TA R E K K . R A J J I , M D, F R C P C

C H I E F, G E R I AT R I C P S Y C H I AT RY D I V I S I O NC E N T R E F O R A D D I C T I O N A N D M E N TA L H E A LT H

A S S O C I AT E P R O F E SS O R O F P S Y C H I AT R YU N I V E R S I T Y O F T O R O N T O

Management of Agitation and Aggression Associated with Alzheimer’s Disease

Disclosures

None

“One of the first disease symptoms of a 51-year-old woman was a strong feeling of jealousy towards her husband. Very soon she showed rapidly increasing memory impairments; … thought that people were out to kill her, then she would start to scream loudly.”

Dr. A. Alzheimer, 1906.

Auguste Deter

“From time to time she was completely delirious, dragging her blankets and sheets to and fro, calling for her husband and daughter, and seeming to have auditory hallucinations. Often she would scream for hours and hours in a horrible voice.”

Dr. A. Alzheimer, 1906

Auguste Deter

“APATHY”Withdrawn

Lack of interestAmotivation

“DEPRESSION”Sad

TearfulHopeless

Low self-esteemAnxiety

Guilt

“AGGRESSION”Aggressive resistancePhysical aggressionVerbal aggression

“PSYCHOSIS”Hallucinations

DelusionsMisidentifications

“MOTOR HYPERACTIVITY”Increased walkingWalking aimlessly

Moving objectsTrailing

McShane, 2000

Behavioral and Psychological Symptoms of Dementia

Behavioral and Psychological Symptoms of Dementia

90% of patients during the course of their illness (Tariot, 1999)

60-90% of patients with dementia suffer from BPSD (Lyketsos et al., 2002)

Agitation & Aggression (75%) Wandering (60%) Depression (50%) Psychosis (30%) Screaming and violence (20%)

Behavioral and Psychological Symptoms of Dementia

Peak during moderate/moderately-severe stages (Reisberg et al., 1987)

Agitation/aggression, apathy may continue to increase (Mega et al., 1996)

Affective symptoms are more common early in the illness (Rubin et al., 1988)

Agitation/Aggression Incidence: 50% over course of illness (Tariot & Blazina, 1994)

Jost & Grossberg, 1996

Cummings, 2003

Aggression & Agitation in Dementia

“Inappropriate verbal, vocal or motor activity not explained by apparent needs or confusion” (Cohen-Mansfield, 1986)

Aggression Agitation

Physical PhysicalVerbal VerbalPhysical Physical

Agitation in Dementia: Subtypes

Cohen-Mansfield,J. 1996. International Psychogeriatrics. 8(3):309.

Treatment Algorithms: Evidence

Algorithm use in clinical practice associated with: Improved quality of care Enhanced patient outcomes Reduced health care costs

Adli. M et al. 2006. Biological Psychiatry. 59. 1029.

Treatment Algorithms: EvidenceStudy year N Intervention TAU ResultsIMPACT(late-life depression)

2002 Int-906Cont-895

-Depression Algorithm-Case manager supervision of primary care

-Primary care practitioner -available mental health services

Significant:-Decline in depressive sxs, - Decreased symptom severity -increased care satisfaction

PROSPECT(late life depression)

2004 Int-320Cont-276

-Depression algorithm-Case manager supervision of primary care

-primary care with education

Significant reduction in:-remission time, -sx severity,-suicidal ideation

TMAP (Texas Medication Algorithm Project)(depression)

2004 Int-175Cont-175

-Depression algorithm-psychoeducation-biweekly expert consultation

- Outpatient care without algorithm use

Significant : improvement in symptom severity and function at 1 year

GAP(German Algorithm Project )(depression)

2009 Int-74Cont-74

-inpatient care with adherence to medication algorithm

-inpatient mental health care

Significant:decreased time to remission, fewer medication changes in remitters.

Why do we need a pathway?

Better Outcomes

More Access

More Data

New Approach

es

Better Knowledg

e

Pathway

Assessment & Medications

Discontinuation

Cognitive Enhancers

(AChEI, Memantine)

Pharmacological

Non-Pharmacologica

l

Zaraa, 2003

Physical Factors Delirium - Dipstix urine, check temperature and bloods e.g.

