Treatment-resistant depression affects up to 70% of patients. In our 8-week, randomized, open-label, prospective study of 34 treatment-resistant depression patients lamotrigine-add-on was compared with lithium-augmentation. Both treatments resulted in clinically significant reduction in Hamilton rating scale for depression score: mean Hamilton rating scale for depression-score declined from 22.7 (SD 3.9) to 11.7 (SD 4.2) in the lamotrigine group and from 21.5 (SD 3.8) to 13.3 (SD 5.7) in the lithium (Li) group. No significant differences were seen in Hamilton rating scale for depression scores between treatment groups at baseline (P=0.82) and after 8 weeks (P=0.11). Twenty-three percent of the lamotrigine group (n=4) and 18% (n=3) of the Li group achieved remission, 53% of the lamotrigine group (n=9) responded to treatment vs. 41% in the Li group (n=7) and 47% of the lamotrigine group (n=8) vs. 35% of the Li group (n=6) showed at least a partial response. Lamotrigine-augmentation was well tolerated. In conclusion, this study demonstrated that the add-on of lamotrigine to antidepressive medication revealed comparable results in most outcome measures as a lithium augmentation. Owing to small sample size no conclusions regarding similar efficacy can be drawn from our data. Larger trials that should include a placebo arm are needed to further investigate lamotriginés role in treatment-resistant depression.