Aggression Management in Alzheimer's Dementia. Sandra Katalinic, BScPharm, Resident

Transcription

1 Aggression Management in Alzheimer's Dementia Sandra Katalinic, BScPharm, Resident

2 Overview Disease state overview Epidemiology Etiology Symptoms and presentation Recommended treatments Literature Medications to avoid Non-pharm care Case

3 Learning Objectives 1) Describe the prevalence of dementia and Alzheimer s disease 2) List and describe the different hypothesized etiologies of agitation in dementia patients 3) List the various drug classes used to treat agitation in dementia 4) Explain the evidence behind the increased risk of death in elderly using antipsychotics

4 Characteristic Delirium Dementia Onset Acute to sub-acute Insidious Course Duration Fluctuating Hours to day, rarely weeks Stable and progressive Months years Dementia, Delerium, Alzheimer s Attention Fluctuates Steady Etiology Psychomotor activity Cognitive function Usually immediate cause identified Increased, decreased or unpredictable Globally impaired, poor attention span No immediate cause Can be normal Poor short term memory, attention span less affected Perception Sleep/wake cycle Hallucinations, common delusions, fleeting Disrupted or reversed, sun downing Sample delusions and hallucinations Fragmented

5 Dementia Affects 15% >65 years old Affects 25% >85 years old Affects >60-80% of dementia cases are Alzheimer's type Duration (onset of sx death) 8-10 years >65 in Canada = >4 million this is a big part of our population!

6 Epidemiology Study of 178 patients with Alzheimer s: 19.7% of patients physically aggressive behaviour 18.5% wandering 36.5% exhibit rage Incidence of agitation increases with declining MMSE score 37.5% mild dementia, 66.5% severe dementia All patients with dementia display agitation at some point during the disease course, but the prevalence increases with late stages of Alzheimer s (Burns et al. 1998)

7 Etiology Many controversial schools of thought regarding causes and etiology of agitation Four main theories: Direct impact of dementia Unmet needs (most favoured) Behavioural Model Environmental Vulnerability

8 Etiology: Direct Impact of Dementia Disinhibition of behaviour Due to pathophysiological neuronal decline

9 Etiology: Unmet Needs Patient is unable to meet own needs or communicate needs to caregivers Example: Pain, need for toileting, physical discomfort, mental discomfort (i.e. In affective states such as depression), lack of social contact, frustration, inadequate stimulation

10 Etiology: Behavioral Model Behaviours are learned and encouraged because they are responded to Example: woman with AD screamed more when nurses talked to her Screaming nurses attention attention = positive reinforcement more screaming

11 Etiology: Environmental Vulnerability Patient environment congruence Patient s abilities should match the demands of the environment they live in

12 Pathophysiology Unknown mechanism of agitation Theories: Altered levels of neurotransmitters Increased or decreased serotonin Increased norepinephrine Decreased dopamine May present as a variety of symptoms

13 Symptoms and Presentation Four types: 1) Physically non-aggressive Hoarding/hiding, aimless wandering or pacing, intentional falling, disrobing, general restlessness 2) Physically aggressive Pushing, hitting, kicking, spitting, sexual advances, throwing things, hurting self or others

14 Symptoms and Presentation 3) Verbally non-aggressive Repetitive questions, constant requests for attention, negativism, complaining 4) Verbally aggressive Cursing and verbal aggression, verbal sexual advances, making strange noises, screaming

15 Recommended Treatment Behavioural interventions /non-drug care These are first line and include: Remove offending agent (i.e. drug, need for toileting, pain) Redirecting or distracting patient

16 Pharmacological Management Antipsychotics atypical or typical Risperidone, ziprasidone, olanzapine Haloperidol, chlorpromazine Benzodiazepines Anticonvulsants Divalproex, carbamazepine

17 Expert Consensus on Use of Antipsychotics

18 Antispychotics Typicals: haloperidol, loxapine, chlorpromazine, promethazine, pimozide, flupenthixol, zuclopenthixol Atypicals: risperidal, olanzapine, aripiprazole, clozapine, ziprasidone, quetiapine

19 Antipsychotics All block the D 2 receptor in the brain Individual drugs vary in degree of antagonism of other neurotransmitters: 5HT 1-2, D 1, D 3, D 4, D 5

