Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia

David A. Lewis, Raymond Y. Cho, Cameron S. Carter, Kevin Eklund, Sarah Forster, Mary Ann Kelly, Debra Montrose

Research output: Contribution to journalArticle

228 Citations (Scopus)

Abstract

Objective: Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABAA) receptors containing α2 subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABAA receptors containing α2 subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Method: Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABAA receptors containing α2 or α3 subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Results: Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was welltolerated. Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at α2 subunit containing GABAA receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

Original languageEnglish (US)
Pages (from-to)1585-1593
Number of pages9
JournalAmerican Journal of Psychiatry
Volume165
Issue number12
DOIs
StatePublished - Dec 2008

Fingerprint

GABA Receptors
Synaptic Transmission
Cognition
Schizophrenia
GABA-A Receptors
Brief Psychiatric Rating Scale
Short-Term Memory
gamma-Aminobutyric Acid
Placebos
Repression (Psychology)
Pyramidal Cells
Benzodiazepines
Electroencephalography
Outcome Assessment (Health Care)
Clinical Trials
7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. / Lewis, David A.; Cho, Raymond Y.; Carter, Cameron S.; Eklund, Kevin; Forster, Sarah; Kelly, Mary Ann; Montrose, Debra.

In: American Journal of Psychiatry, Vol. 165, No. 12, 12.2008, p. 1585-1593.

Research output: Contribution to journalArticle

Lewis, David A. ; Cho, Raymond Y. ; Carter, Cameron S. ; Eklund, Kevin ; Forster, Sarah ; Kelly, Mary Ann ; Montrose, Debra. / Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. In: American Journal of Psychiatry. 2008 ; Vol. 165, No. 12. pp. 1585-1593.
@article{6b3da90ae34e46b5b3f555b0169f1bb0,
title = "Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia",
abstract = "Objective: Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABAA) receptors containing α2 subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABAA receptors containing α2 subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Method: Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABAA receptors containing α2 or α3 subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Results: Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was welltolerated. Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at α2 subunit containing GABAA receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.",
author = "Lewis, {David A.} and Cho, {Raymond Y.} and Carter, {Cameron S.} and Kevin Eklund and Sarah Forster and Kelly, {Mary Ann} and Debra Montrose",
year = "2008",
month = "12",
doi = "10.1176/appi.ajp.2008.08030395",
language = "English (US)",
volume = "165",
pages = "1585--1593",
journal = "American Journal of Psychiatry",
issn = "0002-953X",
publisher = "American Psychiatric Association",
number = "12",

}

TY - JOUR

T1 - Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia

AU - Lewis, David A.

AU - Cho, Raymond Y.

AU - Carter, Cameron S.

AU - Eklund, Kevin

AU - Forster, Sarah

AU - Kelly, Mary Ann

AU - Montrose, Debra

PY - 2008/12

Y1 - 2008/12

N2 - Objective: Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABAA) receptors containing α2 subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABAA receptors containing α2 subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Method: Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABAA receptors containing α2 or α3 subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Results: Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was welltolerated. Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at α2 subunit containing GABAA receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

AB - Objective: Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABAA) receptors containing α2 subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABAA receptors containing α2 subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Method: Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABAA receptors containing α2 or α3 subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Results: Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was welltolerated. Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at α2 subunit containing GABAA receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

UR - http://www.scopus.com/inward/record.url?scp=57349167353&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57349167353&partnerID=8YFLogxK

U2 - 10.1176/appi.ajp.2008.08030395

DO - 10.1176/appi.ajp.2008.08030395

M3 - Article

C2 - 18923067

AN - SCOPUS:57349167353

VL - 165

SP - 1585

EP - 1593

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

SN - 0002-953X

IS - 12

ER -