Inositol depletion, GSK3 inhibition and bipolar disorder

Abstract

Valproic acid and lithium are widely used to treat bipolar disorder, a severe illness characterized by cycles of mania and depression. However, their efficacy is limited, and treatment is often accompanied by serious side effects. The therapeutic mechanisms of these drugs are not understood, hampering the development of more effective treatments. Among the plethora of biochemical effects of the drugs, those that are common to both may be more related to therapeutic efficacy. Two common outcomes include inositol depletion and GSK3 inhibition, which have been proposed to explain the efficacy of both valproic acid and lithium. Here, we discuss the inositol depletion and GSK3 inhibition hypotheses, and introduce a unified model suggesting that inositol depletion and GSK3 inhibition are inter-related.

Keywords: GSK3; MIPS; inositol metabolism; lithium; valproic acid.

Figure 1.. A potential GSK3 phosphorylation site in MIPS.

Both human and yeast MIPS contain a potential GSK3 phosphorylation site (serine-279 of human MIPS and serine-296 of yeast MIPS) within a six-amino acid region of identity [64].

Figure 2.. Model: dual effects of VPA and lithium on inositol depletion and GSK3 inhibition contribute to mood stabilization.

GSK3 is required for optimal de novo synthesis of inositol in yeast. VPA (A) indirectly inhibits MIPS, the rate limiting enzyme of inositol de novo synthesis, possibly by inhibiting GSK3, thereby reducing intracellular inositol. Lithium (B) depletes inositol by inhibiting IMPase, and inhibits GSK3 by multiple mechanisms. In addition to inhibition of MIPS activity, GSK3 inhibition may also affect metabolism of G6P, the substrate for inositol de novo synthesis. Inositol depletion leads to perturbation of numerous cellular functions, some of which are associated with mood stabilization. Inhibition of GSK3 affects cells in numerous ways, some of which are neurotrophic and may contribute to mood stabilization. VPA: Valproic acid.