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 (GABA(A)) receptors containing alpha(2) 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 GABA(A) receptors containing alpha(2) 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 GABA(A) receptors containing alpha(2) or alpha(3) 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 well-tolerated.

Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at alpha(2) subunit containing GABA(A) receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

Trial registration: ClinicalTrials.gov NCT00129441.

Figures

FIGURE 1. Mean Power Values for MK-0777-Treated Group Versus Placebo Group Between Baseline and Week 4 for the High Minus Low Control Condition for Each Epoch of the Preparing to Overcome Prepotency Taska

a The images illustrate EEG findings expressed as the MK-0777 minus placebo group difference between baseline and week 4 for the high minus low control condition for each 250-msec epoch of the Preparing to Overcome Prepotency Task. The top panel illustrates the statistical map of t values. Although statistical significance was not attained, the directionality of the t values are consistent with the hypothesis (that enhancing GABA signaling through GABAA receptors containing an α2 subunit improves the cognitive impairments associated with dorsolateral prefrontal cortex dysfunction in individuals with schizophrenia), particularly during the late-delay period in the left frontal and central parietal regions. The bottom panel illustrates the mean gamma band power values for the same comparison. Frontal area differences across the delay period are shown. Although similar in appearance in some portions of the spatiotemporal layout, the top and bottom panels are not closely matched, since the t values incorporate both mean and variance data, and the power values incorporate only mean values.