Safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania: a 12-week open-label study Jun Chen 1,2 , David J. Muzina 3,4 , David E. Kemp 2 , Carla Conroy 2 , Philip Chan 2 , Mary Beth Serrano 2 , Stephen J. Ganocy 2 , Yiru Fang 1 **, Joseph R. Calabrese 2 and Keming Gao 2 * 1 Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China 2 Department of Psychiatry, Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA 3 Department of Psychiatry, Mood Disorders Program, Cleveland Clinic, Cleveland, Ohio, USA 4 Medco Health Solutions, Inc, Franklin Lakes, New Jersey, USA Objective To examine the safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania. Method Subjects (n = 18) who were acutely manic, did not respond to lithium, anticonvulsants, and neuroleptics, and/or had intolerable side effects to them in previous manic episodes were openly treated with olanzapine monotherapy (5–40 mg/d) for 12 weeks. The primary and secondary outcomes included the change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score, Clinical Global Impression for Bipolar Disorder-Severity Scale (CGI-S), 17-item Hamilton Depression Rating Scale (HAM-D) and Positive and Negative Syndrome Scale (PANSS), and response and remission rate. Results The mean change in YMRS total score from baseline to endpoint was À23.3 Æ 8.4 (p < 0.001). Fifteen (88.5%) patients achieved response (≥50% reduction in YMRS total score) and 14 (77.8%) achieved remission (YMRS total score ≤9 at endpoint). Mean changes from baseline to endpoint in CGI-S for mania and PANSS total score were significant, but not the changes in HAM-D total score or CGI-S for depression. The most common adverse events were sedation, self-reported weight gain, ≥7% increase in body weight, dizziness, and akathisia. Conclusions These preliminary results suggest that olanzapine monotherapy is effective and relatively safe in patients with treatment- resistant bipolar mania. Randomized, double-blind, placebo-controlled study is warranted. Copyright © 2011 John Wiley & Sons, Ltd. key words—bipolar disorder; treatment-resistant mania; olanzapine; second generation antipsychotic; treatment outcome; safety INTRODUCTION Despite a long history of interest in the treatment of treatment-resistant bipolar disorder (Meyers, 1978; Small et al., 1991; Calabrese et al., 1996; Suppes et al., 1999; Green et al., 2000), there is no consensus on the definition of treatment-resistant bipolar disor- der, including resistant bipolar mania (Gitlin, 2006). Lack of consensus on the definition (Gitlin, 2006) has made it difficult to compare findings from previous studies (Meyers, 1978; Small et al., 1991; Suppes et al., 1992; Calabrese et al., 1996; Burt et al., 1999; Suppes et al., 1999; Green et al., 2000; Schaffer et al., 2000). Previously, some studies used non- response or inadequate response to one approved anti- manic agent to define as being treatment-resistance (Barton and Gitlin, 1987; Kramlinger and Post, 1989), and others used more “rigorous” definitions, that is, failure to respond to two or more approved anti- manic treatments and/or intolerable side effects as the threshold for treatment-resistance (Meyers, 1978; Calabrese et al., 1996; Burt et al., 1999; Suppes et al., 1999; Gitlin, 2006). The safety and efficacy of clozapine, donepezil (Burt et al., 1999; Eden Evins et al., 2006), and mexiletine (Schaffer et al., 2000) were studied in the patients with treatment-resistant bipolar disorder using the more rigorous definition, *Correspondence to: K. Gao, MD, PhD, Department of Psychiatry, Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, 10524 Euclid Ave, 12th Floor, Cleveland, Ohio, USA 44106. Tel: 1-216-844-2865; Fax: 1-216-844-2875 E-mail: keming.gao@uhhospitals.org **Correspondence to: Y. Fang, MD, PhD, Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, 600 S. Wan Ping Rd, Shanghai 200030, China. E-mail: yirufang@yahoo.com.cn Dr. Jun Chen was a research scholar funded by the World Psychiatric Asso- ciation from 2/2010 to 2/2011 and was trained in the Department of Psychi- atry, Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio. Received 8 February 2011 Accepted 19 October 2011 Copyright © 2011 John Wiley & Sons, Ltd. human psychopharmacology Hum. Psychopharmacol Clin Exp 2011; 26: 588–595. Published online 15 November 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.1249