Mechanism of Action of Lithium
Primary Molecular Targets
Lithium exerts its therapeutic effects primarily through direct inhibition of glycogen synthase kinase 3 (GSK3α and GSK3β) and inositol monophosphatase, achieved by displacing magnesium as the normal cofactor in these enzymatic pathways. 1, 2, 3
Direct Enzyme Inhibition
- Lithium directly inhibits GSK3 by displacing magnesium, a vital cofactor for numerous signaling pathways, leading to downstream neuroprotective and mood-stabilizing effects 2, 3
- Lithium inhibits inositol monophosphatase within the phosphatidylinositol signaling pathway through uncompetitive inhibition, disrupting receptor-mediated phosphoinositide signaling 3, 4
- The FDA label confirms that lithium alters sodium transport in nerve and muscle cells and effects a shift toward intraneuronal metabolism of catecholamines, though the specific biochemical mechanism in mania remains incompletely understood 1
Effects on Neurotransmitter Systems
- Lithium reduces excitatory neurotransmission (dopamine and glutamate) while increasing inhibitory neurotransmission (GABA), achieving homeostasis through compensatory changes in complex neurotransmitter systems 5
- Lithium acts on dopamine receptor-regulated signaling complexes composed of Akt, protein phosphatase 2A, and beta-arrestin 2 (βArr2), providing an additional mechanism for behavioral regulation 2, 6
- The American Academy of Neurology and Psychiatry suggests that lithium reduces aggression and impulsivity while regulating stress response, contributing to anxiety symptom improvement 7
Second Messenger System Modulation
- Lithium dampens excessive excitatory neurotransmission by targeting the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C (PKC) 5
- Long-term lithium administration regulates PKC isozymes and activity, along with expression of the major PKC substrate MARCKS (myristoylated alanine-rich C-kinase substrate) 4
- Lithium regulates inositol transport and subsequent downstream signaling cascades that modulate neuronal excitability 4
Neuroprotective Mechanisms
- Lithium increases protective proteins including brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2), while reducing apoptotic processes through GSK3 inhibition and autophagy modulation 5
- Lithium reduces oxidative stress that occurs with multiple episodes of mania and depression, providing cellular protection during mood episodes 5
- Lithium preserves or increases the volume of brain structures involved in emotional regulation including the prefrontal cortex, hippocampus, and amygdala, possibly reflecting its neuroprotective effects 5
Unique Anti-Suicidal Properties
- The National Institute of Mental Health recognizes that lithium possesses unique anti-suicidal properties that are independent of its mood-stabilizing effects, setting it apart from other agents 7, 5
- L'American Academy of Child and Adolescent Psychiatry suggests that lithium significantly reduces (8.6-fold) the risk of suicide attempts in patients with bipolar disorder or other major affective disorders 8
Clinical Implications of Complex Mechanisms
- The therapeutic actions of lithium involve sophisticated and inter-related processes operating at multiple levels, from macroscopic changes in mood and brain structure to microscopic effects on neurotransmission and molecular pathways 5
- Lithium's regulation of GSK3 within a signaling network involving multiple molecular targets and cell surface receptors (G protein coupled receptors and receptor tyrosine kinases) may explain its relative pharmacological selectivity and effects on disease mechanisms 2
- Understanding these intricate actions at a systems level may allow rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and fewer side effects 2