7 November 2008. A pilot clinical trial of an experimental drug that selectively targets a subtype of γ-aminobutyric acid (GABA) receptor to treat cognition in schizophrenia has shown enough promise to warrant further study, according to a report published online October 15 in the American Journal of Psychiatry. Researchers led by David Lewis of the University of Pittsburgh present evidence that the drug, MK-0777, is well tolerated in a short trial and may improve performance in subjects with schizophrenia on some tests of cognition and memory. They note, however, that the study was too small to provide robust statistical evidence of cognitive improvement. In support of continuing this line of study, the authors also report preliminary evidence suggesting that the drug increased frontal cortical γ band (30-80 Hz) activity in subjects with schizophrenia during a cognitive task.
Indirect evidence for abnormalities in GABAergic neurotransmission in schizophrenia has been reported by a number of researchers (see, e.g., SRF related news story). One hypothesis that Lewis's group has focused on suggests that working memory deficits in schizophrenia can be traced in part to a subset of prefrontal cortex GABAergic interneurons that fail to synthesize and release enough GABA (see Lewis interview). Among the compensatory responses, there is postulated to be an upregulation of the GABAA receptors in postsynaptic pyramidal neurons, especially receptors containing the α2 subunit. Lewis and colleagues suggest that working memory in schizophrenia might be improved by giving this compensatory response a helping hand using a positive allosteric modulator that boosts GABA's effects at GABAA receptors containing the α2 subunit.
In their current study, Lewis, and colleagues at the University of Pittsburgh and the University of California, Davis, used the experimental benzodiazepine-like drug MK-0777, developed by Merck & Co., because it is relatively selective for receptors containing the α2 subunit, while avoiding those containing the α1 subunit. This would avoid the sedation caused by benzodiazepine drugs, which bind indiscriminately to GABAA receptors.
During the four-week, randomized, double-blind, placebo-controlled trial of 15 men with schizophrenia, there was no effect of the study drug on symptoms, as assessed with the Brief Psychiatric Rating Scale. However, MK-0777 improved performance on several cognitive tests (N-back, X Continuous Performance Test, and Preparing to Overcome Prepotency), but only on the delayed memory domain of the Repeatable Battery of the Assessment of Neuropsychological Status (RBANS) (p = 0.04).
The authors suggest that a large clinical trial might help to determine whether statistically non-significant improvements in other domains of the RBANS represent real clinical benefits or perhaps are due solely to practice effects (see SRF related news story). However, they also suggest the possibility that neuropsychological test batteries such as the RBANS may not be sensitive enough, and "[i]f a drug has its effect on one specific cognitive system (e.g., prefrontal-dependent cognitive control functions regulating working memory and response inhibition), then more fine-grained cognitive measures that target those specific functions (e.g., the N-back task and AX Continuous Performance Test) may provide a more sensitive approach to measuring drug effects."
Coauthors Raymond Cho and Cameron Carter of UC Davis have reported previously that people with schizophrenia have reduced γ band oscillations, measured by electroencephalography, in prefrontal cortex during the Preparing to Overcome Prepotency Task, a measure of cognitive control (see SRF related news story). In the current study, they report trends indicating a "normalization" of this deficit by the experimental drug, but firm conclusions from these data could not be derived from the small sample.—Hakon Heimer.
Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D. Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia. Am J Psychiatry. 2008 Oct 15. [Epub ahead of print] Abstract