Toxoplasma gondii associated with psychotic symptom load and cortisol in severe mental illness

Toxoplasma gondii (TG) is a prevalent parasite that establishes lifelong latency after primary infection. TG has been linked to severe mental illness (SMI), potentially through dopamine dysregulation in the brain. There is a bidirectional interaction between dopamine and the hypothalamic-pituitary-adrenal axis, where dopamine may influence cortisol regulation and cortisol may affect dopamine release. We hypothesised that TG would be associated with elevated circulatory cortisol levels, increased severity of psychotic symptoms, and structural brain aberrations in SMI. Our study included 765 patients with SMI (515 with schizophrenia spectrum disorders and 250 with bipolar disorders) and 541 healthy controls (HC). TG immunoglobulin G seropositivity and circulatory cortisol concentrations were measured with immunoassays, and T1-weighted MRI scans were processed using FreeSurfer. Psychotic symptom scores were evaluated using the Positive and Negative Syndrome Scale. In SMI, TG seropositivity was associated with higher cortisol levels (p = 0.002), but not in HC. Seropositive patients had lower total psychotic symptom scores (p = 0.006) than seronegative patients, driven by the schizophrenia subgroup (p = 0.002). This effect was observed for positive, negative, and general psychotic symptom scores, but only for patients with an illness duration of 10 years or more. In an exploratory analysis, TG seropositivity was nominally associated with smaller thalamus, nucleus accumbens, and middle temporal volumes in SMI, and with smaller fusiform, parahippocampal, and pars triangularis volumes in HC. In conclusion, TG exposure in SMI was linked to elevated cortisol levels and reduced psychotic symptom scores, suggesting that its impact on SMI may be more complex and context-dependent than previously assumed.