Preprint Toxoplasma gondii as a Causal Factor in Schizophrenia: Evidence from Two Large Cohorts, 2025, Israel et al

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

Ariel Israel, Avi Weizman, Sarah Israel, Joshua Stokar, Shai Ashkenazi, Shlomo Vinker, Eli Magen, Eugene Merzon

Background
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, but the clinical significance of this association remains unclear.

Methods
Using electronic health records (EHRs) from a national health system, we systematically examined the impact of medication purchases and past medical conditions on SCZ risk. We compared 3,273 individuals diagnosed with SCZ over the past two decades with 32,730 matched controls, matched on gender, age, ethnicity, socioeconomic status, and year of enrollment. Key findings were validated in the TriNetX collaborative network, which includes over 117 million individuals in the U.S.

Results
In both cohorts, individuals with a history of atovaquone use within the decade preceding the index date had a significantly lower risk of SCZ (adjusted odds ratio = 0.26 in the first cohort and hazards ratio = 0.29 in the TriNetX cohort, both P < 0.001). A significant reduction in SCZ risk was also observed following clindamycin use, consistent with the known efficacy of both atovaquone and clindamycin against toxoplasmosis.

Discussion
Based on several strong epidemiological associations identified by this study, we propose a novel hypothesis for SCZ pathogenesis, in which persistent T. gondii colonization in the gut, combined with repeated self-inoculation 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 later developed SCZ had significantly lower exposure to medications known to eliminate T. gondii, suggesting a causative role for this pathogen and highlighting the potential preventive or therapeutic role of these medications in SCZ. The observed associations provide new insights into the mechanisms linking T. gondii to SCZ, opening novel avenues for future research on disease pathogenesis and intervention strategies.

Link | PDF (Preprint: MedRxiv) [Open Access]

 

Not sure how novel this hypothesis is as there are many other researchers active in this area:

https://www.stanleyresearch.org/pat...pproaches-to-toxoplasmosis-and-schizophrenia/

Interesting that some antipsychotics and mood stabilisers like Sodium Valpraote have anti-protozoal activity.

Another review:

https://www.science.org/content/article/reality-check-can-cat-poop-cause-mental-illness