ANTIPSYCHOTICS IN LONG TERM CARE: Are We Doing More Harm than Good?

ANTIPSYCHOTICS IN LONG TERM CARE: Are We Doing More Harm than Good? STEPHANIE M. OZALAS, PHARMD, BCPS, BCGP VA MARYLAND HEALTH CARE SYSTEM BALTIMORE, MD DISCLOSURES Off-label use of medications will be discussed during this presentation. The speaker served as a content expert for the ASCP geriatrics pharmacy review (GPR) course. 1

PHARMACIST OBJECTIVES 1. Given a patient case, analyze psychotropic regulatory compliance in long term care using the CMS State Operations Manual. 2. Compare and contrast the efficacy of at least 2 different antipsychotics for the treatment of behavioral and psychological symptoms of dementia. 3. Given a patient case, evaluate the appropriateness of antipsychotic prescription and recommend alternatives based on evidence-based literature. TECHNICIAN OBJECTIVES 1. Identify common dose ranges for antipsychotics when used to treat behavioral and psychological symptoms of dementia. 2. Relate antipsychotic adverse effects to their receptor affinities. OUTLINE Background Antipsychotic use in dementia Antipsychotic literature evaluation Alternatives to antipsychotics Treatment approach to behavioral and psychological symptoms of dementia (BPSD) Case breakout session Conclusion 2

BACKGROUND DEFINITION AND EPIDEMIOLOGY OF DEMENTIA EPIDEMIOLOGY Figure: International, A.s.D. World Alzheimer Report; 2015. DEMENTIA DEFINITION Neurocognitive disorder (per DSM-V) Diagnosis Minor Neurocognitive Disorder Major Neurocognitive Disorder *Not due to: delirium, other mental disorder Characteristics Moderate cognitive decline Does not interfere with ADLs Significant cognitive decline Interferes with ADLs American Psychiatric Association. Neurocognitive Disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 5 th ed. 2013. 3

DIAGNOSIS TYPES OF DEMENTIA Alzheimer s disease (AD) Vascular Mixed Lewy Body Parkinson s Fronto- Temporal BPSD DEFINITION Hallucinations Repetitive Activities Delusions BPSD Wandering Paranoia Aggression 4

Dementia population will experience one or more BPSD Unpaid caregiver hours per year provided to those with dementia Quick Facts. Alzheimer s Association. Cincinnati, OH. Modified from: Walters SA. 1/2016. Which form of dementia is characterized by decreased attention, motor dysfunction, and well-formed hallucinations? ANTIPSYCHOTIC USE IN DEMENTIA RISK AND GUIDELINES FOR USE 5

ANTIPSYCHOTICS BLACK BOX WARNING WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. Increased risk of death due to: o Stroke o Sudden cardiac death and heart failure o Infections NNH = 83 This BBW was placed on all atypical antipsychotics in 2005 and then was extended to include typical antipsychotics in 2008 Need to weigh risks versus benefits Improving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. Slide Credit: Walters SA. 1/2016. THE RISK REALIZED 5.5 Million People with AD 90% with BPSD 4.95 Million People with AD and BPSD Antipsychotic Treatment: NNH = 83 ~60,000 potential deaths/year due to antipsychotics Modified from: Walters SA. 1/2016. AMERICAN PSYCHIATRIC ASSOCIATION Assessment Assess type, frequency, severity, pattern, and timing of symptoms Assess potentially modifiable contributors Benefits and Risks Only use when symptoms are severe, dangerous and/or cause significant distress to patient Implement and review response to non-pharmacologic interventions Antipsychotics Use and Monitoring Initiate at low dose and titrate to effective dose If no clinically significant response in 4 weeks, discontinue Discuss dose titrations with patient s surrogate decision maker Avoid short-acting haloperidol for chronic use American Psychiatric Association. Am J Psychiatry 173:5:2016. 6

