; Schizophrenia; Seizures; Signal Transduction; Societies; Substance Use Disorder; Suicide; Symptoms; Testing; Time; Toxic effect; Transferase; Violence; animal data; atypical antipsychotic; base; clinical practice; improved; mortality; neuropsychological; next generation; prototype; response; reward circuitry; valylvaline

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. PUBLIC HEALTH RELEVANCE: Cannabis use disorder, which occurs commonly in patients with schizophrenia, worsens the course of this severe psychiatric disorder. While most medications used to treat schizophrenia do not limit cannabis use in these patients, preliminary data suggest that clozapine, which tends to be rarely used, will limit their cannabis use. The primary goal of this proposal, which involves a full clinical trial of clozapine in patients with schizophrenia and cannabis use disorder, is to provide evidence to support a shift in clinical practice toward increased clozapine use, and, thus, toward improved outcome for these individuals.

描述（由申请人提供）：大麻使用障碍（CUD），在精神分裂症（SCZ）患者中比在一般人群中常见多达十倍，使这种严重精神障碍的病程恶化。由于SCZ发生在1%的人口中，13%至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，大多数用于治疗SCZ患者的抗精神病药物似乎并没有限制他们使用大麻。此外，一种初步数据显示可能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；这是为那些精神疾病无法治疗的病人准备的。然而，这一提议背后的总体想法是CLOZ的使用受到了不合理的限制，应该更广泛地提供给同时发生CUD但精神病不一定对治疗有抵抗力的SCZ患者。我们对CLOZ作用的初步临床和动物数据以及SCZ患者大麻使用基础的神经生物学模型都支持这一观点，该模型为CLOZ的这种作用提供了药理学依据。即使所有的争论都支持CLOZ对SCZ和CUD患者的潜在益处，然而，它的副作用可能会限制它的使用，直到一个充分有力的研究证明它能够减少SCZ患者的大麻使用。本提案旨在开展这样一项研究。如果正如我们假设的那样，这项研究证实并扩展了我们之前关于CLOZ对SCZ和CUD患者的作用的初步数据，它将为在这一人群中扩大CLOZ的使用提供强大的推动力。在拟议的研究中，132名同时患有SCZ和CUD的患者将被随机分配到CLOZ或利培酮（RISP）的12周疗程中。本提案的主要具体目的是：(1)验证使用CLOZ治疗的患者与使用RISP治疗的患者相比大麻使用量减少的假设。辅助目的将进一步阐明CLOZ在这一人群中的作用：(2)a)确定接受CLOZ治疗的患者是否会改善(i)精神症状；（ii）生活质素；（iii）与服用RISP者相比的神经心理功能；b)探讨服用CLOZ的患者是否比服用RISP的患者表现出更好的奖励反应性；(3)探讨COMT Val158Met位点val/val基因型患者是否比没有val/val COMT基因型的患者更有可能在CLOZ治疗期间减少大麻使用。如果这项研究表明CLOZ比RISP更能减少SCZ患者的大麻使用，它将提供开始将临床实践转向在这些患者中使用大麻所需的证据。考虑到SCZ患者与CUD相关的发病率增加，这样做可以显著改善这些个体的临床结果。最后，CLOZ在本研究中的应用也可能反映了它作为治疗SCZ和并发CUD的下一代药物的原型的潜力。