Rethinking Behavioral Problems Associated with Dementia Pennsylvania Medical Directors Association Rethinking Behavioral Problems Associated with Dementia Joel E. Streim, M.D. Professor of Psychiatry University of Pennsylvania Philadelphia VA Medical Center

Overview (of an evolving landscape) How will the new MDS 3.0 change assessment of behavioral symptoms of dementia? How can we identify more effective interventions based on an understanding that behaviors are triggered both by Cognitive deficits due to dementia, as well as Internal and external factors? How should we interpret recent research to inform the use of medications to treat behavioral disturbances in dementia?

Overview of Changes from MDS 2.0 to MDS 3.0 Revised sections based on pilot studies 2003-2005: Cognitive Patterns Delirium Mood Behavior Pain Gait / falls Bladder and bowel Health conditions

Minimum Data Set (MDS) Behavior Section Required completion on admission and at least quarterly Includes section on behavior problems in NH residents MDS 2.0 based on staff observations and ratings MDS 3.0 proposes a shift to the patients’ experience Patients’ voice in depression assessment Patients’ perspective / values in behavior assessment

Overview of Item Content in Behavior Section of MDS 3.0 CATEGORIES Psychotic Symptoms Behavioral Symptoms Rejection of Care Wandering DOMAINS Presence Frequency Alterability Impact on resident Impact on others Change from previous assessment

Domains of Behavior in MDS 3.0

What makes this behavior a “problem”. Impact on the resident = clin What makes this behavior a “problem”? Impact on the resident = clin. significant

What makes this behavior a “problem”? Impact on Others

Rejection of Care: shifting emphasis to resident’s own values and goals

E6 - E9. Rejection of Care - Assessment Protocol Assess whether care rejection behavior is easily addressed or altered by modifying the approach If not easily addressed or altered, determine whether care rejection behavior interferes with receipt of care that is necessary to meet resident’s (or proxy’s) goals for health and well-being. Advance healthcare directives Previously stated goals or preferences Choices made by proxy on behalf of the resident

Wandering: impact and frequency determines whether problematic

E11a-b. Wandering - Impact Does the wandering place the resident at significant risk of getting to a dangerous place? Stairs, hazmat exposure, risk of getting lost, inadvertant exiting Does the wandering significantly intrude on the privacy or activities of others? Interferes with ADLs, leisure activities, or staff restrict programming (group walks, other outings)

MDS 3.0 Field Testing and Validation Study Conducted in 70 community nursing homes (n = 418 residents) 20 VA nursing homes (n = 296 residents) “Gold standard” nurses administered MDS 3.0 Facility nurses administered MDS 2.0 Cohen-Mansfield Agitation Inventory (CMAI) was gold standard for validation of presence of behavioral symptoms Neuropsychiatric Inventory (NPI) was gold standard for validation of presence of psychosis

Comparison of Kappa Coefficients for MDS 2.0 vs 3.0 and CMAI Factor 1 0.2278 (0.0298-0.4258) 0.8561 (0.7429-0.9694) Factor 2 0.3075 (0.1604-0.4545) 0.7250 (0.6117-0.8384) Factor 3 0.2152 (0.1165-0.3138) 0.3224 (0.2201-0.4247)

Factors that cause or contribute to behavioral problems associated with dementia

Assessment of behavioral symptoms in patients with dementia Behavioral symptoms are multiply determined by Cognitive deficits due to dementia Internal and external factors 1. How does cognitive impairment lead to behavioral disturbances? 2. What other factors contribute to behavioral disturbances?

Cognitive Domains Impaired in Dementia Syndrome of memory loss (amnesia) Decline in other cognitive functions Use of language (aphasia) Visual-spatial function Recognition (agnosia) Performing motor activities (apraxia) Initiating/executing sequential tasks (abulia, executive dysfunction)

How does memory impairment lead to behavioral problems? Example Patient is able to dress himself, but can’t remember where his clothes are kept Walks naked into hallway

How does language impairment (aphasia) lead to behavioral problems? Example Patient who can’t verbally communicate her dislike of milk Throws milk carton across the room

How does impaired recognition (agnosia) lead to behavioral problems? Example Patient can maneuver to pull down his pants, but can’t recognize that a toilet is a receptacle for urination Urinates on floor near nurses station

How does impairment in performance of motor tasks (apraxia) lead to behavioral problems? Example Patient is continent of bladder, but cannot unzip or unbutton to pull down her pants Wets her clothing

Apraxia, Disability, and Behavioral Change in Terminal Stages of Dementia Examples: Patient no longer holds or manipulates objects (manual apraxia) Patient sits all day; has difficulty bearing weight and ambulating, even with assistance (gait apraxia) Patient can swallow, but cannot chew effectively (oral apraxia)

What other factors may contribute to behavioral changes in patients with dementia?

