Download the parkinson`s challenge: the road to a better future

THE PARKINSON’S
CHALLENGE: THE ROAD
TO A BETTER FUTURE
Va n e s s a K . H i n s o n ,
MD, PhD
P r o f es s o r o f
Neurology
Medical University
of South Carolina
ROADMAP TO PD RESEARCH
Where are we today?
Where do we need to go?
How do we get there?
WHERE ARE WE TODAY?
 PD: Second most common neurodegenerative disorder
 1 million people in US affected
 43,000 people with PD live in the Carolinas!
WHERE ARE WE TODAY?
WHAT CAUSES PD?
Combination of genetic predisposition and environmental toxins
Examples of harmful toxins:
Manganese, pesticides, insecticides (permethrin,) herbicides (paraquat),
Fungicides (maneb), Agent Orange.
WHAT HAPPENS AT THE BRAIN LEVEL?
 Malfunction and
death of vital nerve
cells in the brain
called neurons
 These neurons
produce a chemical,
dopamine, necessary
for movement and
coordination
 Loss of >50% of
dopamine neurons:
onset of motor
symptoms
WHY DO DOPAMINE CELLS DIE?
 Aging and toxins:
damage to energy
factories of cells
 Damaged factories emit
toxic waste: free
radicals
 Free radicals kill brain
cells
 Genetics and aging:
protein clumps form
 Impaired garbage
disposal system
 Protein clumps kill
brain cells
T YPICAL MOTOR SYMPTOMS OF PD
Tremor
Slowness of movement
Stiffness
Impaired balance and coordination
Shuffling gait
NON MOTOR SYMPTOMS OF PD
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Anxiety
Depression
Cognitive impairment
Constipation
Swallowing problems
Drooling
Urinary issues
Sleep disorders
Dizziness
Syncope
Pain
HOW DO WE TREAT PD SYMPTOMS
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Carbidopa/Levodopa (Sinemet, Rytary,)
Dopamine agonists (Requip, Mirapex, Apomorphine)
COMT inhibitors (Comtan, Stalevo, Tasmar)
MAO B inhibitors (Azilect, Selegiline, Zelapar)
Amantadine
Anticholinergics (Artane)
Procholinergics (Rivastigmine, donepezil)
Blood pressure modulators: Droxidopa, midodrine
Antipsychotics: Quetiapine, clozaril
Treatment of RBD: clonazepam
WHERE DO WE NEED TO GO
WHY IS RESEARCH NECESSARY
 Treatment refractory symptoms remain frustrating
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Dyskinesias
Orthostatic hypotension
Freezing of gait
Balance problems and falls
Cognitive decline and dementia
Apathy
 No definitive diagnostic test
 No cure
RESEARCH
IMPROVING EXISTING THERAPIES
 Rytary
 FDA approved 2015
 Capsules containing time release beads
 Designed to kick in quicker and last longer
 Helpful for people with motor fluctuations, off time,
dyskinesia
 A reduction of dose frequency is often possible (but
not a pill reduction)
 Crossing over from “regular” Sinemet requires careful
calculation. Not interchangeable.
RESEARCH
IMPROVING EXISTING THERAPIES
 DUOPA (levodopa pump)
 FDA approved 2015 for
the treatment of motor
fluctuations in advanced
Parkinson’s Disease
Infusion pump delivers small
amounts of carbidopa/levodopa
directly into the small intestine
DUOPA: PRACTICAL CONSIDERATIONS
 Start the morning using a new cassette
 Early morning booster dose
 Continuous dose
 Extra as needed doses
 Disconnect pump after 16 hours
 Take by mouth nighttime
medication
SAFET Y AND EFFICACY OF DUOPA
 ….established in a 12
week double blind
randomized trial
 People on Duopa had a 4
hour reduction in their
daily “of f” time
 ….and a 4 hour increase
in “on” time without
troublesome dyskinesia
RESEARCH
IMPROVING EXISTING THERAPIES
Pump- Patch system (in research): Microneedles inject levodopa under the skin
RESEARCH
IMPROVING EXISTING THERAPIES
 Levodopa inhaler (in clinical trials now)
 Concept as a fast working rescue drug for off time
 The device is similar to an inhaler used to treat asthma
 Who can participate in this trial: people who are experiencing
bothersome off time
 Participants will come in for 7 visits over 3-4 months
 Randomized to either receive study drug (chance 2/3 ) or placebo
(1/3)
 During the treatment period, people will use the inhaler to treat
their off episodes up to 5 times a day.
Medical University of South Carolina (MUSC) is a study site
RESEARCH
IMPROVING EXISTING THERAPIES
 Sublingual apomorphine (in clinical trials now)
 Sucutanous apomorphine already available
 Injections for treating off episodes
 Sublingual form: designed for better
tolerability , but also fast onset
Medical University of South Carolina (MUSC) is being initiated as a study site
RESEARCH
TREATMENTS BEYOND DOPAMINE
 Kyowa- A2A antagonist study
 New class of drugs that do not work on the dopamine receptor
 Adenosine 2a receptors are co-located with dopamine
receptors on neurons
 One can either activate the dopamine receptor or block the
neighboring adenosine receptor to achieve benefit in PD
 Goal: Reduce of f time without escalating dyskinesia
Medical University of South Carolina (MUSC) is a study site
RESEARCH
TREATMENTS BEYOND DOPAMINE
Zarow et al. Arch of neurology 2003
Loss of locus ceruleus neurons: Cognitive impairment , dementia
Neurons are supposed to produce noradrenaline
Noradrenaline deficiency
RESEARCH
TREATMENTS BEYOND DOPAMINE
 Atomoxetine (noradrenaline reuptake inhibitor)
 In research for mild cognitive dysfunction in PD
 MUSC study (ATM cog) showed subjective improvement of
ability to pay attention and focus on atomoxetine compared to
placebo
 Droxidopa (pro-drug of noradrenaline)
 Crosses BB barrier and gets converted to noradrenaline
 Approved for low BP in PD
 Being looked at as a potential study drug for PD cognitive
impairment
RESEARCH
BIOMARKERS
 Biomarkers: biological clues to the risk, onset, or progression
of a disease
 No biomarkers are available in PD
 If we want to modify or stop the progression of PD, we need to
intervene early
RESEARCH
BIOMARKERS
RESEARCH
BIOMARKERS
 Alpha-synuclein: toxic, misfolded protein that
accumulates and kills brain cells
in PD
 Brain imaging:
RESEARCH
BIOMARKERS
 Tissue biopsies
 Alpha-synuclein has been found in
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Salivary glands
Stomach
Duodenum
Colon
Rectum
 Rush University:
 Alpha synuclein was found in colon in
3 people who later developed PD
RESEARCH
NEUROPROTECTION: DELAY OR STOP PD
How to catch the bad guy
therapies aimed at alpha-synuclein
Stabilizing healthy alpha-synuclein,
Preventing “misfolding”
Enhancing the clearance of alpha-synuclein
Eliminating alpha-synuclein
ALPHA-SYNUCLEIN
 Protein in the human brain
 Plays a role in cell to cell
communication
 May not be crucial for
proper cell function
 Misfolded alpha synuclein
kills brain cells in PD
CELL-TO-CELL TRANSMISSION OF MISFOLDED
ALPHA-SYNUCLEIN?
VACCINES
 Austrian Company AFFiRiS completed the first PD vaccine trial
 Evaluating a vaccine against the toxic protein alpha-synuclein
 Goal: Help people with PD make antibodies against alphasynuclein, so they can clear it from their bodies
 24 patients were injected
 Vaccine seemed safe, was able to induce antibodies and
seemed to lead to disease stabilization
 Path forward:
 Boosters are now given to same subjects
 Slightly different vaccine will be tested
in same protocol
VACCINES
 Prothena
 Infusion of antibody directed against the alpha-synuclein
protein
 In healthy people , this was found to be safe and reduce asynuclein levels up to 96%!
 Trial in PD on the way with sites in FL, TX,CN, MI, CA .
Cancer Drug Helps Parkinson's Patients
by Maggie Foxand Erika Edwards
Parkinson's patients 'walk and talk
again' after receiving cancer drug in trial
Professor who led the study says 'we've seen patients at
end stages of the disease coming back to life'
Nilotinib
NILOTINIB: SEEMS TO STIMULATE THE
CELLULAR GARBAGE DISPOSAL SYSTEM
CANCER DRUG IN PD
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Phase I study in 1 2 subjects with PD and DLB
Open label
6m duration
No control group
Powered to assess safety, not ef ficacy
People “relapsed” af ter stopping the drug
Cost currently ~ $10,000 per month
 Good news: Drug was well tolerated and no serious side ef fects
were obser ved
 Biomarker s indicated that toxic proteins might be reduced by drug
 Some study patients felt subjectively better-motor and cognition
wise
 Georgetown U is planning a larger and more long-term controlled
study
BLOOD PRESSURE MEDICATIONS AND
