Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression

Ketamine has rapid antidepressant effects on treatment-resistant depression, but the biological mechanism underpinning this effect is less clear. Our aims were to examine whether kynurenine pathway metabolites were altered by six infusions of ketamine and whether these biological factors could act as potential biomarkers to predict ketamine's antidepressant effects. Six intravenous infusions of ketamine (0.5 mg/kg) were administered to 84 patients with unipolar and bipolar depression over a 12-d period. Symptom severity and response were assessed using the Montgomery-Asberg Scale (MADRS), and blood samples were collected at baseline and 24 h following the first infusion and at 24 h and 14 d after the sixth infusion (24 h, 13 d and 26 d). Blood samples from sixty healthy controls were collected for comparison with samples from the patients. Serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by the liquid chromatography-tandem mass spectrometry method. At baseline, serum levels of TRP and KYNA and the KYNA/KYN ratio were lower and the KYN/TRP ratio was greater in depressed patients than in healthy controls. Overall, fifty (59.5%) patients responded to ketamine at 13 d. Ketamine responders had a greater KYNA level and KYNA/KYN ratio than nonresponders at 24 h and 13 d (all P 0.05). Elevations in the KYNA levels and KYNA/KYN ratio at 24 h were significantly associated with reductions in MADRS scores at 24 h, 13 d and 26 d in the linear regression analysis (all P 0.05). Our results showed a possible involvement of the kynurenine pathway in the rapid antidepressant effect of ketamine. Early changes in serum KYNA levels and the KYNA/KYN ratio could be potential predictors of antidepressanteffects of repeated ketamine administration.