AMERICAN GERIATRICS SOCIETY A systematic review of prospective studies including 6 single-agent and 7 comparison studies Small study populations and limited methodologies throughout the various studies Rates of delirium resolution in non-medication intervention studies were similar to that of the antipsychotic studies in this review This review does not support using antipsychotics for delirium in hospitalized elderly patients Flaherty JH, Gonzales JP, Dong B. J Am Geriatr Soc. 59 Suppl 2:S269-76, 2011 Nov. CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) REGULATIONS F757: Unnecessary Medications Any drug when used: In excessive dose For excessive duration Without adequate monitoring Without adequate indications for use In the presence of adverse consequences which indicate the dose should be reduced or discontinued Any combinations of the above Centers for Medicare and Medicaid Services. State Operations Manual Appendix PP. 2016. CMS REGULATIONS (cont.) F758: Psychotropic Drugs Definition: any drug that affects brain activities associated with mental processes and behavior Antipsychotic Antidepressant Antianxiety Hypnotic Others: anticonvulsants, antihistamines, anticholinergics, antiemetics, muscle relaxants, mood stabilizers, NMDA receptor modulators Centers for Medicare and Medicaid Services. State Operations Manual Appendix PP. 2016. 7

CMS REGULATIONS (cont.) F758: Psychotropic Drugs [Gradual Dose Reduction (GDR)] Most Psychotropics (including antipsychotics) Twice in first year in two separate quarters Annually Sedative/Hypnotics/Benzodiazepines Quarterly Clinical Contraindication: Resident s symptoms returned or worsened after the most recent GDR attempt AND Attempted further dose reduction would likely impair resident s function or cause psychiatric instability Centers for Medicare and Medicaid Services. State Operations Manual Appendix PP. 2016. CMS REGULATIONS UPDATES F758: Psychotropic Drugs [Duration] PRN Psychotropic Orders Specific condition diagnosed and documented in the medical record 14 day limit unless rationale in medical record PRN Antipsychotic Orders 14 day limit (no exceptions) Renewal requires attending or prescriber evaluation Centers for Medicare and Medicaid Services. State Operations Manual Appendix PP. 2016. What are the most common causes of death related to antipsychotic use in elderly individuals with dementia? 8

ANTIPSYCHOTIC LITERATURE EVALUATION FIRST AND SECOND GENERATION ANTIPSYCHOTICS CATIE-AD METHODS Design Double-blind, placebo-controlled Intervention: Olanzapine v. Quetiapine v. Risperidone v. Placebo Population Outcomes Inclusion: Ambulatory Alzheimer disease, MMSE 5-26, BPSD symptoms for at least 4 weeks Exclusion: Psychotic disorder, delirium, other dementia, substance abuse; new acetylcholinesterase inhibitor or antidepressant medication Primary: Time until discontinuation of treatment for any reason Secondary: Attainment of minimal or greater improvement in CGIC scale at 12 weeks Safety: Weight, prolactin, glucose, cholesterol, triglycerides at weeks 12, 24, 36 Schneider LS, Tariot PN, Dagerman KS, et al. NEJM 2006;355(15):1525-1538. CATIE-AD CHARACTERISTICS Characteristic Olanzapine (n=99) Quetiapine (n=94) Risperidone (n=84) Placebo (n=139) MMSE (n) 15 14.9 15.7 14.7 15 Total NPI, total (n) 31.8 37.6 38.3 39.1 36.9 Delusions (%) 79 82 88 80 82 Hallucinations (%) 42 51 57 48 49 Agitation (%) 84 86 86 89 86 Medications Antidepressant (%) 19 10 21 13 15 Atypical Antipsychotic (%) Cholinesterase Inhibitor(%) Schneider LS, Tariot PN, Dagerman KS, et al. NEJM 2006;355(15):1525-1538. 11 7 12 11 10 67 57 59 58 60 9

CATIE-AD OUTCOMES: EFFICACY Schneider LS, Tariot PN, Dagerman KS, et al. NEJM 2006;355(15):1525-1538. CATIE-AD OUTCOMES: SAFETY Schneider LS, Tariot PN, Dagerman KS, et al. NEJM 2006;355(15):1525-1538. CONCLUSIONS No large clinical benefit of treatment for BPSD with atypical antipsychotic medications compared to placebo Discontinuation of antipsychotic for any reason was similar between groups Discontinuation due to lack of efficacy: Placebo Quetiapine > Risperidone and Olanzapine Discontinuation due to adverse effects: Olanzapine > Quetiapine and Risperidone > Placebo Schneider LS, Tariot PN, Dagerman KS, et al. NEJM 2006;355(15):1525-1538. 10

