BACKGROUNDOne of the main problems in the therapy of depression is the limited efficacy of antidepressants and the limited utility of augmentation strategies. Zinc, a non competitive NMDA receptor antagonist exhibits preclinical antidepressant efficacy. Moreover, a preliminary clinical report suggests augmentation of antidepressant therapy by zinc in depression.METHODSA placebo-controlled, double blind study of zinc supplementation in imipramine therapy was conducted in sixty, 18-55-year old, unipolar depressed patients fulfilling the DSM-IV criteria for major depression without psychotic symptoms. After a one week washout period, patients were randomized into two groups treated with imipramine (approximately 140 mg/day) and receiving once daily either placebo (n=30) or zinc supplementation (n=30, 25 mgZn/day) for 12 weeks.RESULTSNo significant differences in CGI, BDI, HADRS and MADRS scores were demonstrated between zinc-supplemented and placebo-supplemented antidepressant treatment non-resistant patients. However, zinc supplementation significantly reduced depression scores and facilitated the treatment outcome in antidepressant treatment resistant patients.CONCLUSIONZinc supplementation augments the efficacy and speed of onset of therapeutic response to imipramine treatment, particularly in patients previously nonresponsive to antidepressant pharmacotherapies. These data suggest the participation of disturbed zinc/glutamatergic transmission in the pathophysiology of drug resistance.