antipsychotics in long term are are we doing more harm ... · any typical antipsychotic in the...

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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 thispresentation.

▪ The speaker served as a content expert for the ASCPgeriatrics pharmacy review (GPR) course.

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PHARMACIST OBJECTIVES

1. Given a patient case, analyze psychotropic regulatorycompliance in long term care using the CMS StateOperations Manual.

2. Compare and contrast the efficacy of at least 2 differentantipsychotics for the treatment of behavioral andpsychological symptoms of dementia.

3. Given a patient case, evaluate the appropriateness ofantipsychotic prescription and recommend alternativesbased on evidence-based literature.

TECHNICIAN OBJECTIVES

1. Identify common dose ranges for antipsychotics when usedto treat behavioral and psychological symptoms of dementia.

2. Relate antipsychotic adverse effects to their receptoraffinities.

OUTLINE

▪ Background

▪ Antipsychotic use in dementia

▪ Antipsychotic literature evaluation

▪ Alternatives to antipsychotics

▪ Treatment approach to behavioral and psychologicalsymptoms of dementia (BPSD)

▪ Case breakout session

▪ Conclusion

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BACKGROUND

DEFINITION AND EPIDEMIOLOGY OF DEMENTIA

EPIDEMIOLOGY

Figure: International, A.s.D. World Alzheimer Report; 2015.

DEMENTIA DEFINITION

▪ Neurocognitive disorder (per DSM-V)

*Not due to: delirium, other mental disorder

Diagnosis Characteristics

Minor NeurocognitiveDisorder

• Moderate cognitivedecline

• Does not interfere withADLs

Major NeurocognitiveDisorder

• Significant cognitivedecline

• Interferes with ADLs

American Psychiatric Association. Neurocognitive Disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 5 th ed. 2013.

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DIAGNOSIS

TYPES OF DEMENTIA

Alzheimer’s disease (AD)

Vascular

Lewy Body Parkinson’s

Mixed

Fronto-Temporal

BPSD DEFINITION

BPSD

Hallucinations

Delusions

Paranoia

Aggression

Wandering

RepetitiveActivities

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Unpaid caregiver hours per year provided to those with dementia

Dementia population will experience one or more BPSD

Quick Facts. Alzheimer’s Association. Cincinnati, OH. Modified from: Walters SA. 1/2016.

Which form of dementia is characterized by decreasedattention, motor dysfunction, and well-formedhallucinations?

ANTIPSYCHOTIC USE INDEMENTIA

RISK AND GUIDELINES FOR USE

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ANTIPSYCHOTICS BLACK BOX WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITHDEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugsare at an increased risk of death compared to placebo.

• Increased risk of death due to:o Strokeo Sudden cardiac death and heart failureo Infections

• NNH = 83

• This BBW was placed on all atypical antipsychotics in 2005 andthen was extended to include typical antipsychotics in 2008

• Need to weigh risks versus benefitsImproving Antipsychotic Appropriateness in Dementia Patients [Internet].: Iowa Geriatric Education Center 2013. Slide Credit: Walters SA. 1/2016.

5.5 Million People with AD

4.95 Million Peoplewith AD and BPSD

90% with BPSD

Antipsychotic Treatment:NNH = 83

~60,000 potential deaths/yeardue to antipsychotics

THE RISK REALIZED

Modified from: Walters SA. 1/2016.

AMERICAN PSYCHIATRIC ASSOCIATION

• Assess type, frequency, severity, pattern, and timing ofsymptoms

• Assess potentially modifiable contributors

Assessment

• Only use when symptoms are severe, dangerous and/or causesignificant distress to patient

• Implement and review response to non-pharmacologicinterventions

Benefits and Risks

• 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

Antipsychotics Use and Monitoring

American Psychiatric Association. Am J Psychiatry 173:5:2016.

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AMERICAN GERIATRICS SOCIETY

Flaherty JH, Gonzales JP, Dong B. J Am Geriatr Soc. 59 Suppl 2:S269-76, 2011 Nov.

