Augmentation of effect of venlafaxine by folic acid in behavioral paradigms of depression in mice: Evidence of serotonergic and pro-inflammatory cytokine pathways

BackgroundThough venlafaxine is an antidepressant with similar efficacy as selective serotonin receptor inhibitors, dose dependent adverse effects limit its use. Depression is associated with increased levels of pro-inflammatory cytokines.MethodsThe study investigated the effect of combining low/serotonergic dose of venlafaxine with folic acid in mice exposed to chronic forced swim stress for 21 days during which immobility and swimming time following forced swim test (FST) and immobility time in tail suspension test (TST) were measured every 7th, 14th and 21st day. The serum level of pro-inflammatory cytokines (IL-1β and IL-6) and whole brain levels of monoamines (serotonin, norepinephrine and dopamine) were estimated.ResultsAn augmentation of antidepressant effect was observed in both forced swim test and tail suspension test following combination of venlafaxine (2 and 4 mg/kg) with folic acid (5 and 10 mg/kg) after 14 and 21 days of treatment. On brain serotonin level also, a significant augmentation was observed when venlafaxine (4 mg/kg) was combined with folic acid (10 mg/kg). Further, the combination significantly reversed the elevated levels of serum pro-inflammatory cytokines, IL-1β and IL-6 observed in chronic FST-induced stressed mice.ConclusionsCombining low dose venlafaxine with an augmenting agent like folic acid, thus, appears to be an optimum strategy to increase its therapeutic efficacy and to reduce its dose.