1. Behavioral Decompensation in Alzheimer’s Disease: A Systematic and Multimodal Approach to Patient Management

2. Case Study ► 81 y/o veteran longtime smoker w/ COPD, dx AD x 2 yrs, recently dx w/ “inoperable” lung CA sent from NH for control of combative behavior and hospice consultation; pt lost 20# over past month, anorexic, largely unresponsive. ► Rx includes 1,500mg divalproex, risperidone 0.5mg qAM, 1mg qHS, recent addition of haloperidol 0.5mg IM TID to allow for care administration…

3. Peak Frequency of Behavioral Symptoms as AD Progresses Jost BC, Grossberg GT. J Am Geriatr Soc. 1996; 44:1078-1081 Months Before/After Diagnosis -40 -30 -20 -10 0 10 20 30 Frequency (% of Patients) 100 80 60 40 20 0 Agitation Diurnal Rhythm Irritability Wandering Aggression Hallucinations Mood Change Socially Unacc. Delusions Sexually Inappropriate Accusatory Suicidal Ideation Paranoia Depression Anxiety Social Withdrawal

4. Keys To Evaluation Of Behavioral Problems In Dementia I dentify the problem behavior (WHAT) T iming / frequency of the behavior (WHEN) S urroundings / environment (WHERE) O thers involved? (WITH WHOM) V ery troubling / dangerous? E valuation: physical & cognitive status R ecommendations I dentify the problem behavior (WHAT) T iming / frequency of the behavior (WHEN) S urroundings / environment (WHERE) O thers involved? (WITH WHOM) V ery troubling / dangerous? E valuation: physical & cognitive status R ecommendations Gray KF. Clin Geriatr Med. 2004(Feb);20(1):69-82

5. The Delicate Balance of Clinical Decision-making RISKS BENEFITS

6. Behavioral and Psychological Symptoms in Dementia: BPSD ► General descriptive term for heterogeneous group of non-cognitive symptoms & behaviors occurring in dementia ► Symptom Clusters within BPSD include: l Depressive 20% - 40% l Psychotic 30% - 40% l Agitation/aggressive 50% - 80% B. A. Lawlor. J.Clin.Psychiatry 65 Suppl 11:5-10, 2004

7. Criteria for Depression of Alzheimer’s Disease A. (Need 3 or more over 2 wks...) ► Depressed mood and/or ► Decreased positive affect or pleasure ● Appetite disruption ● Sleep disruption ● Psychomotor retardation / agitation ● Irritability ● Fatigue or loss of energy ● Worthlessness, hopelessness, guilt ● Thoughts of death or suicidal ideation B. All criteria met for dx of AD C. Sx cause clinically significant distress or disruption in fxn J. T. Olin, et al. Am.J.Geriatr.Psych 10(2):125-128, 2002 P. B. Rosenberg, et al. Int.J.Geriatr.Psychiatry 20 (2):119-127, 2005

8. TREAT Depression of Alzheimer’s Disease! BENEFITS RISKS ► Rx Mood, anxiety ► Rx Sleep? ► Rx agitation?

9. AAN Practice Parameters 2001 Guideline-Reaffirmed 10/18/2003 AAN practice parameters support the use of first-line nonpharmacologic strategies for agitation, especially when identifiable causes such as pain or environmental triggers are responsible AAN practice parameters support the use of first-line nonpharmacologic strategies for agitation, especially when identifiable causes such as pain or environmental triggers are responsible Doody RS, Stevens JC, Beck C, et al. Neurology. 2001(May 8);56(9):1154-1166

10. Principles of Nonpharmacologic Management ► Safety l Control risk: physical, financial, driving ► Serenity l Manage affects: avoid overt frustration and anger ► Structure l Increase organization: maintain schedules, facilitate good habits ► Sanity l Reduce caregiver strain: seek social support, use respite services Gray KF. Clin Geriatr Med. 2004(Feb);20(1):69-82

