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. Hum Brain Mapp 37:1026–1037, 2016. © 2016 Wiley Periodicals, Inc.
Highlights
There is increasing interest in the development of stratified medicine in neurology and psychiatry, driven by the recognition of patient-to-patient heterogeneity in clinical symptoms and treatment responses [Matthews et al, 2014; Schumann et al, 2014; Stephan et al, 2015]
Previous research has demonstrated that selective noradrenaline and serotonin reuptake inhibitors can improve response inhibition in a subgroup of patients with Parkinson’s disease
This study focuses on response inhibition, in part because of the wealth of animal studies and patient data using response inhibition tasks, and because the potential benefit of atomoxetine has been shown to generalize to other forms of impulsivity [Kehagia et al, 2014]
Summary
There is increasing interest in the development of stratified medicine in neurology and psychiatry, driven by the recognition of patient-to-patient heterogeneity in clinical symptoms and treatment responses [Matthews et al, 2014; Schumann et al, 2014; Stephan et al, 2015]. The objective of patient stratification is to identify likely responders from nonresponders to maximize the likely efficacy and cost-effectiveness of a given treatment. It uses demographic and clinical measures but these may be combined with biomarkers such as brain imaging or genotype. We aimed to build predictive models to identify patient responders in the context of Parkinson’s disease, examining the potential of novel noradrenergic and serotonergic therapies for impulsivity. We take a step further to predict the behavioral impact of the drugs in a larger patient cohort, using basic clinical and imaging measures. The approach is not limited to these drugs or to Parkinson’s disease, but could be implemented in other clinical trials
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