ANTIPSYCHOTICS Typical Antipsychotics (haloperidol, thioridazine, thiothixene, chlorpromazine, trifluoperazine) Haloperidol: Some efficacy for aggression (but not agitation) with drop-out rates due to adverse effects. Thioridazine: Improvement in anxiety, but clinical significance unclear Recommendation: No clear evidence for the effectiveness of any typical antipsychotic in the treatment of dementiarelated symptoms. Haloperidol (1.2-3.5mg/dose) may show some improvement in aggression. Atypical Antipsychotics (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) Risperidone: Both 1mg and 2mg doses showed equiefficacious improvements in BPSD, but the 2 mg dose resulted in significantly higher adverse events. Olanzapine: Only low-dose (5mg/day) showed improvements in overall agitation/aggression, hallucinations and delusions. Quetiapine: No significant improvements on BPSD. Aripiprazole: Mixed results with unclear clinical significance. Recommendation: Risperidone (1mg/dose) and olanzapine (5-10mg/dose) are modestly effective at improving these dementia-related symptoms. Sink K, et al. JAMA: 2005;293(5):596-608. ; Gareri P, et al. J Clin Psychopharmacol 2014;34:109-123. Modified from: Walters SA. 1/2016. EFFICACY SUMMARY: ATYPICALS Aripiprazole Olanzapine Quetiapine Risperidone Dementia Overall Dementia Psychosis Dementia Agitation ++ + + ++ + +/- +/- ++ ++ ++ +/- ++ Improving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. Drug ANTIPSYCHOTIC DOSING GUIDE Starting Dose (mg/day) Max Maintenance Dose (mg/day) Special Dosage Forms Aripiprazole 2.5 10 ODT, L, IM Haloperidol 0.25 2 C, L, IM Olanzapine 2.5 5 7.5 ODT, L, IM Quetiapine 12.5 25 150 SR Risperidone 0.25 0.5 2 ODT, L Abbreviations: C = oral concentrate, L = liquid, IM = short-acting intramuscular, ODT = oral disintegrating tablet, SR = sustained release Improving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. 11

RELATIVE ADVERSE EFFECTS Receptor Haloperidol Aripiprazole Olanzapine Quetiapine Risperidone D 2 Dopamine EPS 5HT 2A Serotonin Anti-EPS 5HT 2C Serotonin Weight Gain α 1 Adrenergic Sedation, Hypotension H 1 Histamine Sedation, Weight Gain M 1 Muscarinic Delirium, Anticholinergic +++ +++ (partial agonist) ++ 0 +++ + ++ +++ + ++++ 0 ++ +++ 0 + ++ + ++ ++ +++ 0 + ++++ ++ +++ 0 0 + 0 0 Richelson E. J Clin Psychiatry 2010;71(9):1243-4. Receptor Haloperidol Aripiprazole Olanzapine Quetiapine Risperidone Hypertriglyerceridemia 0 0 ++++ +++ 0 QT Prolongation +/-? +/- +/- +/- Urinary Incontinence RELATIVE ADVERSE EFFECTS (cont.) ++ +++ ++ ++ ++ Improving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. PIMAVANSERIN 5-HT 2A inverse agonist and antagonist, low affinity for 5-HT 2C receptors No dopaminergic activity FDA approved for psychosis in Parkinson s disease (PD) Dosage: 34mg by mouth Daily Strong CYP3A4 inhibitors: 17mg by mouth Daily Adverse Effects: Orthostatic hypotension, CNS depression, Peripheral edema, Nausea, Constipation, QTc prolongation (rare) 12

