Abstract
Physiology underlying manic depressive illness and treating effects of its most commonly used remedy – “lithium” is yet to be elucidated. Recent years of psychopharmacology research witnessed sparkling developments in our understanding of the mechanisms underlying lithium’s mood stabilizing effects. Recent data on molecular biology and in vivo magnetic resonance spectroscopy suggest that some of the initial actions of lithium may occur through the inhibition of the enzyme inositol monophosphatase (IMPase) and reduction of myo–inositol, which in turn initiate a cascade of events at different levels of signal transduction process and gene expression in brain; such as the effects on protein kinase C, myristoylated alenine rich C kinase substrate protein, glycogen synthase kinase 3β, B cell lymphoma–2 protein, and activator protein–I. It is likely that the enzyme IMPase other that being the key point in initiating lithium’s therapeutic effects, may also play a critical role in the physiology underlying manic depressive illness.
Highlights
Bipolar disorder is a chronic, disabling mental illness that affects at least 1–2% of the adult population and is associated with a substantial risk of suicide among those affected [1,8,10,45]
The most widely accepted hypothetical mechanism of action for lithium proposes that when lithium inhibits the enzyme inositol monophosphatase (IMPase); phosphoinositides and second messengers derived from their hydrolysis are depleted due to inositol deficiency [3,4]
First we summarized available data on the lithium’s effect on the enzyme IMPase in vivo
Summary
Bipolar disorder is a chronic, disabling mental illness that affects at least 1–2% (in recent studies it has been reported as high as 5.5 to 8.3 %) of the adult population and is associated with a substantial risk of suicide among those affected [1,8,10,45]. In vivo data on lithium’s inhibitory effect on the enzyme IMPase is limited and inconsistent [19,30,32,40,41]. In recent years the validity of “inositol depletion hypothesis” has been called into question with some remarkable criticisms [2,16]. First we summarized available data on the lithium’s effect on the enzyme IMPase in vivo. We discussed the validity of the “inositol depletion” hypothesis in the light of recent criticisms. We provided a brief summary of the recent research data on the molecular mechanisms underlying therapeutic effects of lithium with their relevance to the lithium-induced reductions in myo-inositol levels. We made an evidence based discussion on the enzyme IMPase as a potential cornerstone in the pathophysiology of manic depressive illness
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