Augmenting Atypical Antipsychotics with a Cognitive Enhancer (Donepezil) Improves Regional Brain Activity in Schizophrenia Patients: A Pilot Double-blind Placebo Controlled BOLD fMRI Study

Abstract

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.

Relevance of Donepezil in Enhancing Learning and Memory in Special Populations: A Review of the Literature

“…Risch et al (2001) found increased activation of the prefrontal cortex and the basal ganglia, and improvements on cognitive assessments typically used to assess AD such as the Alzheimer's Disease Assessment Scale (ADAS). A second imaging study found increased activity of the left frontal lobe and cingulate and improvements on the Controlled Word Association Task (COWAT) (Nahas et al, 2003). Other studies have found improvements on select behavioral and cognitive assessments.…”

Towards a muscarinic hypothesis of schizophrenia

“…128 Despite these moderate effects in clinical studies, the addition of donepezil resulted in an increase in left frontal lobe and cingulate activity in a functional magnetic resonance imaging study. 129 Moreover, the addition of donepezil to a stable antipsychotic regimen has been found to ameliorate signs of tardive dyskinesia. 130 In contrast to these studies, several other studies failed to find a beneficial effect of the adjunctive use of donepezil in schizophrenia.…”

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…One group found that donepezil normalized fMRI findings on a verbal fluency task (Nahas et al, 2003) and another group found that rivastigmine improved performance on a sustained attention task (Aasen et al, 2005).…”