Lithium and valproate and their possible effects on themyo-inositol second messenger system in healthy volunteers and bipolar patients

Abstract

Over 25 years ago it was suggested that the mechanism by which lithium was clinically effective may be due to a stabilizing effect on the phosphoinositol second messenger system (PI-cycle), which has multiple effects within cells. It was proposed that lithium, which is an inhibitor of one of the key enzymes in the PI-cycle, acted to lower myo-inositol concentrations; termed the ‘inositol-depletion hypothesis’. Initial animal evidence supported this hypothesis, and also suggested that it was possible that sodium valproate could affect the PI-cycle. Since the first magnetic resonance studies in this area in the early 1990s many studies have examined various aspects of this hypothesis in both healthy volunteers and patients utilizing magnetic resonance spectroscopy (MRS). The present review considers research in this area and concludes that, despite initial promise, current evidence suggests that it is unlikely that either lithium or valproate produce clinically relevant changes in myo-inositol concentrations or the PI-cycle. These findings do not suggest that lithium-induced changes in the PI-cycle are the primary mechanism by which lithium or valproate exert their beneficial clinical effects in bipolar disorder. Nonetheless, given the current technical and clinical limitations of the literature to date, this conclusion cannot be considered completely definitive.