CaMKK2 as an emerging treatment target for bipolar disorder

Kaiser, J; Nay, K; Horne, CR; McAloon, LM; Fuller, OK; Muller, AG; Whyte, DG; Means, AR; Walder, K; Berk, M; Hannan, AJ; Murphy, JM; Febbraio, MA; Gundlach, AL; Scott, JW

Author(s): Kaiser, J; Nay, K; Horne, CR; McAloon, LM; Fuller, OK; Muller, AG; Whyte, DG; Means, AR; Walder, K; Berk, M; Hannan, AJ; Murphy, JM; Febbraio, MA; Gundlach, AL; Scott, JW;
Details: Publication Year 2023-09-20,Volume 28,Issue #11,Page 4500-4511
Journal Title: Molecular Psychiatry
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 Ca(2+)-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.
Publisher: NPG
Keywords: Humans; Animals; Mice; *Bipolar Disorder/drug therapy/genetics; Mutation, Missense; Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics/metabolism
Research Division(s): Inflammation
PubMed ID: 37730845
Publisher's Version: https://doi.org/10.1038/s41380-023-02260-3
Open Access at Publisher's Site: https://doi.org/10.1038/s41380-023-02260-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-09-27 08:47:33

Last Modified: 2024-03-11 10:02:37