New insights into lithium’s effectiveness for bipolar disorder

Bipolar disorder, a neuropsychiatric condition that includes manic and depressive episodes, affects about 1% of the population and is strongly influenced by genetics. About half of patients respond very well to lithium salts as a therapy, and treatment responsiveness also depends on genetics. Researchers still have little idea of how lithium works to stabilize mood, but, similar to other anti-depressants, it stimulates proliferation of adult neural progenitor cells (NPC), perhaps leading to the birth of new neurons. Now, a new study opens in new tab/window identifies a specific gene that seems to regulate NPC proliferation in response to lithium.

The study, led by Jason Stein, PhD, at The University of North Carolina at Chapel Hill, appears in Biological Psychiatry opens in new tab/window, published by Elsevier.

“Some people with bipolar disorder show therapeutic responses to lithium, while others do not,” said Dr. Stein. “Previous studies have identified a limited number of genetic variations contributing to lithium’s clinical outcomes. These studies are incredibly important, but are also costly, require large sample sizes, and do not identify cell types or biological processes mediating genetic effects. Here, we took an alternative approach by performing a genome-wide association study (GWAS) in a cell culture system from multiple human donors, either exposed to or not exposed to lithium.”

To measure lithium-induced neural proliferation, the researchers employed a cell culture of human NPCs obtained from fetal brain tissue. Some cultures were exposed to lithium, which increased cell proliferation, whereas other cultures were not. The authors then performed GWAS tests.

“Our cell-culture based GWAS approach identified genetic variation as well as a specific gene that influenced lithium-responsive neural progenitor proliferation,” said Dr. Stein.

John Krystal, MD, editor of Biological Psychiatry, said of the study, "The efficacy of lithium remains one of the great mysteries in psychiatry. Emerging from an accidental discovery, it remains a wonder drug for many patients. This study identifies mechanisms underlying the ability of lithium to stimulate proliferation of neural progenitor cells. In particular, they implicate chromosome 3p21.1 and the guanine nucleotide-binding protein-like 3 (GNL3) gene in this effect. GNL3 has been implicated previously in cell cycle regulation and cellular differentiation."

GNL3 has also been implicated in risk for bipolar disorder, schizophrenia and inter-individual variations in intelligence, suggesting the gene plays an important role in brain function.

Using CRISPR technology, the researchers then increased expression of GNL3 in the cultures, which in turn increased neural proliferation in response to lithium. Conversely, decreasing expression of GNL3 decreased lithium-induced proliferation.

“Though more experiments are required to determine if these results have clinical potential, this study opens up a new approach of identifying pharmacogenomic effects in cell culture systems,” added Dr. Stein.

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Notes for editors

The article is “Cellular genome-wide association study identifies common genetic variation influencing lithium induced neural progenitor proliferation,” by Justin M. Wolter, Brandon D. Le, Nana Matoba, Michael J. Lafferty, Nil Aygün, Dan Liang, Kenan Courtney, Juan Song, Joseph Piven, Mark J. Zylka, and Jason L. Stein (https://doi.org/10.1016/j.biopsych.2022.08.014 opens in new tab/window). It appears as an Article in Press in Biological Psychiatry opens in new tab/window, published by Elsevier opens in new tab/window.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at +1 254 522 9700 or [email protected] opens in new tab/window. Journalists wishing to interview the authors may contact Jason L. Stein at [email protected] opens in new tab/window.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here opens in new tab/window.

About Biological Psychiatry

Biological Psychiatry opens in new tab/window is the official journal of the Society of Biological Psychiatry opens in new tab/window, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 12^th out of 155 Psychiatry titles and 14^th out of 274 Neurosciences titles in the Journal Citations Reports^TM published by Clarivate Analytics. The 2021 Impact Factor score for Biological Psychiatry is 12.810.

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