Toxoplasma gondii as a Causal Factor in Schizophrenia: Evidence from Two Large Cohorts
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Schizophrenia (SCZ) is a debilitating psychiatric disorder with a complex and poorly understood etiology. Numerous studies have reported a high prevalence of Toxoplasma gondii -specific immunoglobulins in SCZ patients, indicating past infection, yet the clinical significance of this association remains unclear.
Methods
We investigated the impact of medication purchases and past medical conditions on SCZ risk in two large cohorts. In a national cohort, we compared 3,273 individuals diagnosed with SCZ to 32,730 matched controls, adjusting for gender, age, ethnicity, socioeconomic status, and year of enrollment. Key findings were validated prospectively on the U.S. TriNetX collaborative network, which includes over 117 million individuals.
Results
In both cohorts, individuals who used atovaquone had a significantly lower risk of developing SCZ over the next decade (adjusted odds ratio = 0.26 in the national cohort; hazard ratio = 0.29 in the TriNetX cohort, both P < 0.001). A similar reduction in SCZ risk was observed with clindamycin use, consistent with the known efficacy of both atovaquone and clindamycin against T. gondii .
Discussion
Based on new epidemiological associations identified by this study, we propose a novel hypothesis for SCZ pathogenesis, in which persistent T. gondii colonization in the microbiome, combined with prolonged dissemination into the central nervous system due to an impaired immune response, liver function, and/or alterations in the skin microbiome, may contribute to SCZ development in genetically susceptible individuals.
Conclusion
Individuals who received medications known to target T. gondii had significantly lower SCZ risk, suggesting a causative role for this pathogen and highlighting potential preventive or therapeutic roles for these medications in SCZ. The observed associations provide new insights into the mechanisms linking T. gondii to SCZ, opening novel avenues for research and intervention strategies.
