Disclosure. Speaker Bureaus. Grant Support. Pfizer Forest Norvartis. Pan American Health Organization/WHO NIA HRSA

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2 Disclosure Speaker Bureaus Pfizer Forest Norvartis Grant Support Pan American Health Organization/WHO NIA HRSA

3 How Common is Psychosis in Alzheimer s Disease? Review of 55 studies 41% of those with Alzheimer s Disease have psychosis 36% Delusions 18% Hallucinations 13% Co-occurring delusions and hallucinations 18.7% Visual hallucinations > 9.2% auditory hallucinations Ropacki, Jeste Am J Psychiatry 162: , 2005

4 Use of Antipsychotics in Dementia by Nursing Homes Based on 2004 National Nursing Home Survey 6103 USA nursing home residents over 64 with dementia 32.9% received antipsychotics Most were atypical agents 31.6% vs. 1.8% Factors associated with use Males > Females More beds in the facility Increased dependence in decision making ability Indicators of depression Indicators of behavioral disturbance Comorbid psychiatric diagnosis of Schizorphenia, Bipolar mania, Anxiety Kamble et al. Drugs Aging 26: , 2009

5 FDA Approved Meds There are no FDA psychopharmacological agents approved for use in managing any behavioral problem in Alzheimer s disease Antipsychotics are not FDA approved for treatment of psychosis or agitation in dementia The only FDA approved drugs in Alzheimer s disease are to manage cognitive decline Donepezil (Aricept) Galantamine (Razadyne) Rivistigmine (Exelon) Tacrine (Cognex) Memantine (Namenda)

6 FDA Approved Use of Antipsychotics Some people with Dementia will have been using antipsychotics prior to dementia for legitimate FDA indications These disorder may not necessarily disappear with the onset of Alzheimer s Disease Schizophrenia Bipolar disorder Major depression As an augmentation (aripiprazole only) Major depression with psychosis Not an indication, but not controversial

7 Differential Diagnosis of Psychosis Psychosis in Alzheimer s Disease Non-affective psychosis including schizophrenia Bipolar disorder Major depression Anxiety disorder Alcohol misuse disorder Delirium Sun downing circadian rhythm disorders Catastrophic reaction Other agitation without psychosis

8 Controversy 1: Do They Work?

9 CATIE-AD Methods The Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer s Disease (CATIE-AD) Objectives: Examine atypical antipsychotics to treat psychosis, agitation, and aggression in Alzheimer s disease 421 outpatients with Alzheimer s disease psychosis, agitation and aggression in 42 sites NIMH sponsored study Placebo control trial with random assignment Olanzapine, quetiapine, or risperdone Followed for 36 weeks Outcome was Clinical Global Impression of Change Examined at 12 weeks All caregivers were given counseling first 18 weeks

10 CATIE-AD Results No significant differences among treatments Similar rates of discontinuation for any reason Olanzapine and risperidone were less likely though to be discontinued due to lack of efficacy Lack of discontinuation due to adverse events favored placebo No difference in groups in improvement on CGIC score Olanzapine 32% improved Risperdone 39% improved Quetiapine 26% improved Placebo 21% improved

11 CATIE-AD What was the behavioral presentation on entry to the study based on the Neuropsychiatric Inventory (NPI)? Delusions 82% Hallucinations 49% Agitation or aggression 86% Depression 61% MMSE Average MMSE 15 Range % required equivalent of nursing home care

12 CATIE-AD What are the issues? What is psychosis in the elderly and how to measure it What is a delusion? Is thinking someone stole your money because you misplaced it the same as believing someone is going to kill you, or that a stranger is in the house? Are visual and auditory hallucinations equivalent? These distinctions were never addressed and perhaps may respond differently to psychopharmacological intervention How are behavioral problems measured CGCI, NPI, BPRS, Cohen-Mansfield Changes in NPI and BPRS not reported in initial report Who reports the behavioral problems and how well do they know the patient

13 CATIE-AD What are the issues? What is the target population This study was done on outpatients but are they the ones who have most of the behavioral issues we treat? What about nursing home patients. What impact did the caregiver support have on the placebo group? Should we use older antipsychotics This study provides no data Safety issues of Parkinsonism and anticholinergic side effects persists with older medications

