TAME-PD - Physical Therapy, Atomoxetine and, Methylphenidate, to Enhance Gait and Balance in Parkinson's Disease: A Single Center, Randomized Pilot Study

Gait impairment and postural instability constitute major sources of disability in Parkinson disease (PD). Increased level of dependence in activities of daily living and augmented risk of falling are the main consequences. About 87% of patients experience at least one fall during their illness, 65% an injury that requires evaluation in an emergency room, and up to 33% sustain one or more fractures.

Pedunculopontine nucleus, locus ceruleus, frontal brain cortex, and striatum play a critical role in gait and balance, with dopamine, noradrenaline and acetylcholine as the main neurotransmitters. Therefore, increased availability of dopamine in the nigrostriatal pathway, and enhanced disposal of central noradrenaline and acetylcholine in the locus ceruleus can in theory, contribute to improvement .

Methylphenidate and atomoxetine are dopamine and noradrenaline reuptake inhibitors approved for the treatment of attention disorders. Interestingly, growing literature suggests a promising role of these medications in gait and balance in PD. Three open-label studies reported efficacy of methylphenidate in gait impairment in patients with PD. Auriel et al used a single 20 mg dose of methylphenidate in 23 patients and found an improvement in gait speed, stride time variability, and timed gait. In a second study, 5 patients received a single 10-mg dose of methylphenidate and improvements were noted in total walking time, total freezing time, number of freezing episodes, and nonfreezing walking time. Another study, which evaluated a 50 to 80 mg dose of methylphenidate over 3 months in 17 patients undergoing concomitant deep brain stimulation, found an improvement in both timed gait and in the number of freezing episodes.

However, the only randomized clinical trial with methylphenidate showed a different result. Twenty-three subjects with PD and moderate gait impairment were screened for this 6- month, placebo-controlled, double-blind study. Subjects were randomly assigned to high dose of methylphenidate (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score obtained through GAITrite (a system that was developed to measure and record temporal and spatial parameters of gait by using a walkway approximately 3 meters long with grids of embedded, pressure-sensitive sensors connected to a personal computer). Seventeen patients completed the trial. There was no change in the gait composite score or any of the secondary or exploratory variables such as fatigue, freezing, depression and daily sleepiness at 12 weeks; however, some improvement was noted in the early phase of the study.

The discrepancy between the results of the open label studies and the randomized study may be explained by dose of methylphenidate substantially higher in the RCT compared to the first two open-label studies. Whereas patients in the RCT received at least 65 mg/day, patients in the first two open-label studies received 10-20 mg/day. It is been suggested that the efficacy of methylphenidate and atomoxetine varies according to the dose administrated. The complex pharmacodynamic of dopamine and noradrenaline reuptake inhibitors in the presence of other dopaminergic therapies such as Levodopa or dopamine agonist, can elicit differences in response regarding the administered dose . During the early phase of the RCT when a trend improvement was noted, smaller doses of methylphenidate were being used as the patients were being titrated to their final dose. Low chronic doses of methylphenidate have not been tested to improve gait and balance in PD in any trial.