TAME-PD - Physical Therapy, Atomoxetine and, Methylphenidate, to Enhance Gait and Balance in Parkinson's Disease

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.

In the one pilot study thus far evaluating atomoxetine for gait freezing, a trend towards
improvement in the gait and balance scale (GABS) was noted. However, this study was
underpowered as only five patients participated in the study .

Simultaneously, diverse modalities of physical therapy (PT) have shown improvement in gait
and balance in PD. A systematic review from Cochrane database concluded that different
physiotherapy interventions were better than placebo over three months, in terms of velocity,
two- or six-minute walk test, step length, Timed Up & Go, Functional Reach Test, Berg Balance
Scale and clinician-rated UPDRS. The grade of improvement varied depending on the
intervention and outcome measure, ranging from 10 to 30%.

To the best of the investigators' knowledge, the combination of medication and physical
therapy has never been evaluated previously in gait and balance in PD.

Inclusion Criteria:

- Patients with PD having significant balance or gait disorder with a score ≥2 in the
Unified Parkinson Disease Rating Scale (UPDRS) 3.10 item 'independent walking but with
substantial gait impairment; not related to off periods' occurring despite
satisfactory motor control by dopaminergic therapy, with a medication regimen unlikely
to change in the next 30 days.

Exclusion Criteria:

- Previous participation in PD-specific PT.

- Presence of signs and symptoms suggestive of atypical parkinsonism.

- Concomitant conditions that may affect significantly the evaluation of balance or
gait, including orthopedic, rheumatologic or other neurological diseases.

- Contraindication for physical therapy

- Comorbidities that contraindicate the use of the methylphenidate or atomoxetine:
history of substance abuse, current severe anxiety, depression or psychosis, epilepsy,
hyperthyroidism, glaucoma, cardiac arrhythmia, history of Tourette syndrome, hepatic
disease, allergy to methylphenidate or atomoxetine.

- Concurrent use of MAO inhibitors, or use in the last two weeks.

- Previous deep brain stimulation procedure.

- Punctuation of 5 in Hoehn and Yard modified scale: 'Wheelchair bound or bedridden
unless aided'.