Parkinson s Disease Foundation. PD ExpertBriefing: Apathy or Depression: Which One Is It?

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1 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)

2 Apathy or Depression Which One Is It? Dawn Bowers, Ph.D., ABPP-CN Professor University of Florida

3 University of Florida J. Robert Cade, Inventor of Gatorade UF Center for Movement Disorders & Neurorestoration

4 UF Center for Movement Disorders and Neurorestoration Our Motivation: Our patients, our parents, our children

5 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

6 Neuropsychiatric Features of Parkinson s Disease Depression Apathy Frightened Anxiety Happy Basal Ganglia Loops Disgusted 20% reducation amygdala volume 30-45% reduction dopamine binding

7 Apathy vs. Depression Depression Apathy THESIS: Depression = Mood disorder Apathy = Motivational disorder signature of PD progression Motivation from the Latin movere, to move

8 What is Apathy? Disorder of motivation Examples of apathetic behavior: 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

9 Apathy as a Syndrome (Marin, 1991) Cognitive Loss of interest, curiosity Apathy Lack of motivation; Failure to initiate goaldirected behavior Emotion Reduced emotional reactivity, reward Behavioral Reduced initiative; Needs others to structure activities (Marin, 1991) Motivation: To move, activate, energize, from Latin, movere

10 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

11 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

12 Measuring Apathy in PD 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 MDC Consensus panel, Leentjens et al., 2008), recommend #2 & #6

13 Apathy Scale 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 Starkstein et al., 1992 Most widely used in PD Ferencz, et al., 2012

14 Lille Apathy Rating Scale (LARS) Sockeel et al., item semi-structured interview tapping 9 domains, items are scored yes-not except 1 st 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)

15 Assessing Apathy using Item 4 from the UPDRS 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 N=301 Idiopathic PD Correlates with AS, but has mediocre ROC, miss too many folks at 0 and 1 Bottom Line: Don t use UPDRS = unified parkinson s disease rating scale Kirsch-Darrow et al., 2009)

16 Our Recommendation 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 MDC Consensus panel, Leentjens et al., 2008), recommend #2 & #6, also 3

17 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)

18 Proposed Apathy Diagnostic Criteria Starkstein & Leentjens, 2008; adapted from Marin, 1991 A. Lack of motivation relative to previous level of functioning or societal norms B. Presence of at least 1 symptom from each of 3 domains must be present for at least 4 weeks 1. Diminished goal-directed behavior e.g., requires others to structure activity, lack of effort 2. Diminished goal-directed Cognition e.g., lack of interest in new experiences, decreased curiosity 3. Diminished emotion reactivity e.g., emotional blunting, decreased physiological reactivity

19 Proposed Diagnostic Criteria Starkstein & Leentjens, 2008; adapted from Marin, 1991 continued C. Symptoms cause clinically significant distress or impairment in social, occupational, & other areas of functioning D. Symptoms not due to reduced level of consciousness or direct physiological effects of substance (meds, drug abuse, etc.)

20 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

21 Diagnosing Depression Clinical interview Depression Scales Self-Rating (Beck; Geriatric Depression Scale) Clinician Ratings (Hamilton, MADRS) DSM-V criteria Structured Clinical Interview (SCID)

DiagnosBc Criteria for Major Depression At least 5 of 9 symptoms,

Diminished Interest/ Pleasure 3. Weight/appetite loss or gain 4.

Fatigue/decreased energy 7. Feelings of worthlessness/guilt 8.

22 DiagnosBc Criteria for Major Depression At least 5 of 9 symptoms, including either or both 1 & 2 * * 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

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

23 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

24 Courtesy of H Fernandez

25 Telling Depression & Apathy Apart Unique & Overlapping Symptoms Depression symptoms Sadness Worthlessness Guilt Hopelessness Helplessness Pessimism Suicidal ideation Overlap Anhedonia Less enthusiasm about usual interests Increased slowness Apathy symptoms Decreased initiative Less interest in starting new activities Less interest in world Emotional indifference Decreased emotional reactivity Unique & Overlapping Symptoms in Apathy and Depression Zahodne et al., 2012; Pagonabarraga et al, 2015

Why It Is Important to Distinguish Apathy & Depression Relates to treatment Use of SSRI s, common medication for depression, may actually worsen apathy!

26 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

27 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

dopa meds Especially dopamine (D2) agonists Neuroimaging decreased binding of dopamine in

28 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

29 Apathy is Higher with Greater Disease Severity (Hoehn Yahr) Apathy Scale Score * * Hoehn Yahr Stage Kirsch et al (2006)

30 Apathy Worsens with Motor Disease Progression N=186 idiopathic PD; Tested over 18 month period Motor Score Apathy Depression Zahodne et al., 2011

31 Apathy & Depression in PD Relationship to Cognitive Status 100 Percentage of Patients who were apathetic or depressed % of Ss % 36% 80% 24% 26% 48% Not Demented N=111 Unknown N=80 Demented N=35 0 Apathy Depression AS & BDI-II cutoffs Kellison et al., 2007

32 Predicting Apathy in Non-demented People with Parkinson s N-111 nondemented people with Parkinson s Apathy Scale (AS) Stroop Interference, Age, & BDI-II Kirsch-Darrow, 2009

33 Differential Influence of Apathy & Depression on Cognition Behavior Emotion Psychophysiology

34 Behavior: Novelty Toy Task Ferencz et al (2012) Lab based task of exploration 100 % Time Playing with Toys % time (10 min) % * 81% 0 Ferencz, et al., 2012 Apathy Nonapathy GROUP

35 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

36 To Recap 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. Implication Apathy is an intrinsic part of Parkinson s disease

37 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

38 Apathy Treatment Adcock et al, Neuron, 2016 Pix from KQED News, NPR

39 Apathy Treatment Pharmacologic No silver bullet Nonpharmacologic Stimulation (rtms) Behavioral approaches

40 Pharmacologic 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 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) Brain Stimulation repetitive Transcranial Magnetic Stimulation To learn whether rtms would improve apathy in people with Parkinson s PD

41 The Restore Study (rtms) Brain Stimulation repetitive Transcranial Magnetic Stimulation 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 Sham rtms Apathetic PD N=24 Real rtms Primary outcome: Apathy Scale Score Fernandez, Bowers et al.

42 The Restore Study (rtms) Brain Stimulation repetitive Transcranial Magnetic Stimulation Results: Terrific! Apathy Improved Apathetic PD N=24 Sham rtms Real rtms Dramatic improvement in apathy, as measured by AS and LARS But true for both groups WHY? Fernandez, Bowers et al. Behavioral Activation? Placebo?

43 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

44 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)

45 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

46 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

47 Getting Motivated - Best Practices 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

48 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

49 Other Tips for Behavioral UF Brain Activity Guide Outings Crafts & Hobbies Music Nature In the Home Verbal Skills Games Reminiscing Activation

50 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.

51 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

52 Thank You! 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

53 Thank You! 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 53

54 Questions and Discussion 54

Resources from PDF Fact Sheets CombaBng Depression Online Seminars A Closer Look at Anxiety and Depression in Parkinson's Disease Under- recognized

55 Resources from PDF 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 Parkinson s HelpLine Available at (800) or info@pdf.org Monday through Friday 9:00 AM 5:00 PM ET 55

Parkinson s Disease Foundation. PD ExpertBriefing: Anxiety in Parkinson s Disease

Parkinson s Disease Foundation PD ExpertBriefing: Anxiety in Parkinson s Disease Led By: Joseph H. Friedman, M.D., Director of the Movement Disorders Program of Butler Hospital and Professor and Division