11. ► Educational programs should be offered to family caregivers to improve caregiver satisfaction and to delay the time to NH placement (Guideline) ► Staff of long-term care facilities should also be educated about AD to minimize the unnecessary use of antipsychotic medications (Guideline) ► Behavior modification, scheduled toileting, and prompted voiding reduce urinary incontinence (Standard) ► Functional independence can be increased by graded assistance, skills practice, and positive reinforcement (Guideline) R. S. Doody, et al. Neurology 56 (9):1154-1166, 2001 AAN Practice Parameters 2001 Guideline-Reaffirmed 10/18/2003

12. Medication Considerations For Non-urgent/Emergent “Agitation” BENEFITS RISKS CholinesteraseInhibitorsandMemantine

13. NPI Scores Following Treatment with Different ChEIs –3 –2 –1 0 1 2 3 Mean change from baseline N = 106 N = 103 N = 98 Improvement Placebo 24 mg/day Placebo 10 mg/d Open-label 3–12 mg/d MMSE = 14.4 MMSE = 11.8 MMSE  12 MMSE = 9.2 MMSE = 10.8 NPI-12 1 NPI-12 2 NPI-10 3 NPI-12 4 NPI-12 5 Nursing Community/Community Nursing Nursing home assisted living home home 1 Tariot et al., 2001; 2 Feldman et al., 2001; 3 Wilkinson et al., 2002; 4 Cummings et al., 2000; 5 Bullock et al., 2001; Cummings, et al., 2004 Placebo 10 mg/d N = 125 N = 119 Baseline N = 113 Open-label 3–12 mg/d GalantamineAricept Rivastigmine Mean Change Per Item After ~ 6 Months in Five Studies

14. Impact of Galantamine on Behavioral Symptoms Efficacy measure Galantamine (N = 1,327) Placebo (N = 686) P Individual NPI domain scores Delusions -0.04 (2.43) 0.19 (2.23) 0.10 Hallucinations -0.02 (1.58) 0.07 (1.24) 0.068 Agitation/aggression 0.10 (2.64) 0.27 (2.30)** 0.050* Depression/dysphoria 0.11 (2.40) 0.13 (2.26) 0.97 Anxiety -0.05 (2.66) 0.19 (2.48) 0.044* Elation/euphoria0.01 (0.96)0.00 (1.02)0.86 Apathy/indifference-0.22 (3.25)**-0.13 (3.21)0.28 Disinhibition 0.00 (1.61) 0.09 (1.33) 0.020* Irritability/lability 0.12 (2.60) 0.20 (2.36)* 0.71 Aberrant motor behavior -0.15 (2.96) 0.12 (2.91) 0.050* a Effect size: difference in mean change scores (galantamine minus placebo) divided by the pooled within-group SD (Cohens’s  ). *p <.05 for between-group comparisons (Val Elteren test, df: 1). ** <.05 for within-group comparisons (Wilcoxon signed-rank tests). N. Herrmann, et al. Am.J.Geriatr.Psychiatry 13 (6):527-534, 2005

15. Effects of Donepezil on Neuropsychiatric Symptoms in Patients with Dementia and Severe Behavioral Disorders ► The total score of the NPI was significantly reduced over the 20 weeks of therapy with donepezil ► 62% pts had at least a 30% reduction in total NPI score - significantly greater than the number with no meaningful response ► More patients had total or partial resolution of depression and delusions than those who had no meaningful change ► Clinically meaningful treatment effect sizes were notable for the delusion factor (0.340) and the mood factor (0.39). ► Significant correlations between the Clinical Global Impression- Improvement and reductions in mood and agitation scores ► The results suggest that donepezil reduces behavioral symptoms, particularly mood disturbances and delusions, in pts with AD with relatively severe psychopathology J. L. Cummings, et al. Am.J Geriatr.Psychiatry 14 (7):605-612, 2006

16. Memantine in Moderate to Severe AD Study: Impact on Behavior - NPI At End Point ► There was no statistically significant difference between the 2 groups for total NPI scores ► There was a statistically significant difference between the treatment groups in favor of memantine in the following domains l Delusions P =.0386* l Agitation/aggression P =.0083* *LOCF analysis Reisberg B, et al. N Engl J Med. 2003;348:1333-1341

