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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 synchronization of pyramidal cell activity that is dependent on GABA neurotransmission through GABAA receptors containing α2 subunits. Consequently, we 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. Fifteen male subjects with chronic schizophrenia were randomly assigned to receive four weeks of treatment with the study drug (MK-0777; n = 9) or matched placebo (n = 6) in a double-blind fashion. Outcome measures included the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Symptoms (RBANS), three tests of working memory and/or cognitive control (N-Back, AX-CPT and POP tasks), and EEG measures of gamma band oscillations induced during the POP task. Compared to placebo, MK-0777 was associated with improved performance on the N-Back, AX-CPT and POP tasks, and increased frontal gamma band power during the POP task. Figure shows the mean gamma band power values expressed as the MK-0777 minus the placebo group difference between baseline and week 4 for the high minus the low control condition for each 250 ms epoch of the POP task. No effects of MK-0777 were detected in BPRS or RBANS scores with the exception of improvement on the RBANS delayed memory index. MK-0777 was well-tolerated. 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 subjects with schizophrenia.

Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D: Subunit-selective modulation of GABAA receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry 165: 1585-1593, 2008.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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