1. © 2006 American Academy of Neurology Practice Parameter: Evaluation and Treatment of Depression, Psychosis and Dementia in Parkinson Disease: An Evidence-Based Review American Academy of Neurology Quality Standards Subcommittee J. Miyasaki, MD; K. Shannon, MD; V. Voon, MD; B. Ravina, MD; G. Kleiner-Fisman, MD; K. Anderson, MD; L.M. Shulman, MD; G. Gronseth, MD; and W.J. Weiner, MD

2. © 2006 American Academy of Neurology The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use.guidelines@aan.com

3. © 2006 American Academy of Neurology Presentation Objectives Review background information on depression, psychosis, and dementia Make evidence-based recommendations for patients with Parkinson Disease (PD)

4. © 2006 American Academy of Neurology Overview Descriptive epidemiology Background and gaps in care AAN guideline process Screening tools and treatments –Depression –Psychosis –Dementia Summary Recommendations for future research

5. © 2006 American Academy of Neurology Descriptive Epidemiology of Parkinson Syndrome Incidence –5–24/10 5 worldwide (ref) –20.5/10 5 USA (ref) Prevalence –57–371/10 5 worldwide (ref) –300/10 5 USA/Canada (Strickland & Bertoni, 2004) –Prevalence of PS/PD rising slowly with aging population

6. © 2006 American Academy of Neurology Background Nonmotor symptoms an increasingly recognized feature in PD –High prevalence Affect autonomic, neuropsychiatric, and sensory domains (Factor & Weiner, 2002) –May result in significant disability

7. © 2006 American Academy of Neurology Background Prospective survey n=99 (Shulman et al., 2001) –88% had at least one of Anxiety, depression, sensory disturbance, fatigue, pain, or sleep disturbance –11% had 5 or more

8. © 2006 American Academy of Neurology Gaps in Care Low physician recognition of nonmotor features in PD Many PD symptoms overlap with features of depression and dementia Validated criteria for depression, psychosis and dementia in PD do not exist

9. © 2006 American Academy of Neurology Seeking Answers How do we find the answers to the questions that arise in daily practice? In order to keep up to date, need to read 29 articles a day, 365 days a year (Didsbury, 2003) Or find someone who has found and summarized the relevant data for you

10. © 2006 American Academy of Neurology American Academy of Neurology Guideline Process Clinical Question Evidence Conclusions Recommendations

11. © 2006 American Academy of Neurology Clinical Question Question should address an area of quality concern, controversy, confusion, or variation in practice Question must be answerable with sufficient scientific data –Potential to improve clinical care and patient outcomes

12. © 2006 American Academy of Neurology Literature Search/Review: Rigorous, Comprehensive, Transparent Search Review abstracts Review full text Select articles Relevant Complete

13. © 2006 American Academy of Neurology AAN Classification for Evidence All studies rated Class I, II, III, or IV Therapeutic Studies –Randomization, control, blinding Diagnostic Studies –Comparison to gold standard; spectrum Prognostic Studies

14. © 2006 American Academy of Neurology AAN Level of Recommendations A = Established as effective, ineffective, or harmful for the given condition in the specified population B = Probably effective, ineffective, or harmful for the given condition in the specified population C = Possibly effective, ineffective, or harmful for the given condition in the specified population U = Data is inadequate or conflicting; given current knowledge, treatment is unproven

15. © 2006 American Academy of Neurology AAN Level of Recommendations A = Requires two consistent Class I studies B = Requires one Class I study or two consistent Class II studies C = Requires one Class II study or two consistent Class III studies U = Studies not meeting criteria for Class I through Class III

16. © 2006 American Academy of Neurology Clinical Questions 1)In patients with PD, what are the most accurate tools to screen for depression, psychosis, and dementia? 2)In patients with PD, what are the best treatments for depression and psychosis? 3)What is the most effective treatment of dementia in PD or dementia with Lewy bodies (DLB)?

17. © 2006 American Academy of Neurology Methods Literature Search: –MEDLINE, EMBASE, CINHAL, and Cochrane Database of Systematic Reviews, and Health and Psychosocial Instruments (1966–2004) Secondary search using bibliography of retrieved articles and knowledge of expert panel At least two authors reviewed each full article

18. © 2006 American Academy of Neurology Methods Risk of bias determined using the classification of evidence for each study (Class I–IV) Strength of practice recommendations linked directly to level of evidence (Level A–U) Conflicts of interests disclosed

19. © 2006 American Academy of Neurology Literature Search/Review of Entire Guideline 20 articles 523 articles Exclusion criteria: -Class IV not considered if Class III studies available -Class III studies not considered if Class II studies available

20. © 2006 American Academy of Neurology Clinical Question 1 In patients with PD, what are the most accurate tools to screen for depression, psychosis, and dementia?

