Background: Previous reports have suggested that lamotrigine is effective as an antidepressant augmentation agent in patients with treatment- resistant unipolar depression. This study is the largest double-blind placebo-controlled study conducted to date of lamotrigine in this role. Method: In this multicenter trial, conducted at 19 sites, patients aged 18-65 years with a DSM-IV/ICD-10 diagnosis of unipolar, nonpsychotic major depressive disorder (confirmed by the Mini-International Neuropsychiatric Interview) who had failed at least 1 adequate trial of an antidepressant (N = 183) were first treated for 8 weeks with open-label paroxetine or paroxetine controlled-release in dosages up to 50 mg/d or 62.5 mg/d, respectively. Individuals with a 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 15 (n = 96) were then randomized on a doubleblind basis to receive either placebo or lamotrigine in dosages titrated upward to a maximum of 400 mg/d for 10 weeks. Sixty-five patients completed the study. The primary outcome measure was the Montgomery- Asberg Depression Rating Scale (MADRS), and the main secondary outcome measures were the HDRS-17 and Clinical Global Impressions-Severity of Illness (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) ratings. Data were collected from 2003 to 2006. Results: Results of the primary efficacy analysis of the randomized patients using the MADRS, HDRS-17, CGI-S, and CGI-I did not demonstrate a statistically significant difference between lamotrigine and placebo groups, although some secondary analyses were suggestive of efficacy, particularly in those patients who completed the study (completer analysis) and in more severely ill patients (HDRS-17 ≥ 25). Conclusions: This add-on study of patients with treatment-resistant depression failed to detect a statistically significant difference between lamotrigine and placebo given for 10 weeks. However, post hoc analyses suggest that future studies of lamotrigine's efficacy might focus on specific subgroups with depression. Trial Registration: clinicaltrials.gov Identifier: NCT00901407. © Copyright 2011 Physicians Postgraduate Press, Inc.