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）：在精神分裂症患者（SCZ）中，大麻使用障碍（CUD）的频率高于普通人群的十倍，这使这种严重的精神疾病的过程恶化了。由于SCZ发生在1％的人口中，因此CUD在13％至42％的患有这种疾病的人中的同时出现，使社会具有重要的公共卫生问题。不幸的是，可用于治疗SCZ患者的大多数抗精神病药似乎并不限制其大麻使用。此外，初步数据表明的一种抗精神病药可能很可能会限制在这些患者中使用大麻，即氯氮平（cloz），并非用于此目的。它保留给精神病患者具有抗治疗性的患者。然而，该提案背后的总体想法是，Cloz的使用受到了不合理的限制，应该为患有共同存在的CUD但精神病不一定具有抗治疗方法的SCZ患者而更广泛地使用。我们的初步临床和动物数据对CLOZ的影响以及我们在SCZ患者中使用大麻使用的基础的神经生物学模型得到了支持，这为CLOZ的这种影响提供了药理原理。即使鉴于所有有利于CLOZ在SCZ和CUD患者中的潜在益处的论点，但其副作用概况可能会限制其使用，直到一项全功率研究表明其减少大麻的能力使用了SCZ的N患者。该建议旨在启动这项研究。如我们假设的那样，这项研究确认并扩展了我们先前关于CLOZ对SCZ和CUD患者影响的初步数据，它将提供强大的动力，以扩大该人群中CLOZ的使用。在拟议的研究中，与CLOZ或利培酮（RISP）合并的132例SCZ和CUD的患者将被随机分为12周的治疗课程。该提案的主要目的是：（1）与接受RISP治疗的患者相比，用CLOZ治疗的患者使用大麻的患者的使用将减少大麻的使用。子公司的目标将进一步阐明CLOZ在该人群中的影响：（2）a）确定接受CLOZ治疗的患者是否会改善（i）精神病症状； （ii）生活质量； （iii）与服用RISP相比的神经心理学功能； b）探索服用CLOZ的患者与服用RISP的患者是否会显示出提高的奖励反应能力； （3）探索COMT Val158met基因座的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降低大麻的使用情况。如果这项研究表明，CLOZ将减少SCZ患者的大麻使用，而不是RISP，则将提供所需的证据，以便开始将临床实践转向其在这些患者中的使用。鉴于SCZ患者与CUD相关的发病率增加，因此可以极大地改善这些人的临床结果。最后，CLOZ在这项研究中的使用也可能反映出其作为下一代药物治疗SCZ和同时发生CUD的原型的潜力。