controversies in management of psychosis
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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
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