Patient selection and 1:1 exact matching

A representative sample cohort of patients with psychotic disorders was constructed using the KNHIS database. From all individuals who had been first diagnosed with a psychotic disorder (schizophrenia, schizoaffective disorder, schizotypal disorder, and/or delusional disorder, ICD-10 codes F20–29) between 2003 and 2017, a representative sample cohort comprised of 20% of the total was randomly selected using systematic stratified random sampling with proportional allocation within each stratum. The strata were established based on sex, age, residential region, and household income level. In this sample population with claims for psychotic disorder, 112,491 individuals who were prescribed antipsychotics between 2003 and 2017 were selected. The incidence date of psychotic disorder was determined as the date when the antipsychotics were prescribed for the first time in individuals with psychotic disorder. For comparison, a representative 20% sample cohort was constructed of healthy controls (n=405,111) who had never been diagnosed for major psychiatric disorders (depression, bipolar disorder, and/or psychotic disorder) between 2002 and 2018 after systematic stratified random sampling based on sex, age, residential region, and household income level. The index date (baseline) was defined as the incidence date of psychotic disorder for individuals with psychotic disorders, and as January 1, 2003 for those without major psychiatric disorders. Among the sample population with psychotic disorders treated with antipsychotics and subjects without any major psychiatric disorder, individuals with missing data in at least one variable, those who died within 90 days after baseline, those who had, before or within 3 months after baseline, claims with codes for diabetes (E10–14), obesity (E66), dyslipidemia (E78), hypertension (I10–15), atherosclerosis (I70), aortic aneurysm and dissection (I71–72), arterial embolism and thrombosis (I74), heart failure (I50), ischemic heart disease (I20–25), or cerebrovascular disease (I61–69), subjects who underwent coronary artery bypass graft operation, percutaneous transluminal coronary angioplasty, percutaneous coronary intervention, or thrombolytic treatment before or within 3 months after baseline, those who had claims for transient ischemic attack (G45) during admission before or within 3 months after baseline, and individuals aged <18 years at baseline were excluded (Supplementary Fig. 1). Finally, 357,382 adults without any metabolic or cardiovascular disease were selected; 48,250 were individuals with psychotic disorders treated with antipsychotics and the remaining 309,132 had never been diagnosed with major psychiatric disorders. Exact 1:1 matching based on age and sex was applied for individuals with psychotic disorders and those without major psychiatric disorders. Finally, 48,162 individuals with psychotic disorders and 48,162 matched control participants without major psychiatric disorders were selected for analysis (Supplementary Fig. 1).