Association of BDNF Val66Met polymorphism with clinical severity, cognitive function, and treatment response in schizophrenia

Abstract

The brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism has been implicated in neuroplasticity, cognitive performance, and variability in antipsychotic treatment response. However, evidence from Indonesian populations, particularly among individuals with schizophrenia from Aceh, remains limited. The aim of this study was to assess the association of BDNF Val66Met polymorphism with clinical symptom severity and cognitive function and to determine its association with clinical and cognitive outcomes after antipsychotic treatment. A prospective cohort study was conducted among Acehnese individuals with schizophrenia. Genotyping was performed using polymerase chain reaction–restriction fragment length polymorphism. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed using the Montreal Cognitive Assessment–Indonesian version (MoCA-INA) at Day 0, Day 14, and Day 42 post-therapy. Genotype–outcome associations were examined using genotype comparisons and genetic models. A total of 207 individuals with schizophrenia were analyzed. The Val/Met genotype was the most frequent genotype (52.2%), followed by Val/Val (28.0%) and Met/Met (19.8%). Baseline PANSS total score was significantly different across all genetic models, with the lowest symptom severity observed in the Val/Val group. In the dominant model, Met-allele carriers had higher PANSS total scores than Val/Val individuals (p<0.001). Baseline cognitive function also differed significantly, with Met-allele carriers showing lower MoCA-INA scores than Val/Val individuals (p<0.001). Clinical symptom improvement was consistently greater in Val/Val individuals, whereas Met-allele carriage was associated with smaller PANSS reductions at Day 14 and Day 42. For cognitive outcomes, Val/Val participants showed the greatest early improvement, while Met-allele carriers demonstrated slower initial recovery followed by later gains, resulting in more comparable cognitive improvement by Day 42 in some models. In conclusion, BDNF Val66Met polymorphism was significantly associated with clinical symptom severity, cognitive function, and treatment-related improvement among Acehnese individuals with schizophrenia. The Val/Val genotype was associated with a more favorable clinical and cognitive profile and stronger early clinical and cognitive response. These findings support the potential relevance of BDNF Val66Met as a population-specific biomarker for clinical stratification in schizophrenia, although further studies with longer follow-up and biological validation are warranted.