Bipolar disorder and myo‐inositol: a review of the magnetic resonance spectroscopy findings

Abstract

The preclinical and clinical MRS findings were generally supportive of the involvement of myo-inositol in bipolar disorder and its treatment. Overall, in bipolar patients who are manic or depressed there are abnormalities in brain myo-inositol concentrations, with changes in frontal and temporal lobes, as well as the cingulate gyrus and basal ganglia. These abnormalities are not seen in either euthymic patients or healthy controls, possibly due to a normalizing effect of treatment with either lithium or sodium valproate. There is also increasing evidence that sodium valproate may also act upon the PI-cycle. Nonetheless, it remains uncertain if these changes in myo-inositol concentration are primary or secondary. Findings regarding the specific inositol-depletion hypothesis are also generally supportive in acutely ill patients, although it is not yet possible to definitively confirm or refute this hypothesis based on the current MRS evidence.

The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells

“…Furthermore, bipolar mood disorder has a strong genetic predisposition but is a complex genetic trait that probably involves combinations of multiple loci (Craddock and Jones, 1999). As yet, no susceptibility gene has been unambiguously identified but, interestingly, many of the candidate genes currently under investigation converge on the PIP 3 -and PKB-mediated signal pathway (Silverstone et al, 2005;Carter, 2007). The results presented here provide a mechanism that might directly couple current genetic studies with a target of lithium therapy.…”

Chronic Lithium Salt Treatment Reduces CRE/CREB-Directed Gene Transcription and Reverses Its Upregulation by Chronic Psychosocial Stress in Transgenic Reporter Gene Mice

“…Among those, inhibition of the inositol monophosphatase was suggested to be a common mechanism of action of three mood stabilizers (Williams et al, 2002). Inhibition of the inositol monophosphatase has been shown to increase inositol monophosphates and to decrease myoinositol concentrations in rat brain (O'Donnell et al, 2000), although in humans, this effect has not consistently been observed (Silverstone et al, 2005). In our study, chronic lithium treatment did not result in significant changes in the levels of those inositol phosphates that have specific roles in cell signalling (Table 3 and Figure 5a).…”

Lithium: the pharmacodynamic actions of the amazing ion

“…Studies have since demonstrated the validity of this hypothesis as an explanation for the therapeutic action of lithium; magnetic resonance spectroscopy (MRS) findings have shown abnormal PI-cycle activity and elevated myo-inositol concentrations in patients with bipolar disorders [Silverstone et al 2005], thus it follows that lithium potentially exerts a therapeutic effect by affecting cell signalling as a result of IMPase inhibition, and subsequent reduction of elevated inositol and phosphatidylinositol levels [Haimovich et al 2012]. …”

“…Within the PI signalling pathway (Figure 1), the enzyme IMPase typically regenerates myoinositol from inositol monophosphates, which in turn leads to the resynthesis of phosphatidylinositol [Silverstone et al 2005]. At therapeutically relevant doses, lithium is a potent inhibitor of various phosphoinositol phosphates involved in inositol phosphate metabolism, including the intracellular enzymes IMPase and inositol polyphosphatase 1-phosphatase (IPP 1) [Allison and Stewart, 1971;Phiel and Klein, 2001]; this inhibition leads to inositol depletion, a consequential reduction in the resynthesis of phosphatidylinositol bisphosphate (PIP2) and prevents regeneration of the second messenger inositol-1,4,5, triphosphate (IP3) [Phiel and Klein, 2001], with subsequent effects on signal transduction [Haimovich et al 2012].…”