From the Guidelines
Lithium's primary mechanism of action involves stabilizing mood by inhibiting the enzyme inositol monophosphatase, which disrupts the phosphatidylinositol cycle and reduces excessive neuronal excitation. This action is crucial in understanding how lithium greatly reduces the rate of both suicides and suicide attempts in adults with bipolar disorder, as noted in the practice parameter for the assessment and treatment of children and adolescents with suicidal behavior 1.
Key Mechanisms of Lithium
- Inhibition of inositol monophosphatase, disrupting the phosphatidylinositol cycle
- Modulation of neurotransmitters like serotonin, dopamine, and glutamate
- Enhancement of neuroprotective factors and reduction of inflammation in the brain
- Regulation of calcium signaling and inhibition of glycogen synthase kinase-3 (GSK-3), playing a role in neuronal function and cell survival
Clinical Considerations
- Lithium is typically prescribed at doses between 600-1200 mg daily for bipolar disorder
- Blood levels should be maintained between 0.6-1.2 mEq/L for therapeutic effect
- Regular blood monitoring is essential due to lithium's narrow therapeutic window, with toxicity possible at levels above 1.5 mEq/L
- Patients should maintain consistent salt and water intake while using lithium to avoid dehydration or sudden changes in sodium levels that can affect lithium concentration and potentially lead to toxicity, as discontinuing lithium treatment in bipolar patients is associated with an increase in suicide morbidity and mortality 1.
From the FDA Drug Label
CLINICAL PHARMACOLOGY Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells and effects a shift toward intraneuronal metabolism of catecholamines, but the specific biochemical mechanism of lithium action in mania is unknown. The mechanism of lithium is not fully understood, but it is known to:
- Alter sodium transport in nerve and muscle cells
- Affect intraneuronal metabolism of catecholamines 2
From the Research
Mechanism of Lithium
The mechanism of lithium is complex and not fully understood, but several studies have shed light on its potential mechanisms of action.
- Lithium has been shown to have neuroprotective effects, reducing oxidative stress and increasing protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2 3.
- It also reduces excitatory neurotransmission (dopamine and glutamate) and increases inhibitory neurotransmission (GABA) 3.
- Lithium targets second-messenger systems, including the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, which may serve to dampen excessive excitatory neurotransmission 3.
- The inhibition of glycogen synthase kinase 3 (GSK3) has been proposed as a key mechanism of lithium's therapeutic actions 4, 5, 6, 7.
- Lithium has been shown to increase the phosphorylation of GSK3, which inhibits its activity, and this has been observed in both in vitro and in vivo studies 4, 7.
- The circadian clock mechanism has also been suggested as a potential target of lithium's therapeutic effects, with GSK3 playing a role in the regulation of the circadian clock 4.
Key Pathways and Mechanisms
Some of the key pathways and mechanisms involved in lithium's therapeutic effects include:
- Inhibition of GSK3 4, 5, 6, 7
- Regulation of second-messenger systems, including the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C 3
- Reduction of oxidative stress and increase of protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2 3
- Modulation of neurotransmission, including reduction of excitatory neurotransmission (dopamine and glutamate) and increase of inhibitory neurotransmission (GABA) 3
- Regulation of the circadian clock mechanism 4
Clinical Implications
The understanding of lithium's mechanisms of action has important implications for its clinical use, including:
- Development of more effective and tolerable pharmacological agents for the treatment of mood disorders and other mental illnesses 5
- Identification of new biologic targets for the treatment of bipolar disorder and other conditions 6
- Potential repurposing of lithium for the treatment of other brain diseases, such as neurodegenerative disorders 6