FBC, U&E, LFT, TFT, ESR, CRP, Glucose, Vitamin B12, folate and ferritin levels

Dehydration – check above blood levels; especially U&E. Commence on fluid balance chart

Pain – complete appropriate pain assessment tool e.g. Abbey Scale

Hunger – monitor and complete fluid and diet charts Constipation – monitor bowel habits Tiredness – chart sleep pattern Medication – side effects Medication withdrawals – e.g. benzodiazepines, opiates Sensory Impairment – sight &/or hearing deficit - refer to

sensory impairment service for assessment and advice (where applicable)

Hypoxia – cyanosis, laboured breathing NHS Forth Valley

Psychological Factors

Depression – observe for any mood or behavioural changes. Complete appropriate assessment tool

Hallucinations – more commonly seeing&/or hearing things. NB exclude delirium

Delusions – more commonly paranoia &/or suspiciousness. NB exclude delirium

Sundowning - increased agitation and activity occurring in the late afternoon/early evening

NHS Forth Valley

Environmental Factors

Noise levels – over stimulation/elevated noise levels can be antagonistic

Lack of social stimulationInappropriate music – ensure age related

and appropriate to the client groupEnvironment/layout

Is it conducive to the specific client group? Could it potentially increase confusion and

disorientation in people suffering from cognitive impairment?

NHS Forth Valley

Attending Physician DIAGNOSTIC WORK-UP: HISTORY YES

NO

Name: Sign: Date: (dd/mm/yyyy)

Agitation or aggression is present 

Clinically suspected to be secondary to Alzheimer’s or mixed Alzheimer’s + vascular dementia 

History consistent with Alzheimer’s or mixed Alzheimer’s vascular dementia 

 

 Attending Physician DECISION TO MOVE FORWARD Y

ES

NO

Name:  Sign:  Date: (dd/mm/yyyy)

Delirium or other causative medication/medical condition identified? Presentation more consistent with non-Alzheimer’s Dementia? If “Yes” exit pathwayIs the Agitation and Aggression: Severe? 

Causing distress to the patient? Or OTHERS? 

Preventing or interfering with providing necessary care to the patient? 

Posing a risk to the patient or to others? 

If “Yes” to ANY questions, proceed with pathway, otherwise exit pathway

Hospitalist DIAGNOSTIC WORK-UP: PHYSICAL EXAM INVESTIGATION YES

NO

Name:  Sign:  Date: (dd/mm/yyyy)

Basic investigation done to rule out other medical causes of cognitive impairment or agitation  Guidelines: vital signs, height, weight, waist circumference, CBC with differential, renal function, liver panel, metabolic/endocrine function, B12, urine analysis, urine C&S, lipid profile, fasting glucose +/- HbA1C, micro albuminuria, extended electrolytes, Delirium screening tool (optional) Examples: Confusion Assessment Method, Delirium Symptom Review, Delirium Rating Scale

Addition investigations performed as indicated (optional)List additional investigations:__________________________________________________________________________________________

Research Fellow   Name   Sign:  Date: (dd/mm/yyyy)

Cohen-Mansfield Agitation Inventory (CMAI)  Initial Score: _________________________

Comments: ________________________________________________ 

________________________________________________

YES 

NO 

Neuropsychiatric Inventory (NPI) Initial Score: _________________________

Comments: ________________________________________________ 

________________________________________________

Montreal Cognitive Assessment (MOCA) Initial Score: _________________________

Comments : ________________________________________________ 

________________________________________________

Alzheimer’s disease assessment scale – cognitive subscale (ADAS-cog) Initial Score: _________________________

Comments : ________________________________________________ 

________________________________________________

Attending Physician   Name   Sign:  Date: (dd/mm/yyyy)

Clinical Global Impression Scale (CGI) Initial Score: _________________________

Comments : ________________________________________________ ________________________________________________

YES 

NO 

Abnormal Involuntary Movement Scale (AIMS) Initial Score: _________________________

Comments : ________________________________________________ 

________________________________________________

Simpson-Angus Scale (SAS) Initial Score: _________________________

Comments : ________________________________________________ 

________________________________________________

Barnes Akathisia Scale (BAS) Initial Score: _________________________

Comments: ________________________________________________ 

________________________________________________

Hospitalist CARDIAC AND METABOLIC ASSESSMENT YES NOName   Sign: 

 Date: (dd/mm/yyyy)

CBC, ECG, Creatinine/BUN, Blood Sugar, Lipid Profile Comments: ____________________________________________________________________________________________ ____________________________________________________________________________________________

Assigned Nurse PAIN ASSESSMENT AND MANAGEMENT YES NOName: Sign: Date: (dd/mm/yyyy)

 Pain Assessment and Management Conducted 

For example:Brief Pain Inventory (BPI) for verbal patientsChecklist of Non-Verbal Pain Indicators (CNPI) for non-verbal patients

Occupational Therapist

FUNCTIONAL ASSESSMENT YES NO

Name: Sign: Date: (dd/mm/yyyy)

 Functional Assessment Staging (FAST) 

