Mechanism of Lithium's Mood-Stabilizing Effects
The specific biochemical mechanism by which lithium stabilizes mood in bipolar disorder remains unknown, though it alters sodium transport in nerve and muscle cells and shifts intraneuronal catecholamine metabolism. 1
What We Know About Lithium's Mechanism
The FDA-approved drug label explicitly states that "the specific biochemical mechanism of lithium action in mania is unknown." 1
Preclinical studies demonstrate that lithium alters sodium transport across nerve and muscle cell membranes, which may contribute to its therapeutic effects. 1
Lithium produces a shift toward intraneuronal metabolism of catecholamines (neurotransmitters including dopamine, norepinephrine, and epinephrine), though how this translates to mood stabilization is not fully understood. 1
Clinical Efficacy Despite Unknown Mechanism
Despite the unclear mechanism, lithium's clinical efficacy is well-established:
Lithium is the only mood stabilizer proven effective in preventing any mood episodes, manic episodes, and depressive episodes in randomized trials not enriched for prior lithium response. 2
Recent placebo-controlled three-arm trials have definitively demonstrated lithium's efficacy in moderate to severe manic episodes. 3
Lithium shows superior efficacy in preventing manic/hypomanic episodes (including mixed episodes) compared to preventing depressive episodes. 3
Long-term lithium therapy provides prophylactic benefits that are independent of any acute response to the medication. 4
Important Clinical Context
The American Academy of Child and Adolescent Psychiatry recommends lithium as a first-line treatment for acute mania/mixed episodes and maintenance therapy, with superior evidence for long-term efficacy. 5
Lithium is FDA-approved for bipolar disorder in patients age 12 and older. 5
Response rates for lithium in acute mania range from 38-62%. 5
Maintenance therapy with lithium must continue for at least 12-24 months, as withdrawal dramatically increases relapse risk within 6 months, with over 90% of noncompliant adolescents relapsing versus 37.5% of compliant patients. 5