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Face and predictive validity of the ClockΔ19 mouse as an animal model for bipolar disorder: a systematic review

Abstract

Mice carrying the circadian locomotor output cycles Kaput delta 19 N-ethyl-N-nitrosoure (ENU) mutation (ClockΔ19) are used as an animal model for bipolar disorder (BD). We aimed to systematically review the face validity (phenotypical and pathophysiological resemblance with BD) and predictive validity (responsiveness to treatments used in BD) of this model in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. We carried out a systematic search of the databases PubMed and Embase, combining search terms covering BD and ClockΔ19. The 22 studies included in the review (from a total of 1281 identified records) show that the behavioral phenotype of the ClockΔ19 mouse is characterized by hyperactivity, decreased anxiety-like behavior, decreased depression-like behavior and increased preference for rewarding stimuli. This is highly consistent with mania in humans. Moreover, the ClockΔ19 mouse exhibits rapid mood cycling (a manic-like phenotype during the day followed by euthymia at night), which is consistent with BD. Chronic administration of lithium, a drug with well established mood-stabilizing effect in humans with BD, reverses the majority of the bipolar-like traits and most of the neurobiological abnormalities observed in the ClockΔ19 mouse. In conclusion, the ClockΔ19 mouse has substantial face validity as an animal model for BD. The predictive validity of the ClockΔ19 mouse has primarily been investigated via studies using lithium challenge. Therefore, further studies are needed to determine how the ClockΔ19 mouse responds to other mood-stabilizing treatments of BD such as valproate, lamotrigine, carbamazepine, oxcarbazepine, antipsychotics, electroconvulsive therapy and various light interventions.

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Acknowledgements

We are thankful to research librarian Helene Sognstrup, Aarhus University Library–Psychiatry, Aarhus, Denmark. SDØ is supported by a grant from the Lundbeck Foundation (R165-2013-15320).

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Ms Kristensen and Dr Østergaard reports no conflicts of interest. Dr Nierenberg reports the following conflicts of interest: Consultancy: Abbott Laboratories, Alkermes, American Psychiatric Association, Appliance Computing (Mindsite), Basliea, Brain Cells, Brandeis University, Bristol Myers Squibb, Clintara, Corcept, Dey Pharmaceuticals, Dainippon Sumitomo (now Sunovion), Eli Lilly and Company, EpiQ, L.P./Mylan, Forest, Genaissance, Genentech, GlaxoSmithKline, Healthcare Global Village, Hoffman LaRoche, Infomedic, Intra-Cellular Therapies, Lundbeck, Janssen Pharmaceutica, Jazz Pharmaceuticals, Medavante, Merck, Methylation Sciences, NeuroRx, Naurex, Novartis, PamLabs, Parexel, Pfizer, PGx Health, Otsuka, Ridge Diagnostics Shire, Schering-Plough, Somerset, Sunovion, Takeda Pharmaceuticals, Targacept and Teva; consulted through the MGH Clinical Trials Network and Institute (CTNI) for Astra Zeneca, Brain Cells, Dianippon Sumitomo/Sepracor, Johnson and Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept and Takeda/Lundbeck Pharmaceuticals, NeuroRx Pharma, Pfizer and Physician’s Postgraduate Press. Grants/Research support: American Foundation for Suicide Prevention, AHRQ, Brain and Behavior Research Foundation, Bristol-Myers Squibb, Cederroth, Cephalon, Cyberonics, Elan, Eli Lilly & Company, Forest, GlaxoSmithKline, Intra-Cellular Therapies, Janssen Pharmaceuticals, Lichtwer Pharma, Marriott Foundation, Mylan, NIMH, PamLabs, Patient Centered Outcomes Research Institute (PCORI), Pfizer Pharmaceuticals, Shire, Stanley Foundation, Takeda/Lundbeck and Wyeth-Ayerst. Honoraria: Belvoir Publishing, University of Texas Southwestern Dallas, Brandeis University, Bristol-Myers Squibb, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, CRICO, Dartmouth Medical School, Health New England, Harold Grinspoon Charitable Foundation, IMEDEX, International Society for Bipolar Disorder, Israel Society for Biological Psychiatry, Johns Hopkins University, MJ Consulting, New York State, Medscape, MBL Publishing, MGH Psychiatry Academy, National Association of Continuing Education, Physicians Postgraduate Press, SUNY Buffalo, University of Wisconsin, University of Pisa, University of Michigan, University of Miami, University of Wisconsin at Madison, APSARD, ISBD, SciMed, Slack Publishing and Wolters Klower Publishing, ASCP, NCDEU, Rush Medical College, Yale University School of Medicine, NNDC, Nova Southeastern University, NAMI, Institute of Medicine, CME Institute, ISCTM, World Congress on Brain Behavior and Emotion, Congress of the Hellenic Society for Basic and Clinical Pharmacology and ADAA. Stock: Appliance Computing (MindSite), Brain Cells, Medavante. Copyrights: Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute (CTNI). Speaker Bureaus: none since 2003.

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Kristensen, M., Nierenberg, A. & Østergaard, S. Face and predictive validity of the ClockΔ19 mouse as an animal model for bipolar disorder: a systematic review. Mol Psychiatry 23, 70–80 (2018). https://doi.org/10.1038/mp.2017.192

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