Management of Agitation and
Aggression Associated with
Alzheimer’s Disease
TAREK K. RAJJI, MD, FRCPC
CHIEF, GERIATRIC PSYCHIATRY DIVISION
CENTRE FOR ADDICTION AND MENTAL HEALTH
ASSOCIATE PROFESSOR OF PSYCHIATRY
UNIVERSITY OF TORONTO
Disclosures
 None
Auguste Deter
“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
Behavioral and Psychological Symptoms of Dementia
“AGGRESSION”
Aggressive resistance
Physical aggression
Verbal aggression
“APATHY”
Withdrawn
Lack of interest
Amotivation
“DEPRESSION”
Sad
Tearful
Hopeless
Low self-esteem
Anxiety
Guilt
“MOTOR HYPERACTIVITY”
Increased walking
Walking aimlessly
Moving objects
Trailing
“PSYCHOSIS”
Hallucinations
Delusions
Misidentifications
McShane, 2000
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)
Jost & Grossberg, 1996
Agitation/Aggression Incidence: 50% over course of
illness (Tariot & Blazina, 1994)
Cummings, 2003
Aggression & Agitation in Dementia

“Inappropriate verbal, vocal or motor activity not
explained by apparent needs or confusion” (CohenMansfield, 1986)
Aggression
Physical
Physical
Verbal
Agitation
Physical
Physical
Verbal
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: Evidence
Study
year
N
Intervention
TAU
Results
IMPACT
(late-life
depression)
2002
Int-906
Cont895
-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-320
Cont276
-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-175
Cont175
-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-74
Cont-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
Better
Knowledge
New
Approaches
More
Access
More Data
Pathway
Assessment &
Medications
Discontinuation
NonPharmacological
Cognitive
Enhancers
(AChEI,
Memantine)
Pharmacological
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 stimulation
 Inappropriate music – ensure age related and
appropriate to the client group
 Environment/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
Hospitalist
DIAGNOSTIC WORK-UP: PHYSICAL EXAM INVESTIGATION
Y
E
S
N
O
Y
E
S
N
O
Y
ES
N
O
Basic investigation done to rule out other medical causes of cognitive impairment or agitation
Name:
Sign:
Date:
(dd/mm/yyyy)
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:
____________________________________________________________________________________
______
Attending Physician
DIAGNOSTIC WORK-UP: HISTORY
Agitation or aggression is present
Name:
Sign:
Date:
(dd/mm/yyyy)
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
Delirium or other causative medication/medical condition identified?
Presentation more consistent with non-Alzheimer’s Dementia?
Name:
Sign:
Is the Agitation and Aggression:
If “Yes” exit pathway
Severe?
Causing distress to the patient? Or OTHERS?
Preventing or interfering with providing necessary care to the patient?
Date:
(dd/mm/yyyy)
Posing a risk to the patient or to others?
If “Yes” to ANY questions, proceed with pathway, otherwise exit pathway
Clinical Global Impression Scale (CGI)
Initial Score:
_________________________
Attending Physician
Abnormal Involuntary Movement Scale (AIMS)
Name
Sign:
Date:
Initial Score: _________________________
Simpson-Angus Scale (SAS)
Initial Score: _________________________
(dd/mm/yyyy)
Barnes Akathisia Scale (BAS)
Sign:
Comments:
________________________________
________________
Initial Score:
_________________________
________________________________
________________
Comments:
___________________________________
_____________
Date:
Montreal Cognitive Assessment (MOCA)
Initial Score: _________________________
(dd/mm/yyyy)
Alzheimer’s disease assessment scale – cognitive
subscale (ADAS-cog)
Initial Score: _________________________
YE
S
NO
___________________________________
_____________
Comments:
___________________________________
_____________
Cohen-Mansfield Agitation Inventory
(CMAI)
Initial Score: _________________________
NO
___________________________________
_____________
Comments :
___________________________________
_____________
___________________________________
_____________
Neuropsychiatric Inventory (NPI)
YE
S
________________________________
________________
Comments :
___________________________________
_____________
Initial Score: _________________________
Research Fellow
Name
Comments :
________________________________
________________
___________________________________
_____________
Comments :
___________________________________
_____________
___________________________________
_____________
Comments :
___________________________________
_____________
___________________________________
_____________
Hospitalist
CARDIAC AND METABOLIC ASSESSMENT
Name
CBC, ECG, Creatinine/BUN, Blood Sugar, Lipid Profile
Sign:
Comments:
___________________________________________________________________________________
_________
Date:
(dd/mm/yyyy)
Assigned Nurse
YES
NO
YES
NO
___________________________________________________________________________________
_________
PAIN ASSESSMENT AND MANAGEMENT
Name:
Pain Assessment and Management Conducted
Sign:
Date:
(dd/mm/yyyy)
For example:
Brief Pain Inventory (BPI) for verbal patients
Checklist of Non-Verbal Pain Indicators (CNPI) for non-verbal patients
Occupational
Therapist
FUNCTIONAL ASSESSMENT
Name:
Functional Assessment Staging (FAST)
Sign:
Date:
(dd/mm/yyyy)
Comments:
____________________________________________________________________________________
________
____________________________________________________________________________________
________
YES
NO
Pathway
Assessment &
Medications
Discontinuation
NonPharmacological
Cognitive
Enhancers
(AChEI,
Memantine)
Pharmacological
Non-Pharmacological Interventions
 Consent
 Caregiver education and support
 Enhance communication with the patient
 Ensure safe environment
 Increase 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
Please check
discipline:
Occupational
Therapist
NON-PHARMACOLOGICAL INTERVENTIONS
IDENTIFIED INITIALLY AS MOST APPROPRIATE*
Social Contact
Pet therapy
One-to-one visit
Recreation
Therapist
Other:_________
______
Sensory
Enhancement/
Relaxation
Hand massage
Individualized
Music
Social Worker
Purposeful Activity
Exercise group
Helping tasks /
Volunteer role
Inclusion in group
programs of
identified interest
Individualized art
Primary Nurse
Physical Activity
Access to outdoors
Indoor/outdoor
walks
Individual exercise
program
Sensory modulation
Name:
Other:_________
______
Sign:
Date:
Other:__________
Other:__________ _____
_____
Multisensory Snoezelen System
Paro Therapeutic Robot
Pharmacological Interventions
Risperidone
Aripiprazole
Quetiepine
Citalopram
Carbamazepine
Gabapentin
For partial responders:
1. Extend the trial
2. Increase the dose
3. Augment with another
agent that showed also partial response
Prazosin
ECT
PRNs:
1. Trazodone
2. Lorazepam
Drugs commonly used for agitation
 Antipsychotics
 Antidepressants

