@article{ad5fb5a2c2674f3b9c23dccf3f206d6e,
title = "A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia",
abstract = "Background In a previous pilot study, MK-0777a γ-aminobutyric acid (GABA)A α2/α3 partial agonistwas reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia. Methods Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. (n = 18); MK-0777 8 mg b.i.d. (n = 21); or placebo (n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures. Results There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects. Conclusions The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABAA receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABAA α2 site might be needed for cognitive enhancement in schizophrenia.",
keywords = "Clinical trial, cognition, functional capacity, schizophrenia, symptoms, γ-amino-butyric acid",
author = "Buchanan, {Robert W.} and Keefe, {Richard S.E.} and Lieberman, {Jeffrey A.} and Barch, {Deanna M.} and Csernansky, {John G.} and Goff, {Donald C.} and Gold, {James M.} and Green, {Michael F.} and Jarskog, {L. Fredrik} and Javitt, {Daniel C.} and David Kimhy and Kraus, {Michael S.} and McEvoy, {Joseph P.} and Mesholam-Gately, {Raquelle I.} and Seidman, {Larry J.} and Ball, {M. Patricia} and McMahon, {Robert P.} and Kern, {Robert S.} and James Robinson and Marder, {Stephen R.}",
note = "Funding Information: Ms. Ball reported consultant services with ePharmaLearning to provide training for a Pfizer trial. Dr. Barch disclosed the receipt of research funding from the National Institute of Mental Health , the McDonnell Center for Higher Brain Function , National Alliance for Research on Schizophrenia and Depression , Allon , and Novartis . Dr. Buchanan has served as a Data and Safety Monitoring Board member for Cephalon, Otsuka, and Pfizer; a consultant to Abbott, GlaxoSmithKline, Sanofi-Aventis, Scherring-Plough; and an Advisory Board member for Abbott, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He has received grant support from Janssen Pharmaceutica . Dr. Csernansky reported receipt of honoraria for service on Data Monitoring Committees for clinical trials sponsored by Eli Lilly and Sanofi Aventis. Dr. Goff has served as consultant and/or adviser to: Xytis, Forest Laboratories, Pfizer, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Solvay, Hoffman-La Roche, and Dianippon Sumitomo; served on a Data and Safety Monitoring Board for Otsuka and Wyeth; and received research funding from Pfizer , Janssen , Novartis , and GlaxoSmithKline . Dr. Gold disclosed royalties from the brief assessment of cognition in schizophrenia (BACS) and has served as a consultant for Pfizer, Solvay, GlaxoSmithKline, AstraZeneca, and Merck. Dr. Green has been a consultant to Abbot Laboratories, Astellas, Cypress Bioscience, Dainippon Sumitomo Pharma, GlaxoSmithKline, Lundbeck, Otsuka, Sanofi Aventis, Takeda, and Wyeth and a speaker for Janssen Cilag. Dr. Jarskog has received grant support from Novartis and GlaxoSmithKline . Dr. Javitt serves as Chair, scientific advisory board, and major shareholder of Glytech and Amino Acids Solutions. Over the past 2 years, Dr. Javitt has served as a consultant for pharmaceutical companies, including Sanofi Aventis, Solvay, Organon, Lundbeck, AstraZeneca, NPS Pharmaceuticals, Takeda, and Sepracor. He currently serves on a new treatment development advisory board for Pfizer, serves on the Scientific Advisory Board for Promentis Pharmaceuticals, and has received research support from the pharmaceutical industry , including, in the past year, Pfizer, Roche, and Jazz Pharmaceuticals. Dr. Keefe reports having received investigator-initiated research funding support from the National Institute of Mental Health , Department of Veterans Affairs , Allon , GlaxoSmithKline , Novartis , and the Singapore National Medical Research Council and an unrestricted educational grant from AstraZeneca . He disclosed receiving honoraria and served as a consultant or advisory board member for Abbott, Acadia, AstraZeneca, BiolioneRx, BrainCells, Bristol-Myers Squibb, CHDI, Cypress Bioscience, Dainippon Sumitomo Pharma, Eli Lilly, En Vivo, Johnson & Johnson, Lundbeck, Memory Pharmaceuticals, Merck, Neurosearch, NeuroCog Trials, Novartis, Orexigen, Orion, Otsuka, Pfizer, Prophase, Roche, SanofiAventis, Shire, Solvay, Takeda, Wyeth, and Xenoport. Dr. Keefe reports being a shareholder in NeuroCog Trials as well as receiving royalties from the BACS testing battery and the MATRICS Consensus Cognitive Battery (BACS Symbol Coding). Dr. Kern receives financial support from MATRICS Assessment , a nonprofit organization that facilitates the distribution of the MATRICS Consensus Cognitive Battery. He also has received consultation fees from Otsuka. Dr. Kimhy has received an instrument grant from VivoMetrics . Dr. Lieberman received grant/research funding from Allon , GlaxoSmithKline , Merck , Novartis , Pfizer , Sepracor , and Targacept and also served on advisory boards for Bioline, Eli Lilly, GlaxoSmithKline, Intracellular Therapies, Pierre Fabre and Psychogenics; and he holds a patent for Repligen. Dr. Marder reports having received consulting fees from the following companies: Wyeth, Otsuka, Pfizer, Schering Plough, Bristol Meyers Squibb, Roche, Lundbeck, Sanofi Aventis, and Acadia. He received research support from Novartis and GlaxoSmithKline . Dr. McEvoy has received grants from GlaxoSmithKline , Pfizer , and Novartis as well as honoraria from Eli Lilly. Dr. Larry J. Seidman reports no financial disclosures or conflicts of interest for the past 2 years. He has been a speaker for Shire Pharmaceuticals and received an unrestricted education grant from Janssen Pharmaceuticals in the past 5 years. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This study was funded by National Institute of Mental Health Contract HHSN278200441003C to the University of California, Los Angeles (SRM, Principal Investigator). Double-blind medications were provided by Merck and Company. We wish to thank the following for their assistance in the conduct of the study: New York State Psychiatric Institute and College of Physicians and Surgeons, Columbia University: Marlene Carlson; Duke University Medical Center: Trina Walker and Leslie Yusko; Massachusetts General Hospital, Harvard Medical School: Shannon Sorenson and Joanne Wojcik; Maryland Psychiatric Research Center: Sharon August and Ilene Verovsky; Washington University in St. Louis School of Medicine: Meghan Flatley and Emily Thomason and UCLA Semel Institute for Neuroscience and Human Behavior: Ayala Ofek and Ewa Witt. ",
year = "2011",
month = mar,
day = "1",
doi = "10.1016/j.biopsych.2010.09.052",
language = "English (US)",
volume = "69",
pages = "442--449",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "5",
}