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

说明(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人都有特别严重的病程。具体地说，与单独患有其中一种疾病的患者相比，同时患有双相情感障碍和大麻使用障碍的患者显示出这两种疾病的复发率更高。同时使用大麻和双相情感障碍的青少年，这两种障碍的结果甚至比类似的成年人更差，患其他物质使用障碍的风险也更高。然而，患有躁郁症和大麻使用障碍的青少年通常被排除在这两种疾病的受控药物治疗研究之外。因此，临床医生对如何治疗这些青少年没有循证指导。对同时患有双相情感障碍和大麻使用障碍的青少年的治疗研究至关重要，因为青春期可能是阻止这些疾病发展为终生药物使用依赖和治疗难治性双相情感障碍的最佳时期，这两者都与严重的发病率和死亡率有关。托吡酯是一种具有双重作用机制的抗癫痫药，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赏和渴望。最近，托吡酯被发现在减少成年人的酒精和可卡因消耗和渴求方面是安全有效的。我们的初步工作表明，托吡酯也可能对双相情感障碍青少年的躁狂症有效。然而，托吡酯作为治疗双相青少年大麻使用障碍的疗效尚未被探索。因此，这项提议的目标是进行一项为期16周的双盲安慰剂对照试点研究，考察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的疗效和耐受性。该提案的目的与RFA-DA-06-002的目标是一致的，其中包括进行“药物治疗物质相关疾病的临床试验”。我们将随机将90名患有当前大麻使用障碍的双相青少年接受托吡酯或安慰剂治疗。所有青少年还将接受奎硫平和单一的激励性访谈，然后是手动的遵从性加强疗法，分别作为躁狂症和大麻使用障碍的标准化治疗。大麻消费的变化是主要的结果衡量标准。我们还将检查托吡酯与奎硫平联合治疗躁狂症状的疗效，并探索大麻使用变化、情绪症状和其他物质使用之间的关系。这项拟议的研究将首次审查治疗双相青少年大麻使用障碍的药物干预措施。该项目的初步数据将为未来更大规模、更明确的托吡酯治疗青少年物质使用障碍的对照研究的设计提供信息和指导。

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.