Toxoplasma gondii as a Causal Factor in Schizophrenia: Evidence from Two Large Cohorts

Schizophrenia (SCZ) is a severe psychiatric disorder with a complex and poorly understood etiology. Previous studies have linked Toxoplasma gondii infection to SCZ, yet its clinical relevance remains unclear. In this study, we systematically screened all medication purchases and medical diagnoses recorded from 10 years to 30 days before SCZ diagnosis to identify factors associated with altered SCZ risk. Using electronic health records spanning over two decades from a national health provider, we retrospectively compared 3,273 SCZ patients with 32,730 controls matched for demographics, socioeconomic status, ethnicity, and year of enrollment. Statistical tests were adjusted for multiple comparisons using a false discovery rate (FDR), with significant associations (FDR<10%) further evaluated in multivariable models to account for residual confounding. Although the analysis included all medication classes, agents targeting T. gondii emerged as the most strongly protective, most notably atovaquone/proguanil, clindamycin, and ophthalmic fluoroquinolones. Protective effects were also observed for agents known to reduce neuroinflammation, such as nonsteroidal anti-inflammatory drugs (NSAIDs), particularly COX-2 inhibitors. In contrast, increased SCZ risk was associated with several other compounds, including neomycin, tramadol, and desmopressin. These findings were validated in the U.S.-based TriNetX research network (>120M individuals), with prospective survival analyses of propensity score-matched cohorts, selected by historical medication exposure, confirming key associations with high statistical significance (P<0.0001). These findings support the hypothesis that T. gondii induced neuroinflammation may contribute to SCZ pathogenesis and suggest that targeted antiparasitic and anti-inflammatory interventions could offer therapeutic potential. Further studies are warranted to explore the clinical relevance of these associations.