PARKINSON’S DISEASE
Population studies have shown that long-term
use of calcium channel blockers is associated
with a reduced risk of Parkinson disease.
WHY CAN BP MEDICATIONS HELP
PARKINSON’S?
 A lack of healthy dopamine neurons in the brain is the
major cause of the motor symptoms of PD
 Dopaminergic nerve cells have their own pacemaking
rhythms.
 These special rhythms are driven by the chemical channels
that are either sodium or calcium.
 With age, these neurons increasingly rely on calcium
channels, which is more energy demanding….
 Reliance on calcium creates a lot of ‘wear and tear’ on
dopamine neurons-aging them more rapidly and making
them vulnerable.
ISRADIPINE: CALCIUM CHANNEL BLOCKER
AND BP MED
 The special rhythm properties can be reversed back to
Sodium with the use of isradipine – a Calcium channel
blocking agent and BP medication!
ISRADIPINE AND PD
STEADY PD
 FDA approved medication for blood pressure
 Isradipine prevented development of parkinsonian signs
in mice treated with toxins that usually are used to
reproduce PD signs in animals
 STEADY-PD is a Phase III trial for people with newly
diagnosed PD who have not yet started symptom
treatment
 People will be followed for 3 years and are allowed to
start symptom treatment one in the trial
 We will establish whether isradipine is ef fective at
slowing the progression of PD
Medical University of South Carolina (MUSC) is a study site
GOUT AND PD
INOSINE
 Elevated urate levels can cause gout----yikes
 But… urate is also a potent anti-oxidant that can help
brain cells become more resistant to stress and live longer
 Seems to be protective in PD
 Safe PD study established that inosine (a urate precurser)
safely elevates urate in PD
 Large phase III study was just funded by NIH and will start up
in early 2016
NEUROPROTECTION
Cell transplantation
Stem cells
Gene therapy
CELL TRANSPLANTATION
Cell transplantation:
>15 y ago: fetal midbrain cells were
transplanted into PD patients
Good graft survival
But: Dyskinesias, Lewy bodies in grafted cells
2 living patients doing well off meds
Transeuro: Plan to graft early disease
STEM CELLS
 No current clinical trials in the US
 Trials recruiting in China and Mexico (using bone-marrow and adipose
tissue derived cells)
GENE THERAPY
 Viral vector technology
 Benign virus is used to deliver the gene to
 1.Increase dopamine production
 2.Bypass the need for dopamine
 3.Provide neuroprotection
GROWTH FACTORS
 GDNF open label direct brain injection trials promising
 Double-blind trial was stopped because of safety
concerns (antibody formation)
 Revised phase I enrolling now at NIH, AAV2 vector
 PD >5y, followed for 5 years
 Neurturin
 Modest , short lasting effect
 Might be more effective in early PD, and in higher doses
 Phase II redesigned trial ongoing now
IN SUMMARY
 Early diagnosis through advanced imaging technologies or
other biomarkers in near future
 Earlier intervention will make treatments more ef fective
 Better understanding of biology of PD helps formulate new
therapies such as PD vaccine
 Many improvements have been made or are on the way for
existing therapies
 Research is going on now, don’t wait
PARTICIPATE!
ON ‘BACK TO THE FUTURE DAY,’ MICHAEL J.
FOX IMAGINES A WORLD WITHOUT
PARKINSON’S
 "Together, we’ll make neurological illness a thing of the past.
And if we all eventually get hoverboards, well—that's a bonus,"
Fox
Motor Problems: Medical &
Surgical Solutions
Gonzalo J. Revuelta, MS, DO, FANA
Associate Professor
Medical Director, Deep Brain Stimulation
MUSC
Outline
• Motor symptoms defined
• How to communicate with your doctor about
motor symptoms
• Medical therapies for motor symptoms
• Surgical therapies for motor symptoms
Objectives
• Understand how your doctor sees your motor
symptoms
• Learn to communicate with your doctor
effectively about your motor symptoms
• Know what to expect from each treatment
Motor Symptoms in PD
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Shaking
Slowness
Stiffness
Cramping
Drawing
“dancing”
Worsening posture
Shuffling
Balance difficulty
Freezing
Bradykinesia: slowness
• Universal in PD: have to have it for the
diagnosis
• Usually more on one side than the other
• Can also be more general
• Affects most tasks from fine motor to walking
Tremor
• Rest tremor: “when you’re not
using it”
• Can also be present with posture,
but it is thought to be the rest
tremor that re-emerges
• Some patients can have more
than one type of tremor (essential
tremor)
• Some patients where tremor is
the biggest problem are thought
to have a different subtype of PD:
tremor predominant PD
Rigidity
Difficulty fully relaxing
Can be more on one side than the other
Can lead to reduced arm swing when walking
Can lead to reduced range of motion around
joints
• Can lead to worsening posture
•
•
•
•
Dystonia
• This is described by patients
are drawing, pulling or
cramping
• Commonly seen in: toes,
foot, hands (cupping), eyes
(blepharospasm), neck/back
• Important to note when it
occurs in relation to
medication dosing
Dyskinesia
• Described by patients as writhing, swaying,
wiggling or “dancing”
• This is caused by too much medicine at one
point in time, but can happen at the end of
dose too
• Patients may not notice it at first, may or may
not be troublesome
Postural Instability
•
•
•
•
Balance difficulty
Tendency to fall backwards
Retropulsion
Common cause of falls
“Shuffling”
• Tendency to drag feet when walking
• Short steps
• Narrow stance
Freezing
• “glued to the floor”
• “can’t get started”
• Triggered by:
– Turns
– Doorways
– Cramped spaces
– Crowds
Festination
• Forward shift of center of
gravity
• Go from walking to
running pace
• Leads to falls commonly
Medical Solutions: Levodopa
• 1911: First synthesis of D/L-Dopa
• 1950’s: Arvid Carlsson
– discovers dopamine in the brain
– Realizes that dopamine deficiency causes
Parkinson’s symptoms
– 2000 Nobel Prize in Medicine and Physiology
• Tretiakov
• 1960’s: George Cotzias
– First clinical trials of IV low dose L-dopa
– First successful report of high dose L-dopa
• 1971: L dopa approved by FDA
• 1973: Sinemet approved by FDA
Medications Currently available to
treat Parkinson’s Disease
Dopamine formulations:
• Carbidopa/levodopa
(Sinemet)
• Sinemet CR
• Rytary
• Levodopa intestinal
gel
MAO-I’s
Selegiline (Zelapar)
Rasagiline (Azilect)
COMT-I’s
Entacapone (Comtan)
Tolcapone (Tasmar)
Dopamine agonists:
Bromocriptine
Mirapex (pramipexole)
Requip (ropinarole)
Requip XL
Mirapex ER
Neupro Patch (rotigotine)
Apokyn (apomorphine)
Anticholinergics:
Trihexyphenidyl (Artane)
Benztropine (Cogentin)
Mixed Mechanism:
Amantadine
Dopa-responsive symptoms
•
•
•
•
•
•
Bradykinesia
Rigidity
Tremor (~50%)
Can improve walking speed
Dystonia (if off)
Freezing (if off)
Dopa-related symptoms
• Dyskinesias, peak dose of biphasic
• On-dystonia
• Wearing off (motor fluctuations)
Non-dopa responsive symptoms
• Postural Instability
• Some types of freezing of gait
• Festination
Plasma LD Concentrations
Motor fluctuations
Dyskinesia
threshold
Therapeutic
window
Efficacy
threshold
“on”
Early disease
“off”
“on”
“off”
Moderate disease
Time (y)
“on”
“off”
Advanced disease
Surgical Solutions to Motor Problems
• Lesioning
• Deep Brain Stimulation
• Levodopa Intestinal Gel
How DBS came about
• 1947-First pallidotomy
• 1955-First thalamotomy for tremorLDOPA
• 1979-animal models
• 1980’s-understanding circuits
• 1989-Thalamic DBS for tremor
• 1997-FDA approves Vim DBS for ET
• 2001-FDA approves STN DBS for PD
• 2015-FDA approves Duopa
Talan 2009
Current state of symptomatic therapy
for Motor symptoms in PD
• Levodopa based therapies are very effective at
treating most symptoms
• Difficult tremors can be effectively treated
with DBS
• Motor fluctuations and dyskinesias are
effectively treated with medications, DBS and
Duopa
• What about walking?
Treatment of Gait dysfunction in PD
• Multidisciplinary approach: PT, meds, surg
• Educate yourself about the types of gait
difficulties (freezing, festinating, balance) and
communicate them to your doctor
• Note relationship to your medication to
maximize treatment of dopa-responsive sx:
diaries
• Recognize situations with high fall risk
Theories for Gait dysfunction in PD
