Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Yian Lin, Adam X. Maihofer, Emma Stapp, Megan Ritchey, Ney Alliey-Rodriguez, Amit Anand, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Abesh Bhattacharjee, Cynthia V. Calkin, Carla Conroy, William Coryell, Nicole D'Arcangelo, Anna DeModena, Joanna M. Biernacka, Carrie Fisher, Nicole Frazier, Mark Frye, Keming GaoJulie Garnham, Elliot Gershon, Kara Glazer, Fernando S. Goes, Toyomi Goto, Elizabeth Karberg, Gloria Harrington, Petter Jakobsen, Masoud Kamali, Marisa Kelly, Susan G. Leckband, Falk W. Lohoff, Andrea Stautland, Michael J. McCarthy, Melvin G. McInnis, Francis Mondimore, Gunnar Morken, John I. Nurnberger, Ketil J. Oedegaard, Vigdis Elin Giever Syrstad, Kelly Ryan, Martha Schinagle, Helle Schoeyen, Ole A. Andreassen, Marth Shaw, Paul D. Shilling, Claire Slaney, Bruce Tarwater, Joseph R. Calabrese, Martin Alda, Caroline M. Nievergelt, Peter P. Zandi, John R. Kelsoe

Research output: Contribution to journalArticlepeer-review


Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Original languageEnglish (US)
Pages (from-to)821-831
Number of pages11
JournalBipolar disorders
Issue number8
StatePublished - Dec 2021


  • bipolar disorder
  • clinical predictor
  • lithium
  • treatment response

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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