The anticonvulsant drug lamotrigine has been shown to produce antidepressant effects in patients with bipolar disorder. To date, only a few preclinical studies have been conducted using lamotrigine treatment in the forced swim test (FST), an animal model of depression with low face validity. The underlying mechanisms by which lamotrigine works have not been well characterized either. This study extends earlier work on the role of brain-derived neurotrophic factor (BDNF) in regulating the antidepressant actions of lamotrigine. We showed that in rats subjected to chronic unpredictable stress, chronic administration of 30 mg/kg lamotrigine ameliorates behavioural deficits of stressed rats in both sucrose preference test (SPT) and novelty-suppressed feeding test (NSFT). In parallel, chronic lamotrigine treatment up-regulates frontal and hippocampal BDNF protein expression in both naive and stressed animals, and restores the stress-induced down-regulation of BDNF levels. In addition, inhibition of BDNF signalling by infusion of K252a, an inhibitor of the BDNF receptor TrkB, blocks the antidepressant effects of lamotrigine in SPT, NSFT and FST. Taken together, this study provides further evidence that BDNF is an essential mediator for the antidepressant effects of lamotrigine.