Large Study Ties Genes to Variable Lithium Response in Bipolar Disorder

John R. Kelsoe, M.D. - Brain & Behavior research expert on bipolar disorder
John R. Kelsoe, M.D.

Lithium is a first-line treatment for bipolar disorder. But it only works well for about one-third of patients. The variation in response is partly due to genetic factors.

Now, in a large study published in The Lancet on January 21st, investigators in the International Consortium on Lithium Genetics (ConLiGen) have reported finding genetic signals on chromosome 21 that affect lithium response.

The investigators compared the lithium response score and genetic differences at six million places in the genomes of 2,563 patients.

A genetic clue about why some people with bipolar disorder don’t respond to lithium treatment. Tweet >

Further support for the results came from a small treatment trial of 73 patients treated with lithium for up to two years. The patients with the "poor responder" gene variants showed a quicker relapse after lithium treatment.

The clinical utility of the finding may be limited, because the vast majority (94 percent) of people carry the responder version of the gene. However, Foundation Scientific Council member Anil Malhotra, M.D., of Zucker Hillside Hospital in Glen Oaks, New York, who was not involved in the study, told the Schizophrenia Research Forum, "The positive lesson is that these kinds of strategies can work for complex drug-response phenotypes, albeit probably with larger sample sizes."

The research team consisted of Scientific Council Members John R. Kelsoe, M.D. (2012 Distinguished Investigator), James B. Potash, M.D. (2000 Young Investigator and 2008 Independent Investigator), J. Raymond DePaulo, Jr., M.D. (1998 and 2003 Distinguished Investigator), and L. Trevor Young, M.D. (1989 Young Investigator and 1995 Independent Investigator). The team also included 2008 and 2015 Young Investigator Fernando S. Goes, M.D., 2013 Young Investigator Liping Hou, Ph.D., 2010 Distinguished Investigator Guy A. Rouleau, M.D., Ph.D., 2009 Independent Investigator Stephanie Jamain, Ph.D., 2009 Young Investigator Alexandre G. Dayer, M.D., 2000 Young Investigator and 2008 Independent Investigator Gustavo X. Turecki, M.D., Ph.D., 2007 Young Investigator Janice M. Fullerton, Ph.D., 2004 and 2007 Young Investigator Francis M. Mondimore, M.D., 2006 Young Investigator Urban Osby, M.D., Ph.D., 2001 and 2006 Young Investigator Roy H. Perlis, M.D., M.P.H, 2000 and 2008 Independent Investigator Tadafumi Kato, M.D., Ph.D., 2002 and 2007 Young Investigator Thomas G. Schulze, M.D., 1994 Young Investigator and 1998 and 2006 Independent Investigator Francis J. McMahon, M.D., 2006 Independent Investigator Mark Andrew Frye, M.D., 2006 Young Investigator Po-Hsiu Kuo, Ph.D., 1999 Young Investigator and 2005 Independent Investigator Michael Bauer, M.D., Ph.D., 2004 Young Investigator Peter P. Zandi, Ph.D., M.P.H., M.H.S., 2004 Independent Investigator Frank Bellivier, M.D., Ph.D., 1999 and 2003 Independent Investigator Martin Alda, M.D., FRCPC, 2002 Young Investigator Jordan W. Smoller, M.D., Sc.D., 2000 Young Investigator Paul D. Shilling, Ph.D., 1998 Young Investigator Glenda M. MacQueen, M.D., Ph.D., and 1992 Young Investigator and 1995 Distinguished Investigator Martin Schalling, M.D., Ph.D.

Read more about this research on the Schizophrenia Research Forum.

Takeaway: Researchers have found a clue – a genetic signal -- that may help explain why some people with bipolar disorder respond to lithium and others don’t. The signal found can only potentially explain non-response in a fraction of patients.