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. Coryell; David 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

doi:10.1038/s41386-018-0273-8

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

Psychiatry and Psychology

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	620-628
Number of pages	9
Journal	Neuropsychopharmacology
Volume	44
Issue number	3
DOIs	https://doi.org/10.1038/s41386-018-0273-8
State	Published - Feb 1 2019

ASJC Scopus subject areas

Pharmacology
Psychiatry and Mental health

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10.1038/s41386-018-0273-8

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McCarthy, M. J., Wei, H., Nievergelt, C. M., Stautland, A., Maihofer, A. X., Welsh, D. K., Shilling, P., Alda, M., Alliey-Rodriguez, N., Anand, A., Andreasson, O. A., Balaraman, Y., Berrettini, W. H., Bertram, H., Brennand, K. J., Calabrese, J. R., Calkin, C. V., Claasen, A., Conroy, C., ... Kelsoe, J. R. (2019). Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacology, 44(3), 620-628. https://doi.org/10.1038/s41386-018-0273-8

McCarthy, MJ, Wei, H, Nievergelt, CM, Stautland, A, Maihofer, AX, Welsh, DK, Shilling, P, Alda, M, Alliey-Rodriguez, N, Anand, A, Andreasson, OA, Balaraman, Y, Berrettini, WH, Bertram, H, Brennand, KJ, Calabrese, JR, Calkin, CV, Claasen, A, Conroy, C, Coryell, WH, Craig, DW, D’Arcangelo, N, Demodena, A, Djurovic, S, Feeder, S, Fisher, C, Frazier, N, Frye, MA, Gage, FH, Gao, K, Garnham, J, Gershon, ES, Glazer, K, Goes, F, Goto, T, Harrington, G, Jakobsen, P, Kamali, M, Karberg, E, Kelly, M, Leckband, SG, Lohoff, F, McInnis, MG, Mondimore, F, Morken, G, Nurnberger, JI, Obral, S, Oedegaard, KJ, Ortiz, A, Ritchey, M, Ryan, K, Schinagle, M, Schoeyen, H, Schwebel, C, Shaw, M, Shekhtman, T, Slaney, C, Stapp, E, Szelinger, S, Tarwater, B, Zandi, PP & Kelsoe, JR 2019, 'Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder', Neuropsychopharmacology, vol. 44, no. 3, pp. 620-628. https://doi.org/10.1038/s41386-018-0273-8

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

abstract = " 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.",

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

note = "Publisher Copyright: {\textcopyright} 2018, American College of Neuropsychopharmacology.",

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doi = "10.1038/s41386-018-0273-8",

language = "English (US)",

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T1 - Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

AU - McCarthy, Michael J.

AU - Wei, Heather

AU - Nievergelt, Caroline M.

AU - Stautland, Andrea

AU - Maihofer, Adam X.

AU - Welsh, David K.

AU - Shilling, Paul

AU - Alda, Martin

AU - Alliey-Rodriguez, Ney

AU - Anand, Amit

AU - Andreasson, Ole A.

AU - Balaraman, Yokesh

AU - Berrettini, Wade H.

AU - Bertram, Holli

AU - Brennand, Kristen J.

AU - Calabrese, Joseph R.

AU - Calkin, Cynthia V.

AU - Claasen, Ana

AU - Conroy, Clara

AU - Coryell, William H.

AU - Craig, David W.

AU - D’Arcangelo, Nicole

AU - Demodena, Anna

AU - Djurovic, Srdjan

AU - Feeder, Scott

AU - Fisher, Carrie

AU - Frazier, Nicole

AU - Frye, Mark A.

AU - Gage, Fred H.

AU - Gao, Keming

AU - Garnham, Julie

AU - Gershon, Elliot S.

AU - Glazer, Kara

AU - Goes, Fernando

AU - Goto, Toyomi

AU - Harrington, Gloria

AU - Jakobsen, Petter

AU - Kamali, Masoud

AU - Karberg, Elizabeth

AU - Kelly, Marisa

AU - Leckband, Susan G.

AU - Lohoff, Falk

AU - McInnis, Melvin G.

AU - Mondimore, Francis

AU - Morken, Gunnar

AU - Nurnberger, John I.

AU - Obral, Sarah

AU - Oedegaard, Ketil J.

AU - Ortiz, Abigail

AU - Ritchey, Megan

AU - Ryan, Kelly

AU - Schinagle, Martha

AU - Schoeyen, Helle

AU - Schwebel, Candice

AU - Shaw, Martha

AU - Shekhtman, Tatyana

AU - Slaney, Claire

AU - Stapp, Emma

AU - Szelinger, Szabolcs

AU - Tarwater, Bruce

AU - Zandi, Peter P.

AU - Kelsoe, John R.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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

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