Activation of indoleamine 2, 3- dioxygenase pathway by olanzapine augments antidepressant effects of venlafaxine in mice.

Recent clinical studies report antipsychotics as a better option to augment the action of antidepressants in treatment resistant cases. However, the proper mechanisms underlying the antidepressant effect of antipsychotics is still not clear. Indolamine 2, 3 dioxygenase (IDO) pathway is considered to be an important pathway in pro-inflammatory cytokine associated stress-induced depression. The present study investigated the antidepressant effect of venlafaxine, olanzapine and their combinations in chronic forced-swim stress-induced depression in mice. In addition, the role of pro-inflammatory cytokines and IDO-mediated pathway was investigated. Swiss albino mice were subjected to chronic forced-swim stress and evaluation for antidepressant-like activity was performed on 7th, 14th and 21st day following which serum levels of pro-inflammatory cytokines (IL-1β and IL-6 levels) and the levels of hippocampal kynurenine (KYN), tryptophan (TRP) and serotonin (5HT) were estimated. The combination exhibited augmentation of antidepressant-like activity of venlafaxine by olanzapine in chronic forced-swim stress model. Further, it reversed the enhanced serum IL-1β and IL-6 and reverted the increased activity of IDO as measured by ratio of hippocampal KYN/TRP and 5HT/TRP in stressed mice. Augmentation of antidepressant effect of venlafaxine by olanzapine is thus mediated by normalising the shift from KYN to TRP pathway in chronic forced swim induced stressed mice.