Brief Report Inositol augmentation of lithium or valproate for bipolar depression Bipolar affective disorder (BPAD) is a chronic mental illness that affects approximately 1% of the adult US population (1, 2) and is associated with a 15% rate of suicide (3). While there are many options for treatment of refractory mania (4–7), bipolar depression that is resistant to treatment with mood stabilizers remains difficult to treat (8). Therapies are available that shorten the duration and reduce the severity of depressive episodes and reduce the risk of recurrence, but up to half of patients do not respond adequately to available treatments for bipolar depression (9). Identification of more effective treatments for the depressed phase of BPAD is a priority. Myo-inositol (inositol), C 6 H 12 O 6 , is an isomer of glucose that is a ubiquitous component of mam- malian cells and is present in the diet in quantities of approximately 1 g/day. Inositol is a precursor in the phosphatidylinositol second messenger system, Evins AE, Demopulos C, Yovel I, Culhane M, Ogutha J, Grandin LD, Nierenberg AA, Sachs GS. Inositol augmentation of lithium or valproate for bipolar depression. Bipolar Disord 2006: 8: 168–174. ª Blackwell Munksgaard, 2006 Objective: Despite promising new therapies, bipolar depression remains difficult to treat. Up to half of patients do not respond adequately to currently approved treatments. This study evaluated the efficacy of adjunctive inositol for bipolar depression. Methods: Seventeen participants with DSM-IV criteria for bipolar depression and a 17-item Hamilton Rating Scale for Depression (HRSD) ‡15 on proven therapeutic levels of lithium or valproate for >2 weeks were randomized to receive double-blind inositol or placebo for 6 weeks. At the end of double-blind treatment, subjects were eligible for an 8-week open-label trial of inositol. Results: Response was defined a priori as >50% reduction in the HRSD and a Clinical Global Impression of 1–2. Four of nine subjects (44%) on inositol and zero of eight subjects on placebo met response criteria (p ¼ 0.053). There was no difference between groups in the average change score for the HRSD or Young Mania Rating Scale (YMRS). Response to inositol was highly variable. Of nine subjects randomized to inositol, two had >50% worsening in HRSD scores at the end of treatment, three had no change and four had >50% improvement. Those who had worsening in depressive symptoms on inositol had significantly higher scores at baseline on the YMRS total score and irritability, disruptive/aggressive behavior and unkempt appearance items. Conclusions: There was a trend for more subjects on inositol to show improvement in bipolar depression symptoms, but, on average, inositol was not more effective than placebo as an adjunct for bipolar depression. Baseline levels of anger or hostility may be predictive of clinical response to inositol. A Eden Evins, Christina Demopulos, Iftah Yovel, Melissa Culhane, Jacqueline Ogutha, Louisa D Grandin, Andrew A Nierenberg and Gary S Sachs Harvard Bipolar Research Program and Department of Psychiatry of the Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Key words: affective disorder – bipolar disorder – depression – inositol – lithium – second messenger – valproate Received 17 August 2004, revised and accepted for publication 16 November 2005 Corresponding author: A Eden Evins, MD, MPH, MGH Schizophrenia Program, 25 Staniford Street, Boston, MA 02114, USA. Fax: +1 617 723 3919; e-mail: a_eden_evins@hms.harvard.edu This work has been presented in part at the Annual Meeting of the Stanley Medical Research Institute, Washington, DC, November 8–9, 2002; at the 5th International Conference on Bipolar Disorder, Pittsburgh, PA, June 2003; and at the 156th Annual Meeting of the American Psychiatric Association, San Francisco, CA, May 2003. The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manu- script. Bipolar Disorders 2006: 8: 168–174 Copyright ª Blackwell Munksgaard 2006 BIPOLAR DISORDERS 168