BACKGROUND Polypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy. RESULTS In designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training. CONCLUSIONS We hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy. TRIAL REGISTRATION ClinicalTrials.gov NCT00796302.

中文翻译：

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严重儿童攻击性 (TOSCA) 研究的治疗：设计挑战。

背景多药疗法（同时使用一种以上精神活性药物）和其他联合干预措施越来越普遍用于治疗仅对单一疗法有部分反应的严重精神问题。这种做法和对其的研究提出了科学、临床和伦理问题，例如附加副作用、相互作用、添加第二种药物的阈值、适当的目标措施和（对于研究）随机化时间。治疗的一个具有挑战性的领域是严重的儿童攻击性。常用药物（通常联合使用）包括精神兴奋剂、抗精神病药、情绪稳定剂和 alpha-2 激动剂，它们在安全性和有效性方面的感知差异很大。结果 在设计我们由 NIMH 资助的多药试验时，我们将注意力集中在第二种药物（利培酮）对第一种药物（兴奋剂）的作用的额外好处上。我们选择这两种药物是因为它们相关的不良事件可能相互抵消（例如，兴奋剂导致的睡眠延迟和食欲下降与抗精神病药导致的镇静和食欲增加）。此外，有大量证据表明每种药物单独用于治疗多动症和儿童攻击行为的有效性。研究样本包括患有多动症和破坏性行为障碍（对立违抗或品行障碍）并伴有严重身体攻击的儿童（6-12 岁）。在分阶段的顺序中，不良反应最少的药物（兴奋剂）在 3 周内公开滴定以达到最佳效果。行为症状未正常化的参与者通过随机分配接受额外的双盲药物治疗，利培酮或安慰剂。因此，使用兴奋剂药物使行为症状正常化的儿童不会接触抗精神病药。所有家庭都参加了一项有经验支持的针对破坏性行为的家长培训计划，因此实际比较是兴奋剂 + 家长培训与兴奋剂 + 抗精神病药 + 家长培训。结论我们希望这里提出的挑战的解决方案对其他研究人员有用，并促进对儿童精神科多药治疗急需的研究。试验注册 ClinicalTrials.gov NCT00796302。因此，使用兴奋剂药物使行为症状正常化的儿童不会接触抗精神病药。所有家庭都参加了一项有经验支持的针对破坏性行为的家长培训计划，因此实际比较是兴奋剂 + 家长培训与兴奋剂 + 抗精神病药 + 家长培训。结论我们希望这里提出的挑战的解决方案对其他研究人员有用，并促进对儿童精神科多药治疗急需的研究。试验注册 ClinicalTrials.gov NCT00796302。因此，使用兴奋剂药物使行为症状正常化的儿童不会接触抗精神病药。所有家庭都参加了一项有经验支持的针对破坏性行为的家长培训计划，因此实际比较是兴奋剂 + 家长培训与兴奋剂 + 抗精神病药 + 家长培训。结论我们希望这里提出的挑战的解决方案对其他研究人员有用，并促进对儿童精神科多药治疗急需的研究。试验注册 ClinicalTrials.gov NCT00796302。结论我们希望这里提出的挑战的解决方案对其他研究人员有用，并促进对儿童精神科多药治疗急需的研究。试验注册 ClinicalTrials.gov NCT00796302。结论我们希望这里提出的挑战的解决方案对其他研究人员有用，并促进对儿童精神科多药治疗急需的研究。试验注册 ClinicalTrials.gov NCT00796302。