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Parkinson’s disease –Non-motor treatments

Jennifer G. Goldman, M.D., M.S., FAAN, FANASection Chief, Parkinson’s Disease and Movement Disorders, Shirley Ryan AbilityLab

Director, Parkinson’s Disease and Movement Disorders Neurorehabilitation Fellowship, Shirley Ryan AbilityLabDirector, Lewy Body Dementia Association Research Center of Excellence

Professor, Department of Physical Medicine and Rehabilitation and Neurology, Northwestern University Feinberg School of Medicine

Chicago, IL

Disclosures

•Grants/research support: Acadia, Davis Phinney Foundation, Michael J. Fox Foundation, Parkinson’s

Foundation

•Consultant/advisory board: Acadia

•Honoraria: International Parkinson Disease and Movement Disorders Society, Parkinson’s

Foundation, Parkinson Study Group, World Parkinson Congress

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Recap…

Braak 2004; Langston 2006; Lim et al., 2009

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• Behavioro Moodo Cognition and dementiao Hallucinations and psychosiso Impulse control disorderso Fatigueo Apathy

• Sleepo Insomniao REM behavior disordero Excessive daytime somnolence

• Autonomic functiono Gastrointestinalo Genitourinaryo Cardiovascularo Thermoregulatoryo Dysphagiao Drooling

• Sensory/musculoskeletal functiono Olfactiono Visual systemo Paino Postureo Skin

Many non-motor features in PD

Schapira et al., Lancet Neurol 2017; Seppi et al., Mov Dis 2019; Goldman and Guerra Neurol Clinics 2020

Disease course

Kalia et al., 2015

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It takes a team approach

Person with PD

PCP

Cardiology

Gastro-enterology

Urology

Ophthalmology

Dermatology

SleepPsychiatry

Neuro-psychology

Social work

Palliative care

Caregiver support

Rehab therapies –

PM&R, PT, OT, SLP

Neuro-surgery

Neurology/

movement disorders

Radder et al., Expert Rev Neurother 2019; Jrl Parkinson Dis 2020

Approved therapeutics for neuropsychiatric symptoms in PD

Symptom FDA approved Medication

Depression ✗

Anxiety ✗

Mild cognitive impairment

✗

Dementia ✓ Rivastigmine (2006)

Psychosis ✓ Pimavanserin (2016)

Apathy ✗

Impulse control disorders

✗

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2019

Mood symptoms

DepressionAnxietyNon-motor fluctuations

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Depression

• Intrinsic, but also reactive etiology

• Neuronal degeneration in mesocortical and mesolimbic DA neuronsorbitofrontal dysfunction

• Disruption in 5HT neurons in dorsal raphe orbitofrontal-basalganglia-thalamic circuit dysfunction

• Decreased 5HT metabolites in CSF

• Decreased DA transporter activity, frontal blood flow, caudate-frontalglucose metabolism in depressed PD patients vs. non-depressed PDpatients

• Altered white matter microstructural integrity in frontal and limbicregions

• Aberrant functional connectivity in depressed PD vs. non-depressedPD patients in networks (salience, executive control, default mode)

Bejjani et al., 1999; Braak et al., 2004; Matsui et al., 2007; Kostic et al., 2010; Vriend et al., 2013; Li et al., 2020; Liao et al., 2021

Treatments for depression

• Few, large double blind, placebo controlled,randomized clinical trials

• TCAs – likely efficacious, but side effects

• SSRI/SNRIs – 3 studies vs. placebo• Nortriptyline vs. paroxetine CR vs. placebo• Desipramine vs. citalopram vs. placebo• Paroxetine vs. venlafaxine XR vs. placebo

• MAO-inhibitors• DA agonists (rotigotine - negative; pramipexole -

positive)

• 5-HTP for depression and apathy (single center, RCT,n=25)

Menza et al., 2008; Devos et al., 2009; Seppi et al., 20197; Meloni et al., 2020

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Cognitive behavioral therapy

• RCT, 10 weeks• 80 depressed PD• HAM-D 17• CBT group - greater reductions in

depression and more treatmentresponders

Dobkin et al., 2011, 2020

• 72 PD randomized to T-CBT + TAU or TAU only• T-CBT weekly for 3 months, then monthly for 6

months; trained care partners to help practice habits• Blind raters assessed outcomes• T-CBT outperformed TAU on all depression, anxiety,

and quality of life measures• Primary outcome (Ham-D) improved significantly in T-

CBT vs. TAU• Mean improvement from baseline was 6.53 points for

T-CBT and −0.27 points for TAU (p < 0.0001); gains persisted over 6-month follow-up (p < 0.0001).

