Background

Infection risk and mortality are increased in schizophrenia spectrum disorders, which was corroborated during the COVID-19 pandemic. However, evidence is lacking regarding the additional impact of antipsychotic drugs, and the highly debated safety of clozapine treatment during large-scale infection outbreaks. Therefore, we aimed to investigate risk of COVID-19 and non-COVID respiratory infections during exposure to antipsychotics.

Methods

We used several nationwide Danish registers (National Prescription Registry, National Hospital Registry, Psychiatric Research Register, Microbiology Database, Vaccination Registry, Cause of Death Registry, and Database for Labour market Research) to investigate all individuals aged 18 years or older with a schizophrenia spectrum disorder (ICD-10: F20–F29) living in Denmark between Jan 1 and March 1, 2020. Antipsychotic exposure groups were defined as prevalent-users and incident-users. The full observation period was March 1, 2020 to Dec 31, 2021. Antipsychotic exposure was defined in a time-varying manner and compared with non-exposure. Risk was calculated for mild infection outcomes (positive SARS-CoV-2 PCR and anti-infective drug prescriptions) and severe infection outcomes (hospitalisation and death) related to COVID-19 and non-COVID-19 respiratory infections. Outcomes were adjusted for demographics, socio-economic factors, and comorbidity.

Findings

Of 85 083 individuals (44 293 men [52·1%] and 40 790 women [47·9%], median age 45·8 years [IQR 31·1–60·2]) with pre-existing schizophrenia spectrum disorders, 30 984 had antipsychotic exposure periods. Ethnicity data were not available. During antipsychotic exposure compared with non-exposed periods, assessing mild infection outcomes, risk of a positive SARS-CoV-2 test was decreased (hazard ratio 0·91 [95% CI 0·85–0·97]) and risk of redeeming an anti-infective drug was not statistically significantly different (1·01 [0·97–1·06]). For severe infection outcomes, COVID-19-related hospitalisation risk was increased (1·28 [1·07–1·52]) although COVID-19-related death was not statistically significantly increased (1·24 [0·82–1·86]). For non-COVID-19 respiratory infections, risk was increased both for hospitalisation (1·61 [1·44–1·79]) and death (1·61 [1·18–2·21]). Specifically, COVID-19 hospitalisation risk was increased in individuals older than 70 years, and non-COVID-19 hospitalisation risk increased in individuals older than 40 years and death risk in age groups of 50–59 years and 70–79 years. Based on homogeneity testing, no apparent excess risk of any outcome was observed with clozapine exposure compared with other antipsychotics.

Interpretation

During antipsychotic exposure compared with unexposed periods, risk of severe infection outcomes increases. It seems reasonable to initiate infection countermeasures, such as pneumococcal vaccination, in people older than 40 years with schizophrenia spectrum disorders, who commence or are treated with antipsychotics. We do not suggest the avoidance of specific antipsychotics but rather adherence to treatment guidelines and a call for increased vigilance regarding this at-risk group.

Funding

Mental Health Services of the Capital Region of Denmark.

中文翻译：

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COVID-19 大流行期间精神分裂症谱系障碍患者的抗精神病药物暴露和感染风险：一项丹麦全国登记研究

 背景

精神分裂症谱系障碍的感染风险和死亡率增加，这在 COVID-19 大流行期间得到了证实。然而，缺乏关于抗精神病药物的额外影响的证据，以及氯氮平治疗在大规模感染暴发期间的安全性存在高度争议。因此，我们旨在调查在接触抗精神病药物期间发生 COVID-19 和非 COVID 呼吸道感染的风险。

 方法

我们使用了几个全国性的丹麦登记册（国家处方登记处、国家医院登记处、精神病学研究登记处、微生物学数据库、疫苗接种登记处、死因登记处和劳动力市场研究数据库）来调查 2020 年 1 月 1 日至 3 月 1 日期间居住在丹麦的所有 18 岁或以上患有精神分裂症谱系障碍（ICD-10：F20-F29）的个体。抗精神病药物暴露组被定义为普遍使用者和事件使用者。完整的观察期为 2020 年 3 月 1 日至 2021 年 12 月 31 日。抗精神病药物暴露以时变方式定义并与非暴露进行比较。计算与 COVID-19 和非 COVID-19 呼吸道感染相关的轻度感染结局（SARS-CoV-2 PCR 阳性和抗感染药物处方）和严重感染结局（住院和死亡）的风险。根据人口统计学、社会经济因素和合并症调整结局。

 发现

在 85 083 名预先存在精神分裂症谱系障碍的个体（44 293 名男性 [52·1%] 和 40 790 名女性 [47·9%]，中位年龄 45·8 岁 [IQR 31·1–60·2]）中，30 984 人有抗精神病药物暴露期。种族数据不可用。与未暴露期相比，在抗精神病药物暴露期间，评估轻度感染结果，SARS-CoV-2 检测阳性的风险降低（风险比 0·91 [95% CI 0·85–0·97]），并且赎回抗感染药物的风险没有统计学意义差异 （1·01 [0·97–1·06]）。对于严重感染结局，COVID-19 相关住院风险增加 （1·28 [1·07–1·52]），尽管 COVID-19 相关死亡没有统计学意义增加 （1·24 [0·82–1·86]）。对于非 COVID-19 呼吸道感染，住院 （1·61 [1·44–1·79]） 和死亡 （1·61 [1·18–2·21]） 的风险均增加。具体来说，70 岁以上人群的 COVID-19 住院风险增加，40 岁以上人群的非 COVID-19 住院风险增加，50-59 岁和 70-79 岁年龄组的死亡风险增加。基于同质性检验，与其他抗精神病药相比，氯氮平暴露未观察到任何结局的明显超额风险。

 解释

与未暴露期相比，在抗精神病药物暴露期间，严重感染结局的风险增加。对于 40 岁以上的精神分裂症谱系障碍患者，开始或接受抗精神病药物治疗，开始接种肺炎球菌疫苗似乎是合理的。我们不建议避免使用特定的抗精神病药物，而是坚持使用治疗指南，并呼吁提高对这一高危人群的警惕。

 资金

丹麦首都地区的心理健康服务。