• A systematic review of prospective studies including 6 single-agentand 7 comparison studies

• Small study populations and limited methodologies throughout thevarious studies

• Rates of delirium resolution in non-medication intervention studieswere similar to that of the antipsychotic studies in this review

• This review does not support using antipsychotics for delirium inhospitalized elderly patients

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 doseshould be reduced or discontinued

▪ Any combinations of the above

Centers for Medicare and Medicaid Services. State Operations Manual Appendix PP. 2016.

CENTERS FOR MEDICARE AND MEDICAIDSERVICES (CMS) REGULATIONS

CMS REGULATIONS (cont.)

F758: Psychotropic Drugs

▪ Definition: any drug that affects brain activities associated withmental processes and behavior

▪ Antipsychotic

▪ Antidepressant

▪ Antianxiety

▪ Hypnotic

▪ Others: anticonvulsants, antihistamines, anticholinergics, antiemetics,muscle relaxants, mood stabilizers, NMDA receptor modulators


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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 GDRattempt AND

▪ Attempted further dose reduction would likely impair resident’sfunction or cause psychiatric instability


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


What are the most common causes of death related toantipsychotic use in elderly individuals withdementia?

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ANTIPSYCHOTIC LITERATUREEVALUATION

FIRST AND SECOND GENERATION ANTIPSYCHOTICS

CATIE-AD METHODS

Design

• Double-blind, placebo-controlled

• Intervention: Olanzapine v. Quetiapine v. Risperidone v. Placebo

Population

• Inclusion: Ambulatory Alzheimer disease, MMSE 5-26 , BPSDsymptoms for at least 4 weeks

• Exclusion: Psychotic disorder, delirium, other dementia,substance abuse; new acetylcholinesterase inhibitor orantidepressant medication

Outcomes

• Primary: Time until discontinuation of treatment for any reason

• Secondary: Attainment of minimal or greater improvement inCGIC scale at 12 weeks

• Safety: Weight, prolactin, glucose, cholesterol, triglycerides atweeks 12, 24, 36

Schneider LS, Tariot PN, Dagerman KS, et al. NEJM 2006;355(15):1525-1538.

CATIE-AD CHARACTERISTICS

CharacteristicOlanzapine

(n=99)Quetiapine

(n=94)Risperidone

(n=84)Placebo(n=139)

Total

MMSE (n) 15 14.9 15.7 14.7 15

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

AtypicalAntipsychotic (%)

11 7 12 11 10

CholinesteraseInhibitor(%)

67 57 59 58 60


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CATIE-AD OUTCOMES: EFFICACY


CATIE-AD OUTCOMES: SAFETY

CONCLUSIONS

▪ No large clinical benefit of treatment for BPSD with atypicalantipsychotic medications compared to placebo

▪ Discontinuation of antipsychotic for any reason was similarbetween groups

▪ Discontinuation due to lack of efficacy:Placebo ≥ Quetiapine > Risperidone and Olanzapine

▪ Discontinuation due to adverse effects:Olanzapine > Quetiapine and Risperidone > Placebo


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Sink K, et al. JAMA: 2005;293(5):596-608. ; Gareri P, et al. J Clin Psychopharmacol 2014;34:109-123.

• Haloperidol: Some efficacy for aggression (but not agitation)with drop-out rates due to adverse effects.

• Thioridazine: Improvement in anxiety, but clinical significanceunclear

• Recommendation: No clear evidence for the effectiveness ofany typical antipsychotic in the treatment of dementia-related symptoms. Haloperidol (1.2-3.5mg/dose) may showsome improvement in aggression.

TypicalAntipsychotics

(haloperidol,thioridazine,thiothixene,

chlorpromazine,trifluoperazine)

• Risperidone: Both 1mg and 2mg doses showed equi-efficacious improvements in BPSD, but the 2 mg doseresulted in significantly higher adverse events.

• Olanzapine: Only low-dose (5mg/day) showed improvementsin 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 thesedementia-related symptoms.

AtypicalAntipsychotics

(clozapine, olanzapine,risperidone, quetiapine,

ziprasidone, andaripiprazole)

ANTIPSYCHOTICS


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.

