human psychopharmacology Hum Psychopharmacol Clin Exp 2005; 20: 309–326. Published online 6 May 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.693 REVIEW ARTICLE A review of the possible relevance of inositol and the phosphatidylinositol second messenger system (PI-cycle) to psychiatric disorders—focus on magnetic resonance spectroscopy (MRS) studies Hyeonjin Kim 1 , Brent M. McGrath 2 and Peter H. Silverstone 2 * 1 Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada 2 Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada Myo-inositol is an important part of the phosphatidylinositol second messenger system (PI-cycle). Abnormalities in nerve cell myo-inositol levels and/or PI-cycle regulation has been suggested as being involved in the pathophysiology and/or treat- ment of many psychiatric disorders including bipolar disorder, major depressive disorder, panic disorder, obsessive-compul- sive disorder, eating disorders and schizophrenia. This review examines the metabolism and biochemical importance of myo-inositol and the PI-cycle. It relates this to the current in vivo evidence for myo-inositol and PI-cycle involvement in these psychiatric disorders, particularly focusing upon the magnetic resonance spectroscopy (MRS) findings in patient stu- dies to date. From this review it is concluded that while the evidence suggests probable relevance to the pathophysiology and/or treatment of bipolar disorder, there is much less support for a significant role for the PI-cycle or myo-inositol in any other psychiatric disorder. More definitive investigation is required before PI-cycle dysfunction can be considered specific to bipolar disorder. Copyright # 2005 John Wiley & Sons, Ltd. key words — myo-inositol; magnetic resonance spectroscopy; bipolar disorder; major depressive disorder; panic disorder; anxiety; obsessive-compulsive disorder; anorexia nervosa; bulimia nervosa; schizophrenia INTRODUCTION Understanding the neurochemical underpinnings of psychiatric disorders remains a goal not yet clearly attained for any psychiatric disorder, although current progress often involves psychopharmacologically dri- ven hypotheses (Rudnick, 2002). Given the complex- ity of neuronal functioning, it is not surprising that numerous abnormalities in neurotransmitter systems have been reported for most psychiatric disorders. However, signal transduction pathways (or second messenger systems) may be of particular relevance since they are in a pivotal position in the central ner- vous system (CNS); forming complex signaling net- works that allow neurons to receive, process and respond to information (Bhalla and Iyengar, 1999). In this way, signal transduction pathways are able to affect the functional balance between multiple neuro- transmitter systems, thus playing an integral role in mediating neuronal signaling and downstream cellular response (Manji and Lenox, 2000). Among the signal transduction pathways currently well understood, the phosphatidylinositol second messenger system (PI-cycle) has been reported to be altered in several psychiatric disorders. The purpose of this review is to examine the evidence that alterations in the chemistry, the regulation and the synthesis of PI-cycle constituents—most notably Received 8 October 2004 Copyright # 2005 John Wiley & Sons, Ltd. Accepted 22 March 2005 *Correspondence to: Professor P. H. Silverstone, Departments of Psychiatry and Neuroscience, University of Alberta, 1E1.07 Mackenzie Center, 8440-112 Street, Edmonton, AB, Canada, T6G 2B7. Tel: þ1-(780) 407-6576. Fax: þ1-(780) 407-6672. E-mail: peter.silverstone@ualberta.ca Contract/grant sponsors: Canadian Institutes of Health Research; Alberta Heritage Foundation for Medical Research.