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 vholt@pdf.org 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

dawnbowers@phhp.ufl.edu

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

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Resources from PDF

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Parkinson’s  HelpLine    • Available  at  (800)  457-­‐6676  or  info@pdf.org  • Monday  through  Friday  • 9:00  AM  –  5:00  PM  ET  

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Online  Seminars  • A  Closer  Look  at  Anxiety  and  Depression  in  Parkinson's  Disease  

• Under-­‐recognized  Nonmotor  Symptoms  of  Parkinson's  Disease