title: Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures.
abstract: Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double-blind randomized three-way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion-weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave-one-out cross-validation (LOOCV) to predict patients' responses in terms of improved stopping efficiency. We identified two optimal models: (1) a "clinical" model that predicted the response of an individual patient with 77-79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion-weighted imaging scan; and (2) a "mechanistic" model that explained the behavioral response with 85% accuracy for each drug, using drug-induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.|Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.|Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Rae
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nombela
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ham
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rittman
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Peter Simon
authors.initials: PS
authors.lastname: Jones
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Patricia Vázquez
authors.initials: PV
authors.lastname: Rodríguez
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Coyle-Gilchrist
authors.affiliation: Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Regenthal
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ellemarije
authors.initials: E
authors.lastname: Altena
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Housden
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Maxwell
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.|Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, United Kingdom.|Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.|Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom.|Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000368:Aged; D000069445:Atomoxetine Hydrochloride / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015283:Citalopram / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011379:Prognosis; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011619:Psychotropic Drugs / Q000627:therapeutic use*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D015283:Citalopram; D011619:Psychotropic Drugs; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Parkinson's disease; impulsivity; machine learning; noradrenaline; response inhibition; serotonin; stratification