• Walking is no longer automatic
• Very difficult to focus on each step, speed,
posture, and adjust to surrounding
• Strategy is to practice to create new motor
programs that make gait automatic again
• Research underway to understand the
pathways in the brain that are involved and
how they can be modulated
Thank You!
Q & A – Dr. Revuelta & Dr. Hinson
NOTES:
Not Just a Movement Disorder:
Exploring the Non-Motor Features
of Parkinson’s Disease
Christina L. Vaughan, M.D., M.H.S.
Assistant Professor
Department of Neurology
Medical University of South Carolina
November 7, 2015
PD: More than a Movement Disorder
Motor
Features
Non-Motor Features
Slowness
Cognitive changes
Rigidity
Orthostatic hypotension
Tremor (+/-)
Constipation
Imbalance
Excessive sweating
Mood disturbance
Urinary urgency, frequency
Loss of sense of smell
Sleep disorders
Sensory changes (pain, tightness, tingling, burning, cramping)
Fatigue
Apathy/poor motivation
Psychosis
Non-motor features of PD
• Non-motor features of PD
are often underrecognized by clinicians
• Non-motor (and nonlevodopa responsive)
symptoms predominate
at 15 years
• Also occur often in people
w/o PD – normal aging
Pfeiffer 2015; Fernandez 2012 & Shulman et al 2002
Non-motor features of PD
• Presenting clinical
complaint in >20%
• May show pattern of
fluctuation
– May delay PD diagnosis
– Pain likely attributed to
orthopedic or
rheumatologic cause
– May appear years (or
decades) before classic
motor features
– ex: during motor OFF
periods
– ~30% report worse
disability from nonmotor (rather than
motor) fluctuations
O'Sullivan et al 2008; Pfeiffer 2015; Witjas et al 2002
Overview: Non-motor features PD
1. Abnormalities of sensation
2. Behavioral changes
a) Impulse Control Disorders
b) Psychosis
c) Cognitive disorders
3. Autonomic dysfunction
4. Sleep disturbances
5. Fatigue
PD: Abnormalities of sensation
• Impaired sense of smell =
most widely recognized
(~90% of people with PD)
– 70% may be unaware of
this loss
– May be useful in screening
(coffee, peppermint, anise)
• Vision problems
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–
–
–
↓Contrast sensitivity
↓ Color discrimination
Convergence insufficiency
Dry eye syndrome
• More common seborrheic
blepharitis, gland disease
• Thinning of retinal nerve
fiber layer and inner
retinal fovea
• Alpha synuclein deposits
in inner retina
Casjens et al 2013; Nowacka et al 2014; Bodis-Wollner et al 2014
PD: Abnormalities of sensation
• Pain (76%)
Musculoskeletal (50%)
Radicular or neuropathic
Dystonia-related
1* or central
parkinsonian
– Akathitic (restless)
discomfort
–
–
–
–
• 1* PD pain
– Due to OFF period
dystonia, related to
dyskinesia, or central
pain
• 2* PD pain
– Musculoskeletal
– Orofacial
– Limb & abdominal pain
Valkovic et al 2015; Pfeiffer 2015
PD: Behavioral changes
• Depression (major:
17%, minor 22%,
dysthymia 13%)
• Anxiety (25-40%)
• Apathy (40%) = lack of
interest, enthusiasm, or
concern; indifference
– Difficult to differentiate
from depression and
fatigue
– Often frustrating for
care-givers
Riejnders et al 2008; Simuni et al 2013; Den Brock et al 2015
PD: Impulse Control Disorders
• Group of behaviors — gambling, shopping,
eating and sexual behaviors — that are
compulsive or impulsive in nature
• ~14% PD patients: > 1 of these behaviors
• Sexual behavior: men>women
• Compulsive shopping or eating: women>men
pdf.org
PD: Impulse Control Disorders
• Most strongly linked to dopamine agonists
– Levodopa may also be associated
• Onset could be with start of new drug or 1-2
years later
• Treatment:
– Sometime subside without intervention
– Reduce dopamine agonist or discontinue
– Psychiatric interventions
– DBS?
PD: Psychosis
• Frequent: ~1/3 on
chronic dopaminergic
therapy
• Common reason for
emergency room visits
• ↑care-giver stress,
worsened quality of life
• Distinguishable in PD
From Frucht & Bernsohn 2002
PD: Psychosis
Common Types
Definition/Examples
Illusions
Misinterpreting something that is really
there;
ex: mistaking a bedpost for a tree
Passage hallucinations
Sensation of a figure passing in the
peripheral visual field
Presence hallucinations
Sensation of someone’s presence when
nobody is there
Formed hallucinations
Occur during wakefulness; can be
pleasant or frightening;
ex: children or small animals
Delusions
False fixed beliefs not based in reality;
ex: spousal infidelity, paranoia, stealing
Vaughan & Goldman 2013
PD: Psychosis – Risk Factors
Older age
Older age at PD onset
Higher amounts of levodopa (or equivalent)
Lower cognitive status
Dementia
Depression
Sleep disturbances (e.g. REM sleep behavioral
disorder)
• Time/advanced disease
• Multiple coexistent medical problems
•
•
•
•
•
•
•
Vaughan & Goldman 2013
PD: Psychosis - Evaluation
• Early hallucinations (<12 months or before
dopaminergic drugs are introduced), may
indicate Dementia with Lewy Bodies (DLB)
– “1-year rule”
– DLB patients may have marked sensitivity to
antipsychotic medications
PD: Psychosis - Evaluation
• Possible causes/contributors:
Infection (ex: UTI, pneumonia)
Systemic illness
Centrally acting medication (sedative, anticholinergic)
Metabolic abnormalities (kidney, liver, blood sugar,
dehydration)
– Overdose of medication/intoxication
– Structural lesion (stroke, bleed, trauma)
– Sensory abnormalities (poor vision or hearing)
–
–
–
–
PD: Psychosis - Treatment
• Most efficacious is clozapine (Clozaril)
– Effective dose of clozapine is usually relatively low:
6.25 - 50 mg/day
– Requires weekly blood draw for at least 6 months
due to risk of low white blood cell count (<0.4%
chance)
• Quetiapine (Seroquel) may also be effective
– Effective dose of quetiapine: 25 mg twice a day or
50 mg at night, but many physicians use up to
100-200 mg/night
PD: Cognitive disorder
• Mild cognitive
impairment ~25% in
early PD
• Dementia ~80% for
those with >20 yrs of
PD
• Note: if dementia
precedes parkinsonism,
consider Lewy Body
Disease
Hely et al 2008; Stefanova et al 2015
PD: Cognitive disorder
• Risk factors for PD Dementia
– Age
– Motor severity
– Older age at PD onset
– Longer PD duration
– No tremor > tremor
– Hallucinations
– Depression +/– APOE4 and genetic forms of PD +/-
PD: Cognitive disorder
• Executive dysfunction: problem solving, making
plans, formulating goals, anticipating
consequences
• Attention difficulties
• Slowed thinking
• Word-finding trouble
• Difficulty learning and remembering information
• Visuospatial trouble: where things are in space
PD: Cognitive disorder
• Treatment
– Exclude other medical
causes of cognitive
problems, especially if
acute
– Address safety and caregiver issues
– Driving evaluations
• Cholinesterase
inhibitors:
1. donepezil (Aricept),
2. Galantamine
(Razadyne),
3. rivastigmine (Exelon)
• NMDA antagonists:
1. memantine (Namenda)
PD: Autonomic Dysfunction
• Prevalence ~ 14-80%
• Manifests most often as:
– orthostatic hypotension
– constipation
– urinary dysfunction
– sexual dysfunction
• If these features are significant early in the
course of the disease, then atypical forms of
parkinsonism should be considered
PD: Orthostatic hypotension (OH)
• Definition:
If symptomatic:
– ↓(systolic blood pressure) > • lightheadedness
20
• fatigue
– and/or ↓(diastolic blood
• unsteadiness
pressure) > 10 after a 3
minute delay
• generalized weakness
– When changing from sitting
• visual blurring
to standing
• headache
• neck tightness
• Prevalence 20% - 60%
• cognitive slowing
– Minority are symptomatic
• leg buckling
• “coat-hanger” headache
• gradual or sudden loss of
consciousness
PD: Orthostatic hypotension (OH)
• Associated with:
– Disease duration
– Disease severity
– Use of higher daily levodopa doses
– Older age
• Increased risk of falls
PD: OH Treatment
•
•
•
•
•
Hydration
Arising slowly
Elevated head of bed
Compression stockings
Medication adjustments
Figueroa et al 2010
PD: GI dysfunction
• Swallowing difficulty
(dysphagia)
• Bowel dysfunction
– ↓Frequency
– Difficulty with the act of
defecation
• Less
frequent/inefficient
swallowing drooling
or aspiration
• Gastroparesis (delayed
gastric emptying)
– early satiety, reduced
appetite, bloating,
abdominal distension,
nausea/vomiting,
progressive weight loss
– May impair levodopa
absorption
