Topiramate for Co-occurring Cannabis Use and Bipolar Disorders in Adolescents

描述（由申请人提供）：双相情感障碍和大麻使用障碍之间存在双向重叠，患有这两种疾病的个体的病程特别严重。具体而言，与单独患有任何一种疾病的个体相比，患有双相情感障碍和大麻使用障碍的患者表现出更高的两种疾病复发率。同时使用大麻和双相情感障碍的青少年，这两种疾病的结果甚至比类似成年人的结果更差，并且发生其他物质使用障碍的风险更高。然而，患有双相情感障碍和大麻使用障碍的青少年通常被排除在这两种疾病的对照药物治疗研究之外。因此，临床医生对如何治疗这些青少年没有任何循证指南。对患有双相和大麻使用障碍的青少年的治疗研究至关重要，因为青春期可能是中断这些疾病进展为终身物质使用依赖和治疗难治性双相障碍的最佳时间，这两者都与显著的发病率和死亡率相关。托吡酯是一种具有双重作用机制的抗癫痫药物，可导致中脑多巴胺神经传递减少，因此，可能有助于减少与大麻使用相关的奖励和渴望。最近，托吡酯已被发现是安全和有效的减少酒精和可卡因的消费和渴望在成年人。我们的初步工作表明，托吡酯也可能是有效的治疗躁狂症的青少年双相情感障碍。然而，托吡酯作为治疗双相青少年大麻使用障碍的有效性尚未探讨。因此，本提案的目标是进行一项为期16周的双盲安慰剂对照试点研究，检查托吡酯作为减少患有双相情感障碍和大麻使用障碍的青少年大麻消费的治疗的疗效和耐受性。本提案的目的与RFA-DA-06 - 002的目标一致，其中包括开展"药物治疗物质相关疾病的试点临床试验"。“我们将随机选择90名患有大麻使用障碍的双相情感青少年，接受托吡酯或安慰剂治疗。所有青少年还将接受quetibrium和一次动机访谈，然后接受手动驱动的依从性增强治疗，分别作为躁狂症和大麻使用障碍的标准化治疗。大麻消费量的变化是主要的结果指标。我们还将研究托吡酯与奎替利联合治疗躁狂症状的疗效，并探讨大麻使用、情绪症状和其他物质使用变化之间的关系。这项拟议的研究将是第一个检查治疗双相青少年大麻使用障碍的药理学干预的研究。该项目的初步数据将为将来更大、更明确的托吡酯治疗青少年物质使用障碍的对照研究提供信息和指导。

DESCRIPTION (provided by applicant): There is a bidirectional overlap between bipolar and cannabis use disorders, with a particularly severe illness course for individuals with both conditions. Specifically, patients with co-occurring bipolar and cannabis use disorders exhibit higher relapse rates of both illnesses compared with individuals with either illness alone. Adolescents with co-occurring cannabis use and bipolar disorders have a poorer outcome of both disorders than even occurs in similar adults and have an elevated risk of developing other substance use disorders. However, adolescents with bipolar and cannabis use disorders are routinely excluded from controlled pharmacological treatment studies of either condition. Thus, clinicians are left with no evidence- based guidance on how to treat these adolescents. Research on the treatment of adolescents with co- occurring bipolar and cannabis use disorders is critical because adolescence may be the best time to interrupt the progression of these illnesses into lifelong substance use dependence and treatment refractory bipolar disorder, both of which are associated with significant morbidity and mortality. Topiramate is an antiepileptic agent with a dual mechanism of action that leads to reduction of midbrain dopamine neurotransmission, and therefore, may be useful to reduce the reward and craving associated with cannabis use. Recently, topiramate has been found to be safe and efficacious for reducing alcohol and cocaine consumption and craving in adults. Our preliminary work suggests that topiramate also may be effective for the treatment of mania in adolescents with bipolar disorder. However, the efficacy of topiramate as a treatment for cannabis use disorders in bipolar adolescents has not been explored. Therefore, the goal of this proposal is to conduct a double-blind placebo-controlled 16-week pilot study examining the efficacy and tolerability of topiramate as a treatment for reducing cannabis consumption in adolescents with co-occurring bipolar and cannabis use disorders. The aims of this proposal are consistent with the goals of RFA-DA-06-002, which include conducting "pilot clinical trials of pharmacotherapies for substance related disorders." We will randomize 90 bipolar adolescents with a current cannabis use disorder to treatment with topiramate or placebo. All adolescents will also receive quetiapine and a single Motivational Interview followed by Compliance Enhancement Therapy that is manual-driven, as standardized treatments for mania and cannabis use disorders, respectively. Change in cannabis consumption is the primary outcome measure. We will also examine the efficacy of topiramate in combination with quetiapine for the treatment of manic symptoms and explore the relationships among changes in cannabis use, mood symptoms, and other substance use. The proposed study would be the first to examine a pharmacological intervention for the treatment of cannabis use disorders in bipolar adolescents. The preliminary data from this project will inform and guide the design of future larger, more definitive, controlled studies of topiramate as a treatment for adolescent substance use disorders.