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21 Antipsychotics Major difference between typicals and atypicals is side effect profile Atypicals have far less incidence of EPS compared with typical antipsychtoics

22 Antipsychotics Adverse effects Somnolence, weight gain/ increased appetite, Dizziness/hypotension/orthostatic hypotension Hyperglycemia, elevated triglycerides and LFTs, Eosinophilia, edema, Constipation, dry mouth, tachycardia, Sexual adverse effects Extra pyramidal side effects (tardive dyskinesia, akathesia) rare, more common with typical antipsychotics

23 Atypical Antipsychotic Dosing Drug Initial Dose Max Dose Risperidone 0.5 mg/day 2 mg/day Quetiapine mg/day 300mg/day Olanzapine mg//day 20 mg/day Ziprasidone 20 mg BID 80 mg/day

24 Typical Antipsychotic Dosing Drug Initial Dose Max Dose Haloperidol mg OD or BID 6 7 mg/day (references vary) Loxapine 20 mg/day 60 mg/day Zuclopenthixol 10 mg BID TID 100 mg/day

25 Atypical Antipsychotics Risperidone, ziprasidone, olanzapine, quetiapine Risperidone most commonly used Considered first line evidence? Greatest effect on calming agitation, especially in pts with worst agitation at baseline More favourable side effect profile than typical antipsychotics Increased risk of death and stroke in elderly with dementia

26 Risperidone MoA: serotonin dopamine antagonist (5-HT 2 >20x D 2 ) Oral dose: mg/day Titrate at intervals 1 week **Oral solution: can mix with water, coffee, juice, milk, NOT with cola or tea IM dose: mg q2weeks

27 Risperidone Metabolism: hepatic active metabolite (70% renally excreted) T½: oral 20 hours; IM 3-6 days Side Effects: somnolence, headache, TIA, stroke dystonia, anxiety, rhinitis, tremor,

28 Typical Antipsychotics Haloperidol, chlorpromazine Haloperidol most commonly used typical Increased side effect profile compared to atypical antipsychotics, higher incidence of EPS Not well studied in this population, not found to have great benefit

29 Haloperidol MoA: blocks postsynaptic mesolimbic dopaminergic D 1 and D 2 receptors in the brain Oral: mg OD or BID Titrate q4-7 days bye mg/day to effect Up to 6mg/day has been studied IM: (for severe agitation): 5-20mg

30 Haloperidol Metabolism: Hepatic to inactive metabolites T½ : Oral 18 hours; IM 24 hours Side Effects: Sedation, neuroleptic malignant syndrome, cardiac arrhythmias, hypotension, EPS (akathesia, difficult to differentiate from agitation), tremor, rigidity,

31 Haloperidol Contraindications: Parkinson's disease, severe CNS depression, caution in cardiac conduction abnormalities or electrolyte disturbances Monitoring: Vital signs; BMI; mental status, abnormal involuntary movement scale, extrapyramidal symptoms; ECG (with off-label intravenous administration)

32 Literature review 1) Evidence for the use of antipsychotics 2) Evidence for the use of haloperidol 3) Evidence behind increased risk of death

33 CADTH Report: Novel Antipsychotics for Agitation in Dementia: a Systematic Review Pwee KH, Shukla VK, Herrmann N, Skidmore B. Ottawa: Canadian Coordinating Office for Health Technology Assessment; Technology report no 36

34 Pwee et al. Purpose: to assess the efficacy and safety of antipsychotic drugs for agitation in dementia. Literature search done, only studies for risperidone and olanzapine were found Other drugs deemed to not be evaluable based on lack of evidence

35 Pwee et al. Search Strategy Databases: MEDLINE, EMBASE, PsycINFO, AgeLine, BIOSIS Previews, Pascal and ToxFile

36 Pwee et al. Olanzepine as effective as lorazepam for acute agitation Less useful for long term treatment (8 weeks): somnolence, abnormal gait From small samples NNT: 3 (5 mg/day); 5 (10 mg/day)