Pfeiffer 2015
PD: Constipation
• Fewer than three bowel movements/week
• Prevalence 28-61% in PD patients compared to 633% in controls
• Contributes to symptoms such as nausea,
bloating, early satiety, and weight loss
• Contributes to irregular absorption of
medications motor fluctuations
PD: Constipation - treatment
• Progression of approaches:
– Maintenance of an active lifestyle
– Moderate physical exercise
– Diet
• daily fiber intake should be in the range of 20–35
grams/day, but the average American only consumes
~14 grams/day
– Stool softener(s)
– Polyethylene glycol electrolyte solution (Miralax)
– Enemas
PD: Urinary dysfunction
• Prevalence 38 to 71%
• Incontinence, frequency, urgency, poor stream, or
incomplete voiding
– Nocturia is most prevalent symptom reported by PD
patients (>60%)
• Proper referral to a urologist is important for
guidance in the assessment and treatment of
urinary dysfunction in PD
PD: Urinary dysfunction
• Detrusor over-activity =
most frequent
urodynamic
abnormality
– Urinary urgency
– Frequency
– Nocturia (overnight
urination)
– Urge incontinence
http://www.gynaecologyspecialistlondon.co.uk/conditions-treatments/urinary-incontinence/
PD: Urinary dysfunction
• Medications that work to block or reduce
bladder overactivity:
– older medicines: oxybutynin (Ditropan) and
tolterodine (Detrol)
– newer medications: solifenacin (Vesicare) and
darifenacin (Enablex), trospium (Sanctura),
Mirabegron (Myrbetriq)
– Botulinum toxin (“Botox”) injections
PD: Sexual dysfunction
• One of the most demoralizing and disabling
features of PD; women and men
• Reduces both desire and function and therefore
the frequency of sexual activity
• In a survey of 75 PD patients
– 68.4% of men reported erectile dysfunction while
87.5% of women had difficulties with arousal
• Contributors: autonomic failure, age, other
comorbidities, personal relationships, sleep
disorders, depression, and drug therapy (such as
antidepressants)
Bronner et al 2004
PD: Thermoregulatory dysfunction
• Episodes of drenching
sweats
• Sweating problems
more common in those
with motor fluctuations
• No effective medication
treatment, but
?improvement after
DBS
Trachani et al 2010
PD: Sleep Disorders
•
•
•
•
Estimated prevalence of 90%
Increase with advanced PD
Most common insomnia is sleep fragmentation
3 main causes:
– 1* disease symptom from neuronal degeneration in
sleep-regulating brain regions
– Disruptions from other PD symptoms, such as
nocturnal motor symptoms (e.g., difficulty turning in
bed) or autonomic dysfunction (ex: nocturia)
– Medications (ex: selegiline, amantadine)
PD: Sleep Disorders
• Most common sleep complaints:
– Difficulty falling and staying asleep
– Excessive daytime sleepiness
– Talking or yelling out while asleep
– Vivid dreaming
– Leg movements, jerking, cramping
– Difficulty turning over in bed
– Waking up to go to the bathroom
http://www.parkinson.org
PD: Sleep Disorders (Day)
Excessive Daytime Sleepiness
– 30-50% of patients with PD
– Common causes
• Poor night’s sleep
• Dopaminergic medications, especially dopamine
agonists (Mirapex and Requip) may cause daytime
sleepiness
– Do not drive while sleepy. The occurrence of motor
vehicle accidents is increased during periods of
drowsiness and may be associated with sudden onset
of sleep (sleep attacks).
http://www.parkinson.org
Excessive Daytime Sleepiness Treatment
1.
2.
3.
4.
5.
6.
7.
Establish good sleep hygiene, which includes a set bedtime and wake-up
time.
Get exposure to adequate light during the day and darkness at night.
Avoid sedentary activities during the day.
Participate in activities outside the home, as they may be helpful in
providing stimulation to prevent daytime dozing.
Get physical exercise appropriate to your level of functioning, which may
also promote daytime wakefulness.
Strenuous exercise, however, should be avoided for 3 to 4 hours before
sleep.
If you are on a dopamine agonist and you experience daytime sleepiness
or sleep attacks you will need to talk to your doctor about possibly
decreasing the dose.
http://www.parkinson.org
PD: Sleep Disorders (Night)
Obstructive sleep apnea (OSA)
Restless legs syndrome (RLS)
REM sleep behavior disorder (RBD)
Return of the tremor and rigidity during the
night
• Patients may have a combination of a few
sleep problems
•
•
•
•
http://www.parkinson.org
PD: Sleep Disorders (Night)
OSA
• Up to 40% PD patients
– Loud snoring
– Restless sleep
– Sleepiness during the
daytime
– Pauses in breathing during
night sleep
• Diagnose: sleep study
• Treat: Continuous positive
airway pressure (CPAP)
RBD
• ~ 50% PD patients
• = Continued ability to
move during REM sleep
• Often precedes the PD
diagnosis by 5-10 years
• ?people with RBD may
have 80-90% risk of later
developing PD
• Treat: clonazepam;
melatonin may help
http://www.parkinson.org
PD: Sleep Disorders (Night):
Restless Leg Syndrome
– Usually at night, or
sometimes during the day
when you sit for long
periods of time
– Creeping, crawling, aching,
pulling, searing, tingling,
bubbling
– Irresistible urge to walk or
move legs, which almost
always relieves the
discomfort
– Sometimes also in upper
leg, feet, or arms
• Treatment:
– Iron replacement (in those
who are deficient)
– Pramipexole
– Ropinirole
– Gabapentin
– Pain medication
PD: Fatigue
• Single most disabling symptom reported by up to 1/3 PD
patients
• Prevalence of 32–58%
• Present early and may predate onset of motor symptoms
• Chronic/intermittent
• Associated frequently with depression, cognitive deficits,
and daytime sleepiness
• Possible treatments: methylphenidate, levodopa,
dopamine agonists?
Summary
• PD is much more than a movement disorder
• Awareness of possible non-motor symptoms
aids in early recognition and treatment
• Proper treatment of non-motor PD symptoms
improves quality of life
• Always discuss non-motor symptoms with
your doctor
MUSC Living with Parkinson’s Disease Symposium
November 7, 2015
Mood Changes in Parkinson’s Disease:
What’s New and What to Do?
Laura Marsh, MD
Executive Director, Mental Health Care Line
Michael E. DeBakey Veterans Affairs Medical Center
Professor, The Menninger Department of Psychiatry
and The Department of Neurology
Baylor College of Medicine
Disclosures
Research Support
Veterans Health Admin; National Parkinson Foundation
Consultancies (< 2 years)
None
Royalties
Taylor & Francis/Informa
Approved/Unapproved Uses
This presentation may discuss use of medications and other interventions
that do not have FDA approval as treatments for psychiatric conditions
treated in non-Mental Health Settings.
Learning Objectives
1.
Recognize the features of mood disturbances in PD.
–
2.
How to distinguish mood disorders from normal emotions
Discuss general approaches to treatment
Outline
I. Context
II. Prevalence and Recognition
III. Treatment
James Parkinson
1755 - 1828
“Involuntary tremulous motion, lessened muscular power
In parts not in action and even when supported;
with a propensity to bend the trunk forward, and
to pass from a walking to a running pace;
the senses and intellects being uninjured.”
1817-Present
Psychiatric Disturbances Under-recognized
• Until l-dopa, severity of motor deficits prevented
assessment of psychopathology
• Development of Neuropsychiatric Assessment Tools
– 1966 - first detailed study of cognitive change in PD
– 1970’s - reports on psychiatric symptoms as inherent to PD
– 1980’s – clinical treatment trials for neuropsychiatric Sx
• 20th century occupational and life demands exposed
cognitive deficits and psychiatric symptoms
Post-1970: Motor Deficits Effectively Treated--Neuropsychiatric Disturbances Exposed
• Concurrent psychopathology
Mid-1970’s----Depression (reactive versus inherent?)
Late 1990’s---Post-surgical psychiatric ‘complications’
• Depression, Impulsivity, anxiety
2000---Cognitive changes
• Treatment-induced psychosyndromes
1970’s-Delirium, Psychosis, Behavioral changes
2000’s-Impulse control disorders
• Pre-PD and Longitudinal Psychopathology
Evident in Epidemiological studies
Motor Features of PD
• Classic Motor Triad:
– Tremor, Rigidity, Bradykinesia/Akinesia
• Gait and Postural Disturbances
– Dragging, Shuffling, Start Hesitation, Festination
