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Parkinson’s Disease Foundation
PD ExpertBriefing: Apathy or Depression: Which One Is It?
Led By: Dawn Bowers, Ph.D., Professor of Clinical & Health Psychology and Neurology, University of Florida; Director, Cognitive Neuroscience
Laboratory at McKnight Brain Institute in Gainesville, FL, and Neuropsychology Director for the UF Center for Movement Disorders
and Neurorestoration.
This session was held on: Tuesday, June 14, 2016 at 1:00 PM ET.
If you have any questions, please contact: Valerie Holt at [email protected] or call (212) 923-4700
Apathy or Depression
Which One Is It?
Dawn Bowers, Ph.D., ABPP-CN Professor
University of Florida
J. Robert Cade, Inventor of Gatorade
University of Florida
UF Center for Movement Disorders & Neurorestoration
UF Center for Movement Disorders and Neurorestoration
Our Motivation: Our patients, our parents, our children
Plan for Today
• Explain difference between apathy & depression
• Discuss why apathy is such a problem in Parkinson’s disease – the what, why, when & how
• Explain why some treatments for depression actually worsen apathy
• Tips for improving apathy
Depression Apathy Anxiety Happy
Frightened
Disgusted
Basal Ganglia Loops
20% reducation amygdala volume 30-45% reduction dopamine binding
Neuropsychiatric Features of Parkinson’s Disease
Apathy vs. Depression
THESIS: Depression = Mood disorder Apathy = Motivational disorder signature of PD progression
Depression Apathy
Motivation – from the Latin “movere”, to move
Disorder of motivation
What is Apathy ?
Difficulty initiating activity Low activity levels Less interested in trying out or learning new things Lack of effort or reduced productivity Not completing tasks that were started Lack of interest in socializing Not concerned about issues that used to be important Needing someone to remind or prompt
Examples of apathetic behavior:
Cognitive Loss of interest, curiosity
Apathy
Behavioral Reduced initiative; Needs others
to structure activities
Emotion Reduced emotional reactivity,
reward
(Marin, 1991)
(Marin, 1991)
Motivation: To move, activate, energize, from Latin, ‘movere’
Lack of motivation; Failure to initiate goal-directed behavior
Apathy as a Syndrome
Apathy: Why is it important?
In many neurologic diseases (AD, stroke, PD), apathy is associated with:
• Reduced daily functioning (ADL’s & IADL’s)
• Increased caregiver stress/distress • Poor illness outcome • Poor treatment compliance • Worse rehabilitation outcome
Average Time Spent in Various Activities by People with Parkinson’s with & without Apathy
Over a 5 Day Period
Apathy Group Not Apathy Group
Beata Ferencz, 2009 Master’s thesis – UF & U. Maastricht
Measuring Apathy in PD
MDC Consensus panel, Leentjens et al., 2008), recommend #2 & #6
1. Apathy Evaluation Scale (AES) 2. Apathy Scale (AS) 3. Lille Apathy Rating Scale (LARS) 4. Apathy subscale from FrSBe 5. Item 7 from Brief Neuropsychiatric Inventory 6. Item 4 from UPDRS
• 14 item scale, modified from Marin • Are you interested in learning new things? • Does someone have to tell you what to do each day? • Are you indifferent to things?
