As medical professionals and clinical researchers gain a deepening understanding of and appreciation for the complex interaction of genetics, diet and lifestyle on disease processes, the influence of circadian rhythms and the importance of a good night’s sleep are emerging as key factors for supporting overall wellness. Disrupted circadian patterns can wreak havoc on physical and psychological wellbeing. In fact, proper sleep-wake cycles and exposure to light and dark at appropriate times are so crucial, that the World Health Organization has classified night shift work as a probable carcinogen.
Circadian disruption is a common feature in psychiatric conditions, in particular, bipolar disorder (BPD). There are elements the human body requires as nutrients in small amounts, such as sodium and potassium. Another element belonging to the same alkali metal group in the periodic table that may be essential for health—particularly mental health—is lithium. Lithium, in the form of lithium orotate, lithium citrate, or lithium carbonate, is frequently prescribed as a mood stabilizer and antidepressant.
Lithium exerts its effects via multiple mechanisms. In general, lithium decreases the release of norepinehphrine and may increase serotonin release, which may partly account for its role in reducing manic episodes. (Lithium’s influence on serotonin release and receptor activity may also explain its potential role in ameliorating depression.) Regarding other neurotransmitters, lithium reduces excitatory dopamine and glutamate, while increasing inhibitory GABA transmission, which could underlie its efficacy for BPD.
One of the better known mechanisms of lithium is its influence on inositol depletion. Research findings are mixed, and experts disagree about the effectiveness of lithium for this purpose, but lithium inhibits the enzyme inositol monophosphatase (IMPase), which plays a role in the de novo synthesis of myo-inositol and recycling it from inositol monophosphate. Inhibition of IMPase results in lower levels of myo-inositol, which is believed to underlie some cases of BPD.
Returning to the role of circadian rhythms in influencing health and behavior, lithium may have a therapeutic effect on regulating some of the “clock genes” that contribute to the genetic aspects of BPD. At least two genes with eight single nucleotide polymorphisms associated with BPD via circadian regulation have been shown to respond favorably to lithium supplementation. The efficacy of lithium for BPD may be dependent on some of these polymorphisms, which may be why patients respond differently to the compound. (Only 30% of patients treated with lithium experience complete remission of BPD.) Lithium’s interaction with circadian rhythm regulating genes may be another contributing factor to its efficacy for depression; depression is often accompanied by sleep disruption.
With such complex effects on enzymes and neurotransmission, it’s not surprising that research is uncovering potential uses for lithium in Alzheimer’s disease and other forms of neurodegeneration. Glycogen synthase kinase-3β (GSK-3β) is an enzyme involved in the phosphorylation of tau proteins, which contribute to stabilization of microtubules and proper construction of cellular cytoskeletons. Hyperphosphorylated tau malfunctions and is unable to maintain proper cell shape and structure, including those of neuronal axons and dendrites. Hyperphosphorylated tau proteins contribute to the neurofibrillary tangles that are one of the hallmarks of Alzheimer’s disease, along with the buildup of insoluble amyloid plaques. Lithium is an effective inhibitor of GSK-3β, opening a possibility for lithium supplementation as part of a multi-faceted approach for Alzheimer’s.
Several neurotransmitter systems interact with GSK-3, including serotonergic, dopaminergic, cholinergic, and glutamatergic systems. Modulating GSK-3 activity may be instrumental in attenuating the symptoms of BPD, depression, and schizophrenia, as well as protecting neural plasticity. The role of GSK-3 in a host of seemingly intractable conditions has attracted enough attention that pharmaceutical GSK-3 inhibitors are being developed and tested in clinical trials. The potential of lithium for this purpose should not be overlooked.