People with schizophrenia die 15-20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random-effects meta-analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all-cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific-cause mortality. Publication bias, subgroup and meta-regression analyses, and quality assessment (Newcastle-Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all-cause mortality was increased in people with schizophrenia versus any non-schizophrenia control group (RR=2.52, 95% CI: 2.38-2.68, n=79), with the largest risk in first-episode (RR=7.43, 95% CI: 4.02-13.75, n=2) and incident (i.e., earlier-phase) schizophrenia (RR=3.52, 95% CI: 3.09-4.00, n=7) versus the general population. Specific-cause mortality was highest for suicide or injury-poisoning or undetermined non-natural cause (RR=9.76-8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79-7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio-cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All-cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001-0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all-cause and suicide-related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide-related mortality risk in incident schizophrenia samples. All-cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all-cause mortality (RR=1.62, 95% CI: 1.47-1.80, n=3). Antipsychotics were protective against all-cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59-0.84, n=11), with largest effects for second-generation long-acting injectable anti­psychotics (SGA-LAIs) (RR=0.39, 95% CI: 0.27-0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34-0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39-0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44-0.63, n=4). Antipsychotics were also protective against natural cause-related mortality, yet first-generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural-cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long-term maintenance antipsychotic treatment and appropriate/earlier use of SGA-LAIs and clozapine could reduce this mortality gap.

中文翻译：

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精神分裂症患者的死亡率：对相对风险和加重或减轻因素的系统评价和荟萃分析

精神分裂症患者过早死亡 15-20 年。了解死亡风险和加重/减弱因素对于缩小这一差距至关重要。我们对前瞻性和回顾性、全国性和有针对性的队列研究进行了系统回顾和随机效应荟萃分析，评估精神分裂症患者与一般人群或与身体合并症相匹配的群体或具有不同精神疾病的群体的死亡风险，同时评估调节因素。主要结果是全因死亡风险比（RR）；关键的次要结局是自杀和自然原因导致的死亡率。其他次要结局包括任何其他特定原因死亡率。进行了发表偏倚、亚组和元回归分析，以及质量评估（纽卡斯尔-渥太华量表）。在 1957 年至 2021 年的 135 项研究中（精神分裂症：N=4,536,447；一般人群对照：N=1,115,600,059；其他精神疾病对照：N=3,827,955），与任何非精神分裂症对照组相比，精神分裂症患者的全因死亡率均有所增加（RR=2.52, 95% CI: 2.38-2.68, n=79），首发（RR=7.43, 95% CI: 4.02-13.75, n=2）和事件（即更早-阶段）精神分裂症（RR=3.52, 95% CI: 3.09-4.00, n=7）与一般人群。自杀或损伤中毒或未确定的非自然原因死亡率最高（RR=9.76-8.42），其次是自然原因肺炎（RR=7.00，95% CI：6.79-7.23），通过感染或非自然原因死亡率降低。内分泌或呼吸或泌尿生殖系统或糖尿病原因（RR=3 至 4），酒精或胃肠道或肾脏或神经系统或心脑血管或所有自然原因（RR=2 至 3），以及肝脏或脑血管，或乳房或结肠或胰腺或任何癌症原因（RR=1.33 至 1.96）。中位研究年的全因死亡率略有增加，但显着增加（β=0.0009，95% CI：0.001-0.02，p=0.02）。与 40 岁以上的人相比，40 岁以下的精神分裂症患者的全因死亡率和自杀相关死亡率增加，并且在精神分裂症事件样本中，更高比例的女性增加了与自杀相关的死亡风险。事件中的全因死亡率高于普遍的精神分裂症（RR=3.52 vs. 2.86，p=0.009）。共病物质使用障碍增加了全因死亡率（RR=1.62，95% CI：1.47-1.80，n=3）。与不使用抗精神病药相比，抗精神病药对全因死亡率具有保护作用（RR=0.71，95% CI：0.59-0.84，n=11），对第二代长效注射抗精神病药（SGA-LAIs）的影响最大（RR= 0.39, 95% CI: 0.27-0.56, n=3)，氯氮平 (RR=0.43, 95% CI: 0.34-0.55, n=3)，任何 LAI (RR=0.47, 95% CI: 0.39-0.58, n =2) 和任何 SGA (RR=0.53, 95% CI: 0.44-0.63, n=4)。抗精神病药也可预防自然原因相关的死亡率，但第一代抗精神病药 (FGA) 与自杀和精神分裂症的自然原因导致的死亡率增加有关。更高的研究质量和用于调整分析的变量数量缓和了更大的自然原因死亡风险，并且最近的研究年份缓和了抗精神病药物的更大保护作用。这些结果表明，精神分裂症的高死亡率与几个可改变的因素有关。针对共病药物滥用、长期维持抗精神病药物治疗和适当/早期使用 SGA-LAI 和氯氮平可以减少这种死亡率差距。