– Later unsteadiness, Imbalance
Motor signs ≠ Disability ≠ Psychological distress
Schrag et al., 2001
Neuropsychiatric Disturbances Occur
at all Stages of PD
Case: 88 year old Female with PD x 16 years
• Masters Swimming Champ-Senior Division
• Age 69 – Onset First Major Depressive Episode
• Age 72 – PD Diagnosed
• 3 yr h/o left foot dragging, 6 mo h/o left hand tremor
•
•
•
•
•
Age 82 – Onset Generalized Anxiety Disorder
Age 82 – Cognitive changes
Age 83 – Intermittent Visual Hallucinations
Age 84 – Cognitive decline
Age 85 – Imbalance
n
51
60
Major Depression Before PD Dx
Major Depression at or after PD Dx
%
46
54
12
14
16
Onset of depression is not related to
disease stage or disability
0
2
4
Frequency
6
8
10
(MOOD-PD Study, Unpublished Data)
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
Duration between Earliest Major Depression Episode Onset and PD Diagnosis (years)
• Ishihara and Brayne 2006 (review)
– On average, mood disturbances precede PD diagnosis by 4 to 6 years
• RR 3.13 (1.95-5.01) Schuurman et al 2002
• RR 2.4 (1.72-2.93) Nilsson et al 2001
• RR 2.40 (2.10-2.70) Leentjens et al 2003
National Comorbidity Study - Any Psychiatric Disorder
High Current and Lifetime Prevalence in General Population
National Comorbidity Study: Kessler, Chiu et al. 2005; Kessler, Berglund et al. 2005
Impact of Depression
• Aggravate motor deficits, dysfunction, progression
• Aggravate cognitive deficits and dysfunction
• Higher rates of concurrent medical and psychiatric
conditions
• Greater carer burden
• Greater healthcare costs
• Broad economic impact on family and society
• Lower quality of life
Schrag 2000; McDonald 2003; Starkstein 1992; Kuopio 2000; Marsh 2004, 2007; Pontone 2011
Depressive Symptoms Influence when
Antiparkinsonian Treatment is Started
NET-PD Study/Neuroprotective Treatment Trials
n=413 early untreated PD
– Depressive symptoms - GDS-15>5
– 27.6% + Depression screen over ~ 15 months
– 40% Depression cases left untreated
– Depressive symptoms predicted
– Increased ADLS (p<0.0002)
– Increased need for symptomatic PD therapy
(HR=1.86; 95% CI 1.29-2.68)
Ravina et al., 2007
Depression Remission Improves
Physical ADLs in PD (n=136)
40
30
20
10
0
Northwestern University Disability Scale (0-50)
50
Group differences in Physical ADLs (NWDS)at baseline and 2-year intervals
0
2
4
6
Years
Symptomatic Depression
Not Depressed
Remitted Depression
c
Marsh et al, 2007; Pontone et all,2015
Neuropsychiatric Features –
Most disabling over Disease Course
Sydney Multi-center Study – 15-year Follow-up
– n=149, 52 surviving (71 + 8; 55-86 years)
– Most disabling long term symptoms
– Cognitive decline - 84%
– Dementia - 48%, MCI - 36%
– Hallucinations – 50%
– Depression – 39%
Hely et al, 2005
In Addition to an Impact on PD Features,
Psychiatric Disturbances, Themselves, are Distressing
• Psychiatric symptoms
– Confusing, “Un-understandable”
– Unpredictable
– Cause patient to be ‘unreliable’
• Non-recognition and Non-treatment add to morbidity
– Versus: “I can cope with PD, as long as I am not depressed.”
• Accurate diagnoses and formulations provide relief and direction
– Plus, treatments are effective
II.
Prevalence and Recognition of
Depression and other Mood
Disturbances in PD
Depressive Disorders in PD
• Epidemiology
• ~40% prevalence (range 3% - 90%)
• Clinically significant depressive symptoms 35%
• Anxiety disorders often co-occur
• Rates of recurrence or treatment resistance unclear
Reijnders 2008; Mayeux, 1981; Starkstein, 1992; Meara, 1999; Global PD Survey, 2002; Weintraub 2004
There is a range of depressive diagnoses
8.0%,
n=20
3.6%,
n=9
41.2%,
n=103
8.4%,
n=21
No Depression
Major Depression
Nonmajor Depression
Nonmajor Other
38.8%,
n=97
Bipolar Affective Disorder
MOOD-PD Study (n=250)
Mean (SD, range) PD Duration= 7.8 (6.4, 0-35 years)
Palanci et al. 2009
Depression remains undertreated
10.3%
n=10
26.8%
n=26
Major Depression, n=97
(MOOD-PD Study)
Asymptomatic, Treated
Symptomatic, Partially Treated
Symptomatic, No Treatment
62.9%
n=61
Current symptomatic major depressive episode (n=86)
Duration = 182.4 (218.8) weeks
Range 2-1612 weeks. Median 104 weeks.
Palanci et al. 2009
Yet, Depressive Symptoms are Under-recognized
Patients Identified (%)
Physician Identification of Psychiatric Symptoms in PD
50
40
30
20
10
0
Depression
Anxiety
ID by standardized test
Fatigue
Sleep
ID by physician
Shulman LM et al. Parkinsonism Relat Disord. 2002;8:193-197.
PD-Depression: Barriers to Recognition
 Motor symptoms
• Define the disease
• Primary focus of care/interest
• Mask psychiatric changes
 Depressive symptoms
• Regarded as ‘understandable’ reactions
• Need to be monitored
• Occur with other mood disorders
• Stigma
• Don’t ask, don’t tell
How to Detect Depression in PD
Problem of Overlapping Features
Is it ‘Normal’ Stress, or Something More?
… Depends on your perspective…
…if there is an elephant in the room,
Yes, I know there is an elephant in the room,
but I don’t want to talk about it.
….chances are it is something more
And, you need to talk about that elephant!
Major Depressive Episode DSM-IV/V
Criteria
1. Depressed or sad mood
AND/OR
2. Decreased interest or pleasure
3. Appetite/Weight changes
4. Sleep disturbances
5. Psychomotor agitation or retardation
6. Fatigue or loss of energy
7. Feelings of Worthlessness/Excessive Guilt
8. Decreased ability to think or concentrate or
indecisiveness
9. Recurrent thoughts of death, suicidal ideation,
or suicidal attempt or plan
Major Depression
Parkinson’s Disease
Motor Psychomotor Retardation
+ Stooped Posture
Restricted/sad affect
Agitation
Bradykinesia
Stooped Posture
Masked Facies
Tremor
Cognitive
Impaired Memory
Impaired Concentration
Vegetative
Decreased Energy
Fatigue
Sleep/Appetite changes
Somatic
Physical Complaints
Sexual, GI, muscle tension
Depression
Depressive Disorder
Depression
• An emotion characterized by sad and unhappy
feelings
• A normal psychological reaction, especially to
loss
• A loosely used term
– Frustration, anger, disgust, anxiety, overwhelmed, apathetic,
tired
Depressive Disorder
• A psychiatric (medical) condition
• An abnormal and persistent mental state
• Accompanied by physical and mental changes
• Affects function and causes significant distress
Major Depressive Disorders have
Persistent Emotional Features
• A pervasive change in Mood
• Persistent sadness
• Decreased interest and enjoyment
• Pessimism, hopelessness
• Negative ruminations
• Inappropriate guilt
• Negative view of sense of self
• Morbid and/or suicidal thoughts
• Feeling overwhelmed, anxious, inability to cope
• Irritability
Anxiety Disorders in PD –
Can be confused with Depression, or be a
part of it
• Several Types
•
•
•
•
Episodic (Panic Disorder)
Situational (Phobias)
Continuous (Generalized Anxiety)
PD-Specific (Wearing-off anxiety/panic)
• Not an understandable reaction to motor symptoms
• Non-motor fluctuations
• Onset of Anxiety may precede PD
• Depressive disorders often co-occur
Kummer et al. 2008; Maricle et al. 1995, Witjas et al. 2002, Arabia 2007, Pontone 2011, Starkstein, 2013
Psychological Features of Anxiety
Excessive
• Worry
• Apprehension
• Avoidance
• Anticipation
• Overly-detailed
• Emotional Reactivity
• Fearfulness
• Somatic concerns
• Ruminative
No pervasive
• Guilt
• Sadness
• Decreased self-worth
• Lack of interest
• Morbid thoughts
Fluctuating Mood States
Motor and “Non-motor” Fluctuations
Motor
Mood
Dyskinetic
Happy
On
Neutral
Off
Sad/
Anxious
Levodopa dosing
Motor state
Mental state
Nonmotor Fluctuations
• Dysautonomic
– Drenching sweats, hot sensation, flushing, dry mouth,
dyspnea, dysphagia, constipation, distal cold sensations,
excessive salivation, urinary urgency, visual complaints,
palpitations, bloating, chest pain
• Cognitive/Psychiatric
– Slowed thinking, mental hyperactivity, impaired memory,
mental emptiness
– Off-Anxiety (81%), Off-depression (63%), On-hypomania
(24%), irritability, psychosis
• Sensory/Vegetative
– Fatigue, akathisia, tightening sensations, tingling, pain
Witjas et al, Neurology 2002; 59: 408-413; Racette et al., J Neuropsychiatry Clin Neurosci 2002; 14: 438-442.
Apathy
• Prevalence
- ~ 30% as a feature of a depressive disorder
- ~ 10% as an independent disorder
