Pilot study of atomoxetine in patients with Parkinson’s disease and dopa-unresponsive Freezing of Gait

Abstract

BackgroundFreezing of gait (FoG) is a common and debilitating condition in Parkinson’s disease (PD) associated with executive dysfunction. A subtype of FoG does not respond to dopaminergic therapy and may be related to noradrenergic deficiency. This pilot study explores the effects of atomoxetine on gait in PD patients with dopa-unresponsive FoG using a novel paradigm for objective gait assessment.FindingsTen patients with PD and dopa-unresponsive FoG were enrolled in this eight-week open label pilot study. Assessments included an exploratory gait analysis protocol that quantified spatiotemporal parameters during straight-away walking and turning, while performing a dual task. Clinical, and subjective assessments of gait, quality of life, and safety were also administered. The primary outcome was a validated subjective assessment for FoG (FOG-Q). Atomoxetine was well tolerated, however, no significant change was observed in the primary outcome. The gait analysis protocol correlated well with clinical scales, but not with subjective assessments. DBS patients were more likely to increase gait velocity (p = 0.033), and improved in other clinical assessments.ConclusionsObjective gait analysis protocols assessing gait while dual tasking are feasible and useful for this patient population, and may be superior correlates of FoG severity than subjective measures. These findings can inform future trials in this population.

Changing views of the pathophysiology of Parkinsonism

“…146 Neurochemically, FOG may be associated with changes in the norepinephrine 147 and/or cholinergic systems. 148 The former is supported by the finding that the catecholaminergic locus coeruleus appears to be damaged in parkinsonian monkeys that show FOG (compared to those without FOG), 149 by neuromelanin MRI findings in parkinsonian patients with and without FOG, 150 and by the (empirically determined) effectiveness of medications that alters catecholamine release or levels in the brain, such as atomoxetine, 151,152 or L-threo-DOPS. [153][154][155][156] Cholinergic dysfunction is implicated by imaging studies that show cholinergic loss in cortical regions, 148,157 and in the striatum 157 of patients with FOG.…”

Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

“…However, a randomized double-blind, placebo-controlled study enrolled 5 patients did not find its efficiency on FOG [87]. Another eight-week open label study enrolled 10 PD patients with dopamine-unresponsive FOG also failed to demonstrate its efficiency [88].…”

Future Therapeutic Strategies for Freezing of Gait in Parkinson’s Disease

“…Drugs that enhance noradrenergic transmission have also been investigated for FOG, given its possible association with noradrenergic neuron loss in the locus coeruleus ( Rommelfanger and Weinshenker, 2007 ; Ono et al, 2016 ). However, current trials have been disappointing including two small, randomised studies of Atomoxetine, a selective noradrenaline reuptake inhibitor, which failed to improve dopamine-resistant FOG ( Jankovic, 2009 ; Revuelta et al, 2015 ). Limited open-label data for droxidopa (L-threo-3,4-dihydroxyphenylserine), a noradrenaline precursor licensed for use for orthostatic hypotension, has suggested that it may be useful in combination with entacapone for treating dopamine-resistant FOG ( Fukada et al, 2013 ).…”