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Glycogen Synthase Kinase-3β as a Putative Therapeutic Target for Bipolar Disorder

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Background: Bipolar disorder (BD) is a debilitating mental ailment characterized by recurrent episodes of mania and depression. Primary mood-stabilizing drugs like lithium and valproate alleviate the hypomanic or mild to moderate manic episodes in patients with BD. One of the extensively studied underlying mechanisms for these pharmacological interventions is inhibition of intracellular signaling cascades associated with glycogen synthase kinase-3 beta (GSK-3β), a multi-functional serine-threonine kinase.

Objective and Method: To summarize the different mechanistic aspects associated with GSK-3β signaling involved in the pathophysiology of BD and highlights drug discovery approaches pursued for the development of GSK-3β inhibition with detailed strength, weakness, opportunity, and threat (SWOT) analysis. In this review, we endeavor to establish the correlation between neuronal GSK-3β inhibition and anti-manic response of different therapeutics used for the treatment of patients with BD.

Results: The gene depletion or pharmacological inhibition of GSK-3β reproduces some of the behavioral effects of lithium including reduction of depression- and manic-like behaviors in rodents, which attested the intracellular GSK- 3β inhibition as one of the critical steps in mediating behavioral effect of mood-stabilizers. Furthermore, converging evidence supported the participation of GSK-3β in the regulation of various neurobehavioral functions governed by neurotransmitters dopamine and serotonin. Apart from its crucial involvement in the mechanism of action of mood stabilizers, GSK-3β signaling pathways have also received attention for their role in the effects of psychoactive therapies like antidepressants, antipsychotics, and neurotrophic factors.

Conclusion: We anticipate that the GSK-3β could be a druggable target for several incurable neuropsychiatric disorders including BD.
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Keywords: Bipolar disorder; GSK-3β; depression; lithium; mania; mood stabilizers

Document Type: Review Article

Publication date: July 1, 2018

This article was made available online on February 7, 2018 as a Fast Track article with title: "Glycogen Synthase Kinase-3β as a Putative Therapeutic Target for Bipolar Disorder".

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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