antipsychotic medications in the treatment of dementia
TRANSCRIPT
Antipsychotic Medications in the
Treatment of Dementia with
Behavior Disturbance
American Association for Geriatric Psychiatry
Los Angeles, CA
March 2013
Copyright 2013 Nash
Maureen C. Nash, MD, MS, FAPA
Medical Director, Tuality Center for Geriatric Psychiatry
CoChair, Clinical Practice Committee,
American Association for Geriatric Psychiatry
Affiliate Assistant Professor of Psychiatry,
Oregon Health and Sciences University
Diplomate, American Board of Internal Medicine
Diplomate, American Board of Psychiatry and Neurology
Copyright 2013 Nash
Disclosures
• Off label use of medications will be discussed
Copyright 2013 Nash
But,
I thought dementia
was a
cognitive disorder?
Copyright 2013 Nash
Dr Alzheimer's CaseAuguste D.
– 1901, 51 year old female at the Frankfurt Asylum
– Hx of progressive cognitive impairments, and…
– Reason for admission: Hallucinations, delusions and psychosocial incompetence
– Example of one of Dr. Alzheimer’s notes:
During physical examination she cooperates and is not anxious.
Auditory Hallucinations: “Just now a child called, is he there?”
Delusions that she was going to be raped…
Maurer K et al: Lancet 349: 1546-9, 1997Copyright 2013 Nash
First Case of Alzheimers
Auguste D.
– She died in 1906
– Case and autopsy findings presented at 37th Conference of Southwest German Psychiatrists Tubingen
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What is Behavior Disturbance
in Dementia?
Neuropsychiatric Inventory (NPI)
Symptom Anytime during illness
Shown in last month
Delusions 50% 35%
Hallucinations 28 20
Agitation/Aggression 63 52
Depression 54 45
Anxiety 50 44
Apathy 76 75
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Craig D et al: Am J Geriatr Psych 13:460-8, 2005
Neuropsychiatric Inventory (NPI)
Symptom Anytime during illness
Shown in last month
Euphoria 17 23
Irritability 63 55
Aberrant Motor Behaviors 65 57
Sleep Disturbance 54 42
Appetite 64 54
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Craig D et al: Am J Geriatr Psych 13:460-8, 2005
Why this topic?• Dementia is common and the number of people suffering
from it is increasing
-AND-
• Behavior disturbance that often accompanies dementia is very common
-BUT-
• Behavior disturbance that often accompanies dementia is TREATABLE!
-BUT-• All treatments have risks and benefits
-AND-
• Some pharmacological treatments are under attack
Copyright 2013 Nash
OBRA 1987
• Formalized “nursing home reform”
• Legislation based on IOM report
• Inadequate care in NH
– Inadequate assessment, poor QOL, violations of
basic rights, failure to recognize and treat
reversible causes of physical and functional
decline
• Application of standards still problematic
Copyright 2013 Nash
CMS announces partnership to improve
dementia care in nursing homes
• Hand in hand training series with an emphasis on non-pharmacological interventions
– “Person centered care”
– “Prevention of abuse”
– “High quality care”
• Stated goal of reducing antipsychotic use by 15%
• Publish every Nursing Home’s antipsychotic use
Copyright 2013 Nash
Staff (and family members)
are in danger
• Aggression towards staff
• 138 nursing assistants at 6 Nursing Homes
• 59% assaulted once per week
• 16% assaulted daily
Gates DM, Fitzwater E, Meyer U. Violence against caregivers in nursing
homes. Expected, tolerated, and accepted. J Gerontol Nurs. 25: 12-22, 1999
Copyright 2013 Nash
Quotes from Family:
• “I don’t want my Mom’s last days filled with
fear and terror because of the delusion that
someone is trying to hurt her or steal her
money.”
• “I don’t want Mom to hurt anyone.”
• “If my Dad knew what he was doing, he would
be so embarrassed.”
• “I’m afraid Dad is going to kill my Mom.”