ANTIPSYCHOTIC DOSING GUIDE

DrugStarting 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


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RELATIVE ADVERSE EFFECTS

Receptor Haloperidol Aripiprazole Olanzapine Quetiapine Risperidone

D2 – DopamineEPS

++++++

(partial agonist)++ 0 +++

5HT2A – SerotoninAnti-EPS

+ ++ +++ + ++++

5HT2C – SerotoninWeight Gain

0 ++ +++ 0 +

α1 – AdrenergicSedation,Hypotension

++ + ++ ++ +++

H1 – HistamineSedation, WeightGain

0 + ++++ ++ +++

M1 – MuscarinicDelirium,Anticholinergic

0 0 + 0 0

Richelson E. J Clin Psychiatry 2010;71(9):1243-4.

Receptor Haloperidol Aripiprazole Olanzapine Quetiapine Risperidone

Hyper-triglyerceridemia

0 0 ++++ +++ 0

QT Prolongation +/- ? +/- +/- +/-

UrinaryIncontinence

++ +++ ++ ++ ++


RELATIVE ADVERSE EFFECTS (cont.)

PIMAVANSERIN

▪ 5-HT2A inverse agonist and antagonist, low affinity for 5-HT2C

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)

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PIMAVANSERIN CLINICAL TRIALS

PARKINSON’S PSYCHOSIS1

▪ Methods: Phase 3 placebo-controlled blinded RCT

▪ Inclusion Criteria: Age >40,diagnosed PD ≥1 year, severe psychotic symptoms weekly,MMSE ≥21

▪ Primary Outcome: Change inSAPS-PD score from baseline toDay 43

▪ 37% v. 14% SAPS-PD improvement(p<0.001)

▪ No significant effects onmovements, orthostasis

ALZHEIMER’S PSYCHOSIS2

▪ Methods: Phase 2 placebo-controlled double-blinded RCT

▪ Inclusion Criteria: Age >50,diagnosed AD and psychosis,severe psychotic symptomsweekly x2 weeks, NPI ≥ 6, NH placement ≥4 weeks without discharge

▪ Primary Outcome: Change in NPI-NH psychotic score from baselineto Day 43

▪ -3.76 v. -1.93 NPI-NH psychosisscore (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 antipsychoticwas not statistically significantly different fromplacebo for the outcome of discontinuation due tolack of efficacy?

Technicians: Which antipsychotic studied for dementiawith BPSD is associated with the least extrapyramidalsymptoms?

ALTERNATIVE TOANTIPSYCHOTICS

NON-PHARMACOLOGIC AND PHARMACOLOGIC OPTIONS

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A• Activator

• What happened just before B?

B• Behavior

• What was the patient doing? Who was present? Wherewas this happening? When was this happening?

C• Consequence

• What happened just after B? Did this make thebehavior better or worse?

KNOW YOUR ABCS OF DEMENTIA

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


▪ 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.

NON-PHARMACOLOGIC ALTERNATIVES


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NON-PHARMACOLOGIC EXAMPLES

▪ Cues, prompts, reminders

▪ Simplified daily routine

▪ Speak in clear, simplephrases

▪ Do not challenge

▪ Personalized or groupactivities

▪ Eliminate distractors

▪ Reduce stress

▪ Reduce clutter

▪ Reduce sources for threats

▪ Adapt environment toreduce exit-seeking

▪ Individualized music

▪ Reassure


ALTERNATIVES

NON-PHARMACOLOGIC

▪ Sensory stimulation

▪ Behavior managementtechniques

▪ Animal-assistedtherapy

▪ Exercise

PHARMACOLOGIC

▪ Antidepressants

▪ Cholinesteraseinhibitors

▪ Mood stabilizers

▪ NDMA-receptorantagonists

▪ Memantine

▪ Dextromethorphan/Quinidine

ANTIDEPRESSANTS

• Sertraline: No effect on neuropsychiatric symptoms, but didshow 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 clinicallysignificant improvement of agitation/aggression and caregiverdistress with citalopram.2,3

- The CitAD trial further showed efficacy for agitation in AD;however, target dose was citalopram 30mg daily, which isassociated with a higher risk of QT prolongation.3

• Recommendation: Although they are well-tolerated,antidepressants do not appear to be very effective overall intreating neuropsychiatric symptoms. Citalopram 20mg daily maybe an option for agitation symptoms.

Antidepressants(SelectiveSerotoninReuptake

Inhibitors [SSRIs])

(fluoxetine,trazodone,

citalopram, andsertraline)

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.

