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) 是一种通常从青春期开始的致残性疾病。我们的长期目标是找到针对强迫症的有效新治疗方法，针对潜在的大脑机制，并帮助预防这种疾病引起的高发病率。在这项合作 R34 中，我们建议评估儿童强迫症新治疗策略的可行性、有效性和潜在因果机制：在血清素再摄取抑制剂 (SRI) 中添加米诺环素。我们的理由是 三重。首先，在儿童和青少年中唯一经过验证的 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对成人有效。然而，许多儿童和青少年无法接受认知行为治疗，有些人拒绝或失败——抗精神病药物有显着的副作用。 需要替代的增强策略。 其次，眶额-纹状体大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（例如利鲁唑、美金刚）在添加到SRIs中后可以减轻强迫症的严重程度。米诺环素还调节谷氨酸，但与利鲁唑和美金刚不同，它已获得美国食品和药物管理局批准用于 8 岁及以上儿童（用于痤疮和细菌感染），并且有通用配方。 因此，它是研究谷氨酸调节剂在儿科强迫症中的作用的一种有吸引力的药物。最后，我们的试点数据表明，尽管进行了充分的 SRI 试验，但仍有症状的青少年，米诺环素可显着减轻强迫症症状。 具体来说，我们将招募 45 名患有强迫症的儿童和青少年（8-2 岁），尽管进行了充分的 SRI 试验，但他们仍具有显着的临床症状。我们将让他们随机服用米诺环素或安慰剂，为期 12 周，同时他们继续服用稳定的 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添加到 SRI 中时的效果~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环素是否会导致纹状体谷氨酸水平发生可检测的变化，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相关。 R34的创新之处在于，它研究了米诺环素（一种具有新颖作用机制的强迫症药物）的作用，同时利用最先进的MRS方法探索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）和促进大脑的发现（目标 1），我们推进 NIMH 战略计划。