PIMAVANSERIN CLINICAL TRIALS PARKINSON S PSYCHOSIS 1 Methods: Phase 3 placebocontrolled blinded RCT Inclusion Criteria: Age >40, diagnosed PD 1 year, severe psychotic symptoms weekly, MMSE 21 Primary Outcome: Change in SAPS-PD score from baseline to Day 43 37% v. 14% SAPS-PD improvement (p<0.001) No significant effects on movements, orthostasis ALZHEIMER S PSYCHOSIS 2 Methods: Phase 2 placebocontrolled double-blinded RCT Inclusion Criteria: Age >50, diagnosed AD and psychosis, severe psychotic symptoms weekly x2 weeks, NPI 6, NH placement 4 weeks without discharge Primary Outcome: Change in NPI- NH psychotic score from baseline to Day 43-3.76 v. -1.93 NPI-NH psychosis score (p=0.045) No difference in total NPI scores 1. Cummings J, Isaacson S, Mills R, et al. Lancet 2014;383:533-540. 2. Ballard C, Banister C, Khan Z, et al. 2018;17:213-222. Pharmacists: In the CATIE-AD trial, which antipsychotic was not statistically significantly different from placebo for the outcome of discontinuation due to lack of efficacy? Technicians: Which antipsychotic studied for dementia with BPSD is associated with the least extrapyramidal symptoms? ALTERNATIVE TO ANTIPSYCHOTICS NON-PHARMACOLOGIC AND PHARMACOLOGIC OPTIONS 13

KNOW YOUR ABCS OF DEMENTIA A B C Activator What happened just before B? Behavior What was the patient doing? Who was present? Where was this happening? When was this happening? Consequence What happened just after B? Did this make the behavior better or worse? Star-VA Program: The ABCs of Dementia. Presentation by French JL, Obrien S. REVERSIBLE CAUSES OF BPSD Unmet physical needs Pain Infection Dehydration/nutrition Sleep disturbances Constipation Unmet psychological needs Loneliness Boredom Environmental causes Noise Lighting Caregiver approaches Lack of cues/prompts Psychiatric causes Depression Anxiety Delirium Improving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. NON-PHARMACOLOGIC ALTERNATIVES Cognitive/Emotion-oriented therapies Reminiscence/ Simulated presence therapy Validation therapy Sensory stimulation Massage and touch, Music therapy, Snoezelen therapy Behavior management Patient-specific behavioral evaluation Animal-assisted therapy Exercise O Neil M et al. Department of Veteran Affairs; 2011. Modified from: Walters SA. 1/2016. 14

NON-PHARMACOLOGIC EXAMPLES Cues, prompts, reminders Simplified daily routine Speak in clear, simple phrases Do not challenge Personalized or group activities Eliminate distractors Reduce stress Reduce clutter Reduce sources for threats Adapt environment to reduce exit-seeking Individualized music Reassure Improving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. ALTERNATIVES NON-PHARMACOLOGIC Sensory stimulation Behavior management techniques Animal-assisted therapy Exercise PHARMACOLOGIC Antidepressants Cholinesterase inhibitors Mood stabilizers NDMA-receptor antagonists Memantine Dextromethorphan/ Quinidine ANTIDEPRESSANTS Antidepressants (Selective Serotonin Reuptake Inhibitors [SSRIs]) (fluoxetine, trazodone, citalopram, and sertraline) Sertraline: No effect on neuropsychiatric symptoms, but did show an improvement in depression in dementia patients. 1 Citalopram: - A significant improvement in agitation and mood lability were seen compared to placebo in a 17 day study. 1 - Further studies supported these findings of clinically significant improvement of agitation/aggression and caregiver distress with citalopram. 2,3 - The CitAD trial further showed efficacy for agitation in AD; however, target dose was citalopram 30mg daily, which is associated with a higher risk of QT prolongation. 3 Recommendation: Although they are well-tolerated, antidepressants do not appear to be very effective overall in treating neuropsychiatric symptoms. Citalopram 20mg daily may be an option for agitation symptoms. 1. Sink K, et al. JAMA: 2005;293(5):596-608.; 2. Pollock BG et al. Am J Geriatr Psychiatry. 2007;15(11):942-52.; 3. Porsteinsson A et al. JAMA. 2014;311(7):682-91. Slide Credit: Walters SA. 1/2016. 15