37 Pwee et al. Resperidone more effective than placebo for symptoms of agitation, aggression, and psychosis (12 week study) Also had increased incidence of ADRs compared to placebo Somnolence, EPS, mild edema NNT: 8 (1mg/day); 6 (2mg/day)

38 Pwee et al. No significant difference in efficacy between haloperidol and risperidone Significantly more EPS in haloperidol group Nausea most common in risperidone; in haloperidol constipation and somnolence were most common

39 Pwee et. al Summary: Risperidone as effective as typical antipsychotic of choice (haloperidol) Fewer side effects than haloperidol Better data for long term (12 week) use than olanzapine or other atypicals (no data)

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41 Ballart et al Purpose: to determine the effectiveness of atypical antipsychotics for the treatment of key psychiatric and behavioural syndromes in Alzheimer s disease.

42 Ballart et al Inclusion Diagnosed Alzheimer s patient >60 years Outpatients or care facilities. Living with or regular contact (>one time per week) Validated method for evaluating aggression +/- agitation) and psychosis were included Exclusion Patients receiving other psychotropic drugs during the course of the study.

43 Ballart et al Summary Only enough evidence to evaluate risperidone and olanzapine Both riperidone and olanzapine have similar efficacy for aggression and psychosis

44 Ballart et al Summary Significant increase in stroke and ADRs compared to placebo Unsuitable for routine use unless patient poses harm to self or others

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46 Lonergan et al Primary goals: To determine the effect of haloperidol on agitation Frequency of adverse effects Examine drop-out rates Effects on caregiver burden Effect of haloperidol on functional status of patients with agitated dementia

47 Lonergan et al Secondary goals: To determine whether response to treatment with haloperidol is influenced by: 1. Dose 2. Type of dementia 3. Manifestations of agitation 4. Degree of dementia 5. Sex of patients 6. Age of patients

48 Lonergan et al Inclusion Criteria: all relevant unconfounded, randomized, placebo controlled, with concealed allocation of subjects. Trials had to include pre- and post- treatment assessment of agitation. Both English and non-english language publications were examined.

49 Lonergan et al Databases: The Cochrane Library EMBASE, MEDLINE, PyscINFO, CINAHL, SIGLE, LILACS 5 Trials included Dosages varied: mg/day Treatment length: 3-16 weeks

50 Lonergan et al Compared with controls, no overall significant affect on agitation symptoms in Alzheimer s dementia patients ** This does not mean there is no effect May be some modest effect on aggression Similar drop out rates between haloperidol and control group

51 Lonergan et al Limitations: Inapplicability of meta-analysis due to heterogeneity in severity of dementia of the subjects Outcome measures used Measures of agitation Dosage and duration of haloperidol treatment.

52 Lonergan et al If haloperidol is chosen: Therapy should be individualized Used only for people displaying aggression Careful attention to response to therapy and to the appearance of drug related side effects.

53 Controversy Increased risk of death reported with typical and atypical antipsychotics used in elderly patients with dementia

54 Increase risk of death 2002 Letter from Janssen Ortho to Health Canada: Analysis of 5 international studies (1230 patients) comparing incidence of CVA s in dementia patients Incidence of CVA w/ placebo = 2% 1 death Incidence of CVA w/ risperidone = 4% 4 deaths

55 Controversy Studies regarding increased mortality are: Unpublished, thus not available for evaluation Unknown quality of data / trial Sponsored by drug companies As a result of unavailable data, actual incidence is unknown: may be more or less

56 Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia Metaanalysis of Randomized Placebo- Controlled Trials Schneider, LS et al. JAMA. 2005: Vol 294(15);

57 Schneider et al Purpose: to assess the evidence for mortality with typical and atypical antispychotics in elderly patients with dementia. Medline and Cochrane Review search terms: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, dementia, Alzheimer disease, and clinical trial

58 Schneider et al Inclusion criteria for RCTs: Parallel, double-blinded, placebo-controlled, random assignment to intervention Dementia Randomization, dropouts, and deaths, sample selection, location, blinding, duration, intervention and outcomes obtainable

59 Schneider et al trials found: 3 aripiprazole trials 5 olanzapine trials (one vs. haloperidol, 1 vs. risperidone) 5 risperidone trials 3 quetiapine trials (1 vs. haloperidol) Duration: 6-26 weeks

