Docosahexaenoic acid modulates myo-inositol and myo-inositol biosynthetic genes expression: implications for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a mood disorder affecting approximately 1–2% of the population. It is treated primarily with mood stabilizers, which have variable efficacy and tolerability. Omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), have emerged as potential adjunctive treatments, though clinical findings and underlying mechanisms remain inconsistent. Given that myo-inositol depletion is proposed as a common mechanism for conventional mood stabilizers, we hypothesized that DHA, which modulates components of the phosphatidylinositol pathway, would alter intracellular myo-inositol and thus modulate myo-inositol homeostasis. The aim of this study was to determine the effect of DHA on intracellular myo-inositol and the expression of key genes involved in its biosynthesis. METHODS: Using an enzymatic assay, intracellular myo-inositol levels were measured in the extracts of cells grown in the presence of DHA. The effect of DHA on the expression of the myo-inositol biosynthetic genes INO1 (inositol-1-phosphate synthase) and INM1 (inositol monophosphatase) was assessed by RT-qPCR. RESULTS: DHA altered intracellular myo-inositol in a concentration-dependent manner, with low concentrations decreasing levels and higher concentrations producing increases relative to untreated controls. RT-qPCR analysis showed corresponding modulation of INO1 and INM1 expression, consistent with changes in myo-inositol homeostasis. While some group differences reached statistical significance, particularly in comparisons with valproate (VPA)-treated controls, most contrasts among DHA-treated groups were not significant. CONCLUSION: These findings provide preliminary evidence that DHA modulates intracellular myo-inositol levels and the expression of key biosynthetic genes in yeast. The biphasic response observed suggests a dose-sensitive effect that may help explain inconsistencies in clinical outcomes. While the results support the idea that omega-3 fatty acids influence inositol homeostasis, they should be considered hypothesis-generating and warrant confirmation in mammalian models and clinical settings. CLINICAL TRIAL NUMBER: Not applicable.