• Clinical features
– Loss of motivation
– Emotional indifference
– Reduced goal-directed activities
– Patients with primary apathy do NOT complain
Emotionalism/Pathological Crying
• Prevalence
– 40-50%
– Associated with Depressive Disorders,
Delirium, Benzodiazapines
• Clinical Features
–
–
–
–
Heightened, excessive sentimentality/tear
Inappropriate, unmotivated, involuntary
Precipitated by a variety of emotions
Social embarrassment/Phobic avoidance
III.
Treatment of Depression
Treatment of Depressive
Disturbances in PD
Mental health is good medicine
But, stigma is its bitter pill
• The myth of non-response
• Treatments are effective 60-80% of the time
• Treatment Works, People Recover
• Remission is the goal of treatment
• Stigma – the greatest barrier to treatment
• Discourages people from getting help when they need it
• Patients and families feel devalued, labeled, marginalized
• Cause of prejudicial behaviors by clinicians---decreased
referrals, work-up, tx choices, dismissal, etc.
• Leading cause of under-diagnosis and under-treatment
• Poorer social adjustment
• Narrowed community of care
• MH patients dismissed by other clinicians
• MH workers are undervalued and marginalized
• MH professionals devalue their patients or patient groups
(Satcher, 1999; Halter 2009)
Treatment Works, People Recover
Lessons from Treatment in the General Population
(STAR*D Study, Sequenced Treatment Alternatives to Relieve Depression)
-
Effectiveness study: 4 levels of care using Meds,Cognitive Therapy
-
Goal of treatment
Remission (relief from depressive episode)
Not just response
-
‘Measurement-based care’
Monitor sx and side effects systematically and modify Tx at critical
decision points
-
Remission occurred with persistent and vigorous treatment
33% - 1 Step 50% - 2 Steps 60% - 3 Steps 70% - 4 Steps
Gaynes 2008
Basic Principles of
Psychiatric Treatment
Practical Approaches to Maintaining
Mental Health
Basic Principles of Psychiatric Treatment
1. Treatment Works, People Recover
2. Make sure your treatment is a MESS
Medications
Education
Skills
Support
3. Measurement-based care is superior to usual care
Rating scales: Quantify Sx, Assist with tx decisions, Monitor tx
response, Assess adverse effects
Gavnes BN, 2008; Guo T, 2015, Yeung AS 2012
Psychiatric Treatment
• Targeted and individualized approach
– Identify the patient’s goals
• Adjust/Optimize anti-parkinsonian regimen
• Treat medical conditions/delirium
• Use specific psychiatric treatments
– Non-pharmacologic approaches
– Psychotherapy
– Medications
• Anti-depressants, Sleep, Anti-anxiety, Anti-psychotics
Start with Non-pharmacologic Treatments
(Medication Education Skills Support)
• Education
– Psychiatric aspects of PD and Safety Issues
– Coping strategies
– Caregiver issues
• Psychotherapy
– Counseling/problem-solving
– Supportive, directive, insight-oriented, grief counseling,
Cognitive-behavioral therapy
– Caregiver support
• Rehabilitative therapies
– Occupational, Physical, Speech Therapies
– Exercise/Exercise classes/Personal trainers
– Relaxation training
• Social Supports
– Day Programs, Safety, Socialization, Support groups, Home
care; Nursing home placement
Cognitive Behavior Treatment
(CBT) Trials for Mood Dos in PD
Armento M 2012
n
Dx
Sessions
Outcome
RCT?
Calleo 2015
16
Depr/Anxiety
8
↓ depr/anxiety
Open Pilot
Dobkin 2006
3
MDD
12-14
Min Δ Anxiety
Case Series
Dobkin 2007
15
MDD
10-14
Trend ↓ anxiety
Pilot study
Dobkin 2011
80
MDD
10-14
↓ Depression
Yes
Dreisig 1999
79
Depression
6
Impr Anx
1 month
Feeney 2005
4
Depr/Anxiety
8 group
No Δ Anxiety
Pilot
Macht 2007
3
Depr, Social
anxiety, freezing
12-18 months
↓ anxiety
Case series
Veazey 2009
14
Anxiety/Depr
9 (8 on phone) ↓ anxiety (BAI)
Yes-CBT vs
Support grp
Components of Various CBT Trials in PD
Patients
Basic CBT components: Automatic thoughts, Triggers, PD specific
adaptations
Problem Solving
Breathing strategies
Exposure
Activity Scheduling
Stress management
Behavior Modification
Sleep Hygiene
Relaxation
Cognitive Restructuring
Caregiver Strategies to reinforce therapy for patient
Self Monitoring
Health Promotion
Symptom (depression/anxiety) management
Social Skills Training
Written strategies
Armento M 2012
Effects of CBT on Depression Severity (HAM-D)
n=80 PD with MDD, 10-week CBT
CBT response 56% vs Monitoring 8% (p<.0001) Dobkin 2011
Pharmacological Treatments
Medications for Depression
The Motion–Emotion Conundrum
Maintain motion
Control emotion
Targeted and individualized approach
Cummings JL. N Engl J Med. 1999;340:801-803.
Elimination of PD Meds
Discontinue First
•
•
•
•
•
•
•
Anticholinergics
Selegiline/Rasagaline
Amantadine
Dopamine agonists
Controlled release meds
COMT inhibitors
Levodopa dosage
Discontinue Last
Investigate non-adherence
• Are the PD meds being taken on time?
• Are the antidepressants being taken?
• Are healthy living strategies in place?
Antidepressants
Class
Reuptake Inhibition
SNRIs
Serotonin-Norepinephrine
Tricyclic Antidepressants, Venlafaxine, Duloxetine
NDRIs
Norepinephrine-Dopamine
Buproprion
SSRIs
Serotonin
Fluoxetine, sertraline, paroxetine, fluvoxamine,
es/citalopram
SARIs
Serotonin Antagonist
Trazodone, nefazodone
NASAs
Norepinephrine/ Serotonin Antagonists
Mirtazipine
ECT, rTMS
Xie CL, 2015
Placebo-Controlled Antidepressant Trials
Multi-site
*Paroxetine, Venlafaxine (SAD-PD) (Richards 2012, NAmer, n=115, 12 wks)
*Pramipexole (Barone 2010, Europe, n=296, 12 wks) (Depressive Sx)
Single site
*Nortriptyline (Andersen 1980, Denmark, n=22, 8wks)
*Selegiline (Allain 1991, France, n=93, 12 wks, Depressive Sx)
Citalopram (Wermuth, 1998, Norway, n=37, 52 wks)
Sertraline (Leentjens 2003, Netherlands, n=14, 10 wks)
*Desipramine and Citalopram (Devos 2008, France, n=48, 4 wks)
Atomoxetine (Weintraub, 2010, Pennsylvania, n=55, 8 weeks)
*Nortriptyline (but not) paroxetine (Menza, New Jersey, n=52, 8 wks)
SAD-PD Response/Remission Rates
• Responders (HAM-D ≥ 50% ↓ baseline to week 12)
(Note: STAR*D had 47% response rate overall)
‾ Paroxetine
68%
‾ Venlafaxine XR 53%
‾ Placebo
44%
• Remitters (HAM-D ≤ 7 at week 12)
‾ Paroxetine
44%
‾ Venlafaxine XR 37%
‾ Placebo
32%
Beware: The prominent placebo
response is not sustained.
SAD-PD Study Richard et al, 2012
Antidepressants are Effective for PDDepression, but Response often Incomplete
• N=52, Major Depression/Dysthymia + PD
– 8 week trial: Nortriptyline vs paroxetine vs placebo
– Clinical response: 50% reduction in Ham-D score
• Nortriptyline superior to placebo and paroxetine
• 16 responders (3 paroxetine, 4 Placebo, 9 NTP)
• 36 nonresponders (15 paroxetine, 13 placebo, 8 NTP)
– Responders
• Sig improved Mood, middle insomnia, interest, somatic anxiety
– Residual symptoms in Responders
• >50% depressed mood, lack of interest, psychic anxiety, low energy
Menza et al., Neurology 2009; Dobkin et al., AGJP 2010
Other ‘Antidepressant’ studies
• Dopamine agonists
– Moller et al., 2005; Reichman et al. 2004
• Open-label pramipexole ↓ PD Depressive symptoms
– Barone et al. 2006, n=67
• 12 wk RCT pramipexole (1.5-4.5 mg/d) vs sertraline (50 mg/day)
• More pts in remission on pramipexole (61% vs 27%)
– Barone et al. 2010, n=287
• 12 wk RCT pramipexole (0.125-1 mg tid) vs Placebo
• Decreased Depressive and Motor Symptoms on pramipexole
• Improved depression independent of motor function
Conclusions
Mood Changes in PD: What’s New and What to do?
• Depressive and other Mood Disorders
–
–
–
–
Not the same as understandable emotional reactions
Common in PD over its course
Have a negative impact, yet are under-recognized
Have features that overlap with motor symptoms of PD as
well as other psychiatric conditions
– Effective treatment, to remission, reduces excess disability
• What to do?
– Recognize, Measure, Treat
– MESS
PARKINSON’S DISEASE
RESEARCH PANEL
DISCUSSION
Margaret Petterson, Lotta Granholm, Travis
Turner, Gonzalo Revuelta, Christina Vaughan
Moderator: Vanessa Hinson
The Power of Exercise
TRAVIS GAWLER, PT, DPT
PHYSICAL THERAPIST
(LSVT BIG CERTIFIED ; PWR! TRAINED)
PALMETTO HEALTH PHYSICAL AND SPECIALTY THERAPY
Agenda
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Quick Review of PD
Motor vs. Non-motor Symptoms
Exercise vs. Physical Activity
Benefits of exercise


