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）患者中的发生率是一般人群的10倍，是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中同时发生CUD，这给社会带来了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，一种抗精神病药物可能会很好地限制这些患者使用大麻，氯氮平（CLOZ），并不用于此目的;它是保留给精神病患者的治疗是耐药的。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，应该更广泛地用于合并CUD但其精神病不一定耐药的SCZ患者。这一概念得到了我们关于CLOZ影响的初步临床和动物数据的支持，以及我们在SCZ患者中使用大麻的神经生物学模型，该模型为CLOZ的这种影响提供了药理学依据。然而，即使考虑到所有支持CLOZ对SCZ和CUD患者的潜在益处的论点，其副作用特征可能会限制其使用，直到一项完全有效的研究证明其能够减少SCZ患者的大麻使用。这项建议旨在发起这样一项研究。如果，正如我们假设的那样，这项研究证实并扩展了我们先前关于CLOZ在SCZ和CUD患者中作用的初步数据，它将为扩大CLOZ在这一人群中的使用提供强大的动力。在拟议的研究中，132例SCZ和CUD共病患者将随机接受12周的CLOZ或利培酮（RISP）治疗。该提案的主要具体目的是：（1）检验与RISP治疗患者相比，接受CLOZ治疗的患者将减少大麻使用的假设。次要目的将进一步阐明CLOZ在该人群中的作用：（2）a）确定与服用RISP的患者相比，用CLOZ治疗的患者是否在（i）精神症状;（ii）生活质量;和（iii）神经心理功能方面有所改善;和B）探索与服用RISP的患者相比，服用CLOZ的患者是否显示出改善的奖励反应性;以及（3）探索在COMT Val 158 Met基因座处具有瓦尔/瓦尔基因型的那些患者是否比没有瓦尔/瓦尔COMT基因型的那些患者更可能在CLOZ治疗期间减少大麻使用。如果这项研究表明，CLOZ将减少大麻使用SCZ患者超过RISP，它将提供所需的证据，开始将临床实践转向其在这些患者中的使用。考虑到SCZ患者中与CUD相关的发病率增加，这样做可以显着改善这些患者的临床结局。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的药物原型的潜力。