• 3 Versions: Self-‐report, clinician raBng, family raBng • Reasonable psychometrics
• Criterion validity -‐ novelty toy task • Test-‐retest
Apathy Scale Starkstein et al., 1992
Ferencz, et al., 2012 Most widely used in PD
33 item semi-structured interview tapping 9 domains, items are scored yes-not except 1st three items; takes 20 minutes to administer
9 DOMAINS 4 Composite Subscales
Everyday productivity Interests
Taking initiative Novelty seeking
Voluntary actions Emotional responses
Concern Social life
Self-awareness
Intellectual Curiosity Emotion Action Initiation (AI) Self-Awareness (SA)
TOTAL SCORE -36 (normal) to +36 (abnormal)
Lille Apathy Rating Scale (LARS) Sockeel et al., 2006
0= normal 1= more passive 2= less initiative/disinterest 3= routine events affected 4= withdrawn, total lack
Easy, but it lacks right mix of sensitivity/specificity Correlates with AS, but has mediocre ROC, miss too many folks at 0 and 1
Bottom Line: Don’t use
N=301 Idiopathic PD
Kirsch-Darrow et al., 2009)
Assessing Apathy using Item 4 from the UPDRS
UPDRS = unified parkinson’s disease rating scale
Our Recommendation
MDC Consensus panel, Leentjens et al., 2008), recommend #2 & #6, also 3
1. Apathy Evaluation Scale (AES) 2. Apathy Scale (AS) 3. Lille Apathy Rating Scale (LARS) 4. Apathy subscale from FrSBe 5. Item 7 from Brief Neuropsychiatric Inventory 6. Item 4 from UPDRS
Prevalence-Incidence of Apathy in PD
• Prevalence/incidence depends on how apathy is assessed – estimates range from 12% to 70% across studies
• Tricky, since no formally recognized diagnostic criteria
for apathy
• Recent meta-analysis: almost 40% across 23 studies; apathy associated with lower MMSE, higher UPDRS, older age (den Brok et al. 2015)
B. Presence of at least 1 symptom from each of 3 domains must be present for at least 4 weeks
A. Lack of motivation relative to previous level of functioning or societal norms
Proposed Apathy Diagnostic Criteria Starkstein & Leentjens, 2008; adapted from Marin, 1991
1. Diminished goal-directed behavior
2. Diminished goal-directed Cognition
3. Diminished emotion reactivity
e.g., requires others to structure activity, lack of effort
e.g., lack of interest in new experiences, decreased curiosity
e.g., emotional blunting, decreased physiological reactivity
D. Symptoms not due to reduced level of consciousness or direct physiological effects of substance (meds, drug abuse, etc.)
C. Symptoms cause clinically significant distress or impairment in social, occupational, & other
areas of functioning
Proposed Diagnostic Criteria continued Starkstein & Leentjens, 2008; adapted from Marin, 1991
Depression in PD
Depressive Disorders Mood Fluctuations
• e.g. major depression,
dysthymia • last from weeks to years • can occur at any stage of
illness
• e.g. shifts from dysphoric to euphoric
• change many times daily • occurs mostly in patients who
have developed motor fluctuations
Diagnosing Depression
• Clinical interview • Depression Scales
• Self-Rating (Beck; Geriatric Depression Scale) • Clinician Ratings (Hamilton, MADRS)
• DSM-V criteria • Structured Clinical Interview (SCID)
1. Sad mood 2. Diminished Interest/ Pleasure 3. Weight/appetite loss or gain 4. Insomnia or hypersomnia 5. Slowing or agitation 6. Fatigue/decreased energy 7. Feelings of worthlessness/guilt 8. Indecision/poor concentration 9. Recurring thought of death
* *
At least 2 weeks in dura5on, disrup5ve , change
DiagnosBc Criteria for Major Depression
At least 5 of 9 symptoms, including either or both 1 & 2
Diagnosis of Depression in PD Can Be Difficult
• Features of PD itself (e.g. bradykinesia, fatigue, insomnia, weight loss, flat affect, concentration problems) can be confused with signs and symptoms of depression
• Syndromic criteria as outlined by DSM may not apply in PD
• Currently available depression rating scales were not designed specifically for use in PD
Courtesy of H Fernandez
Depression symptoms
Apathy symptoms
Sadness Worthlessness Guilt Hopelessness Helplessness Pessimism Suicidal ideation
Anhedonia Less enthusiasm
about usual interests
Increased slowness
Decreased initiative Less interest in starting new activities Less interest in world Emotional indifference Decreased emotional reactivity
Zahodne et al., 2012; Pagonabarraga et al, 2015
Overlap
Unique & Overlapping Symptoms in Apathy and Depression
Telling Depression & Apathy Apart Unique & Overlapping Symptoms
Why It Is Important to Distinguish Apathy & Depression
Relates to treatment • Use of SSRI’s, common medication for
depression, may actually worsen apathy!!
