Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia.
BACKGROUND
Cognitive impairment causes morbidity in schizophrenia and could be due to abnormalities of cortical interneurons using the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).


OBJECTIVE
To test the predictions that cognitive and brain functional responses to GABA-modulating drugs are correlated and abnormal in schizophrenia.


METHODS
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.


METHODS
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.


METHODS
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 flumazenil 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.
Menzies
Lara
L
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
Ooi
Cinly
C
Kamath
Shri
S
Suckling
John
J
McKenna
Peter
P
Fletcher
Paul
P
Bullmore
Ed
E
Stephenson
Caroline
C
D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology*; D004311:Double-Blind Method; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008140:Lorazepam / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data; D008297:Male; D008568:Memory / Q000187:drug effects*; D008875:Middle Aged; D008959:Models, Neurological; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009483:Neuropsychological Tests; D010919:Placebos; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000502:physiology
D018757:GABA Modulators; D010919:Placebos; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D008140:Lorazepam