From the Guidelines
Lithium works in the brain by primarily inhibiting two enzymes: inositol monophosphatase and glycogen synthase kinase-3 (GSK-3), leading to decreased inositol levels and altered second messenger systems, which in turn modifies downstream signaling cascades that regulate neurotransmitter release and receptor sensitivity, particularly affecting glutamate, dopamine, and serotonin systems 1.
Mechanism of Action
The mechanism of action of lithium in the brain is complex and involves multiple signaling pathways that regulate neurotransmission and cellular resilience.
- It inhibits inositol monophosphatase, leading to decreased inositol levels and altered second messenger systems.
- It also inhibits glycogen synthase kinase-3 (GSK-3), which modifies downstream signaling cascades that regulate neurotransmitter release and receptor sensitivity.
- Lithium's effects on these signaling pathways particularly affect glutamate, dopamine, and serotonin systems, which are crucial for mood regulation.
Neuroprotective Mechanisms
Lithium also enhances neuroprotective mechanisms by:
- Increasing brain-derived neurotrophic factor (BDNF) levels, which promotes neuronal survival and growth.
- Promoting anti-apoptotic pathways, which helps to prevent neuronal death.
Stabilization of Neuronal Membranes
Additionally, lithium stabilizes neuronal membranes by competing with sodium and calcium ions at voltage-gated channels, which helps to normalize hyperexcitable neurons.
Effects on Circadian Rhythms
Lithium's effects on circadian rhythms through its action on glycogen synthase kinase may contribute to its mood-stabilizing properties.
Overall Effectiveness
These multiple mechanisms work together to reduce neuronal excitability, stabilize mood, and provide neuroprotection, explaining lithium's effectiveness in treating bipolar disorder and its potential benefits in other neuropsychiatric conditions 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 action of lithium in the brain is not fully understood. However, it is known to:
- Alter sodium transport in nerve and muscle cells
- Affect intraneuronal metabolism of catecholamines 2
From the Research
Mechanism of Action of Lithium in the Brain
The mechanism of action of lithium in the brain is complex and involves multiple pathways. Some of the key mechanisms include:
- Displacement of sodium (Na+) from allosteric Na+-binding sites in neurotransmitter transporters and G-protein coupled receptors (GPCRs), which can stabilize inactive conformations and prevent these receptors from relaying signals to the respective G-proteins 3
- Displacement of magnesium (Mg2+) in enzymes containing highly cationic Mg2+-binding sites, such as glycogen synthase kinase-3β (GSK3β) 3
- Modulation of the rate of phosphoinositide synthesis in neurons, with lithium inhibiting the rate of synthesis and the antidepressant drug fluoxetine stimulating it 4
- Regulation of neurotransmission, with lithium reducing excitatory (dopamine and glutamate) and increasing inhibitory (GABA) neurotransmission 5
- Targeting of second-messenger systems, such as the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, to dampen excessive excitatory neurotransmission 5
- Neuroprotective effects, including reduction of oxidative stress, increase of protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduction of apoptotic processes through inhibition of GSK3β and autophagy 5, 6
- Facilitation of neural plasticity through regulation of the glutamate system and cytoskeletal components, which can help to "unlock" the brain from its maladaptive state in patients with mood disorders 7
Key Targets of Lithium
Some of the key targets of lithium include:
- Inositol monophosphatase (IMPase) 6
- Glycogen synthase kinase-3β (GSK3β) 3, 6
- Neurotransmitter transporters and G-protein coupled receptors (GPCRs) 3
- Phosphoinositide synthesis pathways 4
- Second-messenger systems, such as the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C 5
- Glutamate system and cytoskeletal components 7
Implications for Mood Disorders
The mechanisms of action of lithium have important implications for the treatment of mood disorders, including:
- Reduction of symptoms of mania and depression 5, 6
- Prevention of suicidal behaviors 5, 6
- Facilitation of neural plasticity and "unlocking" of the brain from its maladaptive state 7
- Potential for use in the treatment of other conditions, such as traumatic brain injury and chronic neurodegenerative diseases 3