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


METHODS
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.
Bauer
Michael
M
Department of Psychiatry and Psychotherapy, Charité University Hospital, Humboldt-University at Berlin, Schumannstr. 20/21, 10117 Berlin, Germany. michael.bauer@charite.de
Adli
Mazda
M
Baethge
Christopher
C
Berghöfer
Anne
A
Sasse
Johanna
J
Heinz
Andreas
A
Bschor
Tom
T
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018692:Antimanic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002986:Clinical Trials as Topic; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D018020:Lithium Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome
D000928:Antidepressive Agents; D018692:Antimanic Agents; D018020:Lithium Compounds; D012701:Serotonin