Topiramate for co-occurring alcohol use and bipolar disorders in adolescents

描述（由申请人提供）：在酒精使用和双相情感障碍之间存在双向重叠，对于患有这两种疾病的个体来说，病程特别严重。具体而言，与单独患有任何一种疾病的患者相比，同时患有酒精使用和双相情感障碍的患者表现出恢复较慢、治疗依从性较差、自杀率增加和两种疾病复发率较高。同时发生酒精使用和双相情感障碍的青少年在这两种疾病上的预后甚至比类似的成年人更差。然而，同时发生酒精使用和双相情感障碍的青少年通常被排除在这两种情况的对照药物治疗研究之外。因此，临床医生没有关于如何治疗这些青少年的循证指导。研究同时发生酒精使用和双相情感障碍的青少年的治疗是至关重要的，因为青春期可能是阻止这些疾病发展为终身酒精依赖和治疗难治性双相情感障碍的最佳时期，这两种疾病都与显著的发病率和死亡率相关。托吡酯是一种抗癫痫药物，具有双重作用机制，可减少中脑多巴胺神经传递，因此可能有助于减少与酒精使用相关的奖励和渴望。事实上，托吡酯已经被发现是安全有效的，可以减少成年人的酒精消耗和渴望。我们的初步工作表明，托吡酯也可能有效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酒精使用障碍的疗效尚未被探索。因此，这项为期两年的探索性R21提案的目标是进行一项为期12周的双盲安慰剂对照试验研究，检查托吡酯作为减少酒精使用和双相情感障碍并存的青少年酒精消耗的疗效和耐受性。为了实现这一目标，我们将随机分配50名患有活动性酒精使用障碍的双相青少年（12-20岁）服用托吡酯或安慰剂。所有青少年还将分别接受喹硫平和手动驱动的认知行为疗法，作为双相情感障碍和酒精使用障碍的标准治疗。酒精消费量的变化是主要的结果衡量指标。我们还将研究托吡酯联合喹硫平治疗躁狂和抑郁症状的疗效，并探讨酒精使用变化与情绪症状之间的关系。这项提议的研究将是第一个检验酒精使用和双相情感障碍青少年酒精消费治疗的药理学干预。该试点项目的初步数据将为今后更大规模、更明确的托吡酯治疗青少年酒精使用障碍对照研究的设计提供信息和指导。

DESCRIPTION (provided by applicant): There is a bidirectional overlap between alcohol use and bipolar disorders, with a particularly severe illness course for individuals with both conditions. Specifically, patients with co-occurring alcohol use and bipolar disorders exhibit slower recovery, worse treatment adherence, increased suicidality, and higher rates of relapse of both illnesses compared with individuals with either illness alone. Adolescents with co-occurring alcohol use and bipolar disorders have a poorer outcome of both disorders than even occurs in similar adults. However, adolescents with co-occurring alcohol use and bipolar disorders are routinely excluded from controlled pharmacological treatment studies of either condition. Thus, clinicians have no evidence-based guidance on how to treat these adolescents. Research on the treatment of adolescents with co-occurring alcohol use and bipolar disorders is critical because adolescence may be the best time to interrupt the progression of these illnesses into lifelong alcohol 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 alcohol use. Indeed, topiramate has been found to be safe and efficacious for reducing alcohol 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 alcohol use disorders in bipolar adolescents has not been explored. Therefore, the goal of this two-year exploratory R21 proposal is to conduct a double-blind placebo-controlled, 12-week pilot study examining the efficacy and tolerability of topiramate as a treatment for reducing alcohol consumption in adolescents with co-occurring alcohol use and bipolar disorders. In order to accomplish this goal, we will randomize a total of 50 bipolar adolescents (ages 12-20 years) with an active alcohol use disorder to topiramate or placebo. All adolescents will also receive quetiapine and a manual-driven Cognitive Behavioral Therapy, as standard treatments for bipolar and alcohol use disorders, respectively. Change in alcohol consumption is the primary outcome measure. We will also examine the efficacy of topiramate in combination with quetiapine for the treatment of manic and depressive symptoms and explore the relationship between changes in alcohol use and mood symptoms. The proposed study would be the first to examine a pharmacological intervention for the treatment of alcohol consumption in adolescents with alcohol use and bipolar disorders. The preliminary data from this pilot project will inform and guide the design of future larger, more definitive, controlled studies of topiramate as a treatment for adolescent alcohol use disorders.