Copyright @ Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. A Pilot Study of Adjunctive Atomoxetine Treatment to Second-Generation Antipsychotics for Cognitive Impairment in Schizophrenia Joseph I. Friedman, MD,*y David Carpenter, BA, z Jing Lu, MD, x Jin Fan, PhD,* Cheuk Y. Tang, PhD, z Leonard White, PhD, y Michael Parrella, PhD, y Stephanie Bowler, RN, y Zeinab Elbaz, MD, y Lauren Flanagan, BA, k and Philip D. Harvey, PhD* Abstract: Relationships between altered prefrontal cortical dopa- mine, norepinephrine, and some of the cognitive impairments of schizophrenia support an approach for pharmacological remediation of cognitive symptoms through manipulations of prefrontal cortical dopamine and norepinephrine. Atomoxetine, a selective norepi- nephrine reuptake inhibitor, produces a widespread increase in brain norepinephrine and a secondary and selective increase in prefrontal dopamine. Given this, we evaluated atomoxetine’s cognitive effects in a pilot placebo-controlled trial in patients with schizophrenia. Moreover, a functional magnetic resonance imaging investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine. Twenty participants with schizo- phrenia were randomized to treatment with placebo or atomoxetine 80 mg daily for an 8-week parallel-designed treatment trial. Cognitive performance was assessed with the Brief Assessment of Cognition in Schizophrenia. No significant cognitive improvement was associated with atomoxetine treatment. However, atomoxetine treatment was associated with significantly greater increases in working memory-related activation of the left dorsolateral prefrontal and left posterior cingulate cortices. The negative results of this study conflict with the effectiveness of amphetamine in enhancing the cognitive abilities of schizophrenic patients and may be related to the differential pattern of cortical activation and deactivation pro- duced by amphetamine. (J Clin Psychopharmacol 2008;28:59–63) T here is a great deal of evidence implicating the prefrontal cortex (PFC) in cognitive functions relevant to schizo- phrenia. 1 Moreover, evidence for relationships between altered PFC dopamine (DA), norepinephrine (NE), and some of the cognitive impairments of schizophrenia supports an approach for pharmacological remediation of cognitive symptoms through manipulations of PFC DA and NE. 2 Atomoxetine (Strattera, Eli Lilly & Co, Indianapolis, Ind), a selective NE reuptake inhibitor, produces a wide- spread increase in brain NE and a secondary and selective increase in extracellular DA concentrations in the PFC 3 owing to the nonselectivity of NE transporters in the PFC for both DA and NE 4,5 and the increased competition between NE and DA at these reuptake sites. Given these data, we evaluated atomoxetine’s cognitive effects in a pilot placebo-controlled clinical trial as an ad- junct to ongoing second-generation antipsychotic (SGA) treatment in patients with schizophrenia. Moreover, a func- tional magnetic resonance imaging (fMRI) investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine. PATIENTS AND METHODS Subjects Subjects were recruited from the outpatient psychiatry departments of several New York area hospitals. All subjects provided written informed consent, and this study was carried out in accordance with the Declaration of Helsinki as adopted and promulgated by the National Institutes of Health. All participants met the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition diagnostic criteria for schizophrenia using the Comprehensive Assessment of Symptoms and History structured interview. 6 Potential partic- ipants were receiving stable doses of one of the following SGA medications for a minimum period of 4 weeks before entry into the study: risperidone, olanzapine, quetiapine, or aripiprazole and no other psychotropic medications. Assessments The Positive and Negative Syndrome Scale (PANSS 7 ) was used to assess weekly the severity of positive, negative, and general psychopathology symptoms. Cognitive perfor- mance was measured by the Brief Assessment of Cognition Brief Report 59 Journal of Clinical Psychopharmacology  Volume 28, Number 1, February 2008 *Department of Psychiatry, Mount Sinai School of Medicine, New York; yClinical Neuroscience Center, Pilgrim Psychiatric Center, W. Brent- wood; zDepartment of Radiology, Mount Sinai School of Medicine, New York, NY; xJFK Medical Center, Seton Hall University, Edison, NJ; and kLong Island University, CW Post Campus, Brookville, NY. Received July 13, 2007; accepted after revision November 4, 2007. Funding was provided by the following sources: Eli Lilly and Company, GCRC grant M01-RR-00071 awarded to Mount Sinai School of Medicine, and VA VISN 3 MIRECC. Dr Friedman receives grant support from Eli Lilly and Company. Dr Parella owns shares of Eli Lilly and Company stock. Dr Harvey serves on advisory boards for Eli Lilly Company. Address correspondence and reprint requests to Joseph I. Friedman, MD, Department of Psychiatry, The Mount Sinai Hospital, Box 1230, One Gustave L. Levy Place, New York, NY 10029. E-mail: jfriedman1@rcn.com. Copyright * 2008 by Lippincott Williams & Wilkins ISSN: 0271-0749/08/2801-0059 DOI: 10.1097/jcp.0b013e318161318f