Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson’s disease with clinical and neuroimaging measures.
Hum. Brain Mapp.. 2016-01-12; 37(3): 1026-1037
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1. Hum Brain Mapp. 2016 Mar;37(3):1026-37. doi: 10.1002/hbm.23087. Epub 2016 Jan 12.
Predicting beneficial effects of atomoxetine and citalopram on response
inhibition in Parkinson’s disease with clinical and neuroimaging measures.
Ye Z(1)(2), Rae CL(1)(3), Nombela C(1), Ham T(1), Rittman T(1), Jones PS(1),
Rodríguez PV(1), Coyle-Gilchrist I(1), Regenthal R(4), Altena E(1), Housden
CR(1), Maxwell H(1), Sahakian BJ(5)(6), Barker RA(1), Robbins TW(7)(6), Rowe
(1)Department of Clinical Neurosciences, University of Cambridge, Cambridge,
(2)Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of
Sciences, Beijing, China.
(3)Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United
(4)Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and
Toxicology, University of Leipzig, Leipzig, Germany.
(5)Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
(6)Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
(7)Department of Psychology, University of Cambridge, Cambridge, United Kingdom.
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.
© 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
PMID: 26757216 [Indexed for MEDLINE]