Management of BPSD Shahla Baharlou, MD and Christine Chang, MD

Management of BPSD Shahla Baharlou, MD and Christine Chang, MD
Brookdale Dept of Geriatrics and Adult Development March 5, 2008

Objectives Participants will be able to: Define BPSD Evaluate BPSD
Discuss the Guidelines for Management of BPSD Nonpharmacologic Interventions Pharmacologic Interventions

What Is BPSD?

Behavioral and Psychological Symptoms of Dementia
What Is BPSD? Behavioral and Psychological Symptoms of Dementia

What Is BPSD? Non-cognitive manifestations of dementia
Behavioral Symptoms Psychological Symptoms

What Is BPSD? Behavioral Symptoms “Agitation”
Related to resistiveness to care Physical vs Verbal Aggressive vs Nonaggressive

Psychological Symptoms
What Is BPSD? Psychological Symptoms Mood Symptoms Psychotic Symptoms Sleep Disturbances

Why Is BPSD Important? Lifetime risk is nearly 100%
Associated with increased morbidity and nursing home placement Potentially treatable

Case: Part 1A

1. What Do You Do Next? Start haloperidol 0.5 mg at night
Start risperidone 1 mg at night Increase donepezil to 10 mg Increase oxybutynin to 10 mg twice a day Increase acetaminophen to 1000 mg twice a day Clarify the history and perform a careful physical and neurologic exam

Evaluation of BPSD Obtain a History - clear description of the behavior from the patient & others Temporal onset, course Associated circumstances Relationship to key environmental factors In context of the patient’s medical, family and social history

Evaluation of BPSD Careful Physical & Neurologic Exam
Assess Mental Status Pay attention to: Appearance and Behavior Speech Mood Thoughts and Perceptions Cognitive Function Attention

Evaluation of BPSD Lab Studies
CBC and metabolic panel in all cases of new onset BPSD Brain imaging, EKG, CXR, and urinalysis based on the history and exam

Evaluation of BPSD R/O Delirium
Acute Conditions such as pneumonia, UTI, pain, angina, constipation, poorly controlled diabetes, electrolyte imbalance Medication Toxicity or adverse effects of medications due to new or existing medications

Evaluation of BPSD R/O Environmental Causes
1. Make sure pt’s basic physical needs are met 2. Environmental Precipitant Disruptions in routine Over Stimulation Under Stimulation

Evaluation of BPSD After medical, environmental, and care giving causes are excluded, it can be concluded that the primary cause is progression of the dementia Remember MMSE

Case: Part 1B

Case: Part 2

2. What Do You Do Next? Start haloperidol 0.5 mg at night
Start risperidone 1 mg at night Increase donepezil to 10 mg Start citalopram 10 mg daily Start valproate 250 mg daily Start carbamazepine 100 mg daily Review nonpharmacologic, patient-centered interventions

Guidelines for Management of BPSD
1997 Consensus statement from the American Psychiatric Association 2003 Consensus statement from the American Geriatrics Society and American Association for Geriatric Psychiatry A endorse matching target symptoms to the relevant drug class B recommends atypical antipsychotic as 1st line for treatment of severe behavioral symptoms with psychotic features in patients with dementia and BPSD in nursing homes. SSRI’s are first recommended treatment for patients with dementia presented with depression in this setting. JAGS 51: ,2003

Nonpharmacologic Interventions First 40% of BPSD symptoms spontaneously resolve; “they come and go” Placebo response can be quite substantial No FDA approved medications for psychosis in AD

Nonpharmacologic Strategies: To Minimize Development of BPSD
Maintain a structured daily routine Environmental modifications Utilize good communication skills Encourage independence in ADLs

Nonpharmacologic Strategies: To Minimize Development of BPSD
Person-Centered Showers and Towel Baths Create environment based on patient comfort and preference Cover with towels to maintain warmth and modesty Use no-rinse soap and warm water Use gentle massage to cleanse Modify shower spray

