Improving response inhibition in Parkinson’s disease with atomoxetine.

Zheng Ye, Ellemarije Altena, Cristina Nombela, Charlotte R. Housden, Helen Maxwell, Timothy Rittman, Chelan Huddleston, Charlotte L. Rae, Ralf Regenthal, Barbara J. Sahakian, Roger A. Barker, Trevor W. Robbins, James B. Rowe
Biological Psychiatry. 2015-04-01; 77(8): 740-748
DOI: 10.1016/j.biopsych.2014.01.024

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1. Biol Psychiatry. 2015 Apr 15;77(8):740-8. doi: 10.1016/j.biopsych.2014.01.024.
Epub 2014 Feb 7.

Improving response inhibition in Parkinson’s disease with atomoxetine.

Ye Z(1), Altena E(1), Nombela C(1), Housden CR(2), Maxwell H(3), Rittman T(1),
Huddleston C(4), Rae CL(4), Regenthal R(5), Sahakian BJ(6), Barker RA(1), Robbins
TW(7), Rowe JB(8).

Author information:
(1)Department of Clinical Neurosciences, University of Cambridge, Cambridge,
United Kingdom.
(2)Department of Clinical Neurosciences, University of Cambridge, Cambridge,
United Kingdom; Cambridge Cognition Ltd, University of Cambridge, Cambridge,
United Kingdom; Behavioural and Clinical Neuroscience Institute , University of
Cambridge, Cambridge, United Kingdom.
(3)Department of Experimental Psychology, University of Cambridge, Cambridge,
United Kingdom.
(4)Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United
Kingdom.
(5)Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and
Toxicology, University of Leipzig, Leipzig, Germany.
(6)Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
(7)Department of Experimental Psychology, University of Cambridge, Cambridge,
United Kingdom; Behavioural and Clinical Neuroscience Institute, Cambridge,
United Kingdom.
(8)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. Electronic address: .

BACKGROUND: Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy
but often fail to improve cognitive problems such as impulsivity. This may be due
to the loss of other neurotransmitters, including noradrenaline, which is linked
to impulsivity and response inhibition. We therefore examined the effect of the
selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in
a stop-signal paradigm.
METHODS: This pharmacological functional magnetic resonance imaging study used a
double-blinded randomized crossover design with low-frequency inhibition trials
distributed among frequent Go trials. Twenty-one patients received 40 mg
atomoxetine or placebo. Control subjects were tested on no-drug. The effects of
disease and drug on behavioral performance, regional brain activity, and
functional connectivity were analyzed using general linear models. Anatomical
connectivity was examined using diffusion-weighted imaging.
RESULTS: Patients with Parkinson’s disease had longer stop-signal reaction times,
less stop-related activation in the right inferior frontal gyrus (RIFG), and
weaker functional connectivity between the RIFG and striatum compared with
control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion
to disease severity. Although there was no overall behavioral benefit from
atomoxetine, analyses of individual differences revealed that enhanced response
inhibition by atomoxetine was associated with increased RIFG activation and
functional frontostriatal connectivity. Improved performance was more likely in
patients with higher structural frontostriatal connectivity.
CONCLUSIONS: This study suggests that enhanced prefrontal cortical activation and
frontostriatal connectivity by atomoxetine may improve response inhibition in
Parkinson’s disease. These results point the way to new stratified clinical
trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s
disease.

Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.biopsych.2014.01.024
PMCID: PMC4384955
PMID: 24655598 [Indexed for MEDLINE]


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