Motor
Non-motor
 Exercise Prescription
 ACSM recommendations
 Travis’s Recommendations
 Sedentary lifestyle
 Barriers to exercise
 Future research
 Take home message
Basal Ganglia and Substantia Nigra
 Substantia Nigra

Structure secretes dopamine
to relay messages that plan
and control movement
 Basal Ganglia

Structures in the deep part
of the brain that control
movement
PD Symptoms
•Depression
•Anxiety
•Fear of falling
•Fatigue
•Sleep
disturbances
•Apathy
•Executive
dysfunction
•Attention deficits
•Bradyphrenia
•Recalling learned
information
•Visuospatial
impairments
Motor
Symptoms
Nonmotor
Symptoms
Medication
and
EXERCISE
•Bradykinesia
•Hypokinesia
•Hypophonia
•Swallowing issues
•Imbalance/falls
•Gait changes
•Postural deficits
•Tremor
•Rigidity
Exercise vs. Physical Activity
 Physical Activity (PA)
 “any bodily movement
produced by skeletal muscle
that results in energy
expenditure”
 Exercise
 Subcategory of PA
 “physical activity that is
planned, structured,
repetitive, and purposive in
the sense that improvement
or maintenance of one or
more components of physical
fitness is an objective”
Caspersen et al. 1985
http://millionideas.org/2012/12/07/physical-activity-vs-exerciseunderstanding-the-difference/
Benefits of Exercise
 General Health Benefits for the Older Adult
 effective way to reduce and/or prevent functional decline
associated with aging
 Aerobic exercise
Maintain and improve heart and lung function
 Enhance endurance


Strength/Resistance Training

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Offset loss in muscle mass and strength
Reduce risk factors associated with disease(heart disease,
diabetes, osteoporosis, etc.)
https://www.acsm.org/docs/current-comments/exerciseandtheolderadult.pdf
Benefits of Exercise
 PD: Motor Symptoms

Running protects dopaminergic neurons against inflammationinduced degeneration via the activation of BDNF signaling pathway

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Habitual physical activity may have an enhanced ability to increase
synthesis of dopamine neurons in the Substantia Nigra compared to
sedentary


Wu et al. 2011, Brain, Behavior, and Immunity, Volume 25, Issue 1,
January 2011, Pages 135-146
Foley et al. 2008 Neuromolecular Med. 2008;10(2): 67-80. doi:
10.1007/s12017-008-8032-3.
Improvements with balance training correlated with CNS cells to
modify structure and function

