Deanna , Barch, Steve, Marder, Michael, Harms, Lars, Jarksog, Robert, Buchanan, Will, Cronenwett, Li-Shiun , Chen, Weiss, Markus, Maguire, Paul, Pezous, Nicole, Feuerbach, Dominik, Lopez Lopez, Cristina, Johns, Donald and Gomez-Mancilla, Baltazar (2016) Task-related fMRI responses to a nicotinic acetylcholine receptor agonist in schizophrenia: a randomized trial. Progress in Neuro-Psychiticpharmacology and Biol Psy.

Abstract

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.

Item Type:	Article
Keywords:	AQW051 Schizophreni fMRI
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22797