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CHOLINESTERASE INHIBITORS (AChEIs)

• Donepezil:Conflicting results from 4 RCTs. One showed improvements inagitation/aggression. Another showed improvement indepression, anxiety, and apathy.1

• Continuation of AChEIs in moderate-severe dementia mayhasten cognitive and functional decline.2

• Initiation of AChEIs may reduce BPSD, but clinical significanceunknown.3

• Galantamine: Only the 16mg/dose showed a small butsignificant improvement in the Neuropsychiatric Inventory (NPI)scale compared to placebo.1

• Recommendation: Donepezil and galantamine may providesome small improvement that may not prove clinicallysignificant.1

CholinesteraseInhibitors

(AChEIs)

(rivastigmine,donepezil, andgalantamine)

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 Aging2008;3(4):719-28. Slide Credit: Walters SA. 1/2016.

MOOD STABILIZERS

• Carbamazepine: One 6 week study showed an improvement inagitation compared to placebo; although, another study showedno improvements in these target symptoms.

• Valproate: No significant improvement and increased risk ofADRs.

• Recommendation: The use of valproate is not recommended,due to lack of efficacy and significantly higher ADRs. There iscurrently not enough data to support the use of carbamazepine.

Mood Stabilizers(valproate and

carbamazepine)

Sink K, et al. JAMA: 2005;293(5):596-608. Slide Credit: Walters SA. 1/2016.

• Memantine: Mixed results from 2 RCTs.1 One showed nodifference in symptoms. The other showed a significantdifference compared to placebo due to the placebo-group’sdeclining health and increased symptoms.

• Recommendation: There does not appear to be a direct rolefor memantine in the management of BPSD.

Memantine

• DM/Q: One phase 2, 10 week RCT for treatment of agitationin Alzheimer’s disease. A statistically significant improvementwas seen in agitation/aggression per the NPI. 2

• Recommendation: Dextromethorphan/quinidine may beconsidered as a second or third line agent specifically forsignificant agitation in those with Alzheimer’s disease. Drug-drug interactions with CYP2D6 should be evaluated.

Dextro-methorphan/

Quinidine(DM/Q)

(Nuedexta®)

1. Sink K, et al. JAMA 2005;293(5):596-608. 2. Cummings JL et al. JAMA 2015;314(12):1233-1254.

NMDA RECEPTOR ANTAGONISTS

Slide Credit: Walters SA. 1/2016.

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BPSD TREATMENT ALGORITHM

BP

SD Non-pharmacologic

SSRI Consider DM/Q

AChEI with orwithout

memantine

Atypicalantipsychotic^

SSRI

Carbamazepine

DM/Q

Consultspecialist

Yes

No

*If intervention is effective, monitor for reoccurrence and adverse effects^ Consider pimavanserin for patients with PD and psychosis.

Modified from: Sink K, et al. JAMA: 2005;293(5):596-608.

Depressionor anxiety?

Evaluate forreversible causes

What non-pharmacologic strategies have been proveneffective to decrease BPSD?

CASE BREAKOUT SESSION

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A• Activator

• What happened just before B?

B• Behavior

• What was the patient doing? Who was present? Wherewas this happening? When was this happening?

C• Consequence

• What happened just after B? Did this make thebehavior better or worse?

CASE DISCUSSION

Star-VA Program: The ABCs of Dementia. Presentation by French JL, Obrien S.

Which classes of non-antipsychotic psychotropics haveat least a moderate quality of evidence to supporttheir use for BPSD?

Hopefully, notthese drugs!

CONCLUSION

▪ BPSD is a common symptom associated with dementia.

▪ Use of antipsychotics for the treatment of BPSD is associatedwith an increased risk for death.

▪ Antipsychotic use in long term care facilities is highly regulatedby CMS and GDR documentation is required.

▪ Non-pharmacologic interventions should always be attemptedfirst.

▪ Evidenced based medicine indicates some benefits ofaripiprazole, olanzapine, and risperidone for BPSD.

▪ Some SSRIs and AChEIs may also be helpful in managing BPSD-related syndromes.

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MORE INFORMATION:

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

antipsychotics in long term are are we doing more harm ... · any typical antipsychotic in the...

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