Comments: ____________________________________________________________________________________________ ____________________________________________________________________________________________

Pathway

Assessment & Medications

Discontinuation

Cognitive Enhancers

(AChEI, Memantine)

Pharmacological

Non-Pharmacologica

l

Non-Pharmacological Interventions

ConsentCaregiver education and supportEnhance communication with the patientEnsure safe environmentIncrease or decrease stimulation in the

environment

Non-Pharmacological Interventions

For all BPSD: 31 studies that used RCT-design (1-52 weeks):

Reminiscence mild to moderate depression (7/8)

Pleasant activities with or without social interactions agitation (4/4), depression (2/2)

Personalized music agitation (4/7)

Exercise depression (2/5)

Non-Pharmacological Interventions

Allied Health Professional

NON-PHARMACOLOGICAL INTERVENTIONS IDENTIFIED INITIALLY AS MOST APPROPRIATE*

Please check discipline: Occupational Therapist Recreation Therapist Social Worker Primary Nurse Name:  Sign:  Date:

 Social Contact  Pet therapy   One-to-one visit  Other:_______________

 Sensory Enhancement/ Relaxation Hand massage  Individualized Music   Individualized art   Sensory modulation  Other:_______________

 Purposeful Activity   Helping tasks / Volunteer role   Inclusion in group programs of identified interest   Access to outdoors    Other:_______________

 Physical Activity  Exercise group    Indoor/outdoor walks    Individual exercise program   Other:_______________

Multisensory Snoezelen System

Paro Therapeutic Robot

Pharmacological InterventionsRisperidone

Aripiprazole

Citalopram

Carbamazepine

Gabapentin

Prazosin

ECT

Quetiepine

For partial responders:1. Extend the trial2. Increase the dose 3. Augment with another agent that showed also partial response

PRNs:1. Trazodone2. Lorazepam

Drugs commonly used for agitation

AntipsychoticsAntidepressants

SSRIs, trazodoneCognitive enhancers

Cholinesterase inhibitors, memantineMood stabilizers and Anticonvulsants

carbamazepine valproic acid gabapentin oxcarbazapine topiramate lamotrigine lithium

Antipsychotics

Treatment Trials conducted EvidenceTypicals 11 randomized,

placebo-controlled trials; duration bw 4-16 wks

Modest advantage over placebo

Atypicals 18 placebo-controlled trials (6-12 wks)3 trials 6-12 months)

Best option for short-term (6-12 wks)

1. Schneider L. Am J Geriatr Psych 2006:14(3) 191-212.2. Ceitz et al. Cochrane Review, 2011.3. Ballard & Corbett. 2013:25(3)252-259.

AntipsychoticsMainstay of psychopharmacological treatment

Up to 40% of all dementia patients prescribed antipsychotics1

Atypicals vs. typicals: perceived safety advantage

In patients with dementia, atypicals increase: risk of death (OR=1.5 - 1.7) cerebrovascular adverse events (OR=2.7) rate of cognitive decline

1. Schneider L. Am J Geriatr Psych 2006:14(3) 191-212.2. Ballard & Corbet. Current Opin Pysych. 2013:226(3)252-259.3. Hermann & Lanctôt. Drug Safety. 2006:29(10) 833-843.

Atypical AntipsychoticsAntipsychotic # trials Bottom LineRisperidone 5 RCTs • Provides best

evidence for treating aggression

• Modest but significant improvement vs. placebo

• Biggest effect size: 2 mg daily

Olanzapine 5 RCTs(fixed dose 1-15 mg daily, 6-10 weeks of treatment)

• Conflicting evidence

• More adverse events of hostility, abnormal gait, somnolence

• Not associated with overall efficacy

Schneider L. Am J Geriatr Psych 2006:14(3) 191-212.Ballard et al. Cochrane Review. 2012.

Atypical AntipsychoticsAntipsychotic # trials Bottom LineAripiprazole 2 RCTs • Benefits similar to

risperidone

• Caveat: studied in context of psychosis

Quetiapine 3 RCTs • significantly > cognitive decline

• ineffective in treating agitation

Schneider L. Am J Geriatr Psych 2006:14(3) 191-212.Ballard et al. Cochrane Review. 2012

AntidepressantsSSRI’s # trials Main findings

Meta-analysis of 9 trials, n=692; five studies compared SSRIs to placebo, only two studies included in meta-analysis1.

Limited trials addressing aggression or agitation

Citalopram vs. placebo: ↓ agitation and aggression

Citalopram vs. risperidone: improved effect on agitation, better tolerated

Some benefit shown for sertraline & citalopram for overall BPSD vs placebo; no statistically significant difference vs. antipsychotics.

