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