1/2-Novel Medication Strategies Targeting Brain Mechanisms in Pediatric OCD

1/2-针对儿童强迫症脑机制的新型药物策略

• 批准号: 8660087
• 负责人: Moira Ann Rynn
• 金额: $ 23.98万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660087
• 关键词: Acne; Adolescence; Adolescent; Adult; Adverse effects; Adverse event; Age; Age of Onset; Animal Genetics; Antipsychotic Agents; Bacterial Infections; Biological Markers; Brain; Brain imaging; Caring; Case Study; Characteristics; Child; Childhood; Chronic; Cognitive Therapy; Corpus striatum structure; Data; Dose; Drug Formulations; Family history of; Future; Generic Drugs; Glutamates; Goals; Head; Human; Image; Infection; Intervention; Lead; Magnetic Resonance Spectroscopy; Measurable; Memantine; Mental disorders; Methods; Minocycline; Morbidity - disease rate; National Institute of Mental Health; Obsessive-Compulsive Disorder; Outcome; Patients; Pharmaceutical Preparations; Pilot Projects; Placebos; Population; Randomized; Randomized Controlled Trials; Recruitment Activity; Riluzole; Role; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Severities; Side; Site; Strategic Planning; Symptoms; Therapeutic; United States Food and Drug Administration; aged; base; clinical efficacy; clinically significant; cost effective; drug development; improved; innovation; neurotransmission; novel; pill; placebo controlled study; prevent; randomized placebo controlled trial; response; satisfaction; tool; treatment adherence; treatment effect; treatment response; treatment strategy

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.

描述（由申请人提供）：强迫症（OCD）是一种致命的疾病，通常从青春期开始。我们的长期目标是确定针对大脑机制潜在的OCD的有效新治疗方法，并有助于防止这种疾病引起的压倒性发病率。在此协作R34中，我们建议评估小儿OCD的新型治疗策略的可行性，功效和潜在因果机制：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，唯一可证明的SRI增强策略是增加认知疗法（CBT）〜添加抗精神病药物也已被证明在成年人中也有效。但是，许多儿童和青少年无法访问CBT，有些拒绝或失败〜抗精神病药具有重大副作用。 需要替代增强策略。 其次，据信甲型甲状腺纹状体 - 纹状体脑回路中谷氨酸能神经传递的异常被认为是OCD的基础，而初步研究表明，在加入SRIS中时，调节谷氨酸的药物（例如，Riluzole，Memantine，Memantine，Memantine）减少了OCD灭绝。米诺环素还可以调节谷氨酸，但与Riluzole和Memantine不同，它得到了8岁及以上儿童的食品药物管理局（用于痤疮和细菌感染）的批准，并以通用配方提供。 因此，它是研究谷氨酸调节剂在小儿强迫症中的作用的有吸引力的药物。最后，我们的试验数据表明，尽管经过适当的SRI试验，但米诺环素仍会导致症状性的OCD症状显着降低。 具体来说，我们将招募45名儿童和青少年（8-2岁），尽管SRI进行了足够的试验，但在临床上具有显着症状的OCD。我们将将它们随机以米诺环素或药丸安慰剂的含量12周，而它们继续进行稳定的SRI剂量。与R34机制的辅音，我们的具体目的是：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。为了完成后者，我们将使用最先进的磁共振光谱（MRS）方法来检查添加米诺oc级添加是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还是纹状体谷氨酸水平的变化是否与治疗反应有关。 R34的创新是，它研究了Minocycline的作用，Minocycline是一种具有新颖的作用机理的OCD药物，同时使用先进的MRS方法探索了米诺环素对大脑的潜在影响。通过制定新的干预措施（目标3）并促进大脑发现（目标1），我们可以推进NIMH战略计划。