Adjunctive treatment of lamotrigine compared to other antidepressants in the treatment of partially responsive, poorly functioning patients with unipolar depression was assessed. Fourteen consenting patients with confirmed DSM-IV-R diagnosis of unipolar depression were identified as treatment resistant. All patients failed at least two 8-week treatment trials with antidepressants. All were treated with lamotrigine as an adjunct to other antidepressants for at least 6 months. The primary effectiveness measure was the Clinical Global Impression Severity subscale (CGI-S). Other scales included the Montgomery–Åsberg Depression Scale (MADRS) and the Global Assessment of Functioning Scale (GAF). Monitoring for skin rashes, headache, dizziness, somnolence, and gastrointestinal disturbances was carried out to assess for adverse events. Baseline measures prior to adding lamotrigine were compared to those at 8 weeks and 6 months with adjunctive treatment. Twelve patients of the total (n=14) completed the trial, and two discontinued treatment. There was significant, rapid, and robust resolution in symptoms in all effectiveness measures, including the core symptoms of depression, as shown by the changes from baseline in CGI-S, and MADRS at 8 weeks. Social and occupational functioning was significantly improved at 6 months. Eight patients returned to gainful employment or started schooling. Patients tolerated the adjunctive lamotrigine treatment well. Lamotrigine may have antidepressant properties in patients with unipolar depression and may have an earlier onset of action when given in combination with antidepressants. Depression and Anxiety 23:485–488, 2006. © 2006 Wiley-Liss, Inc.