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“APATHY”Withdrawn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