2. Academic Validation
  3. CaMKK2 as an emerging treatment target for bipolar disorder

CaMKK2 as an emerging treatment target for bipolar disorder

  • Mol Psychiatry. 2023 Nov;28(11):4500-4511. doi: 10.1038/s41380-023-02260-3.
Jacqueline Kaiser 1 2 3,  Kevin Nay 1,  Christopher R Horne 4,  Luke M McAloon 1 2 3,  Oliver K Fuller 1,  Abbey G Muller 1 5,  Douglas G Whyte 3,  Anthony R Means 6,  Ken Walder 7,  Michael Berk 7 8 9,  Anthony J Hannan 9 10,  James M Murphy 1 4 11,  Mark A Febbraio 1,  Andrew L Gundlach 1 2 9 10,  John W Scott 12 13 14
Affiliations

Affiliations

  • 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.
  • 2 St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
  • 3 School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia.
  • 4 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • 5 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.
  • 6 Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 7 The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, VIC, 3220, Australia.
  • 8 Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, 3052, Australia.
  • 9 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia.
  • 10 Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3052, Australia.
  • 11 Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia.
  • 12 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia. John.Scott@monash.edu.
  • 13 St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia. John.Scott@monash.edu.
  • 14 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia. John.Scott@monash.edu.
PMID: 37730845 DOI: 10.1038/s41380-023-02260-3
Abstract

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for Other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the CA2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and Other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.

Figures
Products