A Multidisciplinary Approach to Manage Gait Difficulty in Parkinson Patients

The study team proposes to treat parkinsonian patients with gait difficulty of FOG with the SNRI anti-anxiety medication duloxetine for 4 weeks, followed by an additional anti-dementia medication donepezil for 2 weeks to determine whether antianxiety treatment alone or in combination with the anti-dementia medication can improve gait. Another medication with GABA antagonist property targeting the gait controlling area PPNa (and improving anxiety and cognition as well), modafinil, will be tried for 2 weeks after a 4-week washout period of the previous medications. Specifically, the investigators will propose an open label prospective pilot study using duloxetine to treat 22 parkinsonian patients with FOG, aiming for estimated 80% power of detecting 50%. Each patient will take duloxetine 30mg for 1 week, followed by 60mg qam for 1 week, 90mg qam for 1 week, and 120mg qam for 1 week, if tolerated. The patient will be taking duloxetine for a total of 4 weeks, as described above. The dose of duloxetine will be reduced if the patient cannot tolerate a higher rank dose as designated. This principle will apply to the other two medications used in the study as well. Donepezil will then be added to duloxetine 120mg qam (or the highest dose the patient can tolerate if it is lower than 120mg) by 5mg qd for 1 week, followed by 10mg qd for 1 week. Each patient will visit us 3 times (baseline and at the end of each medication, namely 4 weeks after the duloxetine and 2 weeks after the donepezil), checking UPDRS-III (and PSP scale as well for PSP patients), stand-walk-sit, freezing of gait questionnaire, Montreal cognitive scale (MoCA) for patients before and after Donepezil treatment, and anxiety scale for patients before and after duloxetine treatment (if the patient is on dopaminergic medication). Daily falls, freezing of gait (by the questionnaire) and quality of life (by PDQ-39 scale) over the past week prior to the clinical visit will also be checked. After a 4-week washout period, each patient will take modafinil 100mg qam for 1 week, followed by 200mg qam for 1 week. Each patient will visit us twice (baseline at the end of the 4-week washout period, and at the end of the 2-week modafinil treatment), checking UPDRS (and PSP scale as well if for PSP patient), stand-walk-sit, freezing of gait questionnaire, MoCA, anxiety scale and Epworth sleep scale at each visit before and 1 hour after the dopaminergic medication(s) (if the patient is on dopaminergic medication). Daily falls, freezing of gait and quality of life (by PDQ-39) over the past week prior to the clinical visit will also be checked. A paired t-test will be used to compare the changes under each regimen with that at baseline, with primary outcome on gait difficulty of FOG frequency and severity, and secondary outcome on anxiety, cognition, UPDRS-III (plus PSP scale for PSP patients), and Epworth sleep scale (for modafinil trial) at dopaminergic medication off (after staying off the dopaminergic medication for over night) and on (1 hour after taking dopaminergic medication) state and quality of life assessment. The investigators want to see if the medications of different working mechanism, along or in combination, could improve the FOG and other motor symptoms, through the improvement of anxiety, cognitive dysfunction and wakening state at dopaminergic medications (for parkinsonism) off state and on state.