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

描述（由申请人提供）：强迫症（OCD）是一种通常始于青春期的致残疾病。我们的长期目标是确定有效的治疗强迫症的新方法，以潜在的大脑机制为目标，帮助预防由这种疾病引起的压倒性的发病率。在这一合作R34中，我们建议评估一种治疗儿童强迫症的新策略的可行性、有效性和潜在的因果机制：在5 -羟色胺再摄取抑制剂（SRI）中添加二甲胺四环素。我们的基本原理是

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.