17. * Memantine + Donepezil in Moderate to Severe AD Study: Impact on Behavior * P=.002P=.001 Mean Change From Baseline NPIBGP-Care Worsening Improvement Memantine + Donepezil Treatment Associated With Superior Outcomes in Key AD Domains *LOCF analysis. Bars indicate 95% confidence intervals Tariot P, et al. JAMA. 2004;291:317-324

18. Behavioral effects of memantine in AD pts receiving donepezil treatment ► Pts treated with memantine had significantly lower NPI total scores than pts treated with placebo ► Significant effects for memantine on agitation/aggression, eating/appetite, and irritability/lability ► Pts w/ agitation/aggression at baseline Rx w/ memantine showed significant reduction of symptoms compared with placebo-treated pts ► Memantine-treated pts without agitation/aggression at baseline evidenced significantly less emergence of this symptom compared with similar pts receiving placebo ► Caregivers of pts receiving memantine registered significantly less agitation-related distress J. L. Cummings, et al. Neurology 67 (1):57-63, 2006

19. AAN Practice Parameters 2001 (Reaffirmed 10-18-03) ► Treat agitation, psychosis and depression l The patient's paranoia, suspiciousness, combativeness or resistance to maintaining personal hygiene can seem overwhelming to families and caregivers and significantly impact quality of life. Evidence indicates that several strategies can decrease problem behaviors. If environmental manipulation fails to eliminate agitation or psychosis, use antipsychotics… R. S. Doody, et al. Neurology 56 (9):1154-1166, 2001 Full guidelines available at www.aan.com

20. Diagnostic Criteria for Psychosis of AD ► Diagnosis of Alzheimer’s dementia ► Exclusion of schizophrenia or other causes of psychotic symptoms ► Hallucinations and/or delusions l Late-onset l Present intermittently for  1 month l Disruptive to patient functioning ► Associated agitation, negative symptoms, and depression ► Disturbances do not correlate exclusively with delirium D. V. Jeste and S. I. Finkel. Am.J.Geriatr.Psychiatry 8 (1):29-34, 2000 L. S. Schneider, et al. Am.J.Geriatr.Psychiatry 11 (4):414-425, 2003

21. ANTIPSYCHOTIC USE FOR “AGITATION” RISKS ? BENEFITS ? ► Persistent DANGER to self or others? ► Behaviors impair function? C. Ballard and J. Cream. Int.Psychogeriatr. 17 (1):4-12, 2005

22. The Delicate Balance of Clinical Decision-making RISKS BENEFITS

23. Antipsychotic Documentation ► Severity of symptoms ► Danger to patient and others ► Lack of response to alternative approaches ► Awareness of risks of treatment ► Judgment that potential benefits outweigh risks l Previous benefit? l Previous tolerability? ► Discussion with family ► Monitoring plan ► Plan for dose reduction when stable (Thanks to Ira Katz, MD)

24. Atypical Antipsychotic Treatment for Psychosis & Dangerous Behavioral Dyscontrol in Dementia: ► Olanzapine 2.5 – 10 mg, oral “loading” pts in urgent settings [15-20 mg 1st 24 hr]; IM* ► Risperidone 0.5 – 2 mg, caution w/ doses > 1 mg ‡ ► Quetiapine 25-150 mg, especially w/ parkinsonism, Lewy Body Dementia † ► Aripiprazole 5-10 mg, non-urgent use § ► Ziprasidone 20-60 mg BID, emerging option; IM ¶ *J. S. Street et al. Arch Gen Psychiatry. 2000;57(10):968-976; and R. W. Baker et al. J Clin Psychopharmacol. 2003;23(4):342-348; ‡ I. R. Katz et al. J Clin Psychiatry. 1999;60(2):107-115 and P. P. de Deyn et al. Clin Neurol Neurosurg. 2005; † P. N. Tariot and M. S. Ismail. J Clin Psychiatry. 2002;63 suppl 13:21-26; § De Deyn et al. AAGP 16th Annual Meeting, 2003; ¶ A. Berkowitz. J Psychiatric Practice. 2003;9(6) 469-473

