Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study

J Affect Disord. 2009 Nov;118(1-3):187-95. doi: 10.1016/j.jad.2009.02.014. Epub 2009 Mar 10.


Background: One 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.

Methods: A 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.

Results: No 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.

Conclusion: Zinc 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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents, Tricyclic / administration & dosage*
  • Antidepressive Agents, Tricyclic / adverse effects
  • Depressive Disorder, Major / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Resistance
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Humans
  • Imipramine / administration & dosage*
  • Imipramine / adverse effects
  • Male
  • Middle Aged
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Treatment Outcome
  • Zinc / administration & dosage*


  • Antidepressive Agents, Tricyclic
  • Receptors, N-Methyl-D-Aspartate
  • Zinc
  • Imipramine