title: Task-related fMRI responses to a nicotinic acetylcholine receptor partial agonist in schizophrenia: A randomized trial.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Psychology, Washington University, St. Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: dbarch@wustl.edu.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Barch
authors.affiliation: Semel Institute for Neuroscience at UCLA, Los Angeles, CA, USA; VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, USA. Electronic address: SMarder@mednet.ucla.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Marder
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mharms@wustl.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Harms
authors.affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: lars_jarskog@med.unc.edu.
authors.forename: L Fredrik
authors.initials: LF
authors.lastname: Jarskog
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: rwbuchanan@mprc.umaryland.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buchanan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: w-cronenwett@northwestern.edu.
authors.forename: Will
authors.initials: W
authors.lastname: Cronenwett
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: chenli@psychiatry.wustl.edu.
authors.forename: Li-Shiun
authors.initials: LS
authors.lastname: Chen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: markus.weiss@novartis.com.
authors.forename: Markus
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: paul.maguire@novartis.com.
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Maguire
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: nicole.pezous@novartis.com.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pezous
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: dominik.feuerbach@novartis.com.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: cristina.lopez_lopez@novartis.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lopez-Lopez
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: donald.johns@biogen.com.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Johns
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: rhett.behrje@novartis.com.
authors.forename: Rhett B
authors.initials: RB
authors.lastname: Behrje
authors.affiliation: Novartis Pharma AG, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada. Electronic address: baltazar.gomezmancilla@novartis.com.
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
mesh_terms: D000293:Adolescent; D000328:Adult; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D061212:Memory, Episodic; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D011569:Psychiatric Status Rating Scales; D011725:Pyridines / Q000627:therapeutic use*; D011978:Receptors, Nicotinic; D012559:Schizophrenia / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D055815:Young Adult
chemical_list: C000602881:3-(6-p-tolylpyridin-3-yloxy)-1-azabicyclo(2.2.2)octane; D053961:Azabicyclo Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D010100:Oxygen
keywords: AQW051; Clinical trial; Functional magnetic resonance imaging; Nicotinic acetylcholine receptor (nAChR); Schizophrenia