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Select look at severe NH aggression
• May 2012 86yo M kills 84yo M in MI
• Mar 2011 66yo M kills 80yo M in IL
• Feb 2011 78yo M kills 70yo M in PA
• (2 staff injured)
• Dec 2009 98yo F kills 100 yo F in MA
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Therapeutic Approach to Dementia
Care adapted from I-ADAPT
Identify/ Assess Causes of Behavior
Unmet Physical Needs
Unmet Psychological Needs
Environmental Causes
Psychiatric Symptoms
Key Stage for Assessments of Cognitive and Functional Abilities
Behavioral Rating Scales
Select Interventions based on assessments
Apply Interventions
Caregiving Approaches
Adapt Environment
Evidence Based
Interventions (sensory, activity, communication)
Staff Training
Monitor Outcomes
Behavior Rating Scales
Continued staff training
Individualize interventions based on preference and positive outcomes
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Psychiatric Symptoms often amenable
to treatment with medications
• Sometimes depression
• Paranoia and delusions
• Hallucinations
• Sometimes anxiety
• Pain
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Symptoms not usually amenable to
medications
• Wandering
• Calling out (not related to pain)
• Repetitive questions
• Anxiety related to having memory loss
• Psychomotor agitation
• ?agitation
Copyright 2013 Nash
Informed Consentfor all treatments
including pharmacological
• Discussion and documentation of discussion with patient, family or surrogate decision-maker of:• Risks
• Benefits
• Alternatives (including the risks of no treatment)
• Common risks of no treatment for moderate or severe psychosis and aggression: patient or peers injured, staff injured, loss of place to live, social isolation by being avoided by peers and staff, increased neuropsychiatric symptoms, decreased quality of life, increased institutionalization
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Comparison of Risk of Hospitalization
and Mortality in 4 medicine classes
• 10,900 Nursing Home patients in Canada
• Risks of conventional AP, antidepressants & bzd vs risks of Atypical AP (risk of 1)
• Risk of death:
– Conventional AP and antidepressants 1.47
• Risk of femur fracture:
– Conventional 1.61, Antidepressant 1.29
• Users of BZD
– Risk of death 1.8, Heart Fail 1.54, Pneumonia 1.85Huybrechts K F et al. CMAJ 2011;183:E411-E419
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Kaplan–Meier estimate of the probability of no events over time
Huybrechts K F et al. CMAJ 2011;183:E411-E419©2011 by Canadian Medical Association
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Huybrechts K F et al. Comparison of
risks in 4 classes of medications
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Are antidepressants safe in older
adults?• Cohort (observational) study GP practices in UK
– age 65 to 100
– 60,746 patients in 570 practices
– No mention of dementia status
• Risks that were monitored– Falls, hyponatremia, mortality, attempted suicide/self harm,
stroke/transient ischaemic attack , fracture, and epilepsy/seizures
Coupland C, et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011;343:d4551
Copyright 2013 Nash
Highest adjusted hazard ratios
compared to non-antidepressant use• SSRI
• falls 1.66
• hyponatraemia 1.52
• Other antidepressants (like mirtazapine, trazodone, venlafaxine) • all cause mortality 1.66
• attempted suicide/self harm 5.16
• stroke/transient ischaemic attack 1.37
• fracture (1.64), and
• epilepsy/seizures (2.24)
• Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes.
• Absolute risks over 1 year for all cause mortality were • 7.04% for patients while not taking antidepressants,
• 8.12% for TCA,
• 10.61% for SSRI
• 11.43% for other antidepressants
Coupland C, et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011;343:d4551
Copyright 2013 Nash
Antipsychotic Medications:Treating Psychosis - delusions and hallucinations
the newer anti-psychotics: RIS, OLZ, QTP, ZPS and ARP
• Be careful of dosage, however. For example, in demented patients using RIS for psychosis and agitation, 1 mg/day was associated with a decreased risk of falls, but 2 mg/day increased the risk of falls
• RIS and Haloperidol were compared in dementia patients with behavioral disturbances, risperidone worked better with fewer side effects
• Very few studies have used ZPS or ARP
Katz IR et al, Am J Geriatr Psychiatry 12:499-08, 2004
Suh G, et al, Am J Geriatr Psychiatry 12:509-16, 2004
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Pharmacological strategies • Antipsychotics for “agitation”
• Despite evidence that these drugs can help; other studies cast doubt on the effectiveness for these drugs as anti-agitation drugs in dementia.
