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

Background: There is evidence that differential expression of nicotinic acetylcholine receptor (nAChR) is associated with cognitive impairment in schizophrenia. Further, studies have shown that administration of AQW051, an α-7 nAChR partial agonist, can improve cognitive functioning in rodent models of learning and memory. The primary goal of the current study in chronic stable outpatients with schizophrenia was to evaluate task-related activation in key regions of interest (ROIs) in the brain during performance of a working memory task (WMT) and an episodic memory task (EMT), with both encoding and retrieval components, and to examine the effect of AQW051 on task-related functional brain activation. Methods: Subjects included males and females aged 18–60 years with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders IV criteria. The study was conducted at seven centers in the USA and was a double-blind, randomized, placebo-controlled, multi-center, stratified trial, employing a single-dose, two-period, cross-over design. Subjects were randomized (1:1:1) to receive an active single dose of 7.5 mg, 50 mg or 100 mg AQW051. The primary outcome of the study was the task-related activation as measured by fMRI during performance of working and episodic memory tasks in specific pre-defined ROIs (WMT: dorsolateral pre-frontal cortex, inferior pre-frontal cortex, dorsal parietal cortex; EMT: anterior and posterior hippocampus, anterior and posterior parahippocampal gyrus) under both placebo and AQW051 conditions. Effect sizes of AQW051 administration versus placebo were calculated by dividing mean change in least square means by the pooled total standard deviation of the blood-oxygen-level-dependent response; a moderate effect of the drug was defined as an effect size ≥0.4 occurring in two or more ROIs during a task and a strong effect was defined as an effect size ≥0.7 occurring in one or more ROIs. Safety evaluations included the recording of all adverse events (AEs). Results: Of 68 subjects enrolled, 60 subjects completed the study. Baseline demographics were comparable between dose groups. Significant and predicted changes in fMRI signal (activation) were detected in the placebo conditions during performance of WMT and EMT. No effect on task-related brain activation was detected in response to AQW051 versus placebo during WMT. During the EMT encoding phase, a strong effect on task-related brain activation was detected in response to 7.5 mg AQW051 versus placebo (anterior hippocampus, mean effect size [95% CI]: 0.795 [0.228, 1.362]). No clinically relevant increase in brain activation was detected during the EMT retrieval phase at ROIs in response to AQW051 administration. Reported incidences of AEs during the study were numerically similar for all three dose cohorts (7.5 mg AQW051 cohort: drug, 36.4%; placebo, 47.4%. 50 mg AQW051 cohort: drug, 43.5%; placebo, 34.8%. 100 mg AQW051 cohort: drug, 45.0%; placebo, 50%). Discussion: AQW051 administered in a single dose of 7.5 mg, 50 mg or 100 mg was generally well tolerated. Under placebo conditions, fMRI responses were robustly detected at multiple target ROIs during performance of WMT and EMT, illustrating the feasibility of implementing a multi-site fMRI study to examine treatment effects on cognition in psychiatric disorders. Brain activation in response to AQW051 administration only deviated from placebo during EMT at the lowest dose, suggesting some sensitivity of this approach to measuring treatment efficacy in individuals with schizophrenia. Expanding the lower dose range and testing longer treatment exposures may be required to understand the potential cognitive benefits of AQW051

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

IntroductionAQW051, 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.MethodsThis 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.ResultsOverall, 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.ConclusionsOverall, 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