Nonpharmacologic Strategies:
Agitation/Aggression (<1/wk) Identify the precipitating factor and avoid the triggers Distraction Techniques Behavior Modification Positive reinforcement of desirable behavior

Nonpharmacologic Strategies:
Agitation/Aggression (<1/wk) Environmental Modifications Preferred music Aromatherapy-lavender Light and pet therapy Exercise and structured activity therapies ***Physical restraints should be avoided

Case: Part 3

3. What Do You Do Next? Prescribe zolpidem 5 mg
Recommend melatonin 0.3 mg Prescribe triazolam mg Prescribe trazodone 25 mg Prescribe mirtazapine 7.5 mg Counsel about nonpharmacologic interventions to promote sleep

Matching Target Symptoms Sleep-wake Cycle Disturbance >1 Month
After R/O depression and other psychiatric conditions: Consider: Nonpharmacologic Interventions Only Guidelines for patients with primary sleep disorders exist No RCT of newer agents tested in this population McCurry SM et al. Nighttime insomnia treatment and education for Alzheimer's disease: a RCT. JAGS. 2005 Pilot of Triazolam shown to be ineffective in BPSD Case report of dangerously aggressive agitation with alprazolam in dementia Occ role of ativan for agitation in BPSD 1991 EBM Reviews - Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomni. Database of Abstracts of Reviews of Effects. Issue 4, 2006 Guidance on the use of zaleplon/sonata, zolpidem and zopiclone/lunesta for short-term management of insomnia. London (UK): National Institute for Clinical Excellence (NICE); 2004 Apr. 27

Nonpharmacologic Interventions Follow Structured sleep and rising times that were not to deviate no more than 30 minutes from the selected times Encouraged patients not to nap after 1 PM and limit naps to 30 minutes or less Walk for 30 minutes exercise daily Reduce light/noise levels in their sleeping areas Pilot of Triazolam shown to be ineffective in BPSD Case report of dangerously aggressive agitation with alprazolam in dementia Occ role of ativan for agitation in BPSD 1991 EBM Reviews - Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomni. Database of Abstracts of Reviews of Effects. Issue 4, 2006 Guidance on the use of zaleplon/sonata, zolpidem and zopiclone/lunesta for short-term management of insomnia. London (UK): National Institute for Clinical Excellence (NICE); 2004 Apr. 27

Nonpharmacologic Interventions Switch to decaffeinated drinks and reduce evening fluid consumption If nocturia affected sleep, encourage toileting schedules at night, use of incontinence pads, exclude urinary tract infections Eliminate triggers for nighttime awakenings ie control night time pain, give nightly snack, take activating meds in the AM Pilot of Triazolam shown to be ineffective in BPSD Case report of dangerously aggressive agitation with alprazolam in dementia Occ role of ativan for agitation in BPSD 1991 EBM Reviews - Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomni. Database of Abstracts of Reviews of Effects. Issue 4, 2006 Guidance on the use of zaleplon/sonata, zolpidem and zopiclone/lunesta for short-term management of insomnia. London (UK): National Institute for Clinical Excellence (NICE); 2004 Apr. 27

Case: Part 4

4. Which Is the Most Appropriate Pharmacologic Treatment?
Prescribe diphenhydramine 25 mg Prescribe zolpidem 5 mg Prescribe melatonin 0.3 mg Increase donepezil to 10 mg Prescribe trazodone 25 mg Prescribe mirtazapine 7.5 mg

APPROVED Hypnotics for INSOMNIA BZO R Agonists a. BZO Temezepam, Triazolam b. Non-BZO Zolpidem Zaleplon Eszopiclone Melatonin R Agonist Ramelteon NON-APPROVED for INSOMNIA Sedating Antidepressant Trazodone Mirtazapine Antipsychotics Anticonvulsants NONPRESCRIPTION AGENTS Sedating Antihistamines Melatonin Pilot of Triazolam shown to be ineffective in BPSD Case report of dangerously aggressive agitation with alprazolam in dementia Occ role of ativan for agitation in BPSD 1991 Zolpidem has been studied in elderly patients without dementia and appears to be effective in improving sleep onset, although it does not improve sleep duration because of its short half-life. zolpidem in the elderly person is 5 mg as an increased risk of adverse effects appears to be dose related. Zaleplon has been less extensively studied in the older patient but appears to have similar properties. Guidance on the use of zaleplon/sonata, zolpidem and zopiclone/lunesta for short-term management of insomnia. London (UK): National Institute for Clinical Excellence (NICE); 2004 Apr. 27

GRS 6 Recommends: Trazodone Mirtazapine Zolpidem and zaleplon Avoid: Benzodiazepines Antihistamines especially diphenhydramine Associated with high risk for falls, hip fractures, disinhibition, and cognitive disturbance when prescribed for patients with dementia

Pharmacologic Therapy for primary sleep disturbances when nonpharmacologics fail Benzodiazepine receptor agonists Atypical Antipsychotics Cholinesterase inhibitors Melatonin as a hypnotic in this population appears equivocal *Pandi-Perumal SR, et al. Melatonin and sleep in aging population. Exp Gerontol. 2005 Pilot of Triazolam shown to be ineffective in BPSD Case report of dangerously aggressive agitation with alprazolam in dementia Occ role of ativan for agitation in BPSD 1991 EBM Reviews - Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomni. Database of Abstracts of Reviews of Effects. Issue 4, 2006 Guidance on the use of zaleplon/sonata, zolpidem and zopiclone/lunesta for short-term management of insomnia. London (UK): National Institute for Clinical Excellence (NICE); 2004 Apr. 27

Case: Part 5

5. What Is the Most Effective Initial Management Strategy for This Patient?
Enrollment in Adult Day Health Care Center Caregiver education and training in coping skills Prescribe nortriptyline 25 mg Prescribe sertraline 25 mg ECT (Electroconvulsive Therapy)

Matching Target Symptoms Mood Symptoms in AD: Depression
Depression of 2 weeks’ duration resulting in significant distress or sustained depressive features lasting more than 2 months Consider: Antidepressants –first line: SSRIs Citalopram Sertraline (improved depressive symptoms and ADLS w/o improving cognition in patient with AD and depression) Avoid fluoxetine and paroxetine Antidepressants –first line: SSRIs (consensus statement American Geriatrics Society and American Association for Geriatric Psychiatry. JAGS 51; ,2003) Citalopram, sertraline( sertraline improved depressive symptoms and ADLS w/o improving cognition in patient with AD and depression. Lyketsos CG, DelCampo L, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry Jul;60(7): ) Avoid fluoxetine and paroxetine RCT zoloft+aricept on BPSD 2004—RCT zoloft on BPSD Retrospective Chart review of SSRI-zoloft and BPSD pt open label lexapro in bpsd 2006 Paxil and LBD case report helpful 2005—paxil worsens FTD RCT 2004—paxil helpful for verbal agitation in bpsd in open case series 2000 Although depression is common in people with dementia and many patients are prescribed antidepressants, the evidence to support this practice is weak. However, this conclusion is based on a very small number of studies with small sample sizes, predominately investigating classes of antidepressants not routinely used in clinical practice. Perhaps the main value of this review is to draw attention to this issue. It is not that antidepressants are necessarily ineffective but rather that there is not much evidence to support their efficacy. Given that they may produce serious side-effects clinicians should therefore prescribe with due caution.

Case: Part 6

6. What Would You Do Next? Switch to another agent in same class
Switch to another agent in another class Titrate dose of initial medication Add methylphenidate 5 mg

If a first agent has failed an adequate therapeutic dose for 8 to 12 weeks, consider alternatives: Bupropion Mirtazapine Venlafaxine Tricyclic agents (desipramine and nortriptyline) 2001 case report of 3 with BPSD and mirtazapine-remeron Venlafaxine and bupropion-not in bpsd pop-just geriatric NSGH with dep Nortryp and paxil studies not in BPSD only population-nortryp assoc with cognitive decline in SDAT with depression 1992

For partial responders to an antidepressant, consider augmentation strategies Methylphenidate ???? Usually works within a wk or 2. Helpful in ?FTD 2006 RCT-ritalin 40mg and N=1 trial in geriatric population with apathy and depression ritalin 5 bid 2001 1999 ritalin helpful in bpsd-sleep and behaviour? 1997 ritalin for neg sxs in SDAT?

If depression remains and patient is in danger of serious weight loss or suicidal ideas despite several antidepressant trials, consider ElectroConvulsive Therapy *No RCT in BPSD or geriatric pts

Matching Target Symptoms Mood Symptoms in AD: Manic-like Behavioral Syndromes
Mood syndromes characterized by: Pressured speech, disinhibition, elevated mood, intrusiveness, hyperactivity, and reduced sleep Consider: Mood-stabilizing agents Carbamazepine, lamotrigine, or ?lithium CarbamazepineOL starting at 100 mg bid to 500 bid keeping levels 4-12 (monitor LFTs and CBC q 3mo) Avoid divalproex sodium 125 bid c levels had been recommended but no longer based on literature (SR Sink 2005,Franco 2006).. Case reports of lamotrigine (inhibits presynaptic gaba release) for FTD-aggression, Huntingdon’s 2006 lithium decreased beta amyloid/tau hyperphosphorylation in mice in Japan-?preventative of SDAT?

Matching Target Symptoms Mood Symptoms in AD: Hypersexuality
If hypersexuality occurs in association with a recognizable syndrome such as a mania-like state, treat the specific syndrome first First, try Nonpharmacologic Interventions: Separating pt from others during social situations Change dinner table assignment Switch staffing to male attendants when possible Redirection and distraction

Consider: Antiandrogen Progesterone-MPA Leuprolide acetate Cyproterone acetate, Cimetidine, Spironoloctone, Ketoconazole Estrogen Serotinergics: SSRIs, Effexor, Clomipramine, TCA Gabapentin Antipsychotics Paxil case report helpful 2003 case report of low dose CPA helpful for hypersex Cimetidine, a histamine H2-receptor antagonist, has been shown to be a nonhormonal antiandrogen in rats—and retrospectively shown to help hypersex in BPSD pts antipsychotic is often adopted clinically, given the seriousness of hypersexual behaviors in institutionalized setting; however, there are no controlled studies supporting this use. Presumably, the medication may enhance the cognitive focus of the individual’s perceptions by reducing any psychotic thinking that may in some way be contributing to hypersexual behavior.

Caveat: Fronto-Temporal Dementia is often associated with prominent disinhibition and perseveration. In severe cases, a syndrome of hyperphagia, hyperactivity and hypersexuality may occur related to bilateral temporal lobe atrophy Consider ritalin Case reports of lamotrigine (inhibits presynaptic gaba release) for FTD-aggression, Huntingdon’s

Case: Part 7

7. What Is Your Recommendation?
Refer for nursing home placement Do a time-limited trial of haloperidol 0.5 mg Do a time-limited trial of risperidone 0.5 mg Do a time-limited trial of olanzapine 5 mg Do a time-limited trial of valproate 250 mg

1997 Consensus statement from the American Psychiatric Association endorse: Matching target symptoms to relevant drug class 2003 Consensus statement from the American Geriatrics Society and American Association for Geriatric Psychiatry recommends: Atypical antipsychotic as 1st line for treatment of severe behavioral symptoms with psychotic features in patients with dementia SSRI’s are first recommended treatment for patients with dementia presented with depression Systematic reviews, Meta analysis, Randomized controlled trials 2004+ 2003 Consensus statement from the American Geriatrics Society and American Association for Geriatric Psychiatry recommends atypical antipsychotic as 1st line for treatment of severe behavioral symptoms with psychotic features in patients with dementia and BPSD in nursing homes. SSRI’s are first recommended treatment for patients with dementia presented with depression in this setting. JAGS 51: ,2003

Psychosis in Dementia Clinical criteria for diagnosis of AD with psychosis: Presence of intermittent delusions or hallucinations occur for at least 1 month and must cause distress Retrospective Chart review of SSRI and BPSD pt 1997

Pharmacologic Interventions
If nonpharmacologic interventions fails or if “agitated” behaviors are too harmful to patient or others, consider pharmacologic agents What to prescribe?

Matching Target Symptoms Agitation & Aggression in Dementia
Antipsychotics Atypical (Risperdal, Aripiprazole, Olanzepine) versus conventional (Haloperidol) Cholinesterase Inhibitors SSRI Anticonvulsants/Mood Stabilizers Smaller effects with ambulatory, less severe dementia and for psychosis 2002 RCT citalopram-perphenazine-placebo in hospitalized BPSD and 2 case report that citalopram was helpful for verbal agitation 2000 Trazodone of no help for agitation according to CR 2006 paxil helpful for verbal agitation in bpsd in open case series 2000 Retrospective gabapentin on BPSD pts and case reports only as well as open label in bpsd pt in 2000

Antipsychotics Conventional: Haloperidol
Might be effective in treating aggression in patients with dementia but side effects limits its use; extrapyramidal symptoms Risk for neuroleptic malignant syndrome, tardive dyskinesia, orthostasis, and prolong QTc Might be effective in treating aggression in patients with dementia but side effects limits its use; extrapyramidal symptoms. Longergan E, Luxenberg J, et al. Haloperidol for agitation in dementia. Cochrane Database of Systematic Reviews. 4,2007

Atypical Antipsychotics
Although there is a significant improvement in aggression with risperidone and olanzapine and psychosis with risperidone, the significantly higher risk of serious cardiovascular effects including stroke and extrapyramidal symptoms outweighs the benefit A large multi-center, double-blind, placebo controlled trial comparing olanzapine, risperidone and quetiapine with placebo for patients with Alzheimer dementia with BPSD and MMSE bet 5-26 showed modest trends or no significant effects on symptoms in comparison to placebo Cochrane Database of Systematic Reviews 2006 NEJM 2006;355: Although there is a significant improvement in aggression with risperidone and olanzapine and psychosis with risperidone, the significantly higher risk of serious cardiovascular effects including stroke and extrapyramidal symptoms outweighs the benefit. Ballard C, Waite J, Birk J, Atypical antipsychotics for aggression and psychosis in Alzheimer’s disease. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD DOI: / CD pub2. A large multi-center, double-blind, placebo controlled trial comparing olanzapine, risperidone and quetiapine with placebo for patients with Alzheimer dementia with BPSD and MMSE bet 5-26 showed modest trends or no significant effects on symptoms in comparison to placebo.. Schneider LS, Tariot PN, et al. Effectiveness of atypical antipsychotics drugs in patients with alzheimer’s disease. NEJM 2006;355:

Blackbox Warning for Atypical Antipsychotics
Increased risk of mortality. Rate of death was 1.6 to 1.7 times that of placebo Death appeared to be heart related or from infections (eg, pneumonia) Diabetes mellitus, hyperglycemia, ketoacidosis, and hyperosmolar states

Cholinesterase Inhibitors
Donepezil Not a significant advantage over placebo for treatment of agitation in patients with severe dementia N Engl J Med 2007; 357; 14 ( ) Galantamine Improvement of behavioral symptoms in patients with mild to moderate dementia. The effective dose was 16 mg daily (as effective as 32 mg daily) titrated over 4 weeks. This dose was achieved over 4 weeks. The higher dose might have higher rate of adverse effect without any added benefit Cochrane Database Syst Rev. 2006 Donepezil Not a significant advantage over placebo for treatment of agitation in patients with severe dementia. Robert J Howard, M.R.C. Psych., Edmund Juszcak, B.Sc.et.al. Donepezil for Treatment of Agitation in Alzheimer’s Disease. N Engl J Med2007;357;14( ) Galantamine Improvement of behavioral symptoms in patients with mild to moderate dementia. The effective dose was 16 mg daily( as effective as 32mg daily) titerated over 4 weeks. This dose was achieved over 4 weeks. The higher dose might have higher rate of adverse effect without any added benefit. Loy.C, Schneider L. Cochrane Database Syst Rev Jan25;(1):CD

