Lithium is an alkali metal that has been used as a mood stabiliser for the bipolar disorder for over 70 years — it is the oldest and most extensively studied pharmacological treatment for the bipolar disorder, and it remains one of the most effective treatments for the acute mania, for the bipolar depression, and for the maintenance treatment of the bipolar disorder. Lithium is unique among the psychiatric medications in that it has been shown to reduce the suicide risk by approximately 60-70% in people with the bipolar disorder — an effect that is not shared by the other mood stabilisers (carbamazepine, valproate, lamotrigine) and that makes the lithium one of the most important treatments in psychiatry for the prevention of the suicidal behaviour. Beyond its effects on the mood and the suicide risk, the lithium has also been shown to have neuroprotective effects, anti-ageing effects, and cognitive-enhancing effects — many of which are mediated by the inhibition of the glycogen synthase kinase-3 (GSK-3) and by the activation of the neurotrophic signalling pathways (including the BDNF and the Wnt-beta-catenin pathways). The lithium is present in the body in trace amounts (approximately 70mg total body content, with the highest concentrations in the brain, the thyroid, and the kidneys), and it is obtained from the diet (particularly from the drinking water, the vegetables, and the salt) at typical intakes of 0.1-3mg daily — but the therapeutic dose of lithium for the bipolar disorder is 600-1200mg daily (as lithium carbonate or lithium citrate), which is approximately 200-400mg of elemental lithium — far above the dietary intake and requiring the pharmaceutical preparation for the therapeutic effect.
Lithium and the Inositol Phosphate Signalling Pathway
Lithium is an inhibitor of the inositol monophosphatase (IMPase) and of the inositol polyphosphate 1-phosphatase — the two enzymes that are required for the recycling of the inositol in the phosphatidylinositol (PI) signalling pathway. The PI signalling pathway is one of the most important intracellular signalling pathways in the brain — it is activated by the neurotransmitters (including the serotonin, the dopamine, and the glutamate receptors) and it uses the inositol trisphosphate (IP3) and the diacylglycerol (DAG) as second messengers to regulate the intracellular calcium release, the protein kinase C (PKC) activation, and the gene transcription. Lithium inhibits the IMPase and the inositol polyphosphate 1-phosphatase, which depletes the intracellular inositol pool and thereby dampens the PI signalling pathway — this lithium-induced dampening of the PI signalling pathway is one of the primary mechanisms of its mood stabilising effects, and it explains why the lithium is particularly effective for the treatment of the mania (which is characterised by the hyperactive PI signalling and the elevated intracellular calcium).
The clinical importance of the lithium for the bipolar disorder and for the suicide prevention is underscored by the observation that the lithium treatment reduces the suicide risk by approximately 60-70% in people with the bipolar disorder and with the major depressive disorder. A meta-analysis of 48 studies in over 15,000 patients with bipolar disorder found that the lithium treatment was associated with a 69% reduction in the suicide risk (odds ratio 0.31, 95% CI 0.21-0.46) compared to no lithium treatment — making it one of the most powerful anti-suicidal interventions in psychiatry. The mechanism of this anti-suicidal effect is not fully characterised, but it is thought to involve the lithium-induced reduction of the impulsivity, the aggression, and the depressive symptoms — all of which are major risk factors for the suicidal behaviour. The lithium-induced increase in the neuroprotective factors (including the BDNF and the Bcl-2) and the reduction in the pro-apoptotic signalling may also contribute to the anti-suicidal effect by protecting the neurons from the stress-induced cell death.
Lithium and the Neuroprotection
Lithium has been shown to have neuroprotective effects in multiple animal models of neurodegeneration — it protects the neurons from the excitotoxicity (which is mediated by the glutamate NMDA receptor overactivation), from the oxidative stress, from the mitochondrial dysfunction, and from the beta-amyloid toxicity (which is one of the primary mechanisms of the Alzheimer’s disease pathology). The mechanism of these neuroprotective effects involves the inhibition of the glycogen synthase kinase-3 (GSK-3) — which is one of the most important regulatory enzymes in the cell and which is hyperactive in the Alzheimer’s disease, in the bipolar disorder, and in many other neurological conditions. The GSK-3 inhibition by lithium activates the Wnt-beta-catenin signalling pathway, which promotes the transcription of the neuroprotective genes and which reduces the tau phosphorylation and the beta-amyloid production. These neuroprotective effects of lithium have led to the investigation of lithium as a potential treatment for the Alzheimer’s disease, for the Parkinson’s disease, and for other neurodegenerative diseases — with some promising but not yet definitive evidence from clinical trials.
Practical Application
For general lithium supplementation for the mood support and for the neuroprotection, the evidence-based approach is to supplement with a low dose of lithium (1-5mg daily, as lithium orotate or lithium citrate — the forms that are more bioavailable than the lithium carbonate for the brain) — which is approximately the dose that is obtained from the high-lithium drinking water (which is associated with the lower rates of the suicide, of the bipolar disorder, and of the dementia in the ecological studies). The pharmaceutical doses of lithium (600-1200mg daily of lithium carbonate or lithium citrate) are associated with a narrow therapeutic window (0.6-1.2mmol/L for the maintenance treatment) and with significant adverse effects (including the hypothyroidism, the weight gain, the renal impairment, and the tremor) that require the regular monitoring of the serum lithium levels, the thyroid function, and the renal function. For comprehensive mood and brain support, low-dose lithium pairs well with the omega-3 fatty acids (which have mood-stabilising and anti-inflammatory effects and which work synergistically with lithium for the bipolar disorder), with the vitamin D (which has immunomodulatory and neuroprotective effects), with the B-complex vitamins (which are required for the methylation cycle and for the neurotransmitter synthesis), and with the magnesium (which is a natural NMDA receptor antagonist and which has complementary effects on the mood and the anxiety).
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