Cannabis and Schizophrenia: Self-Medication and Agonist Treatment?

描述（由申请人提供）：大麻使用障碍（CUD）经常发生在精神分裂症（SCZ）患者中，并影响这种严重精神疾病的病程。对这些“双重诊断”患者的治疗是不够的。大多数抗精神病药物似乎对控制大麻的使用价值有限。初步研究表明，有一种抗精神病药物氯氮平（clozapine）有一定的能力限制精神分裂症患者使用大麻，但它有很大的毒性，因此只有一小部分可能从中受益的患者使用。虽然SCZ患者使用大麻的基础尚不清楚，但有些人认为使用物质可能会“自我抑制”阴性症状或抗精神病药物治疗的副作用。我们提出了这种“自我药物假说”的另一种说法--SCZ患者中皮质边缘“大脑奖励回路”（BRC）失调是他们药物使用的基础，而大麻的使用改善了这种失调的回路。使用与fMRI（功能性磁共振成像）相关的货币探针，我们已经证明，与正常受试者相比，SCZ和CUD患者的BRC确实存在缺陷。该应用程序将使我们能够直接测试大麻对SCZ和CUD患者BRC的影响，从而证实我们关于其在这些患者中的影响的假设。此外，该申请旨在评估大麻素激动剂屈大麻酚在给予SCZ和CUD患者时是否也会改善这种BRC缺陷，因此，屈大麻酚是否可以被视为一种潜在的预防性治疗（与抗精神病药物一起使用），以减少他们的大麻使用。这个“概念证明”申请是为了响应RFA“大麻使用障碍药物开发”而提交的。本研究的第一个目的是确定SCZ和CUD患者的BRC缺陷是否会在给予患者大麻或屈大麻酚时正常化：（1a）确认我们的初步数据，即与货币大脑奖励探针相关的fMRI扫描将异常（与对照组相比）;（1b）确定当患者吸食大麻香烟时，这种fMRI测量是否会正常化;以及（1c）确定当患者口服屈大麻酚时，该fMRI测量是否会正常化。第二个目的是进一步评估屈大麻酚在这一人群中的作用：（2a）确定渴望、情绪和阴性症状的测量是否会改善;（2b）确定精神病症状和认知缺陷的测量是否会增加（恶化）。通过探索BRC失调和测试吸食大麻对这种失调的影响，这项研究将有助于阐明“自我药疗”是否可能是这些患者使用大麻的重要组成部分。此外，通过进一步阐明屈大麻酚的作用，这项研究可以导致治疗药物的开发，可能包括屈大麻酚，这可能会限制这些患者使用大麻。 公共卫生相关性：大麻使用障碍在精神分裂症患者中很常见，是这种严重精神障碍的过程。这项药物开发研究旨在确定大麻被这些患者用于“自我药物治疗”，因为它纠正了他们大脑回路的缺陷，此外，批准用于某些医疗条件的口服药物屈大麻酚也可以纠正这种缺陷，因此在限制这些患者使用大麻方面具有价值。寻找可能能够限制大麻使用的药物，从而减少精神分裂症患者的不良后果，这对公共卫生具有重要意义。

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD) occurs frequently in patients with schizophrenia (SCZ) and worsens the course of this severe psychiatric disorder. Treatments available for these "dual diagnosis" patients are inadequate. Most of the antipsychotic drugs appear to be of limited value for controlling their cannabis use. The one antipsychotic medication that preliminary studies have shown to have some ability to limit cannabis use in these patients, clozapine, has substantial toxicity and is thus used by only a small percentage of patients who might benefit from it. New treatments to limit cannabis use in patients with schizophrenia are sorely needed. While the basis of cannabis use in patients with SCZ is not clear, some have suggested that use of substances may "self-medicate" negative symptoms or the side effects they experience from antipsychotic treatment. We have proposed an alternative formulation of this "self-medication hypothesis" -- that a dysregulated mesocorticolimbic "brain reward circuit" (BRC) in patients with SCZ underpins their substance use, and that cannabis use ameliorates this dysregulated circuitry. Using a monetary probe linked to fMRI (functional Magnetic Resonance Imaging), we have demonstrated that patients with SCZ and CUD do indeed have a deficit within their BRC as compared to normal subjects. This application will allow us to directly test the effects of cannabis on the BRC in patients with SCZ and CUD and thus to confirm our hypothesis regarding its effects in these patients. In addition, the application seeks to assess whether the cannabinoid agonist dronabinol, when given to patients with SCZ and CUD, will also ameliorate this BRC deficit, and, thus, whether dronabinol could be considered as a potential adjunctive treatment (given with an antipsychotic medication) to decrease their cannabis use. This "proof of concept" application is submitted in response to the RFA "Medication Development for Cannabis Use Disorders". The first aim of this study is to determine whether a BRC deficiency in patients with SCZ and CUD will be normalized when patients are given cannabis or dronabinol: (1a) to confirm our preliminary data suggesting that an fMRI scan linked to a monetary brain reward probe will be abnormal (compared to controls) in patients at baseline; (1b) to determine whether this fMRI measure will be normalized in patients when they smoke a cannabis cigarette; and (1c) to determine whether this fMRI measure will be normalized when patients are given oral dronabinol. The second aim will serve to further assess the effects of dronabinol in this population: (2a) to determine whether measures of craving, mood and negative symptoms will improve; and (2b) to determine whether measures of psychotic symptoms and cognitive deficits will increase (worsen). By probing the BRC dysregulation and testing the effects of smoked cannabis on this dysregulation, this study will help elucidate whether "self-medication" may be an important component of cannabis use in these patients. Moreover, by further elucidating the effects of dronabinol, this research can lead to development of therapeutic agents, potentially including dronabinol, that may limit cannabis use in these patients. PUBLIC HEALTH RELEVANCE: Cannabis use disorder, which is common in patients with schizophrenia, worsens the course of this severe psychiatric disorder. This medication development study seeks to establish that cannabis is used for "self-medication" by these patients because it corrects a deficit in their brain circuitry, and further, that dronabinol, an orally administered drug approved for certain medical conditions, can also correct this deficit and therefore be of value in limiting cannabis use in these patients. Finding medications that may be able to limit cannabis use and thereby reduce adverse outcomes in patients with schizophrenia is of great public health importance.