Pharmacological Enhancement of Cognition in Individuals with Schizophrenia

Abstract

w n “ i fi a f n d c t o t t T he principal pharmacological treatment for schizophrenia, antipsychotic medications, reduces the severity of positive symptoms but has little or no effect on the cognitive impairents that are the major determinants of long-term social and ccupational outcome. In addition to their limited effectiveness, all edications currently used to treat schizophrenia are derivative of erendipitous discoveries over a half century ago. These problems mphasize the need for a new approach to developing pharmacoogical interventions in schizophrenia that begins with the identifiation of molecular targets on the basis of their role in the pathohysiology of an illness (1). One such target, 2 subunit-containing -aminobutyric acid-A (GABAA) receptors, is the subject of a randomized clinical trial conducted by Buchanan et al. (2) through the National Institute of Mental Health–funded Treatment Units for Research on Neurocognition in Schizophrenia Network and reported in this issue of Biological Psychiatry. The rationale for the study derives from the following hypothesis: increased levels of GABAA receptor 2 subunit protein and mesenger RNA in the dorsolateral prefrontal cortex of subjects with chizophrenia represent a compensatory response to deficient ABA synthesis in the chandelier subclass of parvalbumin-expressng GABA neurons that signal to postsynaptic pyramidal neurons ia 2-containing GABAA receptors (3). Thus, enhancing this signaling with a drug that selectively activates 2-containing GABAA receptors and that does so only when GABA is normally released from presynaptic chandelier neurons would augment the intrinsic compensatory response and improve the function of the affected neural network. Specifically, positive modulation of 2-containing GABAA receptors was predicted: 1) to increase the power of the frontal lobe band (30 – 80 Hz) oscillations that are impaired in schizophrenia (4), and 2) to improve performance on these tasks because working memory and related cognitive control tasks seem to be dependent on oscillations (5). Preclinical studies demonstrated, consistent with this hypothesis, that compounds with relatively selective agonist activity for 2-containing GABAA receptors improved working memory (6) and increased oscillations (7) in pharmacological models of schizophrenia in monkeys and mice, respectively. In healthy human volunteers, TPA023 (a.k.a. MK-0777), a relatively selective positive modulator of GABAA receptors containing 2 or 3 subunits, had a cognitive-sparing profile compared with typical benzodiazepines, which are nonselective positive modulators of GABAA receptors ontaining 1, 2, 3, or 5 subunits (8). Finally, in a small, proof-ofconcept, randomized clinical trial, subjects with schizophrenia treated with MK-0777 showed increased frontal oscillations and improved performance on several working memory tasks, including the AX-type continuous performance test and N-Back, relative to subjects receiving placebo (9). In contrast, in the larger, multisite, randomized clinical trial conducted by Buchanan et al., subjects