60 Schneider et al patients randomized to drug (293 to haloperidol), 1175 randomized to placebo 87% had Alzheimer s Avg age = 81.2 years

61 Schneider et al Deaths Drop-outs Atypicals 118 (3.5%) Haloperidol Not stated 1079 (32.2%) Placebo 40 (2.3%) 551 (31.4%) OR 1.54 Not stated

62 Schneider et al Risk of death among atypical antipsychotics Agent Risk Significance Aripiprazole % CI, 0.01 to 0.03; P=.20 Olanzapine % CI, 0.00 to 0.03; P=.07 Quetiapine % CI, 0.01 to 0.05; P=.22 risperidone % CI, 0.01 to 0.02; P=.33

63 Schneider et al No significant difference in risk of death among studied atypical antipsychotics All but 3 trials showed risk differences in favour of the placebo group

64 Alternate Therapy Benzodiazepines are used for treatment of agitation in elderly Lacking good quality trials to assess efficacy and safety in this population Many safety concerns with benzodiazepines in the elderly

65 Benzodiazepines Therapeutic Options for Agitation Long acting: flurazepam, diazepam Short acting: lorazepam, oxazepam, temazepam, midazolam

66 Benzodiazepines MoA: Bind to GABA receptor and enhances effects of GABA, an inhibitory neurotransmitter

67 Benzodiazepines SE: somnolence, CNS depression, increased reaction time, increased falls, decreased memory, altered sleep cycle Drug interactions: CNS depressants (H 1 blockers, opiates / opiate agonists, EtOH)

68 Meds to Avoid Beer s list Doses of short-acting benzodiazepines greater than: lorazepam 3 mg oxazepam 60 mg alprazolam 2 mg temazepam 15 mg triazolam 0.25 mg

69 Meds to Avoid Beer s list Long-acting benzodiazepines: chlordiazepoxide diazepam flurazepam

70 Benzodiazepine Dosing Drug Initial Dose Max Dose Lorazepam 0.5 mg/day 2 mg/day Oxazepam 10 mg BID-TID 45 mg/day Temazepam N/A as not approved for this indication 15 mg/day (recommended max in elderly)

71 Benzodiazepines Evidence in literature for use of benzos is lacking Studies limited by poorly specified diagnoses, mixed target symptoms limited outcome measures high doses of long-acting agents

72 Benzodiazepines There are no data concerning the efficacy of benzodiazepines after 8 weeks or whether one benzodiazepine is more effective than another.

73 Literature Small, poorly done studies Less effective than antipsychotics More effective than placebo in reducing behavioural problems

74 Comparison of Rapidly Acting Intramuscular Olanzapine, Lorazepam, and Placebo: A Double-blind, Randomized Study in Acutely Agitated Patients with Dementia Meehan, KM. Et al. Neuropsychopharmacology 2002; Vol 26(4): p

75 Meehan et al Multicenter, randomized, double-blind, placebo- controlled parallel study, conducted at 33 sites in the United States, two in Russia, three in Romania. 272 patients randomized to treatment

76 Meehan et al Pts randomized to receive IM olanzapine 2.5 mg x 1 dose IM olanzapine 5.0 mg IM x 1 dose IM lorazepam 1.0 mg x 1 dose IM placebo x 1 dose Results measured in change from baseline PANSS-EC score

77 Meehan et al PANSS-EC scale Measures agitation based on: poor impulse control, tension, hostility, uncooperativeness, excitement each outcome being ranked from 1 7 Maxscore = 35

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79 Meehan et al Levels of sedation, cognitive state, incidence of adverse events, and an objective measure of EPS all indicated that patients in the active treatment groups did not differ significantly from patients treated with placebo in these areas.

