2/2-Novel Medication Strategies Targeting Brain Mechanisms in Pediatric OCD

描述(申请人提供)：强迫症(OCD)是一种致残性疾病，通常始于青春期。我们的长期目标是找到有效的治疗强迫症的新方法，针对潜在的大脑机制，并帮助防止这种疾病造成的压倒性发病率。在这个协作的R34中，我们建议评估一种新的儿童强迫症治疗策略的可行性、有效性和潜在的原因机制：将米诺环素添加到5-羟色胺再摄取抑制剂(SRI)中。我们的理由是 三倍。首先，在儿童和青少年中唯一被证实的SRI增强策略是添加认知行为疗法(CBT)~添加抗精神病药物也被证明在成人中有效。然而，许多儿童和青少年无法获得CBT，一些人拒绝或失败-抗精神病药物有显著的副作用。需要替代的扩大战略。其次，眼眶前额-纹状体脑回路中谷氨酸能神经传递的异常被认为是强迫症的基础，初步研究表明，调节谷氨酸的药物(如利鲁唑、美金刚)在加入SRI时可降低强迫症的严重程度。米诺环素也调节谷氨酸，但与利鲁唑和美金刚不同的是，它得到了美国食品和药物管理局(Food And Drug Administration)的批准(用于8岁及以上儿童的痤疮和细菌感染)，并有仿制药可用。因此，它是研究谷氨酸调节剂在儿童强迫症中作用的一个有吸引力的药物。最后，我们的试验数据表明，米诺环素可显著减少尽管进行了适当的SRI试验但仍有症状的青少年的强迫症症状。具体地说，我们将招募45名患有强迫症的儿童和青少年(8-2岁)，他们尽管进行了充分的SRI试验，但仍有明显的临床症状。我们将随机给他们服用米诺环素或安慰剂，为期12周，同时继续服用稳定的SRI剂量。与R34机制一致，我们的具体目标是：1)通过评估其安全性、可接受性和耐受性来评估该策略的可行性；2)进行一项小型随机对照试验，以评估米诺环素与安慰剂在加入SRIs时的疗效；3)探索米诺环素的潜在作用机制。为了实现后者，我们将使用最先进的磁共振波谱(MRS)方法来检查添加米诺林是否会导致纹状体谷氨酸水平的可检测变化，以及基线纹状体谷氨酸水平或纹状体谷氨酸水平的变化是否与治疗反应有关。这款R34的创新之处在于，它研究了一种具有新作用机制的强迫症药物米诺环素的疗效，同时利用最先进的MRS方法探索了米诺环素对大脑的潜在影响。通过开发新的干预措施(目标3)和促进大脑中的发现(目标1)，我们推进了NIMH战略计划。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a disabling illness that usually begins by adolescence. Our long- term goal is to identify effective new treatment approaches for OCD that target underlying brain mechanisms and help prevent the overwhelming morbidity caused by this illness. In this collaborative R34, we propose to evaluate the feasibility, efficacy, and potential causal mechanism of a novel treatment strategy for pediatric OCD: the addition of minocycline to serotonin reuptake inhibitors (SRI). Our rationale is threefold. First, the only proven SRI augmentation strategy in children and adolescents i the addition of cognitive-behavioral therapy (CBT)~ the addition of antipsychotic medication has also proven to be effective in adults. However, many children and adolescents can't access CBT, and some refuse or fail it~ antipsychotics have significant side effects. Alternative augmentation strategies are needed. Second, abnormalities in glutamatergic neurotransmission in orbitofrontal-striatal brain circuits are believed to underlie OCD, and preliminary studies suggest that medications that modulate glutamate (e.g., riluzole, memantine) reduce OCD severity when added to SRIs. Minocycline also modulates glutamate, but unlike riluzole and memantine, it is approved by the Food and Drug Administration (for acne and bacterial infections) in children ages 8 and above and is available in generic formulation. Thus, it is an attractive agent for investigating the role of glutamate modulators in pediatric OCD. Finally, our pilot data suggest that minocycline leads to significant decreases in OCD symptoms in adolescents who remain symptomatic despite an adequate SRI trial. Specifically, we will recruit 45 children and adolescents (ages 8-2) with OCD who have clinically significant symptoms despite an adequate SRI trial. We will randomize them to minocycline or pill placebo for 12 weeks while they continue on a stable SRI dose. Consonant with the R34 mechanism, our specific aims are: 1) to assess the feasibility of this strategy by assessing its safety, acceptability, and tolerability~ 2) to conduct a small randomized controlled trial to estimate the effects of minocycline versus placebo when added to SRIs~ and 3) to explore minocyline's potential mechanism of action. To accomplish the latter, we will use state-of-the art magnetic resonance spectroscopy (MRS) methods to examine whether adding minocyline leads to detectable changes in striatal glutamate levels and whether either baseline striatal glutamate levels or changes in striatal glutamate levels are associated with treatment response. The innovation of this R34 is that it investigates the effects of minocycline, a medication for OCD with a novel mechanism of action, while simultaneously exploring the potential effects of minocycline on the brain by using state-of-the art MRS methods. By developing new interventions (Objective 3) and promoting discovery in the brain (Objective 1), we advance the NIMH strategic plan.