Antipsychotic Medications in the Treatment of Dementia with Behavior Disturbance American Association for Geriatric Psychiatry Los Angeles, CA March 2013
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
Disclosures Off label use of medications will be discussed
But, I thought dementia was a cognitive disorder?
Dr Alzheimer's Case Auguste 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, 1997
First Case of Alzheimers Auguste D. She died in 1906 Case and autopsy findings presented at 37 th Conference of Southwest German Psychiatrists Tubingen
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 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 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
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
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
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
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.
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
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
Psychiatric Symptoms often amenable to treatment with medications Sometimes depression Paranoia and delusions Hallucinations Sometimes anxiety Pain
Symptoms not usually amenable to medications Wandering Calling out (not related to pain) Repetitive questions Anxiety related to having memory loss Psychomotor agitation?agitation
Informed Consent for 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
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 1.85 Huybrechts K F et al. CMAJ 2011;183:E411-E419
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
Huybrechts K F et al. Comparison of risks in 4 classes of medications
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
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
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
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
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 Risperidone Dose 0.5-4mg/day Mean Dose 1.1 Haloperidol more motor side effects Risperidone more effective at controlling aggression
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
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
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, 2008
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 excluded
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
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 Assistant
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
Typicals have more risk Typical 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
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
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
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
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
Risks of use of BZD and atypical antipsychotics (Ellul et al 2007)
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)?
Title of a LTE that I wrote Death is Not a Question of If
2/14/2013 Larry Tune, M.D. Professor, Department of Psychiatry and Behavioral Sciences and Neurology Emory University School of Medicine Pharmaceutical Trials Expatriate Associate Medical Director for Psychiatric Services at 4 nursing facilities Otherwise 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 1
2/14/2013 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
2/14/2013 Best results coming from a true culture change Interdisciplinary approach involving nurses, CNA s??expanded role for psychiatry consultants Energize the milieu U Pittsburgh U Iowa Mclean Hospital Teepa Snow! We are not immune We NEED TO STUDY THEM AS MUCH AS THEY STUDY US. 3
2/14/2013 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. 4