• (64 sites), prospective study of 500 patients with Dementia patients who had psychosis and associated behaviors – RIS, OLZ and Placebo were compared…
• Results: placebo and drug treatment groups improved
• Reasons:inadequate dose (doubtful)temporary phenomena (possible)patient selection (possible)“agitation” is not a single symptom (probable)
Deberdt WG et al: Am J Geriatr Psychiatry 13:722-30, 2005
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De Deyn et al compared Risperidone to
haloperidol to placebo in 1999 for treating
behavioral symptoms in dementia
• Haloperidol
• Dose 0.5-4mg/day
• Mean dose 1.2
• Haloperidol more motor
side effects
• Risperidone
• Dose 0.5-4mg/day
• Mean Dose 1.1
• Risperidone more
effective at controlling
aggression
Copyright 2013 Nash
Antipsychotics
• And more….
• Risperidone vs. placebo
• 473 patients, randomized 1-1.5 mg/day vs placebo
• Used BEHAVE-AD and CGI-C
• Both groups improved!
• The more severe the dementia, the more likely someone was to benefit from risperidone
Mintzer J et al. AJGP 14(3):280-91, 2006
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Antipsychotics in treatment of
“behavior disturbance” in dementia
• Haldol is effective but there is a high level of acute and chronic
side effects
• Trouble swallowing
• Stooped posture
• Trouble ambulating
• Tremor/stiffness
• Falls
Lonergan et al Cochrane Database Syst Rev. 2002
Dolder et al Biol Psychiatry. 53:1142-1145, 2003
Copyright 2013 Nash
What about CATIE-AD?• Initial publication did not look at efficacy of treating
the symptoms! Reanalysis in 2008 did.
• OLZ, RIS, QTP, Placebo
• Response on NPI and CGIC after 12 weeks no different (range 21-32%), p=.22
• Patients were more likely to stop placebo due to lack of effectiveness and stop drug because of side effects.
• If patient tolerated the medicine and stayed on it, there was improvement in anger, aggression and paranoia. But care needs, functioning did not improve.
Schneider et al. NEJM 155(15):1525-38, 2006
Sultzer et al. AJP 165:844-54, 2008Copyright 2013 Nash
Copyright 2013 Nash
FDA Boxed Warning
• FDA in 2005 added a boxed warning on all atypicals - Risperidone, Clozapine, Olanzapine, Ziprasidone, Aripiprazole and Quetiapine.
The warning is for increased mortality with the off-label use of antipsychotics in the elderly/dementia population
Data upon which warning was based:
• average age 85
• Medications not prescribed for psychosis
• causes of mortality were varied
• People who were dying not excludedCopyright 2013 Nash
Effect of FDA warning
• Within one year of 2005 warning, 19% decreased use of atypical antipsychotics among those with dementia
• By 2008, 50% decrease in use of atypical antipsychotics among those with dementia
• Use of atypical antipsychotics decreased for everyone, not just those with dementia
Dorsey et al Arch Int Med 2010
Copyright 2013 Nash
Discussion with Dr Laughren and Dr
Matthis of the FDA March 29, 2012• “We don’t understand the signal”
• Meta-analysis of data collected prior to 2005
• Data NOT for treatment of those with psychosis or aggression but a mix of “behavior disturbance” without any definition of what this is
• Age where risk most notable: 85 and older!!!
• Causes of death “all over the map”-no clear physiological etiology
• Risk highest at start of treatment, Dr Laughren theorizes that increased risk is due to excess sedation (though EPS causing swallowing problems seems much more likely to me)
• “The boxed warning is not a contraindication to using these medications.”
Phone conference between Dr Nash and FDA Psychiatric Director and AssistantCopyright 2013 Nash
FDA Boxed Warnings
• Later, for unstated reasons, FDA recognized that typical antipsychotics are dangerous
• Based on a study in 2007, FDA added the boxed warning on typical or first generation antipsychotics
• The warning is for increased mortality with the off-label use of antipsychotics in the elderly/dementia population
Copyright 2013 Nash
Typicals have more riskTypical antipsychotics are riskier
• 2 year period in patients older than 65 receiving Haloperidol (299) versus OLZ (1,254), – 21.4% died in the Haloperidol group, 4.75% in the OLZ
group.
• In another large retrospective study, with 649 cases and 2962 controls – the use of older antipsychotics in the elderly was associated with nearly a 2-fold increased risk of hospitalization due to Ventricular arrhythmias or cardiac arrest – no increased risk was found with the atypicals.
