BDNF/BDNF-AS Gene Polymorphisms Modulate Treatment Response and Remission in Bipolar Disorder: A Randomized Clinical Trial

<b>Background:</b> Bipolar disorder (BD) is a chronic condition associated with treatment resistance, cognitive decline, structural brain changes, and an approximately 13-year reduction in life expectancy compared to the general population. Depression in BD substantially impairs quality of life, while neuroinflammation and excitotoxicity are thought to contribute to the recurrence of mood episodes and disease progression. Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal growth and function, with its dysregulation being linked to various psychiatric disorders. This study is an extension of a previously published clinical trial and was conducted to assess the effects of three BDNF and BDNF-AS gene polymorphisms (rs1519480, rs6265, and rs10835210) on treatment outcomes and serum BDNF levels in patients with treatment-resistant bipolar disorder depression (TRBDD) over an eight-week period. <b>Methods:</b> This study included 41 participants from a previously conducted randomized clinical trial, all of whom had available BDNF serum samples and genotype data. The participants, aged 21 to 65, were diagnosed with bipolar disorder, and treatment-resistant depression was assessed using the Maudsley Staging Method. Participants were randomly assigned to receive either escitalopram plus a placebo (ESC+PBO) or escitalopram plus celecoxib (ESC+CBX) over an 8-week period. Statistical analyses included a mixed ANOVA and chi-square tests to compare the minor allele carrier status of three SNPs with treatment response and remission rates. <b>Results:</b> Non-carriers of the rs6265 A allele (<i>p</i> = 0.005) and carriers of the rs10835210 A allele (<i>p</i> = 0.007) showed a significantly higher response to treatment with adjunctive celecoxib compared to escitalopram alone. Additionally, remission rates after adjunctive celecoxib were significantly higher in both carriers and non-carriers across all three SNPs compared to escitalopram alone. However, remission rates were notably higher in non-carriers of the rs1519480 G allele and rs10835210 A allele, as well as in carriers of the rs6265 A allele. <b>Conclusions:</b> This study suggests that genetic variations in BDNF and BDNF-AS genes significantly influence treatment response to and remission with escitalopram and celecoxib in bipolar disorder.