21. © 2006 American Academy of Neurology Depression Screening Tools

22. © 2006 American Academy of Neurology Depression in PD Supporting endogenous etiology –Precede motor symptoms –More prevalent in PD than other chronic illnesses –Not necessarily correlated with severity of disease

23. © 2006 American Academy of Neurology Depression Characteristics Less guilt Less risk suicide Bradyphrenia vs psychomotor slowing Loss of appetite Sleep disturbance Feelings of worthlessness

24. © 2006 American Academy of Neurology Clinical Question 1a: In patients with PD, what are the most accurate tools to screen for depression?

25. © 2006 American Academy of Neurology Depression Diagnosis No clear criteria for PD DSM IV –Depressed mood most of day, nearly every day –Markedly diminished interest or pleasure in all or most activities –Significant weight loss –Insomnia or hypersomnia –Psychomotor agitation or retardation –Fatigue –Feelings of worthlessness –Inability to concentrate or indecisiveness –Recurrent thoughts of death

26. © 2006 American Academy of Neurology Depression Screening Beck Depression Index I (BDI-1) –Self completed –21 items –>13 www.beckinstitute.org

27. © 2006 American Academy of Neurology Depression Screening Hamilton Depression Rating Scale (HDRS) –Physician administered –Requires about 20 minutes –17 items –>13

28. © 2006 American Academy of Neurology Depression Screening Montgomery Asberg Depression Rating Scale (MADRS) –10 items requires 20–25 min –>14

29. © 2006 American Academy of Neurology Literature Search/Review for Depression Screening 3 articles 37 articles Exclusion Reasons: -Did not examine diagnostic accuracy -Patients did not have PD

30. © 2006 American Academy of Neurology Recommendations for Depression Screening BDI-1 and HDRS should be considered for depression screening in PD (Level B) MADRS may be considered for depression associated with PD (Level C) Cannot recommend one screening test over the other

31. © 2006 American Academy of Neurology Insufficient evidence to support or refute the usefulness of other rating scales for depression in PD (Level U) Recommendations for Depression Screening

32. © 2006 American Academy of Neurology Psychosis Screening Tools

33. © 2006 American Academy of Neurology Psychosis in PD Often a marker of dementia Although associated with the treated state, resolving psychosis often reveals significant cognitive decline Marker for nursing home placement

34. © 2006 American Academy of Neurology Clinical Question 1b In patients with PD, which are the most accurate tools to screen for psychosis?

35. © 2006 American Academy of Neurology Psychosis Screening No gold standard for diagnosis of psychosis in PD Hallucinations, delusions, agitation, and hostility ( Chou et al., 2005)

36. © 2006 American Academy of Neurology Psychosis Screening Parkinson Psychosis Rating Scale Not validated in all PD – only psychotic PD Good correlation with Brief Psychosis Rating Scale (BPRS) and Nurses’ Observation Scale for Inpatient Evaluation (NOSIE) – –Psychosis items Visual hallucinations Illusions/misidentification of persons Paranoia Sleep disturbance (RBD) Sexual preoccupation Clinical Global Impression

37. © 2006 American Academy of Neurology Literature Review for Psychosis Screening 1 article 31 articles Exclusion Reasons: -Did not examine diagnostic accuracy -Did not include patients with PD

38. © 2006 American Academy of Neurology Recommendation for Psychosis Screening No recommendation made for psychosis screening in PD –No validated psychosis scales –Psychosis in PD characterized by Hallucinations Paranoid delusions, delusions of spousal infidelity Classification of RBD unclear

39. © 2006 American Academy of Neurology Dementia Screening Tools

40. © 2006 American Academy of Neurology Dementia in Parkinson Disease 4x risk of age matched controls Diagnosis may be late due to masking by bradyphrenia and loss of motivation Hallucinations correlated with dementia

41. © 2006 American Academy of Neurology Clinical Question 1c In patients with PD, which are the most accurate tools to screen for dementia?

42. © 2006 American Academy of Neurology Literature Review for Dementia Screening 2 articles 24 articles Exclusion Reasons: -Did not examine diagnostic accuracy -Did not include patients with dementia

43. © 2006 American Academy of Neurology Recommendations for Dementia Screening Tools The Mini-Mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCog) should be considered as screening tools for dementia in patients with PD (Level B) Insufficient evidence to support or refute the use of EEG as a screening tool (Level U)

44. © 2006 American Academy of Neurology Dementia Screening Tools MMSE (Hobson, 1999) –>25 normal MMSE –Shorter than CAMCog –As sensitive –Less specific

45. © 2006 American Academy of Neurology Clinical Question 2: In patients with PD, what are the best treatments for depression and psychosis?

46. © 2006 American Academy of Neurology Depression Treatment

47. © 2006 American Academy of Neurology Clinical Question 2a: In patients with PD, what is the best pharmacologic treatment for depression?