Exercise and neuromodulation

Wu et al., 2017; De Lima et al., 2019; Kwok et al., 2019; Shin et al., 2016; Brys et al., 2016

• RCT, 8 weeks

• Mindfulness yoga vs. PRE

• 138 PD

• HADS

• Effective and safe

• Yoga better than PRE (p<0.001)

• Anxiety and depression

• Perceived hardship

• HR QOL

• Repetitive TMS• DLPFC• Sham-controlled• Vary in frequency, design• Mixed results

• + Shin et al., 2016 • - Brys et al., 2016

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Anxiety in PD

• Common in PD and also under recognized…

• Prevalence range: 5-40%

• Contexts:• Depression• Generalized anxiety disorder• Panic disorder• Phobias (social, agoraphobia)

• Obsessive-compulsive disorder

and as…• Non-motor fluctuations, particularly “off” state

Lauterbach et al., 2004; Pontone et al., 2009; Leentjens et al., 2011; Dissanayaka et al., 2010, 2014

Neurobiology of anxiety

• Decreased DA levels• Non-motor “offs”

• Reduced DAT availability:

• Increased anxiety correlated with lower left putamen DAT availability

• De novo PD patients with anxiety had significantly decreased DAT availability on 123I-FP-CIT in caudate and L putamen, compared to non-anxious PD patients

• Decreased 5HT and NE• Degeneration of raphe nucleus and locus ceruleus

• Limbic dysfunction: amygdala and hippocampus• Mesolimbic DA pathway projects to the amygdala

• Reduced volume on VBM

• Higher BAI total score correlated with volume of left amygdala on VBM

Weintraub et al., 2005; Erro et al., 2012; Vriend et al., 2015; Van Mierlo et al., 2015

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Treatments for anxiety

• Non-pharmacological treatment

• Psychotherapy, relaxation/biofeedback, cognitive-behavioral therapy, mindfulness

• If anxiety/panic symptoms relate to:• “Off” periods modify dopaminergic regimen

• Underlying depression use antidepressants

• Medications• Benzodiazepines with short half life - watch for sedation, falls, confusion• SSRIs - frequently used

– Citalopram - if depression also presented– EKGs

• SNRIs - may be well tolerated– Venlafaxine - can cause initial increase in anxiety symptoms– Mirtazapine - can help with sleep, weight gain; elderly

• Buspirone

Prediger et al., 2012

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Sleep symptoms

NightDay

REM sleep behavior disorder

• Safe environment• Counseling• Exclude mimics and minimize exacerbating factors

• Medications• Melatonin 3-18 mg before bedtime• Clonazepam 0.25-2 mg before bedtime• Others with anecdotal efficacy

– Dopamine agonists– Cholinesterase inhibitors: donepezil, rivastigmine– Clonidine– Carbamezapine?

• Bed alarm system

Seppi et al., 2019; McGrane et al., 2015; Jug 2016; Kakhaki et al., 2020; Videnovic et al., 2020

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Nocturnal sleep problems

Intrinsic sleep problems• Apnea

• CPAP, BiPAP

• RLS/PLMS• Dopamine agonists, gabapentin,

opioids

• Good sleep hygiene**• Sedative-hypnotics

- Eszopiclone

Nocturnal PD sxs• Controlled release

levodopa/carbidopa• Additional doses• Entacapone or C/L/E• Longer acting agonists

Medication effects– Avoid selegiline or amantadine

in evening– Decrease night-time

dopaminergic medications

Neuropsychiatric– Treat depression– Manage psychosis

Daytime sleepiness• Treat nocturnal problems including OSA

• Decrease concomitant sedating medications

• Reduce dose of dopaminergic agent

• Evaluate for other medical conditions, treat OSA (CPAP)

• Treat depression

• Counsel patients about driving

• Use activating meds?• Modafinil

• Meta-analysis of the three trials evaluating modafinil showed a significant reduction in sleepiness,as assessed by the Epworth Sleepiness Scale (ESS) (- 2.24 points, 95% CI - 3.90 to - 0.57, p < 0.05),but has not improved Mean Wakefulness Test or Mean Sleep Latency Test

• Atomoxetine

• In one study, improved ESS scores vs. placebo in PD and depression

• Caffeine

• In one study, treatment with caffeine was associated with a non-significant improvement of 1.71points in ESS (95% CI, - 3.57 to 0.13)

