Advanced

Improving response inhibition in Parkinson's disease with atomoxetine

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L; Regenthal, Ralf and Sahakian, Barbara J, et al. (2015) In Biological Psychiatry 77(8). p.8-740
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
@article{88924004-9efc-46dd-8af9-c8e32bebce70,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Ye, Zheng and Altena, Ellemarije and Nombela, Cristina and Housden, Charlotte R and Maxwell, Helen and Rittman, Timothy and Huddleston, Chelan and Rae, Charlotte L and Regenthal, Ralf and Sahakian, Barbara J and Barker, Roger A and Robbins, Trevor W and Rowe, James B},
  issn         = {0006-3223},
  keyword      = {Adrenergic Uptake Inhibitors,Aged,Aged, 80 and over,Atomoxetine Hydrochloride,Brain,Choice Behavior,Cognition Disorders,Cross-Sectional Studies,Double-Blind Method,Female,Humans,Image Processing, Computer-Assisted,Inhibition (Psychology),Male,Middle Aged,Neural Pathways,Neuropsychological Tests,Oxygen,Parkinson Disease,Reaction Time,Journal Article,Randomized Controlled Trial,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {04},
  number       = {8},
  pages        = {8--740},
  publisher    = {Society of Biological Psychiatry Published by Elsevier Inc.},
  series       = {Biological Psychiatry},
  title        = {Improving response inhibition in Parkinson's disease with atomoxetine},
  url          = {http://dx.doi.org/10.1016/j.biopsych.2014.01.024},
  volume       = {77},
  year         = {2015},
}