• Retrospective study at UF, N=181 people with Parkinson’s 42% with apathy, 17% with co-occurring depressive symptoms, only 2% had depression only
• Use of SSRI’s, but not other antidepressants associated with increased apathy
Apathy in PD: What We Know
• Distinct from depression • Largely dopaminergic related • Associated with psychophysiological blunting to
emotional pictures (SCR, startle, ERP) • Associated with worsening motor symptoms in medically
managed PD and worsening cognitive status • Associated with older age
Neural Systems Underlying Apathy
• Dopaminergic depletion in brain’s motivation circuitry (mesolimbic, D2)
• Mesolimbic • Mesocortical • Nigro-striatal
Evidence: • Worse apathy if taken off dopa meds • Especially dopamine (D2) agonists • Neuroimaging – decreased binding of dopamine in ventral striatum • DBS - reduction of dopa-meds results in increased apathy; tx with dopa agonists improves this
Apathy is Higher with Greater Disease Severity (Hoehn Yahr)
Hoehn Yahr Stage
Apa
thy
Scal
e Sc
ore
*
*
Kirsch et al (2006)
Apathy Depression
Motor Score
Zahodne et al., 2011
Apathy Worsens with Motor Disease Progression
N=186 idiopathic PD; Tested over 18 month period
Apathy & Depression in PD Relationship to Cognitive Status
Not Demented N=111 Unknown N=80
Demented N=35
0
20
40
60
80
100
36%
80%
51%
24% 26%
48%
Apathy Depression
% o
f Ss
Kellison et al., 2007
Percentage of Patients who were apathetic or depressed
AS & BDI-II cutoffs
Predicting Apathy in Non-demented People with Parkinson’s A
path
y Sc
ale
(AS)
N-111 nondemented people with Parkinson’s
Stroop Interference, Age, & BDI-II
Kirsch-Darrow, 2009
Differential Influence of Apathy & Depression on …
Cognition Behavior Emotion Psychophysiology
Behavior: Novelty Toy Task
Lab based task of exploration
% ti
me
(10
min
)
Apathy Nonapathy GROUP
100 80 60 40 20 0
% Time Playing with Toys
38%
81%
Ferencz, et al., 2012
*
Ferencz et al (2012)
Emotion Reactivity
Psychophysiology blunting • Skin conductance, startle • Hypoarousal
Electrophysiology blunting • Reduced ERP to emotion pix • Reduced novelty detection (P300)
Bowers et al., 2006; Miller et al., 2009, Dietz et al, 2015; Kaufman et al., 2016
Apathy is an intrinsic part of Parkinson’s disease
• Apathy common in PD, disBnct from depression • Occurs in both demented and non-‐demented PD
• Best cogniBve predictors of apathy in non-‐demented PD are “frontal” tasks such as the Stroop
• Associated with physiologic blunBng to emoBonal pictures • Related to disease severity and age.
To Recap
Implication
Apathy in PD: What we don’t know
• Is apathy merely a signature for disease progression?
• How to best treat apathy? What are the best
approaches for bolstering motivation and drive? • Pharmacologic • Nonpharmacologic
Adcock et al, Neuron, 2016 Pix from KQED News, NPR
Apathy Treatment
No “silver bullet” Pharmacologic Nonpharmacologic • Stimulation (rTMS) • Behavioral approaches
Apathy Treatment
• Relatively few randomized clinical trials – these are ‘gold standard’ • Most studies involve increasing some variant of dopamine • Only a few have made “apathy” the main focus; for most, apathy is
secondary
Pharmacologic
1. Dopamine agonists • Pramipexole vs. Ropinirole (Julez et al., 2015)*
• Piribedil (D2-D3) • Rotigotine (aka Neupro®)
2. Methylphenidate 3. Rivastigmine (Exelon® patch)- (Devos et al, 2014)*
(cholinergic – nondemented PD)
The Restore Study (rTMS)
To learn whether rTMS would improve apathy in people with Parkinson’s PD participants with apathy randomly assigned to rTMS or to Sham condition; Tx = 2 weeks
Apathetic PD N=24 Real rTMS
Sham rTMS
Primary outcome: Apathy Scale Score
Fernandez, Bowers et al.
Brain Stimulation – repetitive Transcranial Magnetic Stimulation
The Restore Study (rTMS)
Results: Terrific! Apathy Improved
Apathetic PD N=24
Real rTMS
Sham rTMS
Fernandez, Bowers et al.
