MTHFR and MTRR Polymorphisms Predict Sex-Dependent Psychotic Symptom Improvements, Not Metabolic Changes

We investigated whether antipsychotic treatment response was influenced by the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR), and A66G of methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR)-genes central to folate and homocysteine metabolism and methylation, pathways often altered in schizophrenia patients. To our knowledge, no study has examined associations of C677T and A1298C with changes in schizophrenia symptom severity after antipsychotic treatment, while studies on metabolic outcomes remain sparse and inconsistent. The MTRR A66G has been assessed only once for metabolic parameters-not symptom severity-and sex-stratified analyses are lacking for all polymorphisms. A total of 186 antipsychotic-naïve first-episode or nonadherent chronic psychosis patients and 242 controls were genotyped using PCR-RFLP. Clinical assessments-including Positive and Negative Syndrome Scale (PANSS) scores, PANSS factor scores, and metabolic parameters (fasting plasma lipids and glucose levels, and body mass index)-were conducted at baseline and after 8 weeks. Genotype and allele frequencies did not differ between patients and controls. Significant associations emerged only for symptom changes, specifically within PANSS factor domains, in a sex-dependent manner. Female MTHFR 1298-A allele carriers (AA and AC) showed greater improvement in PANSS negative factor scores, whereas male MTRR 66-G allele carriers (GG and AG) showed reduced improvement in PANSS cognitive factor scores. Effect sizes were strong to very strong, with relatively modest contributions. MTHFR A1298C and MTRR A66G have sex-dependent impacts on symptomatic improvement-but not metabolic outcomes-after antipsychotic treatment. Accordingly, folate-homocysteine genetic markers and sex-specific factors can guide the development of personalized antipsychotic treatment approaches.