engleski

Association of MHTFR genotypes and executive functions in patients with the first-episode psychosis

Background: Schizophrenia has a heterogeneous clinical presentation with symptoms usually divided into five clusters: positive, negative, affective, psychomotor and cognitive. As neurocognitive impairment forms during the period of neurodevelopment, these symptoms are often regarded as the “core” symptoms of schizophrenia and are presumed to have the strongest genetic predisposition. In comparison with other symptoms, neurocognitive symptoms have a strong impact on the overall treatment outcome, but seem to be relatively resistant to current therapeutic methods. Various neurocognitive impairments are pointed out as the most problematic in terms of achievement of stable functional remission and positive treatment outcome. Previous studies tried to find potential pharmacogenetic markers that could serve as predictor of treatment response. Methylenetetrahydrofolate reductase (MTHFR) gene was previously associated with schizophrenia, metabolic risk and side-effects, neurocognitive functions (especially executive functions), but it also showed potential as a treatment outcome marker. The aim of our study was to investigate the association of MHTFR C677T polymorphisms with treatment response measured by changes in executive functioning in patients with first-episode psychosis (FEP). Methods: We performed a longitudinal, prospective cohort study with the sample of previously untreated patients with FEP recruited from two Croatian psychiatric clinics between year 2014 and year 2017. Patients were assessed with neurocognitive tests for the assessment of executive functioning at baseline and after 18 months of follow-up. Genotyping of blood samples was preformed according to usual practice. Associations of baseline neurocognitive tests with genotypes and baseline with follow-up neurocognitive tests were done using ANOVA. A test for Hardy–Weinberg equilibrium using Markov chain method was performed, using the Genepop software. Results: Out of 159 initially recruited patients with FEP, 30 were lost to follow-up and seven refused to give blood samples for genotyping so we analyzed the data for 122 patients with FEP. Our results showed statistically significant associations of MTHFR C677T variants and neurocognitive tests assessing executive functions. Patients with FEP who were the carriers of the MTHFR C677T risk alleles (TT) had significantly worse baseline results of the Clock Drawing Test (F=6.72, p=0.03). For changes in the neurocognitive tests’ results, the carriers of the risk alleles showed significantly better treatment response for tests measuring executive functions: the Clock Drawing Test (F=7.82, p=0.02) and the Trial Making Test B (F=6.46, p=0.04). We did not find other statistically significant associations. Conclusions: Although we included relatively small sample for a pharmacogenetic study (N=122), this study has three major strengths. First, we included patients who were previously not treated with pharmacotherapy. Second, the sample is homogeneous regarding age, age of starting the treatment and treatment duration. Third, patients were followed-up during a longer period of time, sufficient for the assessment of long-term outcome and recovery achievement. In conclusion, our study showed that MHTFR C677T polymorphism could be considered as a possible marker of treatment response in FEP measured with neurocognitive symptoms, or more specifically, with executive functioning.

MTHFR ; genotyping ; first-episode psychosis ; follow-up ; executive functions

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