25. Efficacy and Adverse Effects of Atypical Antipsychotics for Dementia: Meta-analysis of Randomized, Placebo-controlled Trials ► Efficacy on rating scales was observed by meta- analysis for aripiprazole and risperidone, but not for olanzapine ► There were smaller effects for less severe dementia, outpatients, and patients selected for psychosis ► Approx 1/3 dropped out w/o overall differences between Rx & placebo ► Adverse events mainly somnolence & UTI or incontinence across Rx, and EPS or abnormal gait with risperidone or olanzapine L. S. Schneider, et al. Am.J Geriatr.Psychiatry 14 (3):191-210, 2006

26. Efficacy and Adverse Effects of Atypical Antipsychotics for Dementia: (con’t) Meta-analysis of Randomized, Placebo-controlled Trials ► ► Cognitive test scores worsened with drugs ► ► There was no evidence for increased injury, falls, or syncope ► ► Significant risk for cerebrovascular events, especially with risperidone ► ► Increased risk for death overall was reported elsewhere ► ► The modest efficacy and uncertain response rates combined with the risks detailed here suggest that antipsychotics should be used with more deliberate consideration L. S. Schneider, et al. Am.J Geriatr.Psychiatry 14 (3):191-210, 2006

27. Risk of Death In Elderly Users of Conventional vs. Atypical Antipsychotic Medications ► “If confirmed, these results suggest that conventional antipsychotic medications are at least as likely as atypical agents to increase the risk of death among elderly persons and that conventional drugs should not be used to replace atypical agents discontinued in response to the FDA warning.” P. S. Wang, et al. N Engl J Med 353 (22):2335-2341, 2005

28. Antipsychotic Equivalencies Based On D2 Receptor Occupancy & Expert Consensus Guidelines ► Quetiapine = 300-400 mg ► Chlorpromazine = 100 mg ► Ziprasidone » 80 mg ► Aripiprazole= 10 mg ► Loxapine= 15 mg ► Olanzapine = 10 mg ► Risperidone = 2.5 mg ► Haloperidol = 2 mg Kane et al. J Clin Psychiatry. 2003;64 (suppl 12):5-19; Kapur et al. Am J Psychiatry. 2001;158(3):360-369 Schotte et al. Psychopharmacology (Berl).1996;124 (1-2):57-73

29. Non-neuroleptic Options For “Agitation” ?? “BENEFITS” RISKS LIMITED PROOF OF EFFICACY K. M. Sink, et al. JAMA 293 (5):596-608, 2005 K. N. Franco and B. Messinger-Rapport. J Am.Med Dir.Assoc. 7 (3):201-202, 2006

30. Alternative Rx FOR “AGITATION” ► SSRI REDUCE IRRITABILITY: non-psychotic pts, psychosis? ► TRAZODONE (25-50 mg BID-TID) during day, qHS ► DIVALPROEX, CARBAMAZEPINE, GABAPENTIN ► ADJUNCTIVE BENZODIAZEPINES ► HORMONES for SEXUAL AGGRESSION: (medroxyprogesterone acetate 150 mg IM q4wks) ► Propranolol * (~100 mg/d) ** Gray KF. Clin Geriatr Med. 2004(Feb);20(1):69-82 * W. K. Summers. J Alzheimers.Dis. 9 (1):69-75, 2006; ** E. R. Peskind, et al. Alzheimer Dis.Assoc.Disord. 19 (1):23-28, 2005

31. Behavioral Decompensation in AD ► Medications do not work alone ► Fewer expectations late in day ► Distract with tasks or food ► Remind and assist; don’t take over! ► Be willing to compromise ► Back off and let patient relax; redirect as appropriate ► “They can’t resist if you don’t insist” Last Words for Caregivers Gray KF. Clin Geriatr Med. 2004(Feb);20(1):69-82