SSRIs, trazodone
 Cognitive enhancers

Cholinesterase inhibitors, memantine
 Mood stabilizers and Anticonvulsants







carbamazepine
valproic acid
gabapentin
oxcarbazapine
topiramate
lamotrigine
lithium
Antipsychotics
Treatment
Trials conducted
Evidence
Typicals
11 randomized, placebocontrolled 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 shortterm (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.
Antipsychotics
 Mainstay 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 Antipsychotics
Antipsychotic
# trials
Bottom Line
Risperidone
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)
Schneider L. Am J Geriatr Psych 2006:14(3) 191-212.
Ballard et al. Cochrane Review. 2012.
• Conflicting evidence
• More adverse events of
hostility, abnormal
gait, somnolence
• Not associated with
overall efficacy
Atypical Antipsychotics
Antipsychotic
# trials
Bottom Line
Aripiprazole
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
Antidepressants
SSRI’s
# trials
Main findings
Meta-analysis of 9 trials, n=692; five
studies compared SSRIs to placebo,
only two studies included in metaanalysis1.
Some benefit shown for
sertraline & citalopram
for overall BPSD vs
placebo; no statistically
significant difference vs.
antipsychotics.
Limited trials addressing aggression
or agitation
Citalopram vs. placebo: ↓ agitation
and aggression
May have role in treating
aggression and agitation
Citalopram vs. risperidone:
improved effect on agitation, better
tolerated
Better tolerated than
antipsychotics
Indicated if depression
present
1. 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
Antidepressants
Trazodone studies
# placebo-controlled
RCTs
Bottom line
Martinon et al.
2 placebo-controlled
RCT’s (n=104; dosage 50300 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
1. Martinon et al., Cochrane Review, 2008
2. Henry et al. Am J Alz Dis & Other Dementias 2011:26(3) 169-183.
Cognitive Enhancers
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
Rodda et al. Int. Pyschoger 2009:21:5;813-24
Anticonvulsants & mood stabilizers
Drug
Overall findings for
agitation & aggression
Bottom Line
Carbamazapine
- Few clinical trials
(1 meta-analysis, 3 clinical
trials)
- Conflicting evidence
Promising for global
BPSD, esp. agitation &
aggression
(dose 300-600 mg over
6-8 wks)
- ↑ risk drug-drug interactions,
poorly tolerated in long-term
use
Not recommended for
routine treatment of
agitation
- 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
Valproate
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
cognition
Use not supported in
BPSD
Lamotrigine
Case series, case reports,
no RCTs using objective
measures
May be effective
Adverse 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
Risperidone
Assessment &
Medications
Discontinuation
Aripiprazole
Citalopram
NonPharmacological
Carbamazepine
Cognitive
Enhancers (AChEI,
Memantine)
Pharmacological
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