- The phosphatidylinositol (PI) cycle represents a key signal-transduction system for many neurotransmitters in the brain (Berridge et al 1982). Inositol is present in high concentration in brain tissue (Sherman et al 1985) and reduction of inositol levels by lithium (Li) treatment may be related to Ll 's mechanism of action (Berridge et al 1982). Indeed, addition of inositol to Ll-treated rats reverses several of iithium's behavioral effects in vivo (Kofman and Belmaker 1990) as well as many of its biological effects in vitro (Busa and Gimlich 1989). As a second-messenger system for numerous neurotransmitters, the PI cycle may well be involved in psychiatric disorders other than manic-depressive illness (Kaiya et al 1989). Recently, we found that inositol-lphosphatase was elevated in red blood cells of chronic schizophrenic patients (Zilberman-Kaufman et al 1992). This suggested to us that inositol might be lacking in such patients and that the increased enzyme activity represented an attempted physiological compensation. We therefore decided on a clinical trial of inositol therapy in schizophrenia. lnositol passes the blood-brain barrier poorly (Spector 1988). The behavioral effects noted in rats were done with intracerebroventricular (ICV) inositol (Kofman and Belmaker 1990). However, Belmaker et al (1992) showed that large doses of inositol IP reversed Ll-pilocarpine seizures as effectively as small doses given ICV. As in the history of L-Dopa therapy (Marks 1974), it may be that simple compounds can have psychoactive effects only when given at high doses.