Postuma et al., 2012; Neikrug et al., 2014; Seppi et al., 2019

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• Approved in US and EU for EDS in narcolepsy and OSA

• Phase 2, double-blind, 4-week, crossover trial

• Doses 75, 150, 300 mg/day and placebo

• PD and EDS (n=66)

• Outcomes: Safety/tolerability (primary), ESS, MWT

• SE: nausea, dizziness, dry mouth, HA

• ESS decreased in both placebo and drug groups (p>0.05)

• MWT improved dose-dependently (p=0.0098)

• No change in motor functionVidenovic et al., 2021

Bright light therapy - mood and sleep

• Meta-analysis – 5 RCT studies

• 173 PD

• Improved depression and insomnia symptoms

Lin et al., 2021

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Behavioral symptoms

ApathyPsychosisImpulse control disorders

Apathy

Pagonabarraga et al., 2015

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Treatments of apathy

Pagonabarraga et al., 2015; Devos et al., 2014

2013

2014

2016

Onofrj et al., 2007

Neurochemical changes in DA, NE,

and 5HT

Visual system involvement

from retina to visual cortex

Relationship with REM and other sleep disturbances

Alterations in attentional networks

Medication effectsPsychosis

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Management - especially if acute

Vaughan and Goldman 2012

Management strategies for psychosis

• Treat underlying medical illness, if needed

• Discontinue medications that may exacerbate hallucinations

• Reduce or discontinue PD meds

• Non-pharmacologic strategies

• Antipsychotics

• Cholinesterase inhibitors

• AVOID DA blocking meds!

Olanow et al., 2001; Diederich et al., 2003; Goldman et al., 2011

Anticholinergics Amantadine

Selegiline, rasagalineDopamine agonists

COMT inhibitorsLevodopa

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Management - coping strategies

• Visual aids and techniques• Night lights• Redirection• Reassurance• Verification• Art therapy• Humor

Frucht 2002; Diederich et al., 2003

Treatment of psychosis

• Quetiapine• 3 DB-PC trials without change in psychosis or motor function• Low doses (12.5 – 150 mg/daily)• Insufficient data, acceptable safety, no specialized monitoring, investigational

• Clozapine• 3 DB-PC trials favoring clozapine > placebo• Low doses (6.25-100 mg/daily)• CBC monitoring, sedation, hypotension• Efficacious, acceptable safety, specialized monitoring, clinically useful

Seppi et al., 2019

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Treatment of psychosis

• Pimavanserin• 5HT-2A inverse agonist/antagonist• RCT 199 PDP patients, 6 weeks• FDA approved for PDP (April 2016), 34 mg/day• Studied in MMSE > 21, larger change in cognitive impairment

(MMSE 21-24)

• Retrospective analysis of adverse event case reports• FDA's Adverse Event Reporting System 2016 to 2019, Q3• Metrics for quetiapine, clozapine, and other atypical

antipsychotics were similar in magnitude

• Open-label extension from 3 DB-PC studies• 424 PDP patients• Continued efficacy in 4 week open label study

Cummings et al., 2014; Espay et al., 2018; Seppi et al., 2019; Brown et al., 2021; Ballard et al., 2020; Isaacson et al., 2021

Impulse control disorders

• Dopaminergic stimulation and dysfunction D2/D3• Medication effects• Imaging

• Disrupted neural-network modeling• Hyperactivity of the ventral striatum and OFC• Hypoactivity of the anterior cingulate• Altered connectivity in salience and central executive

networks

• Genetic risk?• Many polymorphisms studied but variable and contradictory

results• DRD1, 2, 3SLC22A1, DDC - associations

Voon et al., 2013; Biundo et al., 2015; Carriere et al., 2015; Santangelo et al., 2019; Kelly et al., 2020;

Meta-analytic findings: significant brain activation increases in L ventral striatum cluster and significant brain activation decrease in R anterior cingulate cortex cluster.

