Antipsychotics and the Risk of Unexpected Death in Children and Youth

每年估计有130万≤24岁的人接受700万抗精神病药物治疗 虽然抗精神病药物的主要适应症是精神分裂症和相关疾病， 精神病，没有其他治疗选择，估计90%的抗精神病药物处方， 儿童和青少年是其他不太严重的情况，包括注意力缺陷/多动症 注意缺陷多动障碍（ADHD）、破坏性或攻击性行为、情感障碍（包括双相情感障碍）和焦虑。 然而，对于患有这些疾病的儿童和青少年， 被认为具有较少的不良影响。 抗精神病药物会增加成人心血管疾病和全因死亡的风险， 对儿童和青少年的心血管、代谢、呼吸和神经系统的不良影响， 可能会增加这一人群的死亡风险。我们最近发现服用抗精神病药物的人 剂量> 50 mg氯丙嗪当量（起始剂量中位数）的患者， 意外死亡，导致总死亡率增加64%（HR = 1.64 [1.03-2.63]）。而反观 调整后的受伤或自杀死亡风险没有增加， 减少抗精神病药物剂量的原因 我们的数据表明，抗精神病药物增加意外死亡的风险，特别是心血管死亡。 增加的风险具有临床意义：高剂量抗精神病药物中意外死亡的发生率 使用者的死亡率与受伤和自杀的死亡率相当，占儿童死亡人数的三分之二， 青少年。因此，在为患者开具抗精神病药时，应将死亡视为一种潜在危害。 儿童和青年。然而，为了指导临床实践，需要数据来定义抗精神病药物相关的 死亡率：1）根据抗精神病药物适应症; 2）根据从业者认为 可以控制：a）单个药物，B）剂量，和c）并发中枢神经系统（CNS）抑制剂。 我们将使用国家医疗补助分析提取（MAX）数据库来解决这些问题， 包括超过15年的纵向数据，这些数据可以与死亡证明联系起来， 39%的美国儿童是医疗补助计划的参与者。有两个具体目标： 目的1：检验以下假设： 是抗精神病药物新使用者，患有a）ADHD或行为/行为障碍，B）单相抑郁或 焦虑症，或c）双相情感障碍大于可比患者开始替代治疗 药物治疗 目的2：确定儿童和青少年服用抗精神病药物后意外死亡的风险和总死亡率 新使用者随a）个体药物、B）剂量和c）并发CNS抑制剂而变化。

Each year an estimated 1.3 million persons ≤24 years of age receive 7 million antipsychotic prescriptions in the U.S. Although the primary indications for antipsychotics are schizophrenia and related psychoses, with no other treatment alternatives, an estimated 90% of antipsychotic prescriptions for children and youth are for other, less serious conditions, including attention-deficit/hyperactivity disorder (ADHD), disruptive or aggressive behaviors, affective disorders including bipolar disorder, and anxiety. However, other recommended therapeutic interventions for children and youth with these disorders are thought to have fewer adverse effects. Antipsychotics, which increase the risk of cardiovascular and all-cause mortality in adults, have serious adverse cardiovascular, metabolic, respiratory, and neurologic effects in children and adolescents that plausibly increase the risk of death in this population. We recently found that antipsychotic users of doses>50mg chlorpromazine equivalents (median starting dose) had a greater than 3-fold increased risk of unexpected death, leading to a 64% increase in total mortality (HR = 1.64 [1.03-2.63]). In contrast, the adjusted risk of deaths from injuries or suicides did not increase nor was there increased risk of death from any cause for lower doses of antipsychotics. Our data indicate antipsychotics increase risk of unexpected deaths, particularly cardiovascular deaths. The increased risk is clinically meaningful: the incidence of unexpected death in higher-dose antipsychotic users equaled that of injuries and suicides, which account for two-thirds of deaths in children and adolescents. Thus, death should be considered as a potential harm when prescribing antipsychotics for children and youth. However, to guide clinical practice, data are needed that define antipsychotic-related mortality: 1) according to antipsychotic indication; and 2) according to important factors that practitioners can control: a) individual drug, b) dose, and c) concurrent central nervous system (CNS) depressants. We will address these questions using the national Medicaid Analytical Extract (MAX) database, which includes more than 15 years of longitudinal data that can be linked to death certificates for the estimated 39% of children in the U.S. who are Medicaid enrollees. There are two specific aims: Aim 1: Test the hypothesis that the risk of unexpected deaths and total mortality in children and youth who are antipsychotic new users with a) ADHD or disorders of behavior/conduct, b) unipolar depressive or anxiety disorders, or c) bipolar disorders is greater than that for comparable patients starting alternative medications. Aim 2: Define how risk of unexpected deaths and total mortality in children and youth who are antipsychotic new users varies with a) individual drug, b) dose, and c) concurrent CNS depressants.