ImportanceAntipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia.ObjectiveTo estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia.Design, Setting, and ParticipantsThis cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023.ExposuresUse of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (<0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to <1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high.Main Outcomes and MeasuresThe primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference.ResultsThe study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P < .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P < .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P < .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk.Conclusions and RelevanceResults of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.

中文翻译：

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精神分裂症的肺炎风险、抗精神病药物剂量和抗胆碱能负担


重要性在观察性研究中，抗精神病药物（尤其是氯氮平）与肺炎有关。尽管研究了抗精神病药物使用与新发肺炎之间的关联，但尚不清楚抗精神病药物的使用在多大程度上与肺炎风险增加相关，是否存在剂量反应关联，以及哪些药物与新发肺炎具体相关。目的评估与特定抗精神病药物相关的肺炎风险，并检查多药治疗、给药和受体结合特性是否与精神分裂症患者的肺炎相关。设计、设置和参与者这项队列研究从 1972 年至 2014 年的芬兰全国登记册中确定了 16 岁或以上的精神分裂症或分裂情感障碍（以下简称精神分裂症）患者。有关诊断、住院护理和专业门诊护理的数据来自医院出院登记册。有关门诊药物配药的信息可从处方登记处获得。研究随访时间为 1996 年至 2017 年。数据分析时间为 2022 年 11 月 4 日至 2023 年 12 月 5 日。按剂量建模的抗精神病药为低 （<世界卫生组织定义的每日剂量 [DDD] 的 0.6 倍/天）、中等 （0.6 至 <每天 1.1 个 DDD）或高剂量（每天 ≥1.1 个 DDD）;抗精神病药物多药治疗;抗精神病药根据其抗胆碱能负荷分为低、中和高。主要结局和测量主要结局是因新发肺炎住院。使用调整后的个体内 Cox 比例风险回归模型分析肺炎风险，不使用抗精神病药物作为参考。结果该研究包括 61 889 名精神分裂症患者 （平均 [SD] 年龄，46.2 [16.0] 岁;31 104 名男性 [50.3%]）。在 22 年的随访中，8917 名患者 （14.4%） 因肺炎住院 1 次或多次，1137 名 （12.8%） 在入院后 30 天内死亡。与不使用抗精神病药物相比，总体上任何抗精神病药物的使用与肺炎无关（校正风险比 [AHR]，1.12;95% CI，0.99-1.26）。与不使用抗精神病药相比，使用单一疗法与肺炎风险增加相关 （AHR，1.15 [95% CI，1.02-1.30];P = .03），但多药治疗使用不是。当按抗胆碱能负荷分类时，只有使用具有高抗胆碱能负荷的抗精神病药物与肺炎相关 （AHR，1.26 [95% CI，1.10-1.45];P < .001）。在特异性药物中，大剂量喹硫平 （AHR，1.78 [95% CI，1.22-2.60];P = .003）、高剂量和中剂量氯氮平 （AHR， 1.44 [95% CI， 1.22-1.71];P < .001 和 AHR，1.43 [95% CI，1.18-1.74];P < .001）和高剂量奥氮平 （AHR，1.29 [95% CI，1.05-1.58];P = .02） 与肺炎风险增加相关。结论和相关性该队列研究的结果表明，在 精神分裂症 患者中，与肺炎相关的抗精神病药物不仅包括氯氮平（剂量 ≥180 mg/d），还包括喹硫平 （≥440 mg/d） 和奥氮平 （≥11 mg/d）。此外，单药治疗抗精神病药和高抗胆碱能负荷的抗精神病药与肺炎风险增加呈剂量依赖性相关。这些发现需要针对需要高危抗精神病药的精神分裂症患者制定预防策略。