title: Targeting impulsivity in Parkinson's disease using atomoxetine.
abstract: Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.
authors.affiliation: 1 Department of Neuroimaging, Institute of Psychiatry, King's College London, London SE5 8AF, UK angie.kehagia@gmail.com.
authors.forename: Angie A
authors.initials: AA
authors.lastname: Kehagia
authors.affiliation: 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK3 Cambridge Cognition Limited, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Housden
authors.affiliation: 5 Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Regenthal
authors.affiliation: 6 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK7 Adult ADHD Service, Cambridgeshire and Peterborough NHS Foundation Trust, UK.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.affiliation: 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK6 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK8 MRC Cognition and Brain Sciences Unit, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Rowe
authors.affiliation: 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.affiliation: 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK9 Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000368:Aged; D000069445:Atomoxetine Hydrochloride; D001288:Attention; D003657:Decision Making / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005717:Games, Experimental; D006801:Humans; D007175:Impulsive Behavior / Q000188:drug therapy* / Q000209:etiology*; D007266:Inhibition, Psychological; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000150:complications*; D011437:Propylamines / Q000097:blood / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D014706:Verbal Learning / Q000187:drug effects
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride