PHARMACOLOGIC INTERVENTIONS IN
THE MANAGEMENT IN BEHAVIORAL
PROBLEMS IN DEMENTIA
Bruce Gerlich, R.Ph.
Consultant Pharmacist
Omnicare
12 March 2013
Disclosure
 Bruce Gerlich has no financially relevant
relationships with any commercial entity
pertaining to this activity
Objectives
 Describe risks and benefits of psychoactive
medication use in elderly with dementia
 Understand the limits of benefit of
pharmacologic tx in this population
Algorithm for Drug Therapy of Behavior Problems in Senile Dementia
ACHEIs ±
memantine
Depression
SSRI
Antidepressants
Agitation/
Aggression
SSRI
antidepressants
trazodone
Carbamazepine
Valproic acid
Atypical
antipsychotics
Clinical Geriatrics 2011
19(6); 31-2; 34-40
psychosis
Atypical
antipsychotics
If monotherapy fails
use combination tx
judiciously
When to Initiate Drug Therapy
BPSD pose a danger to the patient or caregiver or
cause…
 Subjective distress
 Impairment in function
 Interference with care
 Balance of benefits and risks
 Specific symptoms likely to respond to drug
therapy
 American Association for Geriatric Psychiatry, position
statement, 2006
General Principles of Drug
Therapy
 Target specific symptoms
 Set goals of therapy
 Start low and go slow
 Attempt to withdraw medication at regular
intervals
 Remember that response can be
unpredictable
“Normal” Behaviors Associated with Degenerative
Dementias Generally Unresponsive to Psychoactive
Medications
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Wandering*
Disrobing
Persistent disruptive vocalization (swearing, offensive comments,
yelling/screaming)*
Restlessness/repeated attempts to unsafely arise from chair or climb out of bed*
Inappropriate urination/defecation
Hiding/hoarding
Eating inedibles
Annoying repetitive activities, including “exit seeking”
Climbing into bed with other residents
Sleep disturbance, diurnal reversal*
Pushing wheelchair-bound residents
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* may be related to pain or discomfort
Dementia drugs for Non-cognitive sx
 Early use may prevent of delay behavioral sx
 Behavioral outcomes typically secondary, post-hoc
analysis
 Target sx vary
•Acetylcholinesterase
•Inhibitors (AChEIs)
•• Mood (depression, anxiety)
• Apathy
2005;293(5):596-608
Alzheimers Dement. 2008;4(1):49-60
J Clin Psychiatry. 2008;69(3):341-8
Curr Psychiatry Rep. 2012;14(4):298-309
Memantine
• Irritability
•Agitation/Aggression
Depression – Consensus?
Organization
Year
Country
Recommendations regarding
antipsychotic alternatives
AAN
2005
USA
SSRIs> TCA, MAO-B inhibitors
APA*
2007
USA
SSRIs > venlafaxine, mirtazapine,
bupropion
AGS
2011
USA
SSRIs > SNRIs , TCAs , bupropion,
mirtazapine, trazodone
NICE*
2006
UK
SSRIs > TCAs, venlafaxine
CCSMH*
2006
Canada
SSRIs , venlafaxine, mirtazpine,
bupropion
EFNS
2007
Europe
SSRIs, and other newer
antidepressants > TCAs
*Guidelines recommend ECT in cases of refractory depression
AAN –American Academy of Neurology
AGS- American Geriatric Society
CCSMH –Canadian Coalition for Seniors Mental Health
Mood Stabilizers for
Agitation/Aggression
Valprioc Acid
(VPA)
Carbamazepine
(CBZ)
- Limited
-Inconclusive
evidence
- Black Box
warning
For hematologic
toxicity
- Drug –Drug
Interactions
evidence to
support short
acting or long
acting
Formulations
-Sedation is
common
JAMA -2005;
293(5):596-608
Clin Interv Aging: 2007;
Lithium
- Mostly
anecdotal
evidence
Agitation/Aggression – Consensus?
