Lithium is an alkali metal that is present in trace amounts in the human body (with a total body lithium content of approximately 70mg, primarily in the bones, the liver, and the kidneys), and it is best known as the primary mood stabilising medication for the bipolar disorder — a psychiatric condition that is characterised by the alternating episodes of mania (elevated mood, increased energy, decreased need for sleep, grandiosity, racing thoughts) and of depression (low mood, anhedonia, fatigue, worthlessness, suicidal ideation) that can be devastating for the individuals who suffer from it and for their families. The mood stabilising effect of lithium was discovered accidentally in the 1940s by the Australian psychiatrist John Cade, who was investigating the use of lithium as a treatment for the gout and observed that it had a remarkable calming effect on the guinea pigs that were used in his experiments. Subsequent clinical trials in the 1950s and 1960s established lithium as the first and most effective mood stabiliser for the bipolar disorder, and it remains the gold standard treatment for this condition — not because it cures the bipolar disorder, but because it reduces the frequency and the severity of the manic and depressive episodes and reduces the risk of suicide in people with the bipolar disorder.
Glycogen Synthase Kinase 3 and the Mood Stabilising Mechanism
The mechanism by which lithium stabilises the mood is thought to involve the inhibition of the glycogen synthase kinase 3 (GSK3) enzyme — a serine/threonine kinase that is encoded by the GSK3A and GSK3B genes and that is expressed ubiquitously in the brain, where it phosphorylates a wide range of substrate proteins that are involved in the regulation of the neuronal survival, of the synaptic plasticity, of the circadian rhythm, and of the stress response. Lithium is a non-competitive inhibitor of GSK3 — it binds to the magnesium-binding site of the enzyme and prevents the access of the ATP to the active site, thereby reducing the kinase activity. The inhibition of the GSK3 by lithium has multiple downstream effects that are consistent with the mood stabilising action — it increases the neuroplasticity (by activating the CREB and the Wnt/beta-catenin signalling pathways), it promotes the neurogenesis (by activating the BDNF expression), it reduces the excitotoxicity (by inhibiting the NMDA receptor signalling), and it modulates the circadian rhythm (by stabilising the PER and the CRY proteins). These neuroprotective and neuroplastic effects of the GSK3 inhibition are thought to underlie the long-term mood stabilising action of lithium.
The clinical importance of the GSK3 inhibition for the mood stabilising effect of lithium is underscored by the observation that other GSK3 inhibitors (including the valproic acid, the lithium, and the novel GSK3 inhibitors that are currently in development) also have mood stabilising effects — suggesting that the GSK3 inhibition is a common mechanism of action for the mood stabilisers. A study in 46 patients with the bipolar disorder found that the response to the lithium therapy was associated with the genetic polymorphisms in the GSK3B gene — patients who had the T-allele of the GSK3B -50T/C promoter polymorphism had a better response to the lithium therapy than patients who were homozygous for the C-allele — supporting the hypothesis that the GSK3 inhibition is the primary mechanism of the mood stabilising action of lithium.
Lithium and the Neurodegenerative Diseases
Beyond its mood stabilising effect, lithium has also been studied for its potential neuroprotective effects in the neurodegenerative diseases — particularly the Alzheimer disease, the Parkinson disease, and the amyotrophic lateral sclerosis (ALS). The mechanism of the lithium neuroprotection involves the same GSK3 inhibition and neuroplasticity enhancement that underlie the mood stabilising effect, as well as the induction of the autophagy (the cellular process by which the damaged proteins and the dysfunctional organelles are degraded and recycled). The lithium-induced autophagy is thought to be particularly important for the neurodegenerative diseases because it reduces the accumulation of the disease-specific protein aggregates — the amyloid-beta plaques in the Alzheimer disease, the alpha-synuclein Lewy bodies in the Parkinson disease, and the TDP-43 aggregates in the ALS — and thereby slows the progression of these diseases.
Practical Application
For general lithium supplementation, the evidence-based approach is to use lithium only under the supervision of a physician who can monitor the blood lithium levels and the renal and the thyroid function — because the therapeutic window of lithium is narrow (the therapeutic blood level is 0.6-1.2 mmol/L, and the toxic level is above 1.5 mmol/L), and because the lithium can produce serious adverse effects (including the renal impairment, the hypothyroidism, the weight gain, the tremor, and the toxicity at high blood levels) that require careful monitoring. The lithium is not recommended for the general population as a dietary supplement — the claims of the cognitive enhancement and the anti-ageing effects of the low-dose lithium supplementation have not been substantiated by rigorous clinical evidence, and the potential risks of the lithium supplementation outweigh the unproven benefits. For comprehensive mood support, lithium (when prescribed as a medication for the bipolar disorder) pairs well with the omega-3 fatty acids (which have been shown to have mood stabilising effects in people with the bipolar disorder), with the folate and the B12 (which are required for the methylation cycle and for the synthesis of the neurotransmitters), and with the N-acetylcysteine (which has been shown to reduce the depressive symptoms in people with the bipolar disorder).
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