B. Sehm, M. Taubert, V. Conde, D. Weise, J. Classen, J. Dukart, et al.,
Structural brain plasticity in Parkinson's disease induced by balance
training, Neurobiol. Aging 35 (2014) 232e239.
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Aerobic Exercise Training
Treadmill training
 Improvements :
 gait velocity
 stride length
 cadence
 postural stability
 gait rhythmicity
 joint excursion

Duchesne et al. 2015
http://davidkanigan.com/tag/treadmill/
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Resistance Training
Quad strengthening;
generalized leg
strengthening; eccentric
strengthening
 Improvements:
 muscle force
 Gait quality and
efficiency
 Decreased bradykinesia/
hypokinesia(per UPDRS)
 QOL

Dibble et al. 2015
http://bell-wellness.com/2015/08/simple-exercises-to-keep-seniors-fit-and-healthy/
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Cycling
Forced increase in cadence
was most beneficial
 Improvements:
 Gait quality
 Balance
 Motor function

http://www.davisenterprise.com/local-news/tandem-cycling-programtargets-parkinsons-sufferers/
http://www.theracycle.com/m
odel/Theracycle-200.aspx
Ridgel et al. 2015
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Yoga
emphasizes postural
alignment and movement
within postures
 progression from body
awareness to relaxation to
flexibility to strength
activities
 Improvements :
 posture
 strength
 balance
 gait quality
 flexibility

Colgrove et al. 2012
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Tai Chi
Focuses on dynamic
postural control through
exercises that focus on
weight shifting
 Involves cognitive
engagement
 Improvements:
 Gait
 Maximum joint
excursion
 Reduced falls

Petzinger et al. 2013
http://www.dailymail.co.uk/health/article-2098643/An-hour-Tai-Chiday-help-people-Parkinsons-disease-walk.html
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Boxing
Dynamic balance
 Multi-directional
movements
 Large amplitude
movements
 Improvements:
 Balance
 Gait
 Testimonial QOL
improvements

Petzinger et al. 2013
https://www.rocksteadyboxing.org/programs/parkinsons-class/
Benefits of Exercise
 PD: Motor Symptoms:
what type of exercise?

Dancing
cognitive engagement
through coordination with
a partner in addition to
the cueing and increased
attention provided by the
music and rhythm
 12 months tango:
 Improved balance,
walking, and dual
tasking

http://www.examiner.com/article/tango-dancing-improvessymptoms-of-parkinson-s-disease
Foster et al. 2013; Duncan et al. 2012
Benefits of Exercise
 PD: Motor Symptoms: what type of exercise?

Home exercise vs. Group Exercise vs. Individual Exercise

King et al. 2015
 Sensori-motor based Agility Boot Camp(ABC)
 Group class
• greatest gait improvements
• greatest quality of life gains

Individual group
• Greatest overall motor and most non-motor improvements
• only to improve in self-efficacy

Home exercise group
• least effective to improve mobility
• Most effected by comorbidities
• Lowest compliance rates with exericsing
Benefits of Exercise
 PD: Non-Motor Symptoms
 Aerobic Exercise (Duchesne et al. 2015; Petzinger et al. 2013)


Tai Chi (Nocera et al. 2014)


Improvments :
 Executive function, cognitive function (working memory),
verbal fluency, motor-sequence learning
Improvements in QOL
Resistance Training (Uhrbrand et al. 2015)

Improvements in QOL
Sedentary Lifestyle
 Snider et al. 2015
 Sedentary life style outside of exercise?



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At risk for negative health affects
Low levels of non-exercise PA associated with more severe
motor symptoms (bradykinesia; not tremor or rigidity)
Findings suggest non-exercise PA improves gait and balance
“Standup, sit-less, move-more” intervention strategies deserve
further studies
Snider et al. 2015
Exercise Prescription
 ACSM Recommendations

Cardiorespiratory Exercise
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150 minutes of moderate-intensity exercise per week.
30-60 minutes of moderate-intensity exercise (five days per week) or 2060 minutes of vigorous-intensity exercise (three days per week).
One continuous session and multiple shorter sessions (of at least 10
minutes) are both acceptable
Gradual progression of exercise time, frequency and intensity is
recommended for best adherence and least injury risk.
People unable to meet these minimums can still benefit from some
activity.
Resistance Training
Flexibility Training
Neuromotor Exercise
http://www.acsm.org/about-acsm/media-room/news-releases/2011/08/01/acsm-issues-new-recommendations-on-quantity-and-quality-of-exercise
Exercise Prescription
 ACSM Recommendations
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
Cardiorespiratory Exercise
Resistance Training
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Adults should train each major muscle group two or three days each week
using a variety of exercises and equipment.
Very light or light intensity is best for older persons or previously sedentary
adults starting exercise.
Two to four sets of each exercise will help adults improve strength and power.
8-12 repetitions improve strength and power, 10-15 repetitions improve
strength in middle-age and older persons starting exercise, and 15-20
repetitions improve muscular endurance.
Adults should wait at least 48 hours between resistance training sessions.
Flexibility Training
Neuromotor Exercise
http://www.acsm.org/about-acsm/media-room/news-releases/2011/08/01/acsm-issues-new-recommendations-on-quantity-and-quality-of-exercise
Exercise Prescription
 ACSM Recommendations

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
Cardiorespiratory Exercise
Resistance Training
Flexibility Training
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2-3 days each week
Hold for 10-30 seconds to the point of tightness or slight discomfort.
Repeat each stretch 2-4x, accumulating 60 seconds per stretch.
Flexibility exercise is most effective when the muscle is warm.
 Try light aerobic activity or a hot bath to warm the muscles before
stretching.
Neuromotor Exercise
http://www.acsm.org/about-acsm/media-room/news-releases/2011/08/01/acsm-issues-new-recommendations-on-quantity-and-quality-of-exercise
Exercise Prescription
 ACSM Recommendations




Cardiorespiratory Exercise
Resistance Training
Flexibility Training
Neuromotor Exercise
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sometimes called “functional fitness training”
2-3x/week for 20-30 min
should involve motor skills (balance, agility, coordination and gait),
proprioceptive exercise training and multifaceted activities (tai chi and yoga)
to improve physical function and prevent falls in older adults.
http://www.acsm.org/about-acsm/media-room/news-releases/2011/08/01/acsm-issues-new-recommendations-on-quantity-and-quality-of-exercise
Exercise Prescription
 Travis’s Recommendations

Start exercising now and never stop!!
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Be physically active outside of just exercising
Exercise most days of the week
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Use ACSM as your guidelines
Check with your MD if you are not sure if your safe to exercise
Have variety to your exercise regiment
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Exercise is medicine
ACSM domains: cardiorespiratory exercise, resistance training,
flexibility training, neuromotor exercise
Incorporate exercise supported by research
Do something you enjoy!!!!
Be safe
Barriers to Exercise
 Perceived barriers are
more predictive of
adherence to exercise
than motivators
 Perceived barriers:
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Low outcome expectations
Fear of falling
Lack of time
http://www.pharmicaconsulting.com/digital-medicine-is-there-an-app-formotivation/
Ellis et al. 2013
Barriers to Exercise
 How do we knock down
these barriers?

Low outcome expectations
education
 goal setting
 feedback

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Fear of falling
realistic self-assessment of
the risk of falling
 risk-taking training
 physical therapy

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Lack of time
prioritizing activities
 scheduling exercise as part
of daily routine

Ellis et al. 2013
Direction of Future Research
Additional research into non-motor benefits using
different modes of exercise
2. Research on benefits of exercise for PWP in later
stages(Hoehn and Yahr stages 3+)
3. Research on benefits of exercise for PWP post-DBS
surgery
4. Determining specific exercise prescription for PWP
1.
Take Home Message
 Medication does not address all aspects of PD
 Exercise and PA outside of exercise are both
important!
 Exercise has many PD specific and general health
benefits!


Take an active role in your treatment
Benefits are noted across many types of exercise
 1:1 and group exercise are best compared to HEP
 Parkinson Wellness Recovery(www.pwr4life.org)
 ACSM and Travis’s Recommendations as guidance
 Address barriers to exercise
 Start exercising today and never stop!!!
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