Disclosure Speaker Bureaus

Pfizer

Forest

Norvartis

Grant Support

Pan American Health Organization/WHO

NIA

HRSA

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: 2022-2030, 2005

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 26:483-492, 2009

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)

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

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

Controversy 1: Do They Work?

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

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

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 5 -26

17% required equivalent of nursing home care

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

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

Newer Analysis on CATIE-AD

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

Cochrane Review 2006

Cochrane Review 2006 16 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

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

Cochrane Review 2006 Resperdone vs Placebo

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

Controversy 2: Cost Benifit

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

Controversy 3: Side Effects and Mortality

Increased Weight

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

Dementia Death and Atypical Antipsychotics

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

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

Dementia Death and Typical Antipsychotics

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

Meta-analysis of Studies

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

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

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?

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