May have role in treating aggression and agitation

Better tolerated than antipsychotics

Indicated if depression present1. Ballard & Corbegtt. Current Opin Psychiatry. 2013 26(3) 252-

259.2. Pollock, BG, Mulsant, BH, Rosen J et al. Am J Pscychiatry 2002; 159:450-465.3. Pollock, Mulsant, Rosen et al. Am J Geriatr Psychiatry 2007;15:942-952

Antidepressants

1. Martinon et al., Cochrane Review, 20082. Henry et al. Am J Alz Dis & Other Dementias 2011:26(3) 169-

183.

Trazodone studies # placebo-controlled RCTs

Bottom line

Martinon et al. 2 placebo-controlled RCT’s (n=104; dosage 50-300 mg, up to six weeks)

No significant benefit vs. placebo

Henry et. al. 3 original trials• 1 trial vs. placebo)

• 2 trials vs. haloperidol

• trazodone > haldol

• trazodone = haldol=placebo

Cognitive Enhancers

Rodda et al. Int. Pyschoger 2009:21:5;813-24

Cognitive enhancer

#P-C RCTs included

Outcome on agitation

donepezil 9 2 positive

1 trial positive for continuing vs. placebo after initial open label treatment phase

galantamine 3 1 positive

rivastigmine 2 0 positive

Anticonvulsants & mood stabilizersDrug Overall findings for

agitation & aggressionBottom Line

Carbamazapine - Few clinical trials(1 meta-analysis, 3 clinical trials)

- Conflicting evidence

- ↑ risk drug-drug interactions, poorly tolerated in long-term use

Promising for global BPSD, esp. agitation & aggression(dose 300-600 mg over 6-8 wks)

Not recommended for routine treatment of agitation

Valproate - Meta-analysis: unacceptable rate of adverse effects (esp. sedation) > 15mg/kg/d

- 3 RCTs: no improvement in aggression; 1 RCT: worsened hostility;

Higher quality studies including RCTs and meta-analyses do not support use for agitation; may worsen aggression

Yi-Chun & Ouyang. Kaoh J of Med Sci (2012): 28, 185-193.

Drug Overall findings for agitation & aggression

Bottom line

Gabapentin No meta-analysis or RCTs Data limited (11 case reports, 3 case series, 1 retrospective chart review)

well tolerated, some effectiveness for overall BPSD, (mean dose 900 mg daily) - dearth of data

Oxcarbazepine One RCT on agitation & aggression

Negative results

Topiramate Lack of RCTs Adverse effect on cognitionUse not supported in BPSD

Lamotrigine Case series, case reports, no RCTs using objective measures

May be effectiveAdverse effects: rash, somnolence, tremor

Lithium Case series, most > 20 y o, lack of valid instruments

Conflicting results

Yi-Chun & Ouyang. Kaoh J of Med Sci (2012): 28, 185-193.

Anticonvulsants & mood stabilizers

Summary:

CBZ most promising mood stabilizer for patients with aggression, hostility and (possibly) agitation Also effective for global BPSD Effective dose range: 300-600 mg daily over 6-8

weeks

Electro-Convulsive Therapy (ECT)Case series, 4 patients, failed psychotropics

2 to 4 ECT sessions meaningful reduction in symptoms for 3 to 12 months (Grant et al. 2001)

Case series, 3 patients with manic-like symptoms, failed psychotropics 1-2 weeks of ECT followed improvement in mania and agitation (McDonald et al. 2001)

 92 year-old female, vascular dementia, failed haloperidol 2 ECT sessions BPSD resolves for 3 months (Katagai et al. 2007)

Electro-Convulsive Therapy (ECT)

16 hospitalized patients (mean age = 66.6, SD = 8.3) with mild to severe dementia. 12 patients bilateral ECT 3 patients right unilateral ECT bilateral ECT 1 patient only right unilateral ECT

On average, 9 treatments (range: 2 to 15) All patients improving except for one

Ujkaj et al. 2012

Pathway of Care

Assessment & Medications

Discontinuation

Cognitive Enhancers

(AChEI, Memantine)

Pharmacological

Non-Pharmacological

Risperidone

Aripiprazole

Citalopram

Carbamazepine

Gabapentin

Prazosin

ECT

Quetiepine

• Dr. Amer Burhan• Dr. Simon Davies • Dr. Donna Kim

• Dr. Benoit Mulsant

• Dr. Bruce Pollock• Dr. Vincent Woo

• Ms. Rong Ting• Dr. Sawsan

Kalache• Ms. Saima

Aiwan• Mr. Christopher

Uranis