80 Meehan et al Comparable in efficacy between all agents at the 2-h time-point All groups improved from baseline Olanzapine and lorazepam significantly superior to placebo Olanzapine 2.5 superior PANSS-ES score

81 Duration of therapy Mild (non-aggressive) agitation taper down after 2-3 months Severe (aggressive) agitation taper down after 6-9 months

82 Non-Drug Care Should be used in all severities of agitation Often forgotten about Three categories Educating caregivers Structuring environment Behavioural interventions

83 Educating Care Givers Join support groups Educate about the progression and typical symptoms of dementia and agitation Learn about options for behavioural interventions and how to structure environment Encourage spending time with agitated patient

84 Structured Environment Provide daily routine Orienting objects clocks, calendars, pictures Control door access to prevent wandering and getting lost Bright daytime light to prevent day time napping and orient the patient to day and night Remove loud disruptive people from quiet ones (prevent overstimulation)

85 Behavioural Interventions Identify what is causing agitation (if possible) Use verbal reassurance, talk to and calm the agitated patient Allow pacing if it does not put patient in danger Provide pleasurable stimuli pets, arts, crafts, recreation, socialization

86 To Summarize Non drug measures such as providing routine, orienting the person, and removing the source of agitation should always be first line therapy Educating caregivers on the care of agitated Alzheimer s patients can help relieve caregiver burden and increase the use of non-drug therapies

87 To Summarize Antipsychotics have the most good quality evidence for use in agitated patients with Alzheimer s dementia Only risperidone has long term (12 weeks) Increased risk of stroke (caution in patients with cardiovascular risks) Not enough evidence to advocate regular use unless benefit > risk

88 To Summarize Antipsychotics Higher incidence of side effects than placebo Comparable side effects within their own class (i.e. Atypicals) Greater side effects with typical antipsychotics than atypicals Haloperidol only found effective to decrease aggression

89 To Summarize Benzodiazepines have been used to treat agitation in dementia Poor quality of evidence to support its use As effective as quetiapine for acute agitation Not supported for long term use secondary to side effects (altered gait, increased risk of falls, somnolence)

90 References Grey, J. Therapeutic choices. 5th ed. Ottawa: Canadian Pharmacists Association; p. 1-10, Koda-Kimble MA, Young LY, Guglielmo B J, Kradjan WA. Handbook of applied therapeutics. 8th ed. Washington: Lippincott Williams & Wilkins. 1992; American Psychiatric Asssociation Steering Committee on Practice Guidelines. Practice Guidelines for Treatment of Patients with Alzheimer s Disease and Other Demetias Acessed from URL: pum8vaguxkc&oi=fnd&pg=pa1&dq=causes+of+agitation+in+alzheimer's&ots=kqdbqaetcj&sig=xx7jjy2fxz8pn63ai2o92kgiivu# v=onepage&q=causes%20of%20agitation%20in%20alzheimer's&f=false Pwee KH, Shukla VK, Herrmann N, Skidmore B. Novel antipsychotics for agitation in dementia: a systematic review. Ottawa: Canadian Coordinating Office for Health Technology Assessment; T echnology report no 36. P Ballard CG, Waite J, Birks J. Atypical Antipsychotics for Aggression and Psychosis in Alzheimer s Disease (Review). Cochrane Database of Systematic Reviews Issue 4. P Lonergan E, Luxenberg J, Colford JM, Birks J. Haloperidol for agitation in dementia (Review). Cochrane Database of Systematic Reviews Issue 2. P Schneider, LS et al. Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia Meta-analysis of Randomized Placebo- Controlled Trials. JAMA. 2005: Vol 294(15); Meehan, KM. Et al. Comparison of Rapidly Acting Intramuscular Olanzapine, Lorazepam, and Placebo: A Double-blind, Randomized Study in Acutely Agitated Patients with Dementia. Neuropsychopharmacology 2002; Vol 26(4): p Fick DM et al. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Results of a US Consensus Panel of Experts. Arch Intern Med. 2003; Vol 163: p Hermann N, et al. Atypical Antipsychotics and Risk of Cerebrovascular Accidents. Am J Psychiatry 2004; Vol 161: Caine ED, et al. Clinical Perspectives on Atypical Antipsychotics for Treatment of Agitation. J Clin Psych. 2006; Vol 67 (suppl 10): p Tariot PN, et al. Efficacy of Atypical Antipsychotics in Elderly Patients With Dementia. J Clin Psych. 2004; Vol 65 (suppl 11); p Want PS, et al. Risk of Death in Elderly Users of Conventional vs. Atypical Antipsychotic Medications. NEJM. 2005; Vol 353:p