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Mishra HK, Ying NM, Luis A, et al. Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies. Mol Psychiatry. 2021;26(7):3383-3394doi: 10.1038/s41380-021-01048-7.
Mishra, H. K., Ying, N. M., Luis, A., Wei, H., Nguyen, M., Nakhla, T., Vandenburgh, S., Alda, M., Berrettini, W. H., Brennand, K. J., Calabrese, J. R., Coryell, W. H., Frye, M. A., Gage, F. H., Gershon, E. S., McInnis, M. G., Nievergelt, C. M., Nurnberger, J. I., Shilling, P. D., Oedegaard, K. J., Zandi, P. P., Kelsoe, J. R., Welsh, D. K., & McCarthy, M. J. (2021). Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies. Molecular psychiatry, 26(7), 3383-3394. https://doi.org/10.1038/s41380-021-01048-7
Mishra, Himanshu K, et al. "Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies." Molecular psychiatry vol. 26,7 (2021): 3383-3394. doi: https://doi.org/10.1038/s41380-021-01048-7
Mishra HK, Ying NM, Luis A, Wei H, Nguyen M, Nakhla T, Vandenburgh S, Alda M, Berrettini WH, Brennand KJ, Calabrese JR, Coryell WH, Frye MA, Gage FH, Gershon ES, McInnis MG, Nievergelt CM, Nurnberger JI, Shilling PD, Oedegaard KJ, Zandi PP, Kelsoe JR, Welsh DK, McCarthy MJ. Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies. Mol Psychiatry. 2021 Jul;26(7):3383-3394. doi: 10.1038/s41380-021-01048-7. Epub 2021 Mar 05. PMID: 33674753; PMCID: PMC8418615.
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Mol Psychiatry. 2021 Jul;26(7):3383-3394. doi: 10.1038/s41380-021-01048-7. Epub 2021 Mar 05.

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies.

Molecular psychiatry

Himanshu K Mishra, Noelle M Ying, Angelica Luis, Heather Wei, Metta Nguyen, Timothy Nakhla, Sara Vandenburgh, Martin Alda, Wade H Berrettini, Kristen J Brennand, Joseph R Calabrese, William H Coryell, Mark A Frye, Fred H Gage, Elliot S Gershon, Melvin G McInnis, Caroline M Nievergelt, John I Nurnberger, Paul D Shilling, Ketil J Oedegaard, Peter P Zandi, John R Kelsoe, David K Welsh, Michael J McCarthy

Affiliations

  1. VA San Diego Healthcare System, San Diego, CA, USA.
  2. Department of Psychiatry and Center for Circadian Biology, University of California San Diego, La Jolla, CA, USA.
  3. Department of Psychiatry, Dalhousie University Halifax, Halifax, NS, Canada.
  4. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
  5. Departments of Neuroscience and Psychiatry, Icahn School of Medicine at Mt Sinai, New York, NY, USA.
  6. Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA.
  7. Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
  8. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
  9. Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA.
  10. Department of Psychiatry, University of Chicago, Chicago, IL, USA.
  11. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
  12. Department of Psychiatry, Indiana University, Indianapolis, IN, USA.
  13. Section for Psychiatry, University of Bergen and Norment and KG Jebsen Centre for Neuropsychiatry, Division of Psychiatry Haukeland University Hospital, Bergen, Norway.
  14. Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
  15. VA San Diego Healthcare System, San Diego, CA, USA. [email protected].
  16. Department of Psychiatry and Center for Circadian Biology, University of California San Diego, La Jolla, CA, USA. [email protected].

PMID: 33674753 PMCID: PMC8418615 DOI: 10.1038/s41380-021-01048-7

Abstract

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

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