CHOLINESTERASE INHIBITORS (AChEIs) Cholinesterase Inhibitors (AChEIs) (rivastigmine, donepezil, and galantamine) Donepezil: Conflicting results from 4 RCTs. One showed improvements in agitation/aggression. Another showed improvement in depression, anxiety, and apathy. 1 Continuation of AChEIs in moderate-severe dementia may hasten cognitive and functional decline. 2 Initiation of AChEIs may reduce BPSD, but clinical significance unknown. 3 Galantamine: Only the 16mg/dose showed a small but significant improvement in the Neuropsychiatric Inventory (NPI) scale compared to placebo. 1 Recommendation: Donepezil and galantamine may provide some small improvement that may not prove clinically significant. 1 1. Sink K, et al. JAMA: 2005;293(5):596-608. 2. Howard R et al. N J Engl Med 2014;366(10):893-903. 3. Campbell N, et al. Clin Inter Aging 2008;3(4):719-28. Slide Credit: Walters SA. 1/2016. MOOD STABILIZERS Mood Stabilizers (valproate and carbamazepine) Carbamazepine: One 6 week study showed an improvement in agitation compared to placebo; although, another study showed no improvements in these target symptoms. Valproate: No significant improvement and increased risk of ADRs. Recommendation: The use of valproate is not recommended, due to lack of efficacy and significantly higher ADRs. There is currently not enough data to support the use of carbamazepine. Sink K, et al. JAMA: 2005;293(5):596-608. Slide Credit: Walters SA. 1/2016. NMDA RECEPTOR ANTAGONISTS Memantine Memantine: Mixed results from 2 RCTs. 1 One showed no difference in symptoms. The other showed a significant difference compared to placebo due to the placebo-group s declining health and increased symptoms. Recommendation: There does not appear to be a direct role for memantine in the management of BPSD. Dextromethorphan/ Quinidine (DM/Q) (Nuedexta ) DM/Q: One phase 2, 10 week RCT for treatment of agitation in Alzheimer s disease. A statistically significant improvement was seen in agitation/aggression per the NPI. 2 Recommendation: Dextromethorphan/quinidine may be considered as a second or third line agent specifically for significant agitation in those with Alzheimer s disease. Drugdrug interactions with CYP2D6 should be evaluated. 1. Sink K, et al. JAMA 2005;293(5):596-608. 2. Cummings JL et al. JAMA 2015;314(12):1233-1254. Slide Credit: Walters SA. 1/2016. 16

BPSD TREATMENT ALGORITHM BPSD Yes Nonpharmacologic No SSRI AChEI with or without memantine Consider DM/Q Atypical antipsychotic^ SSRI Carbamazepine DM/Q Evaluate for reversible causes Depression or anxiety? Consult specialist *If intervention is effective, monitorfor reoccurrence and adverse effects ^ Consider pimavanserin for patientswith PD andpsychosis. Modified from: Sink K, et al. JAMA: 2005;293(5):596-608. What non-pharmacologic strategies have been proven effective to decrease BPSD? CASE BREAKOUT SESSION 17

CASE DISCUSSION A B C Activator What happened just before B? Behavior What was the patient doing? Who was present? Where was this happening? When was this happening? Consequence What happened just after B? Did this make the behavior better or worse? Star-VA Program: The ABCs of Dementia. Presentation by French JL, Obrien S. Which classes of non-antipsychotic psychotropics have at least a moderate quality of evidence to support their use for BPSD? Hopefully, not these drugs! CONCLUSION BPSD is a common symptom associated with dementia. Use of antipsychotics for the treatment of BPSD is associated with an increased risk for death. Antipsychotic use in long term care facilities is highly regulated by CMS and GDR documentation is required. Non-pharmacologic interventions should always be attempted first. Evidenced based medicine indicates some benefits of aripiprazole, olanzapine, and risperidone for BPSD. Some SSRIs and AChEIs may also be helpful in managing BPSDrelated syndromes. 18

MORE INFORMATION: Iowa Geriatric Education Center: IA-ADAPT Toolkit: https://igec.uiowa.edu/ia-adapt 19