What is the mechanism of action of lithium in treating bipolar disorder?

Mechanism of Action of Lithium in Bipolar Disorder

Primary Mechanisms at the Molecular Level

Lithium exerts its mood-stabilizing effects primarily through inhibition of glycogen synthase kinase 3β (GSK-3β) and modulation of second messenger systems, particularly the phosphoinositide pathway, which dampens excessive excitatory neurotransmission and promotes neuroprotection. 1, 2

Direct Enzyme Inhibition

• Lithium directly inhibits GSK-3β at clinically relevant concentrations, which is considered one of its most important molecular targets for mood stabilization 2
• This inhibition reduces apoptotic processes and enhances cell survival pathways, contributing to lithium's neuroprotective properties 1, 2
• Lithium modulates the phosphoinositide (PI) second-messenger system, altering receptor-mediated activity and dynamic regulation of receptors coupled to this intracellular response 3, 4

Signal Transduction Pathways

• Lithium affects multiple components of signal transduction pathways, including G proteins, adenylyl cyclases, and protein kinase C (PKC) isozymes 4
• The modulation of the adenyl cyclase and phosphoinositide pathways serves to dampen excessive excitatory neurotransmission 1
• Lithium regulates the arachidonic acid and protein kinase C signaling cascades at therapeutic concentrations 3

Neurotransmitter System Modulation

Excitatory and Inhibitory Balance

• Lithium reduces excitatory neurotransmission mediated by dopamine and glutamate while simultaneously increasing inhibitory GABA neurotransmission 1
• These broad effects are achieved through complex compensatory changes in neurotransmitter systems that work to achieve homeostasis 1
• Lithium modulates serotonin release at presynaptic sites and affects receptor-mediated supersensitivity in the brain 3

Receptor-Level Effects

• Subtypes of muscarinic receptors in the limbic system represent particularly sensitive targets for lithium's effects on the PI second-messenger system 3
• The regulation of signal transduction within critical brain regions affects the function of multiple neurotransmitter systems simultaneously 4

Neuroprotective and Neurotrophic Effects

Cellular Protection Mechanisms

• Lithium increases protective proteins including brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) 1, 2
• It reduces oxidative stress that occurs with multiple episodes of mania and depression 1
• Lithium indirectly regulates factors involved in cell survival pathways, including cAMP response element binding protein (CREB), BDNF, Bcl-2, and mitogen-activated protein kinases (MAP kinases) 3

Structural Brain Changes

• Lithium preserves or increases the volume of brain structures involved in emotional regulation, including the prefrontal cortex, hippocampus, and amygdala 1
• These volumetric changes likely reflect lithium's neuroprotective effects and may contribute to its disease-modifying properties 1, 5
• The structural preservation occurs through mechanisms associated with neuronal plasticity 2

Gene Expression and Long-Term Effects

• Lithium significantly affects the regulation of gene expression in the central nervous system, which may play a major role in long-term mood stabilization 4
• These neurotrophic effects bring about delayed long-term beneficial effects that are under-appreciated but clinically significant 3
• The disease-modifying properties of lithium affect surrogate markers from the DNA and cellular levels to brain structure and function 5

Clinical Implications of Mechanism

• The anti-suicidal properties of lithium (reducing suicide attempts 8.6-fold and completed suicides 9-fold) may be related to its central serotonin-enhancing properties and are independent of its mood-stabilizing effects 6, 7
• Lithium's ability to modulate multiple interconnected neurotransmitter pathways explains its efficacy in protecting against spontaneous, stress-induced, and drug-induced cyclic affective episodes 4
• The sophisticated and inter-related processes underlying lithium's therapeutic actions suggest it functions as a disease-modifying agent rather than simply a symptomatic treatment 5

Important Caveats

• The precise mechanisms are not fully elucidated despite decades of research, and the therapeutic effects likely result from multiple inter-related processes rather than a single mechanism 1, 3
• The behavioral and physiological manifestations of bipolar disorder are mediated by a network of interconnected neurotransmitter pathways, making it difficult to isolate individual mechanisms 3
• Lithium's effects at therapeutic concentrations (0.8-1.2 mEq/L for acute treatment) are selective and clinically relevant, distinguishing it from non-specific effects at toxic doses 6, 3