Schizophrenia causes people to die 15-20 years earlier. To close this gap, it was critical to understand mortality risk and aggravating/attenuating variables. For a study, researchers performed a systematic review and random-effects meta-analysis of prospective and retrospective, nationwide, and targeted cohort studies comparing the risk of death in people with schizophrenia to the general population, groups matched for physical comorbidities, or groups with different psychiatric disorders, as well as moderators. The primary outcome was the all-cause mortality risk ratio (RR); significant secondary outcomes were suicide and natural causes of death. Other secondary outcomes included any other cause of death. The researchers investigated publication bias, subgroup and meta-regression analyses, and quality evaluation (Newcastle-Ottawa Scale). 

All-cause mortality was higher in people with schizophrenia versus any non-schizophrenia control group (RR=2.52, 95% CI: 2.38-2.68, n=79) in 135 studies spanning 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), with the highest 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. Suicide or injury-poisoning or an undetermined non-natural cause had the highest risk of death (RR=9.76-8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79-7.23), infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), alcohol or gastrointestinal or renal or nervous system or cardio-cerebrovascular or all-natural causes (RR=2 to 3), and liver or cerebrovascular, With each study year, all-cause mortality increased modestly but considerably (beta=0.0009, 95% CI:0.001-0.02, P=0.02). In incident schizophrenia samples, those under the age of 40 had greater all-cause and suicide-related mortality than those under the age of 40, and a higher percentage of females had a higher suicide-related mortality risk. In incident schizophrenia, all-cause mortality was greater than in prevalent schizophrenia (RR=3.52 vs. 2.86, P=0.009). All-cause mortality increased with comorbid drug use disorder (RR=1.62, 95% CI: 1.47-1.80, n=3). Antipsychotics were found to be protective against all-cause mortality (RR=0.71, 95% CI: 0.59-0.84, n=11), with the 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 Although antipsychotics were found to be protective against natural cause mortality, first-generation antipsychotics (FGAs) were linked to increased suicide and natural cause death in incident schizophrenia. 

Larger natural-cause mortality risk was tempered by higher research quality and the number of factors used to alter the analyses, while antipsychotics’ protective effects were moderated by a more recent study year. These findings suggested that higher mortality in schizophrenia was linked to a number of modifiable variables. The mortality disparity might be narrowed by focusing on concomitant drug misuse, long-term maintenance antipsychotic therapy, and appropriate/earlier use of SGA-LAIs and clozapine.