title: Ziskind-Somerfeld Research Award 1993. Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression.
abstract: Lithium (Li) reduces brain inositol levels by inhibiting the enzyme inositol monophosphatase. The enzyme inositol-1-phosphatase was measured in human red blood cells of controls, Li-free bipolar patients, and Li-treated bipolar patients and was found to be reduced by 80% in Li-treated bipolars, thus supporting the concept that chronic Li at therapeutic concentrations inhibits this enzyme. Two behaviors in rats caused by Li, reduction of rearing, and Li-pilocarpine seizures, are reversed by intracerebroventricular replenishment of inositol. The reversal is stereospecific to the naturally occurring myo-inositol; whereas the stereoisomer L-chiro-inositol is ineffective. The reversal is dose-dependent, requiring a dose consistent with known quantities of brain inositol depletion; and is time-dependent, as inositol must be given 1-8 h before stimulation. High-dose peripheral inositol also reverses the limbic seizures induced by Li-pilocarpine, and using gas chromatography was shown to increase brain inositol levels that had been reduced by Li treatment. Low-dose inositol could be shown to reverse a peripheral Li-induced side effect, polyuria/polydipsia, in rats and in patients treated with Li. A higher dose of inositol markedly reduced Hamilton Depression Ratings in 9 of 11 unipolar major depressive disorder patients previously unresponsive to tricyclics, in an open design, but had no effect on chronic schizophrenics in a controlled double-blind randomized crossover trial. A new inositol monophosphatase inhibitor, a fungal product originally discovered as a complement inhibitor, was found to act like Li and lower the seizure threshold for subconvulsant doses of pilocarpine. These data suggest that inositol monophosphatase inhibition is a key mechanism of Li's therapeutic action and that design of new inositol monophosphatase inhibitors may be a practical strategy to create new compounds with Li-like therapeutic effects.
authors.affiliation: Ministry of Health Mental Health Center Faculty of Health Science, Ben Gurion University of the Negev Beersheva, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Kofman
authors.forename: R H
authors.initials: RH
authors.lastname: Belmaker
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002986:Clinical Trials as Topic; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007294:Inositol / Q000378:metabolism* / Q000627:therapeutic use; D008094:Lithium / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology
chemical_list: D007294:Inositol; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase