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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Folate and homocysteine metabolism, crucial for methylation, are often altered in schizophrenia.
• The roles of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms, and methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G in antipsychotic treatment response are not well-established.
• Previous studies on these genetic markers and metabolic outcomes in schizophrenia are limited and inconsistent, with a lack of sex-stratified analyses.

Purpose of the Study:

• To investigate the influence of MTHFR (C677T, A1298C) and MTRR (A66G) polymorphisms on antipsychotic treatment response in schizophrenia patients.
• To examine the association of these genetic polymorphisms with changes in symptom severity and metabolic parameters.
• To conduct sex-stratified analyses to determine potential gender-specific effects.

Main Methods:

• Genotyping of MTHFR C677T, A1298C, and MTRR A66G polymorphisms using PCR-RFLP in 186 antipsychotic-naïve patients and 242 controls.
• Clinical assessments including Positive and Negative Syndrome Scale (PANSS) scores and factor scores were conducted at baseline and after 8 weeks.
• Metabolic parameters (fasting plasma lipids, glucose levels, and body mass index) were also assessed.

Main Results:

• No significant differences in genotype or allele frequencies were observed between patients and controls.
• Sex-dependent associations were found for symptom changes: female MTHFR A1298C A-allele carriers showed greater improvement in negative symptoms, while male MTRR A66G G-allele carriers showed reduced improvement in cognitive symptoms.
• These genetic polymorphisms did not show significant associations with changes in metabolic parameters.

Conclusions:

• MTHFR A1298C and MTRR A66G polymorphisms exert sex-dependent effects on symptomatic improvement in antipsychotic treatment for schizophrenia.
• These genetic markers, in conjunction with sex-specific factors, may inform the development of personalized antipsychotic treatment strategies.
• The study highlights the importance of considering genetic background and sex in optimizing schizophrenia treatment.