CaMKK2 as an emerging treatment target for bipolar disorder

Journal article


Kaiser, Jacqueline, Nay, Kevin, Horne, Christopher R., McAloon, Luke, Fuller, Oliver K., Muller, Abbey G., Whyte, Douglas G., Means, Anthony R., Walder, Ken, Berk, Michael, Hannan, Anthony J., Murphy, James M., Febbraio, Mark A., Gundlach, Andrew L. and Scott, John W.. (2023). CaMKK2 as an emerging treatment target for bipolar disorder. Molecular Psychiatry. pp. 1-12. https://doi.org/10.1038/s41380-023-02260-3
AuthorsKaiser, Jacqueline, Nay, Kevin, Horne, Christopher R., McAloon, Luke, Fuller, Oliver K., Muller, Abbey G., Whyte, Douglas G., Means, Anthony R., Walder, Ken, Berk, Michael, Hannan, Anthony J., Murphy, James M., Febbraio, Mark A., Gundlach, Andrew L. and Scott, John W.
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.

Year2023
JournalMolecular Psychiatry
Journal citationpp. 1-12
PublisherSpringer Nature
ISSN1476-5578
Digital Object Identifier (DOI)https://doi.org/10.1038/s41380-023-02260-3
PubMed ID37730845
Scopus EID2-s2.0-85171543261
Open accessPublished as ‘gold’ (paid) open access
Page range1-12
FunderNational Health and Medical Research Council (NHMRC)
Australian Catholic University (ACU)
Operational Infrastructure Support (OIS) Program, Victorian Government
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online20 Sep 2023
Publication process dates
Accepted08 Sep 2023
Deposited09 Oct 2023
Grant ID2001817
1156072
2017131
1116936
1194141
1172929
9000719
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