48. © 2006 American Academy of Neurology Literature Search/Review for Depression Treatment (Pharmacologic) 6 articles 31 articles Exclusion Reasons: -Populations of PD without depression -Not randomized controlled trials -Class IV articles

49. © 2006 American Academy of Neurology Depression Treatment Class I study (Wermuth L, Sorensen P, et al.,1998) Citalopram vs placebo 6 weeks No benefit but underpowered –Evidence is unclear about the benefit of citalopram for depression associated with PD

50. © 2006 American Academy of Neurology Depression Treatment Class II study (Leentjens AF et al., 2002) Amitriptyline – benefit in mod to severe depression (allocation not concealed) Sertraline – no benefit - underpowered

51. © 2006 American Academy of Neurology Recommendations for Depression Treatment Amitriptyline may be considered for depression associated with PD (Level C) –Not necessarily the first choice for treatment Insufficient evidence to make recommendations for other pharmacologic depression treatments in PD (Level U)

52. © 2006 American Academy of Neurology Clinical Question 2b: In patients with PD and depression, what are the best nonpharmacologic treatments?

53. © 2006 American Academy of Neurology Literature Search/Review for Depression Treatment (Nonpharmacologic) 1 article 6 articles Exclusion Reasons: -High risk of bias -Class IV articles

54. © 2006 American Academy of Neurology Recommendations for Depression Treatment (Nonpharmacologic) One Class II study downgraded to Class III –Underpowered –Absense of placebo comparison group Insufficient evidence to support or refute the efficacy of transcranial magnetic stimulation or ECT (Level U) –All Class IV evidence

55. © 2006 American Academy of Neurology Psychosis Treatment

56. © 2006 American Academy of Neurology Clinical Question 2c In patients with PD and psychosis, what is the best treatment?

57. © 2006 American Academy of Neurology Literature Search/Review for Psychosis Treatment 4 articles 63 articles Exclusion Reasons: -Did not address psychosis treatment -Did not include patients with PD -Review articles -Class III and Class IV articles

58. © 2006 American Academy of Neurology Psychosis Treatment Class I –Clozapine superior to placebo –BPRS, CGI, SAPS (PSG, 1999) Class II –Clozapine vs quetiapine –Both improved psychosis (Morgante 2002)

59. © 2006 American Academy of Neurology Psychosis Treatment Class II –Olanzapine vs placebo –Psychosis did not improve –Parkinsonism worsened (Breier, 2002; Ondo, 2002)

60. © 2006 American Academy of Neurology Psychosis Treatment Clozapine –Baseline ECG, LFT. Absolute neutrophil count –Weekly neutrophil count x 6 months –Q2weekly x 6 months –12.5 mg qhs x 1 week –12.5 mg bid x 1 week etc

61. © 2006 American Academy of Neurology Recommendations for Psychosis Treatment For patients with PD and psychosis –Clozapine should be considered (Level B) –Quetiapine may be considered (Level C) –Olanzapine should not be routinely considered (Level B) Worsens motor function

62. © 2006 American Academy of Neurology Psychosis Treatment Clozapine use –Associated with agranulocytosis that may be fatal –Absolute neutrophil count must be monitored –Monitoring requirements may vary by country

63. © 2006 American Academy of Neurology Clinical Question 3 What is the most effective treatment for dementia in PD or dementia with Lewy bodies (DLB)?

64. © 2006 American Academy of Neurology Literature Review for Dementia Treatment 3 articles 331 articles Exclusion Reasons: -Did not include patients with PD -Not randomized controlled trials -Did not examine dementia treatment -Review articles -Included patients without dementia -Criteria for dementia not adequately defined

65. © 2006 American Academy of Neurology Recommendations for Dementia Treatment Donepezil should be considered for the treatment of dementia in PD (Level B) –Magnitude of benefits is modest Rivastigmine should be considered for the treatment of dementia in PD or DLB (Level B) –Magnitude of benefits is modest –Tremor may be exacerbated

66. © 2006 American Academy of Neurology Summary Screening tools available for depression and dementia in patients with PD, but need more specific, validated tools No widely used, validated tools for psychosis screening in PD

67. © 2006 American Academy of Neurology Summary Clozapine successfully treats psychosis in PD Cholinesterase inhibitors effective in treating dementia in PD, but improvement is modest and motor side effects may occur

68. © 2006 American Academy of Neurology Recommendations for Future Research Depression –Determination of the most sensitive, specific and practical depression screening tools for patients with PD –Need for randomized, double-blinded, placebo-controlled studies to assess antidepressants, psychotherapies, and other somatic therapies (i.e. ECT and TMS)

69. © 2006 American Academy of Neurology Recommendations for Future Research Psychosis –Evaluation of the PPRS in non-psychotic and psychotic patients with PD –Identification of alternatives to clozapine treatment –Need for Class I studies to evaluate the efficacy of quetiapine

70. © 2006 American Academy of Neurology Recommendations for Future Research Dementia –Development of an appropriate scale that reliably incorporates executive function into a screening test for PD dementia –More Class I studies to assess the role of cholinesterase inhibitors and other medications in the treatment of dementia associated with PD

71. © 2006 American Academy of Neurology To access the full guideline please visit: AAN.com/Guidelines Neurology® April 11, 2006 vol. 66 no. 7;996-1002

72. © 2006 American Academy of Neurology Questions, Comments?

73. © 2006 American Academy of Neurology Thanks for your participation!