Task-related fMRI responses to a nicotinic acetylcholine receptor partial agonist in schizophrenia: A randomized trial

Abstract

Introduction: AQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia.

Methods: This was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability.

Results: Overall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile.

Conclusions: Overall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

Keywords: AQW051; Clinical trial; Functional magnetic resonance imaging; Nicotinic acetylcholine receptor (nAChR); Schizophrenia.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Fig. 1.

Study design and participant flow. Of the eight participants who discontinued the study, three discontinued due to adverse events (claustrophobia, numb right arm, worsening of underlying disease), three discontinued due to protocol deviations, one discontinued due to administrative issues and one participant was lost to follow-up and subsequently withdrawn.

Fig. 2.

Mean effect size (95% CI) of task-related brain activation in the a priori ROIs in response to AQW051 administration versus placebo in the overall study population (pharmacodynamic analysis set). Brain regions assessed during A) change from 0- to 2-back in the WMT, B) EMT encoding phase, and C) EMT retrieval phase. Effect sizes of 0.4 and 0.7 are noted via dashed lines. The pharmacodynamic analysis set included all randomized participants that received at least one dose of study drug with available pharmacodynamic data. BOLD: blood-oxygenation-level dependent; Dorsal pariet. cortex: dorsal parietal cortex; EMT: episodic memory task; Hippo. ant.: hippocampus, anterior; Hippo. post.: hippocampus, posterior; Parahippo. gyrus, ant.: parahippocampal gyrus, anterior; Parahippo. gyrus, post.: Parahippocampal gyrus, posterior; PFC: prefrontal cortex; ROIs: regions of interest; WMT: working memory task.