Common modifiable causes of behavioral disturbances Unmet needs (physical and psychological) Environmental / social irritants Adverse drug effects Medical conditions / somatic discomfort Psychiatric conditions

Unmet needs that can lead to behavioral disturbances Physical needs Nutrition, hydration, toileting, exercise, rest Psychological needs Security, autonomy, affection, self-worth

Environmental irritants that can lead to behavioral disturbances Physical Noise Confusing visual stimuli Uncomfortable temperature Unfamiliar surroundings Social Changes in routines Provocative social interactions

Adverse drug effects that can cause behavioral disturbances Nuisance symptoms Anticholinergic effects Antihistaminic effects Paradoxical excitation / disinhibition Intoxication or withdrawal states Akathisia

Medical conditions and somatic discomfort that can lead to behavioral disturbances Arthritis Dehydration Prostatic hypertrophy COPD Cerebrovascular disease CHF Somatic discomfort Pain Constipation Urinary urgency Shortness of breath Dizziness Fatigue

Psychiatric conditions that can cause behavioral disturbances Delirium Depression Anxiety Psychosis

Psychotic symptoms and agitation in dementia 10% to 73% have delusions 21% to 49% have hallucinations Visual hallucinations characteristic in Lewy Body dementia Sensory deprivation increases risk 60% to 75% exhibit agitated behavior Finkel. J Clin Psychiatry. 2001;62(suppl 21):3. Cohen-Mansfield and Billig. J Am Geriatr Soc. 1986;34:711.

So… if the patient has dementia with agitated behaviors associated with psychosis, is it appropriate to use antipsychotic medication in 2008?

Prior Evidence for Efficacy and Safety of Antipsychotic Drugs Meta-analyses of conventional antipsychotic drug studies found significant efficacy, but small effect sizes (Schneider et al, 1990) Efficacy studies of atypical antipsychotic drugs showed drug significantly better than placebo for psychosis, agitation, aggression (Katz et al 1999, Street 2000, Mintzer 2008) Atypical antipsychotics associated with less Parkinsonism; but sedation, gait disturbance and falls occur at higher doses

Regulatory Interpretation of Risks FDA warning about risk of diabetes (Sept. 2003) Applies to the class for all ages, conditions FDA warnings about CVAEs (April 2003, Jan. 2004, March 2005) applies to risperidone, olanzapine, and aripiprazole in elders with dementia FDA advisories about mortality (April 2005, June 2008) applies to atypical AND conventional antipsychotics in dementia Includes a reminder that these drugs are not FDA-approved for this indication

Risk of Cerebrovascular Adverse Events (CVAEs) in Elderly Patients With Dementia # of trials CVAEs Numbers Needed to Harm Active drug Placebo Risperidone 4 3.8% (29/764) 1.5% (7/466) 44 Olanzapine 5 1.3% (15/1178) 0.4% (2/478) 118 Aripiprazole 3 1.3% (8/595) 0.6% (2/343) 112 In US, letters to healthcare professionals were sent and warning added in prescribing information UK Committee on Safety of Medicines guideline: Avoid use in BPSD of dementia Limited to short-term and under-specialist advice for the management of acute psychotic conditions with risperidone Consider risk in treating patients with previous history of stroke or transient ischemic attack and assess cerebrovascular disease risk factors including hypertension, diabetes, smoking, and atrial fibrillation In 2 separate Health Canada Advisories, pooled analyses of 4 placebo-controlled trials of risperidone in dementia with 1230 patients and 5 placebo-controlled trials of olanzapine in dementia with 1662 patients demonstrated an increased risk of CVAEs with risperidone and olanzapine compared with placebo. Data from the advisory letters are presented on the slide.1,2 In response to these findings, letters to US healthcare providers were sent and changes in the prescribing information of olanzapine and risperidone were made to include a warning on the increased risk as well as reminding clinicians that these agents are not approved for use in patients with dementia-related psychosis.3,4 In the UK, the Committee on Safety of Medicines advised that risperidone and olanzapine should not be used for treatment of BPSD and that the use of risperidone for acute psychotic conditions in elderly should be limited to the short term and under specialist advice.5 Further, in patients with a previous history of stroke or transient ischemic attack, risk of cerebrovascular events should be carefully considered including risk factors such as hypertension, diabetes, current smoking, and atrial fibrillation. References: 1. Health Canada Advisory for Health Professionals. Risperdal® (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials. October 11, 2002. Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/risperdal1_e.html. Accessed May 26, 2004; 2. Health Canada Advisory for Health Professionals. Zyprexa® (olanzapine) and cerebrovascular adverse events in placebo-controlled elderly dementia trials. March 10, 2004. Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/zyprexa_hpc_e.html. Accessed May 26, 2004; 3. Risperdal® (risperidone) [package insert]. Titusville, NJ: Janssen Pharmaceutica Products, LP; 2003; 4. Zyprexa® (olanzapine) [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2004; 5. Committee on Safety of Medicines. Atypical antipsychotic drugs and stroke. Available at: http://www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/antipsystroke_9304.htm. Accessed March 31, 2004. Health Canada Advisory for Health Professionals. Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd- dpt/risperdal1_e.html and http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/zyprexa_hpc_e.html. Accessed May 26, 2004; Committee on Safety of Medicines. Available at: http://www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages. Accessed March 31, 2004.

