OBJECTIVE: Lamotrigine's possible efficacy in the treatment of depressive disorders has been suggested. This naturalistic study investigated clinical response to lamotrigine augmentation in patients with treatment-resistant depression. Characteristics of the lamotrigine-responders were also explored. METHODS: Clinical data from 40 lamotrigine- treated patients with treatment-resistant unipolar depression were analyzed. The subjects were diagnosed with DSM-IV major depressive disorder and resistant to at least 2 antidepressants. Efficacy of lamotrigine treatment was measured by the changes in mean scores of the Clinical Global Impression Severity subscale (CGI-S), which were extracted from the prospective mood chart and structured interviews. Response was defined as a decrease of at least 2 or more from baseline on the CGI-S. Untoward effects associated with lamotrigine treatment were also assessed through medical records. RESULTS: Significant reduction in the CGI-S mean score was observed from baseline through 8 week lamotrigine augmentation in 40 patients with treatment-resistant unipolar depression (t=5.7, df=39, p<.01), and the magnitude of treatment effect was large (r(effect size)=0.68). Drop-outs were mainly attributable to lamotrigine-associated rash (N=5). Greater rate of improvement was associated with responder group (N=14) compared to non-responder group (N=17) from week 3 onward. CONCLUSION: The results of current study lend support to the potential benefit of lamotrigine augmentation in a subpopulation of patients with treatmentresistant unipolar depression. Continuation of lamotrigine add-on for more than 3 weeks may be needed to assess clinical outcome. Lamotrigine augmentation was generally well-tolerated. Large scale, double-blind studies are necessary to confirm its use as an augmentation agent.