This is part two of Dr. Greenblatt's Nutritional Lithium series. Part one can be found here.
Epigenetics & Psychiatry
The field of epigenetics has far-reaching implications for psychiatry. As acquired epigenetic alterations can be transferred to the next generations, what scientists used to label as an inherited psychiatric disease may in fact be the result of epigenetic changes in a family’s shared environment.
Many psychiatric diseases are consistent with the theory of epigenetic dysregulation because of their fluctuating nature and disease course. Single gene and whole genome epigenetic analyses have shown atypical epigenetic markers in the blood and brain of individuals with psychiatric diseases including abnormalities in DNA methylation, histone modifications and microRNA expression.
Among genes that potentially protect against the development of mood disorders, the brain derived neurotrophic factor (BDNF) gene has been the focus of study for the past several years, as it is associated with neural development and proliferation. BDNF is the most prevalent growth factor in the central nervous system. Because it plays a critical role in the development of plasticity of the brain, methylation of BDNF takes a toll on brain health and resilience. The BDNF gene modulates how much or how little environmental experiences become encoded within the neurons and neural circuits and thereby lead to long-lasting effects. BDNF promotes the growth and formation of new neurons, and it is responsible in part for the remarkable effect of exercise on the brain and for the increase in hippocampus size that is linked with improved memory (D’Addario et al., 2012).
Mood disorders are associated with methylation of BDNF. Adverse experiences like major depression can lower BDNF levels and are linked with hippocampal shrinkage, a phenomenon that helps explain some of the cognitive impairments that are a hallmark of depression. Studies have revealed higher levels of DNA methylation at the BDNF gene promoter in patients with major depressive disorder and bipolar disorder II compared to levels in patients with bipolar I (Dell’Osso et al., 2014).
Lithium’s Influences on Genes
I believe lithium deficiency is the most common mineral deficiency associated with nearly every type of psychiatric disorder. Lithium is a powerful epigenetic factor that can be used to dim the expression of genes that lead to aggression and mental illness while stimulating the expression of health-enhancing genes. Genes that are altered by lithium treatment are involved in many functions such as cell communication, immune response, protein metabolism, nucleic acid regulation/metabolism, and cell growth. A study of rat frontal cortex showed chronic treatment with lithium led to the significant up-regulation of 57 genes and down-regulation of 151 genes. Four of those genes have been specifically associated with bipolar disorder (Fatemi, Reutiman, & Folsom, 2009).
Lithium changes gene expression through two basic channels: DNA methylation, and histone modification. Lithium acts by preventing the process of DNA methylation, which is critically important to improving mental health and preventing mental and emotional disorders. At least three studies have demonstrated that lithium decreases DNA methylation of the BDNF gene promoter. In other words, lithium increases the expression of the BDNF gene.
The increased synthesis of BDNF contributes to robust neural growth and healthy dendritic branching. In one study of hippocampal neurons, lithium increased mRNA expression of BDNF by 67%. At a higher lithium dose there was a 100% increase. Likewise, the protein level of BDNF was increased by 53% with the lower lithium dose and by 89% with the higher lithium dose. By ensuring that the BDNF gene is left in the “on” position, lithium promotes the consistent release of protective neurotrophins that protect and nourish the brain (Dwivedi & Zhang, 2015).
BDNF levels are diminished in the brain and serum of Alzheimer’s patients. Alzheimer’s patients treated for ten weeks with lithium showed a significant increase in their BDNF serum levels. They also saw a significant decrease of cognitive impairment compared with placebo-treated Alzheimer’s patients. Reduction of cognitive impairment was inversely correlated with lithium serum concentration (Leyhe et al., 2009).
BDNF also contributes to degradation of amyloid-β, a component of the amyloid plaques found in the brains of Alzheimer’s patients. In addition, BDNF is capable of inactivating GSK-3β (Leyhe et al., 2009). Abnormal regulation and expression of GSK3β is associated with an increased susceptibility towards Alzheimer’s disease and bipolar disorder. Lithium’s ability to enhance the synthesis of BDNF has far reaching implications for improving a wide range of neuropsychiatric disorders.
Lithium affects multiple pathways in the brain which may explain its remarkable effectiveness for the treatment of bipolar disorder.
