Creatine’s effects on brain energy metabolism raise the possibility of developing a new therapeutic strategy in depression focusing on the treatment of metabolic hypoactive brain areas. Previous creatine augmentation studies in patients with major depression showed a beneficial effect. Eighteen patients (14 women) with major depression not responding to previous 3 weeks of antidepressant treatment were enrolled into a pilot, dose finding, 4-week double-blind parallel augmentation study where creatine monohydrate 5 or 10 g daily or placebo was added to ongoing SSRIs/SNRIs/NASA treatment. Rating scales included the Hamilton Depression Rating Scale and the Clinical Global Impression Severity scale. Overall, there was no difference between creatine administered at 5 or 10 g daily and its corresponding placebos. Two female patients on creatine augmentation, but none on the placebo, showed early improvement of more than 50% reduction in Hamilton Depression Rating Scale after 2 weeks of creatine treatment. No clinically relevant side effects were reported. This preliminary study seems to suggest that the strategy using creatine augmentation in major depressive women showing no ‘real-life response’ to 3 weeks of treatment with SSRIs/SNRIs/NASA treatment is of no advantage compared with placebo. However, such creatine augmentation may still induce a more rapid response in a small subgroup of these female patients.