14 Newer Analysis on CATIE-AD

15 Maybe There are Clinical Benefits? Re-analysis of outcome measures from baseline to last observation BPRS no difference with placebo CGCI Risperidone showed greater improvement from baseline to last observation than placebo NPI Olanzapine or risperidone showed greater improvement from baseline to last observation than placebo Specific symptoms on BPRS Risperidone greater imiprovment on psychosis factor than placebo Olanzapine or risperidone greater improvement on hostile suspiciousness factor than placebo Olanzapine worsening symptoms on withdrawn depression factor than placebo ADLS Olanzapine worse functioning than placebo

16 Cochrane Review 2006

17 Cochrane Review RTC s 5 Risperdone 3 Olanzapine 3 Quetiapine 3 Aripipraozole 1 Risperdal and Olanzopine Arms 1 CATIE-AD All but one were multi-center 3 studies were in non-institutional setting Outcome measures CAMI Behave-AD NPI-NH

18 Cochrane Review 2006 Does treatment reduce psychosis compared with controls? Risperidone had a significant beneficial effect upon psychosis High placebo response rates also Doses 1 mg 2 mg / day were effective Greater effect size than in Cochrane review for typical antipsychotic haldoperidol Olanzapine Significant benefit of olanzapine at 5-10 mg Other antipsychotics Insufficient data to meaningfully evaluate

19 Cochrane Review 2006 Resperdone vs Placebo

20 Cochrane Review 2006 Side effects Risperidone 4 fold increased risk of serious cerebrovascular adverse events 2 fold increase in extrapyramidal symptoms Increased risk for somnolence, upper respiratory infection, edema, urinary tract infection, and fever High drop out rate Olanzapine Increased risk for somnolence, abnormal gait High drop out rate

21 Controversy 2: Cost Benifit

22 Cost Benefit Analysis CATIE-AD secondary data analysis Found that the placebo group had overall lower health costs There was no difference in treatment efficacy between placebo and anti-psychotics

23 Controversy 3: Side Effects and Mortality

24 Increased Weight

25 Metabolic Syndrome Atypical antipsychotics are associated with the metabolic syndrome in patients with schizophrenia In CATIE-AD women showed significant weight gain Greater than 7% of body weight Men no clinically significant weight change Olanzapine and Quietapine were significantly assoicated with weight gain Olanzapine Increased girth Decrease in HDL cholesterol No changes in Glucose Triglycerides Blood pressure The full Metabolic syndrome is not necessarily as big of a risk

26 Dementia Death and Atypical Antipsychotics

27 Mortality Meta-analysis examined 15 randomized placebo controlled trials 9 are unpublished 3 Aripiprazole (Abilify) 5 Olanzapine (Zyprexa) 3 Quetiapine (Seroquel) 5 Risperidone (Risperadal) Death was greater in those randomized to atypical antipsychotics, 3.5% vs 2.3% OR = 1.54 No differences in individual drugs

28 Mortality by Individual Drugs Not statistically significant for any individual drug 1% excess risk of death in 8 12 week trial 4% 5% increase risk of death in one year of treatment

29 Dementia Death and Typical Antipsychotics

30 Mortality Both atypical and conventional antipsychotics are associated with increased mortality in dementia compared to non-users What is the risk 1% at 12 weeks to 4% - 5% over one year

31 Meta-analysis of Studies

32 Alternatives to Antipsychotics 6 RTCs show modest statitistically significant results for risperdone and olanzapine However, associated with increased risk of stroke 5 RTCs Antidepressants showed no benefit other than treating depression except one study of citalopram 3 RTCs no efficacy for valproate 2 RTC conflicting results of carbamezapine 2 RTCs conflicting results of memantine 6 RTCs showed small statistical benefit for acetylcholinesterace inhibitors

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34 Conclusions on Treating Psychosis What to do is controversial Antipsychotics have a black box warning for early mortality and cerebrovascular events The CATIE-AD study suggested that there was little benefit in dementia psychosis for antipsychotics versus placebo Many antipsychotics can cause weight gain, metabolic syndrome may be a concern, and drug induced Parkinsonism

35 Conclusions on Treating Psychosis Does the symptom really merit treatment Is the patient distressed by it? Are there non-pharmacological interventions that can be made? Who are we treating the staff, caregiver or patient? Is the behavior disruptive to other residents? Will the behavior result in loss of placement?

36 Conclusions on Treating Psychosis If the symptoms are mild consider Acetylcholinesterase inhibitor Memantine If an antipsychotic needs to used Document informed consent from the patient and/or caregiver Response may occur with small dosages Unless the patient is chronically mentally ill