Lithium also acts through histone modification. Histone function is particularly important for the encoding of high-level cognitive functions including learning and memory. In fact, diminished memory, as seen in patients with Alzheimer’s disease, has been linked to problems with histone metabolism. In experiments with laboratory animals, lithium has been shown to increase histone acetylation by weakening the binding of the DNA to its spool, making it more available to proteins that enhance memory (Lee et al., 2015). Although studies in humans are needed to further delineate the exact mechanism, lithium may be beneficial in preventing the genetic changes associated with the development of Alzheimer’s disease and other neurodegenerative conditions.
These biological mechanisms are also important in lithium’s efficacy in bipolar disorder. Lithium affects multiple pathways in the brain which may explain its remarkable effectiveness for the treatment of bipolar disorder. BDNF has been consistently reported to be decreased in bipolar patients. One study found that bipolar patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. However, for those on lithium treatment, BDNF levels correlated positively with lithium levels (Tunca, 2014).
Lithium has distinct and often dramatic neurotrophic effects, encouraging the survival and growth of nerve cells. Lithium ions modulate multiple biological cascades involved with nerve cell development. Lithium increases levels of key proteins such as BDNF and NT-3, which are known to be directly involved in nerve cell development. Other studies have found that lithium salts are neuroprotective, working to minimize inflammation, enhance mitochondrial function, and increase antioxidants to provide the optimal environment for neurons to thrive. Imaging studies have provided visual evidence that patients taking lithium salts experience increases in brain tissue volume over time, particularly in the gray matter of the brain, which holds the nerve cell bodies. At the cellular level lithium exerts powerful influences on neuroprotection and brain health.
Lithium promotes epigenetic modifications that affect the expression of more than 50 genes, including signaling proteins, transcription factors, activators, cell adhesion proteins, oncogenes, and tumor suppressors (Farah et al., 2013). As research expands our knowledge of how to regulate gene expression and suppression, targeted use of nutritional lithium will enable us to prevent and treat psychiatric disorders that now incapacitate those who suffer from them. By acting directly on the epigenome, lithium restores neural function and improves brain health in ways that just a few years ago were not dreamed possible.
Adapted from Nutritional Lithium: The Cinderella Story written by James Greenblatt, MD and Kayla Grossman, RN (CreateSpace, 2016, https://www.createspace.com/5433178).
About the Author
James M. Greenblatt, MD, is chief medical officer and vice president of medical services at Walden Behavioral Care. Dr. Greenblatt is board-certified in child and adult psychiatry. Dr. Greenblatt is a clinical faculty member in the psychiatry department at Tufts Medical School as well as the Geisel School of Medicine at Dartmouth College in New Hampshire. Dr. Greenblatt is the author of six books including those on depression, eating disorders and ADHD. He can be reached at: (781) 647-2901. For more information on Dr. Greenblatt please visit www.jamesgreenblattmd.com.
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 D’Addario, C., Dell’Osso, B., Palazzo, M.C., et al. (2012). Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology, 37, 1647-1655.
 Dell’Osso, B., D’Addario, C., Palazzo, M.C. et al. (2014). Epigenetic modulation of BDNF gene: differences in DNA methylation between unipolar and bipolar patients. Journal of Affective Disorders, 166, 330-333.
 Dwivedi, T., & Zhang, H. (2015). Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins. Frontiers In Neuroscience, 8, article 457, 1-8.
 Farah, R., Khamisy-Farah, R., Amit, T., Youdim, M. H., & Arraf, Z. (2013). Lithium’s Gene Expression Profile, Relevance to Neuroprotection A cDNA Microarray Study. Cellular And Molecular Neurobiology, 33(3), 411-420.
 Fatemi, S. H., Reutiman, T. J., & Folsom, T. D. (2009). The role of lithium in modulation of brain genes: relevance for aetiology and treatment of bipolar disorder. Biochemical Society Transactions, 37(Pt 5), 1090-1095.
 Lee, R. S., Pirooznia, M., Guintivano, J., et al. (2015). Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene. Translational Psychiatry, 5e600.
 Leyhe, T., Eschweiler, G. W., Stransky, E., Gasser, T., Annas, P., Basun, H., & Laske, C. (2009). Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. Journal Of Alzheimer’s Disease, 16(3), 649-656.
 Tunca, Z., Ozerdem, A., Ceylan, D., et al. (2014). Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium. Journal Of Affective Disorders, 166, 193-200.