Brain Stimulation – repetitive Transcranial Magnetic Stimulation
Dramatic improvement in apathy, as measured by AS and LARS But true for both groups
WHY? Behavioral Activation? Placebo?
Behavioral Approaches for Improving Apathy
1. Dance Therapy 2. Music Therapy 3. Exercise 4. Cognitive Training 5. Behavioral Activation - PAL program
Cognitive Training
• Studies in normal aging (ACTIVE TRIAL; VITAL) and mild cognitive impairment; improvements and generalization • Changes in dopamine D1 receptors following working memory training (Klingberg et al., 2009) • Tasks: computer based programs; video games, crossword puzzles, bingo, cards, etc.
• Parkinson’s Disease: Several studies in Parkinson’s disease. Improvement in processing speed; trends for apathy. (Pena et al., 2014)
Parkinson’s Active Living (PAL) Butterfield et al., in press
Behavioral Activation & Goal Setting program • developed specifically for Parkinson’s disease • Targeted outcome = apathy • 6 weeks, telehealth
Key Elements • Identified 5 goals during initial in-person session
2 for Week 1, 3 for Wk 2, 4 for Wk 3, all 5 for remaining Weeks • Developed specific plans & schedules • Weekly telehealth session with program coach • I-Ping reminders
Parkinson’s Active Living (PAL) Butterfield et al., in press
This was single arm ‘unblinded’ study Goals – was this feasible & acceptable?
would this approach improve apathy?
Results: Feasibility: 4 of 32 dropped out (12% attrition) Acceptability: satisfaction 87.5 on 100 scale Apathy significantly improved: AES QOL significantly improved No changes in caregiver burden/stress
Goal Setting - cornerstone of motivation • Specific • Attainable (realistic) • Not too easy • Commitment - self-set goals best • Positive feedback - a reward
Implementation • Specific plans – when, where, how • Prepare for potential setbacks
External Cues • Reminders, schedule
Getting Motivated - Best Practices
Other Tips for Motivation
Be SMART in selecting goals
S - specific goals M - measurable A - attainable R - realistic T - timely
From Butterfield et al, in press
Other Tips for Behavioral Activation
UF Brain Activity Guide
Outings Crafts & Hobbies Music Nature In the Home Verbal Skills Games Reminiscing
Bottom Line Apathy is a motivational disorder whereas Depression is a mood disorder Tip: Sadness, guilt, worrisomeness, hopelessness all point to depression. Not apathy. Tip: Decreased initiation, loss of ‘get up and go’ may point to apathy. Apathy worsens with disease progression and is associated with dopaminergic depletion in the brain’s motivational circuits. It has impact on daily activities, treatment outcomes and caregiver distress.
Bottom Line
Treatment approaches are pharmacologic and behavioral • Tip: Make sure patient is on optimal doses of dopa
medications, particularly dopamine agonists (if possible)
• Tip: Avoid SSRI’s if possible • Tip: KEEP MOVING; Use some variant of behavioral
activation and goal setting! • Even if patient cannot do own goal setting, keeping
active (behavioral activation) is critical There is great individual variability – what is not
variable is to keep moving…
• I am happy to take questions
• Thank you to my funding sources at the NIH, Michael J. Fox Foundation, the National Parkinson Foundation, and the state of Florida.
• Thank you to the staff at the Parkinson’s Disease Foundation
• For updates, go to http://movementdisorders.ufhealth.ufl.edu
Thank You!
Thank You!
53
“My Parkinson’s diagnosis in 2008 may have closed the door on my piloting career, but it opened a new one to the world of woodworking. Through my craft, I have not only found a way to retain my fine motor skills, I have also regained my
purpose.” Carousel Studio, Bart Kadleck
PDF Creativity and Parkinson’s Project
Questions and Discussion
54
Resources from PDF
55
Parkinson’s HelpLine • Available at (800) 457-‐6676 or [email protected] • Monday through Friday • 9:00 AM – 5:00 PM ET
Fact Sheets • CombaBng Depression
Online Seminars • A Closer Look at Anxiety and Depression in Parkinson's Disease
• Under-‐recognized Nonmotor Symptoms of Parkinson's Disease