The Role of Lithium in the Body
Lithium plays a crucial role in the body as a neuroprotective and neurotrophic agent that regulates neurotransmission, inhibits glycogen synthase kinase 3β (GSK3β), and enhances cellular resilience through multiple pathways.
Physiological and Therapeutic Functions
Neurological Effects
- Lithium inhibits glycogen synthase kinase 3β (GSK3β), a key enzyme that regulates multiple cellular processes 1
- It upregulates neurotrophins including brain-derived neurotrophic factor (BDNF), nerve growth factor, and neurotrophin-3 in the brain 1
- Stimulates proliferation of stem cells, including neural stem cells in the subventricular zone, striatum, and forebrain 1
- Increases brain cell density and volume in patients with bipolar disorders 1
- Enhances brain concentrations of neuronal markers n-acetyl-aspartate and myoinositol 1
Neurotransmitter Regulation
- Reduces excitatory neurotransmission (dopamine and glutamate) 2
- Increases inhibitory neurotransmission (GABA) 2
- Alters sodium transport in nerve and muscle cells 3
- Shifts toward intraneuronal metabolism of catecholamines 3
Neuroprotective Properties
- Remarkably protects neurons against glutamate, seizures, and apoptosis due to various neurotoxins 1
- Reduces oxidative stress that occurs with multiple episodes of mania and depression 2
- Increases protective proteins such as BDNF and B-cell lymphoma 2 2
- Reduces apoptotic processes through inhibition of GSK3β and autophagy 2
Clinical Applications
Bipolar Disorder Management
- FDA-approved for treatment of manic episodes and maintenance therapy in bipolar disorder 3
- Normalizes manic symptomatology within 1-3 weeks 3
- Reduces frequency and intensity of manic episodes when used as maintenance therapy 3
- Effective in treating acute manic, mixed, and depressive episodes 4
Suicide Prevention
- Uniquely effective in reducing suicide risk in mood disorders 5
- Maintenance treatment reduces suicide attempts 8.6-fold in adults with bipolar or other major affective disorders 5
- Discontinuation of lithium increases suicide attempts 7-fold and completed suicide 9-fold 5
- Anti-suicidal effects may be due to its central serotonin-enhancing qualities 5
Emerging Applications
- Low-dose lithium (≤0.5 mM) may benefit cardiovascular, musculoskeletal, metabolic, and cognitive function 6
- Shows potential for treating neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's diseases 7, 4
- May reduce cognitive decline through its neuroprotective effects 2
Pharmacokinetics and Dosing
Absorption and Distribution
- Rapidly and completely absorbed from the gastrointestinal tract after oral administration 7
- Initially highest in serum before redistribution to various tissue compartments 7
- Not metabolized; over 95% excreted unchanged through the kidneys 7
Therapeutic Window and Monitoring
- Effective dose range: 0.6-1.0 mM in serum 1
- Narrow therapeutic window requiring careful monitoring 7
- Levels >1.5 mM may cause mild and reversible toxic effects on kidney, liver, heart, and glands 1
- Levels >2.0 mM may cause neurological symptoms including cerebellar dysfunction 1
- Prolonged intoxication >2.0 mM can cause permanent brain damage 1
Clinical Considerations and Cautions
Safety Profile
- Low mutagenic and carcinogenic risk 1
- Requires careful third-person supervision in children and adolescents as overdoses may be lethal 5
- When prescribing for suicidal patients, consider risk of overdose 5
Special Populations
- The only agent with FDA approval for bipolar disorder in youths (age 12 years and older) 5
- Studies in children and adolescents are limited by small sample sizes and diagnostic variability 5
- Questions remain about ongoing efficacy in adolescents due to high relapse rates in some studies 5
By understanding lithium's complex mechanisms of action in the body, clinicians can better appreciate its therapeutic value beyond its traditional role in bipolar disorder management, while remaining vigilant about its narrow therapeutic window and potential toxicity.