Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

Michael J. McCarthy, Heather Wei, Caroline M. Nievergelt, Andrea Stautland, Adam X. Maihofer, David K. Welsh, Paul Shilling, Martin Alda, Ney Alliey-Rodriguez, Amit Anand, Ole A. Andreasson, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Kristen J. Brennand, Joseph R. Calabrese, Cynthia V. Calkin, Ana Claasen, Clara Conroy, William H. CoryellDavid W. Craig, Nicole D’Arcangelo, Anna Demodena, Srdjan Djurovic, Scott Feeder, Carrie Fisher, Nicole Frazier, Mark A. Frye, Fred H. Gage, Keming Gao, Julie Garnham, Elliot S. Gershon, Kara Glazer, Fernando Goes, Toyomi Goto, Gloria Harrington, Petter Jakobsen, Masoud Kamali, Elizabeth Karberg, Marisa Kelly, Susan G. Leckband, Falk Lohoff, Melvin G. McInnis, Francis Mondimore, Gunnar Morken, John I. Nurnberger, Sarah Obral, Ketil J. Oedegaard, Abigail Ortiz, Megan Ritchey, Kelly Ryan, Martha Schinagle, Helle Schoeyen, Candice Schwebel, Martha Shaw, Tatyana Shekhtman, Claire Slaney, Emma Stapp, Szabolcs Szelinger, Bruce Tarwater, Peter P. Zandi, John R. Kelsoe

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP 3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Original languageEnglish
Pages (from-to)620-628
Number of pages9
Issue number3
StatePublished - 1 Feb 2019


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