Cerebrovascular Adverse Events: Pooled Analyses of Dementia RCTs Sample Size CVAEs Exposure RR (95% CI) subject-yrs (drug/PBO) (drug/PB0) (drug/PBO) Risperidone 1009/712 33/8 171.8/118.9 2.85 (1.29-7.15) Olanzapine 1175/478 15/2 336.7/134.2 2.99 (0.7-26.9) Aripiprazole 598/340 8/2 95.2/54.1 2.27 (0.45-22.0) Quetiapine 355/213 3/4 54.7/32.7 0.50 (0.11-2.33) Ziprasodone no available clinical trials data in dementia patients Haloperidol 1.27 (0.30-4.20) Re-order this way OL RIS ARP QUE ZIP NB: 95% CI includes 1 for nearly all drugs studied !! Adapted from Schneider L. Paper presented at Annual Meeting of the American Association for Geriatric Psychiatry, San Diego CA, March 5, 2005.

Mortality in Dementia Trials: Meta-analysis of RCTs Schneider examined 15 randomized, placebo-controlled trials 6 were published Most were 10-12 weeks duration Sample 3353 patients randomized to atypical antipsychotics 1757 patients randomized to placebo Death rates 3.5% in treatment group 2.3% in control group Risk difference = 0.01 95% Confidence Interval, 0.004-0.02 (P=.01) Schneider LS, et al. JAMA 2005, 294:1934-1943.

Relative Risk of Death: Conventional vs. Atypical Antipsychotics Model Hazard Ratio (95% CI) Unadjusted analysis 1.51 (1.43-1.59) Adjusted analysis* Use of any conventional APM 1.37 (1.27-1.49) Low dose of conventional APM (<median) 1.14 (1.04-1.26) High dose of conventional APM (>median) 1.73 (1.57-1.90) Adjusted analysis of death** <40 days after beginning therapy 1.56 (1.37-1.78) 40-79 days after beginning therapy 1.37 (1.19-1.59) 80-180 days after beginning therapy 1.27 (1.14-1.41) Adjusted analysis of patient subgroups** With dementia 1.29 (1.15-1.45) Without dementia 1.45 (1.30-1.63) In a nursing home 1.26 (1.08-1.47) Not in a nursing home 1.42 (1.29-1.56) *APM=antipsychotic medication CI=confidence interval **Hazard ratios adjusted for age, sex, cardiovascular and cerebrovascular disease, psychiatric disorders, other medications used, and residential status. Wang P et al. N Engl J Med. 2005;353:2335-2341.

Deaths per person-year Days after initiation of medicine Risk of Death in Elderly Patients: Atypical vs Conventional Antipsychotics 0.6 Conventional antipsychotics Atypical antipsychotics 0.5 0.4 Deaths per person-year 0.3 0.2 0.1 20 40 60 80 100 120 140 160 180 Days after initiation of medicine Wang P et al. N Engl J Med. 2005;353:2335-2341.

CATIE-AD: Effectiveness of Atypical Antipsychotic Drugs in Outpatients with Alzheimer’s Disease 42-site, double blind, RCT N=421 patients with AD + psychosis, agitation or aggression Randomized to Olanzapine (mean dose 5.5 mg/d) Quetiapine (mean dose 56.5 mg/d) Risperidone (mean dose 1.0 mg/d) Placebo Primary outcomes: Time to all-cause discontinuation Number of patients with at least minimal improvement on CGIC at 12 weeks Schneider LS et al. N Engl J Med 2006;355:1525-1538

CATIE-AD: Primary Outcomes No significant differences among groups on CGIC (P=0.22) No significant differences in time to discontinuation for any reason (P=0.52) Schneider LS et al. N Engl J Med 2006;355:1525-1538

CATIE-AD: Summary of Results Time to discontinuation due to lack of efficacy favored olanzapine and risperidone (P=0.002) Time to discontinuation due to adverse events or intolerability favored placebo (P=0.009) Schneider LS et al. N Engl J Med 2006;355:1525-1538

CATIE AD: Conclusions Atypical antipsychotic drugs appear more efficacious than placebo, but… Adverse events limit overall effectiveness Use may be appropriate for patients who have no or few adverse effects, and for whom benefits can be discerned Schneider LS. Presented at Annual Meeting of the AAGP, March 2, 2007, New Orleans LA.

Incorporating Risk Tolerance in Making Treatment Decisions When is the balance between expected benefits and known risks acceptable to the patient or surrogate decision-maker?

Documentation is Crucial Inform patient or proxy of benefits and risks Discuss acceptability of treatment Document discussion, including concurrence with treatment plan

Summary MDS 3.0 Behavior items Perform better than MDS 2.0 at detecting presence of target behaviors Clarify when behaviors are problems Respect resident values and preferences Behavioral symptoms in dementia may be explained by Deficits in various cognitive domains Other factors such as unmet needs, environmental irritants, drug effects, medical and psychiatric conditions

Summary Antipsychotic drugs may benefit selected nursing home residents, but it is advisable to: Discuss risks, including stroke and death Document that balance between expected benefits and known risks is acceptable to patient or proxy

Questions ???