Systematic screening identifies medication and disease factors associated with schizophrenia risk.

Schizophrenia (SCZ) is a severe psychiatric disorder with a complex and poorly understood etiology. Previous studies have linked Toxoplasma gondii infection to SCZ, though its clinical relevance remains uncertain. To identify factors associated with SCZ risk, we analyzed electronic health records from a national Israeli health provider, retrospectively comparing 3,273 individuals with SCZ to 32,730 matched controls. We systematically screened all medication purchases and medical diagnoses recorded from 10 years to 30 days before SCZ onset. Significant associations, adjusted for residual confounding, were further evaluated in the TriNetX network, where large propensity score-matched cohorts were compared for incident SCZ following medication exposure. Among all medication classes screened, strong protective associations were detected for specific antimicrobials, notably atovaquone/proguanil, clindamycin, and ophthalmic fluoroquinolones. Nonsteroidal anti-inflammatory drugs, particularly COX-2 inhibitors, were also linked to reduced SCZ risk, whereas neomycin, tramadol, and desmopressin were associated with increased risk. Key associations were confirmed within TriNetX with high statistical significance. These observational findings, reproduced across two national cohorts, are hypothesis-generating and may reflect multiple, non-exclusive mechanisms, including antimicrobial, anti-inflammatory, and microbiome-related pathways, with T. gondii elimination through antiprotozoal activity representing one compelling explanatory hypothesis that warrants further investigation.