Mechanism of Action of Lithium in Bipolar Disorder
Primary Mechanism
Lithium's specific biochemical mechanism of action in treating bipolar disorder remains unknown, though it alters sodium transport in nerve and muscle cells and shifts intraneuronal catecholamine metabolism. 1
Established Molecular Targets
Direct Enzyme Inhibition
Glycogen synthase kinase-3β (GSK3β) inhibition represents the most well-established mechanism, with this pathway mediating neuroprotective, anti-oxidative, and neurotransmission effects that likely underlie lithium's therapeutic benefits. 2, 3
Lithium directly inhibits inositol monophosphatase at clinically relevant concentrations, potentially altering the phosphatidylinositol (PI) second-messenger system and affecting receptor-mediated activity and dynamic regulation. 4, 5
Neurotransmitter Modulation
Lithium modulates serotonin release at presynaptic sites and affects receptor-mediated supersensitivity in the brain, particularly targeting muscarinic receptor subtypes in the limbic system. 4
Chronic lithium administration upregulates glutamate reuptake, decreasing synaptic glutamate availability, which may contribute to antimanic effects by reducing excitatory neurotransmission. 6
Neuroprotective and Neurotrophic Pathways
Cell Survival Mechanisms
Lithium indirectly regulates multiple factors involved in cell survival pathways, including cAMP response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), bcl-2, and mitogen-activated protein kinases (MAPK). 4
Lithium induces increases in the anti-apoptotic factor Bcl-2, producing delayed long-term beneficial effects through neurotrophic mechanisms that enhance neuronal plasticity. 4, 3
Signal Transduction Cascades
Lithium regulates the arachidonic acid signaling cascade and protein kinase C (PKC) pathways, affecting multiple downstream cellular processes. 4
These effects on second messenger systems and signal transduction contribute to lithium's ability to modulate neuronal function at the molecular level. 4
Clinical Translation
The therapeutic manifestations result from lithium's ability to modulate interconnected neurotransmitter pathways and cellular mechanisms, though the precise translation from molecular changes to clinical mood stabilization remains incompletely understood. 4, 2
Recent research demonstrates that lithium-induced cellular changes correlate with structural brain findings and behavioral modifications, though neural circuitry mechanisms in bipolar disorder require further elucidation. 2
Important Caveats
Many proposed mechanisms (such as GSK3β inhibition) occur at concentrations that may be more relevant to lithium's toxic effects than therapeutic effects, complicating interpretation of their clinical relevance. 6
The inositol depletion hypothesis, while supported by rodent data, may be less applicable to primates and humans due to higher baseline inositol levels. 6
Some lithium effects (such as PAP phosphatase accumulation) occur predominantly in peripheral tissues rather than brain, potentially explaining peripheral side effects rather than central therapeutic actions. 6