Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder

Objectives: Kynurenic acid (KYNA), an end metabolite of tryptophan degradation, antagonizes glutamatergic and cholinergic receptors in the brain. Recently, we reported elevated levels of cerebrospinal fluid (CSF) KYNA in male patients with bipolar disorder. Here, we investigate the relationship between symptomatology and the concentration of CSF KYNA in patients with bipolar I disorder. Methods: CSF KYNA levels from euthymic male {n = 21; mean age: 41 years [standard deviation (SD) = 14]} and female [n = 34; mean age: 37 years (SD = 14)] patients diagnosed with bipolar I disorder were analyzed using high-performance liquid chromatography (HPLC). Results: Euthymic bipolar I disorder patients with a lifetime occurrence of psychotic features had higher CSF levels of KYNA {2.0 nM [standard error of the mean (SEM) = 0.2]; n = 43} compared to patients without any history of psychotic features [1.3 nM (SEM = 0.2); n = 12] (p = 0.01). Logistic regression, with age as covariate, similarly showed an association between a history of psychotic features and CSF KYNA levels [n = 55; odds ratio (OR) = 4.9, p = 0.03]. Further, having had a recent manic episode (within the previous year) was also associated with CSF KYNA adjusted for age (n = 34; OR = 4.4, p = 0.03), and the association remained significant when adjusting for a lifetime history of psychotic features (OR = 4.1, p = 0.05). Conclusions: Although the causality needs to be determined, the ability of KYNA to influence dopamine transmission and behavior, along with previous reports showing increased brain levels of the compound in patients with schizophrenia and bipolar disorder, may indicate a possible pathophysiological role of KYNA in the development of manic or psychotic symptoms.