Effects of γ-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia

Context: Cognitive impairment causes morbidity in schizophrenia and could be due to abnormalities of cortical interneurons using the inhibitory neurotransmitter,gamma-aminobutyric acid (GABA). Objectives: To test the predictions that cognitive and brain functional responses to GABA-modulating drugs are correlated and-abnormal in schizophrenia. Design: Pharmacological functional magnetic resonance imaging study of 2 groups, each undergoing scanning 3 times, using an N-back working memory task, after placebo, lorazepam, or flumazenil administration. Setting and Participants: Eleven patients with chronic schizophrenia were recruited from a rehabilitation service, and 11 healthy volunteers matched for age, sex, and premorbid IQ were recruited from the local community. Intervention: Participants received 2 mg of oral lorazepam, a 0.9-mg intravenous flumazenil bolus followed by a flumazenil infusion of 0.0102 mg/min, or oral and intravenous placebo. Main Outcome Measures: Working memory performance was summarized by the target discrimination index at several levels of difficulty. Increasing (or decreasing) brain functional activation in response to increasing task difficulty was summarized by the positive (or negative) load response. Results: Lorazepam impaired performance and fluma zenil enhanced it; these cognitive effects were more salient in schizophrenic patients. Functional magnetic resonance imaging demonstrated positive load response in a frontoparietal system and negative load response in the temporal and posterior cingulate regions; activation of the frontoparietal cortex was positively correlated with deactivation of the temporocingulate cortex.,After placebo administration, schizophrenic patients had abnormally attenuated activation of the frontoparietal cortex and deactivation of the temporocingulate cortex; this pattern was mimicked in healthy volunteers and exacerbated in schizophrenic patients by lorazepam. However, in schizophrenic patients, flumazenil enhanced deactivation of the temporocingulate and activation of the anterior cingulate cortices. Conclusions: The GABA-modulating drugs differentially affect working memory performance and brain function in schizophrenia. Cognitive impairment in schizophrenia may reflect abnormal inhibitory function and could be treated by drugs targeting GABA neurotransmission.