Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.
Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.
Nahas
Ziad
Z
Brain Stimulation Laboratory, Center for Advanced Imaging Research, Department of Psychiatry, Medical University of South Carolina, Charleston, SC 29425, USA. nahasz@musc.edu
George
Mark S
MS
Horner
Michael D
MD
Markowitz
John S
JS
Li
Xingbao
X
Lorberbaum
Jeffrey P
JP
Owens
Susan D
SD
McGurk
Susan
S
DeVane
Lindsay
L
Risch
S Craig
SC
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D018592:Cross-Over Studies; D000077265:Donepezil; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory; D008875:Middle Aged; D010045:Outpatients; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D010919:Placebos; D012559:Schizophrenia / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D010919:Placebos; D000077265:Donepezil