Nasarallah HA et al: Am J Geriatr Psych 12:437-9, 2004
Liperoti R et al: Arch Intern Med 165:696-701, 2005
Copyright 2013 Nash
Typicals have more risk
• Mortality ratio for risperidone 1.3
• Mortality ratio haldol 2.14
• CV or infectious causes were the major reasons for death, and could not be directly associated with the drugs.
• Highest period of risk within 40 days of starting prescription
Schneeweiss S, et al CMAJ 176:627-32, 2007
Gill SS et al Ann Int Med 146:775-86, 2007
Copyright 2013 Nash
Typicals have more risk
• Wang et al did retrospective of nearly 23,000 patients
over 65 years old in Pennsylvania who received
conventional or atypical antipsychotics from 1994-
2003.
• Conventional/Typicals were associated with a
significantly higher risk of death than atypicals in all
subgroups. Highest risk was early in therapy and at
higher doses.
Wang PS et al: NEJM 353:2335-41, 2005
Copyright 2013 Nash
Evidence of risk?
• There’s more evidence about antipsychotics:
• Another large retrospective study:
– 1,130 cases with 3,658 case controls
– NH patients, using either typicals or atypicals.
– No increased risk for stroke for any group or particular
drug
– Trend for OLZ to increase risk of CVA, but not
statistically significant
Liperoti et al. J Clin Psychiatry, 66(9):1090-96, 2005
Copyright 2013 Nash
Quantity or quality of life?
• Quality of Life (QOL)
• None of these studies (FDA or others) looked at Quality of Life (QOL) issues for the patients and caregivers
• Improving behavioral symptoms (as noted on the NPI) through medications has been shown to improve QOL measures for both patients and CG
• Given all this information, I strongly recommend the continued careful use of atypicals for psychotic symptoms and life threatening aggression with informed consent for this population when and if necessary
Il-Seon S et al: Am J Geriatr Psychiatry 13:469-74, 2005
Copyright 2013 Nash
Risks of use of BZD and atypical
antipsychotics (Ellul et al 2007)
Copyright 2013 Nash
Personal Thoughts on Ellul study
• This study did not control for why these medications were prescribed.
• Does the presence of hallucinations, delusions and other psychotic symptoms indicate someone is nearing end of life?
• Does “agitation” or aggression severe enough that clinician’s prescribe an antipsychotic predict nearing the end of life in some or even most patients with end-stage dementia?
• Do psychotic symptoms represent unrecognized delirium in patients with dementia (delirium has a very high mortality rate in older patients with dementia)?
Copyright 2013 Nash
Title of a LTE that I wrote
Death is Not a Question of If
Copyright 2013 Nash
2/14/2013
1
Larry Tune, M.D.Professor, Department of Psychiatry
and Behavioral Sciences and NeurologyEmory University School of Medicine
Pharmaceutical Trials ExpatriateAssociate Medical Director for
Psychiatric Services at 4 nursing facilitiesOtherwise nothing
“The absence of proof is not proof of absence”
Some dementia psychopathology responds to antipsychotics…..and they may need to stay on their antipsychotics• Anger, aggression, paranoia
Sultzer, et al, 2008; Devanand, et al, 2012
And some symptoms don’t…..• Wandering, calling out, repetitive questions, anxiety,
agitation Huybrechts, et al, 2011
2/14/2013
2
Announced in 2005, by 2008 there was a 50% reduction in the use of atypicals
Did make us think (and worry) for that we should be grateful
Antipsychotics aren’t entirely safe …physicians and families of patients need to be informed
Special concerns:• Subsyndromal delirium…sedation is one area of
concern• Swallowing difficulties Due to sedation Or independent motor side effect
No.Any questions?
Well, not very many of them…and perhaps they shouldn’t be.
2/14/2013
3
‘Best results’ coming from a true culture change• Interdisciplinary approach involving nurses,
CNA’s• ??Expanded role for psychiatry consultants
• Energize the milieu
U PittsburghU IowaMclean Hospital
Teepa Snow!
‘We are not immune’
We NEED TO STUDY THEM AS MUCH AS THEY STUDY US.
2/14/2013
4
Start low, go slow….Restore the ‘biopsychosocial approach’
• KNOW your patients• Support/get to know/collaborate with your local
Alzheimer’s Association
The absence of proof is not proof of absence.