Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: A randomized double-blind study ☆ , ☆☆ ,★,★★ Robert C. Smith a, b, ⁎, Hua Jin c, d , Chunbo Li e , Nigel Bark f, g , Anantha Shekhar h , Sauburah Dwivedi i , Catherine Mortiere j , James Lohr c, d , Qiaoyan Hu k , John M. Davis l a Nathan Kline Institute for Psychiatric Research, NY, United States b Department of Psychiatry NYU Medical School, New York, United States c Department of Psychiatry, University of California, San Diego, CA, United States d San Diego VA Health Care System, San Diego, CA, United States e Shanghai Mental Health Center, Shanghai, China f Bronx Psychiatric Center, Bronx, New York, United States g Albert Einstein College of Medicine, Bronx, New York, United States h University of Indiana School of Medicine, Department of Psychiatry and Dean's Office, Indianapolis, ID, United States i School of Public Health, Downstate Medical Center, Brooklyn, New York, United States j Kirby Forensic Psychiatric Center, New York, NY, United States k Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States l Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, United States abstract article info Article history: Received 3 May 2012 Received in revised form 16 October 2012 Accepted 17 October 2012 Available online 29 November 2012 Keywords: Pioglitazone Schizophrenia Diabetes Glucose metabolism Depression Cognition Background: Schizophrenic patients treated with antipsychotic drugs (AP) have an increased frequency of glucose–lipid metabolic abnormalities and diabetes. Pioglitazone has been shown to be effective in the treat- ment of glucose and lipid abnormalities in diabetes and decreasing longer-term conversion of impaired glu- cose tolerance to frank diabetes. Some studies also suggest possible pro-cognitive and antidepressant effects of pioglitazone. We studied the effects of pioglitazone on potential metabolic, symptomatic and cognitive benefits in schizophrenic patients treated with AP. Methods: 54 schizophrenic patients with at least both a)impaired glucose and b) triglycerides ≥120 mg/dL and/or low HDL levels, participated in a double-blind placebo controlled study of 3 month treatment with Pioglitazone (30–45 mg/day) or matched placebo, at 5 sites (4 U.S., 1 China). Fasting glucose and lipid pa- rameters, and psychopathology (PANSS scale) were assessed monthly, and patients had a glucose tolerance test and cognitive testing (RBANS and CPT) at baseline and at the end of study. Statistical analysis used mixed model repeated measures analysis, supplemented by completer and LOCF analysis. Results: In the total sample there was an overall effect (P's b .05 to b .01) of pioglitazone on preventing dete- rioration in fasting glucose and improving HDL and PANSS depression scores; in the pioglitazone group com- parison of baseline vs 3 month values also showed significant (P b .05) decreases in fasting insulin, 2 h glucose in GTT and insulin resistance (HOMA-IR). However there were marked differences between the re- sponses of patients in the U.S. sites vs the China site. In the U.S. sample, patients treated with pioglitazone, when compared to placebo treated patents, had significantly lower fasting glucose (F = 3.99, P = 0.02), im- proved insulin sensitivity (lower H0MA-IR, F = 6.24, P = .002), lower triglycerides (F = 2.68, P = .06) and in- creased HDL (F = 6.50, P = .001). By the end of the study 52% of the pioglitazone treated patients compared to 15% of the placebo patients had fasting glucose in the normal range (Fisher's exact test P = .02). Pioglitazone also significantly improved PANSS depression factor scores (F = 2.82, P = 0.05). It did not improve cognitive performance on the RBANS or CPT tasks. Pioglitazone did not increase weight or produce any other signifi- cant side-effects. In the small mainland China site sample, pioglitazone treatment, as compared to placebo, did not show greater improvement in metabolic parameters or psychopathology ratings. Schizophrenia Research 143 (2013) 18–24 ☆ When this work was done, Drs. Smith and Dwivedi were also associated with Manhattan Psychiatric Center, New York, New York. ☆☆ Supported by a grant from the Stanley Medical Research Foundation to Dr. Smith (PI). Pioglitazone and matching placebo were supplied by Takeda Pharmaceuticals. At the San Diego site the study was also supported by VA Center for Excellence For Stress and Mental Illness. ★ Clinical Trial Registration: NCT00231894, Clinical Trials.gov. ★★ Presented at the NCDEU Annual Meetings, June 14, 2011, Boca Raton, Florida. ⁎ Corresponding author at: Nathan Kline Institute for Psychiatric Research, N109E, 140 Old Orangeburg Road, Orangeburg, NY, United States. Tel.: +1 516 569 1810, +1 845 398 6531; fax: +1 516 569 1755. E-mail addresses: Robert.Smith2@nyumc.org, rsmith@nki.rfmh.org (R.C. Smith). 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2012.10.023 Contents lists available at SciVerse ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres