1. Behavioral Decompensation in Alzheimers 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. 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… 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. DOCTOR, WEVE GOT A PROBLEM... ITS OVER!

5. 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

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

7. Behavioral and Psychological Symptoms in Dementia: BPSD General descriptive term for heterogeneous group of non-cognitive symptoms & behaviors occurring in dementia General descriptive term for heterogeneous group of non-cognitive symptoms & behaviors occurring in dementia Symptom Clusters within BPSD include: 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

8. Criteria for Depression of Alzheimers Disease A. (Need 3 or more over 2 wks...) Depressed mood and/or Depressed mood and/or Decreased positive affect or pleasure Decreased positive affect or pleasure Appetite disruption Appetite disruption Sleep disruption Sleep disruption Psychomotor retardation / agitation Psychomotor retardation / agitation Irritability Irritability Fatigue or loss of energy Fatigue or loss of energy Worthlessness, hopelessness, guilt Worthlessness, hopelessness, guilt Thoughts of death or suicidal ideation 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

9. TREAT Depression of Alzheimers Disease! BENEFITS RISKS Rx Mood, anxiety Rx Sleep? Rx agitation?

10. 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

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

12. Educational programs should be offered to family caregivers to improve caregiver satisfaction and to delay the time to NH placement (Guideline). 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). 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). 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). 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

13. Medication Considerations For Non-urgent/Emergent Agitation BENEFITS RISKS CholinesteraseInhibitorsandMemantine

14. 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

15. 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 (Cohenss ). *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

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 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 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*4 *LOCF analysis. Sources: Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. Data on file, Forest Laboratories, Inc.

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. Source: Tariot P, et al. JAMA. 2004;291:317-324.

18. AAN Practice Parameters 2001 (Reaffirmed 10-18-03) Treat agitation, psychosis and depression 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

19. Diagnostic Criteria for Psychosis of AD Diagnosis of Alzheimers dementia Diagnosis of Alzheimers dementia Exclusion of schizophrenia or other causes of psychotic symptoms Exclusion of schizophrenia or other causes of psychotic symptoms Hallucinations and/or delusions Hallucinations and/or delusions l Late-onset l Present intermittently for 1 month l Disruptive to patient functioning Associated agitation, negative symptoms, and depression Associated agitation, negative symptoms, and depression Disturbances do not correlate exclusively with delirium 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

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

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

22. Antipsychotic Documentation Severity of symptoms Severity of symptoms Danger to patient and others Danger to patient and others Lack of response to alternative approaches Lack of response to alternative approaches Awareness of risks of treatment Awareness of risks of treatment Judgment that potential benefits outweigh risks Judgment that potential benefits outweigh risks l Previous benefit? l Previous tolerability? Discussion with family Discussion with family Monitoring plan Monitoring plan Plan for dose reduction when stable Plan for dose reduction when stable

23. 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* 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 Risperidone 0.5 – 2 mg, caution w/ doses > 1 mg Quetiapine 25-150 mg, especially w/ parkinsonism, Lewy Body Dementia Quetiapine 25-150 mg, especially w/ parkinsonism, Lewy Body Dementia Aripiprazole 5-10 mg, non-urgent use § Aripiprazole 5-10 mg, non-urgent use § Ziprasidone 20-60 mg BID, emerging option; IM ¶ 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

24. 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 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 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 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 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

25. Efficacy and Adverse Effects of Atypical Antipsychotics for Dementia: (cont) Meta-analysis of Randomized, Placebo-controlled Trials Cognitive test scores worsened with drugs Cognitive test scores worsened with drugs There was no evidence for increased injury, falls, or syncope There was no evidence for increased injury, falls, or syncope Significant risk for cerebrovascular events, especially with risperidone Significant risk for cerebrovascular events, especially with risperidone Increased risk for death overall was reported elsewhere 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 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

26. Antipsychotic Equivalencies Based On D2 Receptor Occupancy & Expert Consensus Guidelines Quetiapine = 300-400 mg Quetiapine = 300-400 mg Chlorpromazine = 100 mg Chlorpromazine = 100 mg Ziprasidone » 80 mg Ziprasidone » 80 mg Aripiprazole= 10 mg Aripiprazole= 10 mg Loxapine= 15 mg Loxapine= 15 mg Olanzapine = 10 mg Olanzapine = 10 mg Risperidone = 2.5 mg Risperidone = 2.5 mg Haloperidol = 2 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

27. Non-neuroleptic Options For Agitation ?? BENEFITS RISKS LIMITED PROOF OF EFFICACY K. M. Sink, et al. JAMA 293 (5):596-608, 2005

28. Alternative Rx FOR Agitation SSRI REDUCE IRRITABILITY: non-psychotic pts, psychosis? SSRI REDUCE IRRITABILITY: non-psychotic pts, psychosis? TRAZODONE (25-50 mg BID-TID) during day, qHS TRAZODONE (25-50 mg BID-TID) during day, qHS BUSPIRONE (10-60 mg/day): may take 2-4 wks BUSPIRONE (10-60 mg/day): may take 2-4 wks DIVALPROEX, CARBAMAZEPINE, GABAPENTIN DIVALPROEX, CARBAMAZEPINE, GABAPENTIN ADJUNCTIVE BENZODIAZEPINES ADJUNCTIVE BENZODIAZEPINES HORMONES for SEXUAL AGGRESSION: (medroxyprogesterone acetate 150 mg IM q4wks) HORMONES for SEXUAL AGGRESSION: (medroxyprogesterone acetate 150 mg IM q4wks) Gray KF. Clin Geriatr Med. 2004(Feb);20(1):69-82

29. Behavioral Decompensation in AD Medications do not work alone Medications do not work alone Fewer expectations late in day Fewer expectations late in day Distract with tasks or food Distract with tasks or food Remind and assist; dont take over! Remind and assist; dont take over! Be willing to compromise Be willing to compromise Back off and let patient relax; redirect as appropriate Back off and let patient relax; redirect as appropriate They cant resist if you dont insist They cant resist if you dont insist Last Words for Caregivers