Εffects of MTR and AS3MT variants on antipsychotic response: prospective evidence from a naturalistic study in Greece

Pharmacol Rep. 2025 Nov 7. doi: 10.1007/s43440-025-00802-w. Online ahead of print.

ABSTRACT

BACKGROUND: Schizophrenia and related psychotic disorders represent a major cause of global disability, while patients show wide variability in their response to antipsychotic therapy. Genetic variants in one-carbon metabolism (folate and vitamin B12-dependent), catecholamine degradation, and methylation pathways may influence symptom severity and treatment outcomes. This study aimed to assess whether polymorphisms in these pathways are associated with baseline symptomatology and treatment response in a naturalistic setting.

METHODS: In this prospective observational study, we examined common polymorphisms in methylenetetrahydrofolate reductase (MTHFR; rs1801133), methionine synthase (MTR; rs1805087), methionine synthase reductase (MTRR; rs1801394), catechol-O-methyltransferase (COMT; rs4680), and a variable number tandem repeat in arsenite methyltransferase (AS3MT) in relation to baseline symptoms and four-week treatment response in 163 patients with schizophrenia spectrum or other psychotic disorders. Symptoms were assessed with the Positive and Negative Syndrome Scale and the Calgary Depression Scale.

RESULTS: The COMT rs4680 polymorphism was associated with higher baseline severity of negative symptoms in methionine homozygotes and with greater reduction in depressive symptoms. The MTR rs1805087 polymorphism was significantly associated with improvement in positive symptoms, particularly in patients with higher baseline vitamin B12 levels, whereas the AS3MT variable number tandem repeat showed a nominal association with positive symptom improvement in patients with lower B12 levels. No significant effects were observed for MTHFR rs1801133 or MTRR rs1801394.

CONCLUSIONS: Polymorphisms in one-carbon metabolism, particularly MTR rs1805087, may predict positive symptom response under adequate vitamin B12 conditions, while AS3MT variation may influence outcomes at lower B12 levels. COMT rs4680 is linked to both negative symptom severity and improvement in depressive symptoms. Although limited by modest sample size, lack of dietary and homocysteine data, and inclusion of non-drug-naïve patients, these findings support the potential of genetic and metabolic profiling for personalized antipsychotic treatment.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:41201764 | DOI:10.1007/s43440-025-00802-w