The Association of Kynurenine Pathway Metabolites with Neurocognitive Function in Unaffected Offspring of Parents with Bipolar Disorder

Introduction: The study aimed to investigate whether alterations in tryptophan (TRP) metabolites reflect dysregulation of the kynurenine pathway, which has been implicated in bipolar disorder (BD) and to examine their relationship with cognitive functioning by assessing TRP metabolite levels alongside executive performance in non-affected offspring of individuals diagnosed with BD. Methods: The study included 32 healthy offspring of parents with BD Type I as the case group and 31 healthy offspring of parents without any psychiatric disorders as controls. Psychiatric screening was conducted using the Turkish adaptation of the Schedule for Affective Disorders and Schizophrenia for School Age Children – Present and Lifetime Version (K-SADS-PL-DSM-5). Executive functioning was examined using a neuropsychological battery that included the Stroop, Serial Digit Learning (SDLT), and Cancellation (CT) tests. Serum levels of TRP, kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA), as well as metabolite ratios (KYN/TRP, KYNA/KYN, 3-HK/KYN, and KYNA/3-HK), were measured. Logistic regression analysis was applied as part of the statistical approach to evaluate whether these metabolites and ratios could distinguish the offspring of individuals with bipolar disorder from healthy controls. Results: Neurocognitive performance was significantly poorer in the case group than in the control group. Serum levels of TRP (t=3.568, p=0.001), KYN (t=3.772, p=0.001), KYNA (t=2.797, p=0.007), and the ratios of KYN/TRP (t=2.550, p=0.014) and KYNA/3-HK (z=-2.557, p=0.011) were significantly decreased in cases, whereas KYNA/KYN (t=-2.562, p=0.013) and 3-HK/KYN (z=-3.368, p=0.001) ratios were significantly elevated. Correlation analyses showed significant associations between executive function deficits and TRP (r=0.367, p=0.039), KYN (r=0.380, p=0.032), KYNA (r=0.488, p=0.005), 3-HK (r=0.492, p=0.004), and the 3-HK/KYN ratio (r=0.408, p=0.020). Logistic regression analysis indicated that lower KYN levels distinguished cases from controls (OR=0.986, 95% CI=0.978–0.995, p=0.002). Conclusions: The findings indicate that metabolism within the kynurenine pathway in the offspring of individuals with bipolar disorder shows a shift toward its neurotoxic branch, reflected by increased 3-HK/KYN ratios and decreased KYNA-related indices, and this was associated with deficits in executive functioning. These findings indicate that alterations in TRP metabolism may play a role in altered cognitive processing among individuals with a familial predisposition to BD. Further research employing larger cohorts and dimensional analyses is needed to elucidate these relationships more precisely.