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: 8507191
• 负责人: ALAN I GREEN
• 金额: $ 87.85万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507191
• 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; public health relevance; 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.

描述（由申请人提供）：大麻使用障碍（CUD）在精神分裂症（SCZ）患者中的发病率是普通人群的十倍，会加剧这种严重精神疾病的病程。由于 SCZ 发生在 1% 的人口中，因此 13% 至 42% 的患有这种疾病的人同时出现 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使用大麻。此外，初步数据表明氯氮平（CLOZ）可能会很好地限制这些患者使用大麻，但它并不用于此目的；它是为那些对治疗有抵抗力的精神病患者保留的。然而，该提案背后的总体想法是，CLOZ 的使用受到不合理的限制，应该更广泛地提供给同时患有 CUD 但其精神病不一定对治疗有抵抗力的 SCZ 患者。我们关于 CLOZ 作用的初步临床和动物数据以及我们在 SCZ 患者中使用大麻的基础的神经生物学模型支持了这一观点，该模型为 CLOZ 的这种作用提供了药理学原理。然而，即使考虑到所有支持 CLOZ 对 SCZ 和 CUD 患者潜在益处的论点，其副作用也可能会限制其使用，直到一项充分有力的研究证明其能够减少 SCZ 患者使用大麻的能力。本提案旨在开展这样的一项研究。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。在拟议的研究中，132 名同时患有 SCZ 和 CUD 的患者将被随机分配接受为期 12 周的 CLOZ 或利培酮 (RISP) 治疗疗程。该提案的主要具体目标是：(1) 检验以下假设：与接受 RISP 治疗的患者相比，接受 CLOZ 治疗的患者会减少大麻使用。次要目标将进一步阐明 CLOZ 在此人群中的作用： (2) a) 确定接受 CLOZ 治疗的患者是否会改善 (i) 精神症状； (二) 生活质量； (iii) 与服用 RISP 的人相比的神经心理学功能； b) 探讨服用 CLOZ 的患者与服用 RISP 的患者相比是否会表现出改善的奖赏反应性； (3) 探讨 COMT Val158Met 基因座具有 val/val 基因型的患者是否比不具有 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，那么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。鉴于 SCZ 患者与 CUD 相关的发病率增加，这样做可以显着改善这些个体的临床结果。最后，CLOZ 在本研究中的使用也可能反映出其作为下一代治疗 SCZ 和并发 CUD 药物原型的潜力。