Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms

Can J Psychiatry. 2003 Aug;48(7):440-8. doi: 10.1177/070674370304800703.


Objective: This systematic review examines the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depressive episodes. It also examines hypotheses on the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems, and proposes recommendations for future research.

Method: We searched the Medline computer database and the Cochrane Library for relevant original studies published in English from January 1966 to February 2003. The key words were as follows: lithium, augmentation strategies, lithium augmentation, major depression, refractory depression, treatment-resistant depression, neuroendocrinology, and serotonin.

Results: Of 27 prospective clinical studies published since 1981, 10 were double-blind, placebo-controlled trials, 4 were randomized comparator trials, and 13 were open-label trials. Five of 9 acute-phase placebo-controlled trials demonstrated that lithium augmentation had substantial efficacy. In the acute-treatment trials, the average response rate in the lithium group was 45%, and in the placebo group, 18% (P < 0.001). One placebo-controlled trial showed the efficacy of lithium augmentation in the continuation-phase treatment. Summarizing the open and controlled data, approximately 50% of patients responded to lithium augmentation within 2 to 6 weeks. Animal studies offer robust evidence that lithium augmentation increases 5-HT neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways.

Conclusions: Augmentation of antidepressants with lithium is the best-documented augmentation therapy in the treatment of refractory depression. Emerging data from animal studies suggest that the 5-HTergic system is involved in the augmentatory effect of lithium.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage*
  • Antidepressive Agents / adverse effects
  • Antimanic Agents / administration & dosage*
  • Antimanic Agents / adverse effects
  • Brain / drug effects*
  • Brain / physiopathology
  • Clinical Trials as Topic
  • Depressive Disorder, Major / diagnosis
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Drug Therapy, Combination
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiopathology
  • Lithium Compounds / administration & dosage*
  • Lithium Compounds / adverse effects
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiopathology
  • Serotonin / metabolism*
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology
  • Treatment Outcome


  • Antidepressive Agents
  • Antimanic Agents
  • Lithium Compounds
  • Serotonin