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Impulse control disorders

• Adjustment of PD medicationso Reduce oral DA agonist, etc

o Monitor for dopamine withdrawal syndrome

• Psychiatric managemento Antidepressants, atypical neuroleptics (antipsychotics)

• Cognitive behavioral therapy (likely efficacious,insufficient evidence, Seppi et al., 2019)

• DBS

• Research (opioid, cannibinoid, and nicotinic orother dopamine systems; naltrexone)

Pappay et al., 2014; Samuel et al., 2015

Education Prevention

Surveillance

Cognitive symptoms

Mild cognitive impairmentDementia

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Cognitive changes

Aarsland et al., 2021

Management of cognitive problems

• Objective assessments (baseline, serial)

• Exclude other causes, especially if acute (infections, mood, etc)

• Review medications (both PD and non-PD)

• Consider medications for dementia

• Non-pharmacological strategies

• Assess safety at home, driving, etc

• Discuss work, if appropriate

• Address adjustments and psychosocial impact for patient and caregiver

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Treatment for PD dementia

Only rivastigmine is FDA approved

for PDD

Aarsland et al., 2021

Treatment of PD mild cognitive impairment

Aarsland et al., 2021

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Autonomic symptoms

Blood pressureBowelsSexualThermoregulatory

Orthostatic Hypotension

• Nonpharmacological• Elevation of head of bed by

30 degrees

• Increase salt and fluid intake

• High pressure thigh/waisthigh compression stockings

• Abdominal binders

• Small frequent meals

Palma and Kauffman 2018

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Orthostatic Hypotension

• Pharmacological• Reduce antihypertensives and/or dopaminergic drugs as able

• Agents to increase blood pressure

• First line

• Fludrocortisone, doses 0.1-0.5 mg/day

• Midodrine, doses 5-10 mg TID

• Droxidopa (prodrug of NE, crosses BBB)

• Pyridostigmine, domperidone, indomethacin

GI symptoms

Palma and Kauffman 2018; Seppi et al., 2019

• Nausea/vomiting• Take meds with light snack, add extra carbidopa• Avoid DA blocking meds (metoclopramide,

prochlorperazine)• Consider domperidone, trimethobenzamide,

ondansetron

• Constipation• Exercise• Maximize dietary factors (water, fiber)• Medications:

• Colace, Senna, Bisacodyl, Magnesium sulfate, lactulose• Miralax (Polyethylene glycol): more evidence• Lubiprostone (Ondo et al., 2012)• Probiotics (Ibrahim et al., 2020; Tan et al., 2021)• Enemas

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Bladder dysfunction

• Standard agents for neurogenic bladder dysfunction• Anticholinergics: oxybutynin, tolterodine, solifenacin, etc

• Monitor for side effects (hypotension, constipation, cognition)• Solifenacin (Zesiewicz et al., 2015; DB-PC RCT, 8 weeks, no change primary

outcome)• Muscarinic agonists (bethanechol)• B3 adrenergic agonist (mirabegron)

• Catheterization• Pelvic floor physical therapy• Behavioral therapies, bladder training

• McDonald et al., 2020; 12 week RCT, improved patient perceptions but not urgency episodes

• Botulinum toxin: OnabotulinumtoxinA (FDA approved for overactive bladder)

Sakikibara et al., 2015

23 patientsDid not meet primary outcome

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Sexual dysfunction

• Few studies

• Sildenafil - DB, cross-over study

• Hussain et al., 2001

• n=24, 10 weeks, for erectile dysfunction in PD and MSA

• Improvement in ED, QoL sex life domain

• Bernard et al., 2017

• n=20, 8 weeks, for PD

• Improvement in ED (International index)

• Neither study with significant improvement on quality of life

Hussain et al., 2001; Seppi et al., 2011; Bronner et al., 2015; Bernard et al., 2017

Thermoregulatory dysfunction

• Symptoms include:• Hyperhidrosis, excessive sweating• Intolerance of hot environments• Flushing

• May relate to timing of PD medication response cycle with• “Off” or “on” periods, including peak dose dyskinesia

• Hypothalamic dysfunction

• Limited treatments – adjust meds, propranolol, cool packs

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Speech, swallowing, drooling

• Speech• LSVT-LOUD and other amplitude-based strategies• Communication strategies

• Swallowing• Speech therapy

• Drooling• Oral medications

• Amitriptyline (caution)• Glycopyrrolate

• Sublingual atropine• Ipratropium spray• Botulinum toxin

Pal et al., 2000; Mancini et al., 2003; Guidubaldi et al., 2011; Ramig et al., 2018; Cheng et al., 2019

Musculoskeletal issues

• Dopaminergics

• Anticholinergics

• Botulinum toxin injections toparaspinal muscles

• Orthotics

• PT/postural rehab

• DBS – PPN?

• Spinal stimulation?

• Variable results, small studies

Michel et al., 2015; Etoom et al., 2020

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Summary

• Multiple systems involved in PD

• Need to involve multiple disciplines and take a broad approach tomanaging PD

• Many good therapies for non-motor symptoms, but many more, andspecifically for PD, are needed

Thank you for your attention!

jgoldman02@sralab.org@JenGoldmanMD