A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia

Robert W. Buchanan; Richard S.E. Keefe; Jeffrey A. Lieberman; Deanna M. Barch; John G. Csernansky; Donald C. Goff; James M. Gold; Michael F. Green; L. Fredrik Jarskog; Daniel C. Javitt; David Kimhy; Michael S. Kraus; Joseph P. McEvoy; Raquelle I. Mesholam-Gately; Larry J. Seidman; M. Patricia Ball; Robert P. McMahon; Robert S. Kern; James Robinson; Stephen R. Marder

doi:10.1016/j.biopsych.2010.09.052

A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia

Robert W. Buchanan, Richard S.E. Keefe, Jeffrey A. Lieberman, Deanna M. Barch, John G. Csernansky, Donald C. Goff, James M. Gold, Michael F. Green, L. Fredrik Jarskog, Daniel C. Javitt, David Kimhy, Michael S. Kraus, Joseph P. McEvoy, Raquelle I. Mesholam-Gately, Larry J. Seidman, M. Patricia Ball, Robert P. McMahon, Robert S. Kern, James Robinson, Stephen R. Marder

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

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 GABA_A receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA_A α2 site might be needed for cognitive enhancement in schizophrenia.

Original language	English (US)
Pages (from-to)	442-449
Number of pages	8
Journal	Biological Psychiatry
Volume	69
Issue number	5
DOIs	https://doi.org/10.1016/j.biopsych.2010.09.052
State	Published - Mar 1 2011
Externally published	Yes

Keywords

Clinical trial
cognition
functional capacity
schizophrenia
symptoms
γ-amino-butyric acid

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2010.09.052

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Buchanan, R. W., Keefe, R. S. E., Lieberman, J. A., Barch, D. M., Csernansky, J. G., Goff, D. C., Gold, J. M., Green, M. F., Jarskog, L. F., Javitt, D. C., Kimhy, D., Kraus, M. S., McEvoy, J. P., Mesholam-Gately, R. I., Seidman, L. J., Ball, M. P., McMahon, R. P., Kern, R. S., Robinson, J., & Marder, S. R. (2011). A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biological Psychiatry, 69(5), 442-449. https://doi.org/10.1016/j.biopsych.2010.09.052

Buchanan, RW, Keefe, RSE, Lieberman, JA, Barch, DM, Csernansky, JG, Goff, DC, Gold, JM, Green, MF, Jarskog, LF, Javitt, DC, Kimhy, D, Kraus, MS, McEvoy, JP, Mesholam-Gately, RI, Seidman, LJ, Ball, MP, McMahon, RP, Kern, RS, Robinson, J & Marder, SR 2011, 'A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia', Biological Psychiatry, vol. 69, no. 5, pp. 442-449. https://doi.org/10.1016/j.biopsych.2010.09.052

@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: 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",

}

TY - JOUR

T1 - A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia

AU - Buchanan, Robert W.

AU - Keefe, Richard S.E.

AU - Lieberman, Jeffrey A.

AU - Barch, Deanna M.

AU - Csernansky, John G.

AU - Goff, Donald C.

AU - Gold, James M.

AU - Green, Michael F.

AU - Jarskog, L. Fredrik

AU - Javitt, Daniel C.

AU - Kimhy, David

AU - Kraus, Michael S.

AU - McEvoy, Joseph P.

AU - Mesholam-Gately, Raquelle I.

AU - Seidman, Larry J.

AU - Ball, M. Patricia

AU - McMahon, Robert P.

AU - Kern, Robert S.

AU - Robinson, James

AU - Marder, Stephen R.

N1 - 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.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - 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.

AB - 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.

KW - Clinical trial

KW - cognition

KW - functional capacity

KW - schizophrenia

KW - symptoms

KW - γ-amino-butyric acid

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A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia

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