Objectives of the study: 1) to assess the efficacy of zinc supplementation in the hastening and augmentation of the response to imipramine (IMI), 2) to assess if the serum zinc is a marker of depression. A double blind study was conducted in 60 (18-55-year old), unipolar, moderately or severely depressed patients (ICD-10 criteria), randomized into two groups treated with IMI (100-200 mg daily) + placebo (n=30) or IMI + zinc hydroaspartate (0.15g daily); (one week washout period + 12 weeks of active treatment). The efficacy of antidepressant therapy was assessed by: BDI, HORS, MADRS, CGI. Staging of depression based on prior treatment response was made according to treatment resistant criteria by Thase and Rush. In depressed patients and in a group of healthy volunteers (n=25) blood samples were drawn for the assay and comparison of serum zinc. Comparison between whole groups of patients revealed no superiority of zinc supplementation over placebo. However comparison between the subgroups of patients scored before entering the trial as stage ≥1 of drug resistance revealed: I )significantly higher ratio of remitters or treatment responders and significantly greater reduction of BDI, HADRS and MADRS scores in the zinc treated group (n=l3) than in placebo group (n=11), after 12 weeks of treatment. Serum zinc level was: l)significantly lower in acute depressed patients than in healt ; hy volunteers, 2) inversely correlated with staging of prior treatment non-response, 3) significantly rose and normalized in treatment responders or remitters. There was no significant correlation between serum zinc and CGI, BDI, HADRS or MADRS scores.