Anticonvulsants Valproate (Cochrane Database of Systematic Reviews 2007 Issue 4) Low dose is ineffective and high dose is associated with increased rate of adverse effects Side effects: somnolence, thrombocytopenia, infection Gabapentin (International psychogeriatrics; Nov 2007) No RCT Generally well tolerated but has reported alarming side effects including case reports of abrupt aggravation in patients with Lewy body dementia Carbamazepine (International psychogeriatrics; Nov 2007) Equivocal information on efficacy of carbamazepine based on limited RCT trials. Additionally safety and tolerability are other concerns Another concern is drug-drug interaction Valproate Low dose is ineffective and high dose is associated with increased rate of adverse effects. ET Lonergan, J Luxenberg, Valproate preparations for agitation in dementia: Cochrane Database of Systematic Reviews 2007 Issue 4 Common side effects: somnolence, thrombocytopenia and infection Gabapentin No RCT Generally well tolerated but has reported alarming side effects including case reports of abrupt aggravation in patients with Lewy body dementia. S. Konovalov, S Muralee et al. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: International psychogeriatrics; Nov 2007 Carbamazepine Equivocal information on efficacy of carbamazepine based on limited RCT trials. Additionally safety and tolerability are other concerns. S. Konovalov, S Muralee et al. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: International psychogeriatrics; Nov 2007 *Another concern is drug-drug interaction

Other Treatments Memantine SSRI
Two out of three RCT showed that patients with moderate and severe Alzheimer dementia displayed less agitation on Memantine 20 mg /day at 6 months. Unpublished data shows no clinically detectable effect in patients with mild to moderate dementia. Cochrane Database of Systematic Reviews 2007 Issue 4 SSRI Limited studies. No Cochrane review In a RCT double blind trial of Citalopram comparing to Perphenazine and placebo in pts with dementia (mean MMSE ) and BPSD in acute inpatient showed significant improvement in agitation, aggression, psychosis, lability, and tension factor with short course of both Citalopram and Perphenazine. Additionally cognition and retardation significantly improved in Citalopram group. No difference in side effect profile among 3 groups. Am J Psychiatry 2002; 159: Memantine Two out of three RCT showed that patients with moderate and severe Alzheimer dementia displayed less agitation on Memantine 20 mg /day at 6 months. Unpublished data shows no clinically detectable effect in patients with mild to moderate dementia. R McShane, A Areosa Sastre, N Minakaran,Memantine for dementia: Cochrane Database of Systematic Reviews 2007 Issue 4. SSRI Limited studies. No Cochrane review. In a RCT double blind trial of citalopram comparing to perphenazine and placebo in pts with dementia( mean MMSE bet )and BPSD in acute inpatient showed significant improvement in agitation, aggression, psychosis, labiality,and tension factor with short course of both citalopram and perphenazine. Additionally cognition and retardation significantly improved in citalopram group. No difference in side effect profile among 3 groups. Pollock BG, Mulsant BH, et al. Comparison of Citalopram, Perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry 2002; 159:

Other Treatments Trazodone
Limited trial indicates no significant difference between Trazodone (dose of mg daily) and placebo in treatment of behavioral and psychosocial manifestation of dementia. Cochrane Database of Systematic Reviews. 4, 2007 Limited trial indicates no significant difference between trazodone( dose of mg daily) and placebo in treatment of behavioral and psychosocial manifestation of dementia. Martinon-Torres G, Fioravanti M, et al. Trazodone for agitation in dementia. Cochrane Database of Systematic Reviews. 4, 2007.

Take Home Points Always obtain a thorough history about the “disturbance” Rule out delirium and other environmental factors contributing to the disturbance Use nonpharmacologic interventions for BPSD first Consider “targeted,” time-limited pharmacologic trials for severe or persistent BPSD symptoms given modest evidence of efficacy and moderate potential for harm

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Management of BPSD Shahla Baharlou, MD and Christine Chang, MD

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