SSRI-Induced Activation Syndrome In Pediatric OCD

描述（由申请人提供）：简介：FDA对精神疾病儿科临床试验（N约4400）的重新分析发现，与安慰剂（2%）相比，抗抑郁药（4%）的自杀意念和行为（自杀倾向）风险显著更高。这些数据表明，自杀信号并不局限于抑郁症：患有强迫症和其他焦虑症的受试者也表现出这种较高的风险。虽然负责这种效应的机制是未知的，诱导“激活综合征”（例如，易怒、不安、情绪不稳定等）可能代表一种促进自杀倾向的中间状态变化。SSRI诱导的激活综合征被临床医生广泛接受，并被认为是常见的，特别是在儿童和青少年中。然而，有一个缺乏的现象学和量化的这种假定的综合征的经验数据。我们将激活综合征概念化为行为毒性（一种不良事件），其发生相对独立于基础诊断，同时承认各种因素可能改变易感性和表达（例如，年龄、剂量、药物遗传学、合并症等）。激活综合征及其时间的更好表征可能指向介导这种不良反应的机制以及缓解方法。具体目标是：1。正式和量化的行为副作用的SSRIs集群，被称为“激活综合征”和2。确认SSRI治疗期间激活综合征的发生和时间。方法：第一阶段将需要一个迭代过程，在与激活综合征对应的内容域上达成共识，选择和修订措施，创建一个复合措施，并在SSRIs治疗的各个阶段对儿童和青少年的代表性样本进行可靠性测试。在第二阶段，患有强迫症的儿童和青少年将以双盲方式随机分配至1）标准剂量的舍曲林（RegSert）; 2）舍曲林缓慢滴定（SloSert）;或3）药丸安慰剂（Pla），持续18周。所有组将在第4周后开始接受CBT治疗OC症状。我们预测，与PLA相比，RegSert期间早期（第一天或2周）激活综合征的指标将升高。我们将探讨与RegSert相比，SloSert是否降低了激活综合征的频率或强度。在强迫症中进行这项研究提供了实用的优势（例如，诊断的清晰度），但结果应推广到其他诊断组。意义：SSRIs诱导激活综合征（包括易怒、激动、情绪波动等）可能是某些人自杀倾向的前兆提高对激活综合征的认识和理解应促进干预（例如，减缓抗抑郁药的剂量），这可能会降低发展自杀倾向的风险。激活综合征测量工具的开发将在未来测试激活综合征与自杀之间关系的大规模临床试验中有用。

DESCRIPTION (provided by applicant): Intro: An FDA re-analysis of pediatric clinical trials (N about 4400) in psychiatric conditions found that the risk of suicidal ideation and behavior (suicidality) was significantly higher with antidepressants (4%) compared to placebo (2%). These data revealed that the suicidality signal was not limited to depression: subjects with OCD and other anxiety disorders also exhibited this higher risk. Although the mechanism responsible for this effect is unknown, induction of an "activation syndrome" (e.g., irritability, restlessness, emotional lability, etc.) may represent an intermediary state change that promotes suicidality. SSRI-induced activation syndrome is well-accepted by clinicians and thought to be common, particularly in children and teens. However, there is a dearth of empirical data on the phenomenology and quantification of this putative syndrome. We conceptualize activation syndrome as behavioral toxicity (an adverse event) that occurs relatively independent of the underlying diagnosis, while acknowledging that various factors may modify susceptibility and expression (e.g., age, dosing, pharmacogenetics, comorbidity, etc.). Better characterization of activation syndrome and its timing might point to the mechanisms mediating this adverse effect as well as approaches to its mitigation. Specific Aims are: 1. To formalize and quantify a cluster of behavioral side effects of SSRIs, referred to as "activation syndrome" and 2. To confirm the occurrence and timing of activation syndrome during SSRI treatment. Approach: The first phase will entail an iterative process of arriving at consensus on the content domains corresponding to activation syndrome, selection and revision of measures, creation of a composite measure and testing of reliability in a representative sample of children and adolescents at various stages of treatment with SSRIs. In the second phase, children and adolescents with OCD will be randomized in double-blind fashion to either 1) sertraline at standard dosing (RegSert); 2) sertraline slow titration (SloSert); or 3) pill placebo (Pla) for 18 weeks. All groups will receive CBT for their OC symptoms starting after week 4. We predict that measures of activation syndrome will be elevated early (first days or 2 weeks) during RegSert compared to PLA. We will explore if SloSert reduces frequency or intensity of activation syndrome compared to RegSert. Conducting this study in OCD offers pragmatic advantages (e.g., clarity of diagnosis), yet findings should be generalizable to other diagnostic groups. Significance: SSRIs induce an activation syndrome (consisting of irritability, agitation, mood swings, etc.) that may be a precursor to suicidality in some individuals. Improved recognition and understanding of activation syndrome should prompt interventions (e.g., slower dosing of antidepressants) that might reduce the risk of developing suicidality. Development of an activation syndrome measurement tool will be useful in future large-scale clinical trials that test the relationship between activation syndrome and suicidality.