Organization
Year
Country
Recommendations regarding antipsychotic
alternatives
AAN
2005
USA
Little evidence for mood stabilizers, AChEIs, BZDs,
antihistamines, MAO B inhibitors, SSRIs
APA
2007
USA
SSRIs, trazodone, VPA, CBZ if antipsychotics not
effective
-Low-dose BZDs for prominent anxiety,or PRN
AGS
2011
USA
-anxiety, mild-moderate irritability; buspirone,
trazodone
-Agitation/aggression –CBZ, VPA (or IM olazapine)
NICE
2006
UK
-ACHEIs (donepezil)
-BZDs, antipsychotics for urgent tx
-insufficient evidence for mood stabilizers
CCSMH
2006
Canada
-Antidepressants (SSRIs, Trazodone), antipsychotics;
CBZ, short or intermediate acting BZDs
EFNS
2007
Europe
-ACHEIs ± other agents
-inconsistent evidence for mood stabilisters
Aging Res Rev 2012 11(1) 78-80
THE HEADLINES
 Mortality Risk in Elderly Dementia Patients May
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Rise With Newer Antipsychotics
Antipsychotics Increase Risk for Stroke in Elders
Psych Drugs Linked to MI Risk in Dementia
Again, Higher Mortality with Antipsychotics in
Patients with Dementia
Rapid Serious Adverse Events with Antipsychotics
in Dementia
Antipsychotics Linked to Increased Risk for
Hyperglycemia in Older Patients with Diabetes
Antipsychotics Increase Risks for Sudden Cardiac
Death
Pathophysiology of BPSD
The causes of BPSD are unclear; however changes in behavior
may be caused by biological, psychological, or environmental
factors
- Biological
› disruption in neurochemical mechanisms may be
underlying cause of BPSD; ↑ dopaminergic
neurotransmission; altered serotonergic modulation of
dopaminergic transmission
> Use of antipsychotics to target these pathways
Front Neurol 2012:3:73 (Epub 2012 May 7)
Neurochem Int 2008 May;52(6):1052-60
Conventional Antipsychotics
Efficacy
Since their approval for Schizophrenia in the 1950s, conventional
antipsychotics have been used to treat BPSD despite lack of
evidence
- Agent of choice
- Haloperidol has been the agent of choice among the
conventional antipsychotics given its affinity for D2
receptor and clinician experience
- Early trials using Haloperidol observed only a modest
improvement when tx BPSD when compared to placebo
J Am Geriatric Soc. 1990; 38(5); 553-563
Adverse Drug Reactions
Conventional Antipsychotics
 Sedation
 Anticholinergic Activity
 Prolactin elevation
 Sexual Dysfunction
 Extrapyramidal Sx (EPS)
 Pseudoparkinsonism -Akathesia
 Acute dystonia - Tardive dyskinesia
Br J Psychiatry 2010; 196(6); 434-439
Atypical Antipsycotics
efficacy
Trial
Intervention Dose
(n)
Type
Setting Duration
(weeks)
BPSD
(scale)
Katz et al.
1999
Risperidone vs
placebo
0.5-2.0mg
(625)
AD, VaD,
mixed
NH
12
BEHAVE-AD
De Deyn
Et al 1999
Risperidone vs.
haloperidol
vs.placeb
*1.1 mg
Risperidone
*1.2mg
Haloperidol
(344)
AD,VaD,
mixed
NH
13
BEHAVE-AD,
CMAI, CGI
Brodaty et
al 2003
Risperidone vs
placebo
*0.95mg
*1.2mg
Haloperidol
(309)
NH
12
BEHAVE-AD,
CMAI, CGI
*average
dose
AD- alzheimer
disease
VaD- vascular
dementia
Mixedmixed
dementia
*average dose
AD-alzheimer disease
VaD-vascular dementia
mixed-mixed dementia
Curr Neuropharmacol. 2008 6(2) 117-24
Curr
Neuropharacol.
2008
6(2); 117-24
Atypical Antipsychotics
efficacy
Trial
Intervention
Dose
(n)
Type
Setting
Duration
(weeks)
BSPD scale
De Deyn et
al 2004
Olanzapine
vs placebo
1-7.5mg
(652)
AD
NH
10
NPI-NH
Schneider
et al 2006
Olanzapine
vs quetiapine
vs
risperidone
vs placebo
*5.5mg
olanzapine
*56.5mg
quetiapine
*
risperidone
(421)
AD
Outpatien
t
36
CGIC and time
to d/c
Zhong et al
2007
Quetiapine
vs placebo
*120mg
quetiapine
(333)
AD
Nursing
home
10
PANSS-EC, CGI,
NPI-NH, CMAI
*Average dose
Curr Neuropharmacol 2008:6(2); 117-24
Effectiveness in Dementia
 Antipsychotic effect takes 3-7 days to start working
 Very sedating medication - acute effect is most likely
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due to sedating effect not antipsychotic effect
In RCTs, recipients do a little bit better than placebo
but the effect beyond 3 months is unclear
Not everyone who receives the meds improve
A large number of people getting the placebo
improve
The net effect is that 10 to 20 people out of 100 who
receive the medication improve due to the
medication
Adverse Drug Reactions
Atypical Antipsychotics
 Weight gain – risk of diabetes
 QTc prolongation
 Tardive dyskinesia
 Extrapyamidal Symptoms
 Orthostatic hypotension
 BLACK BOX WARNING
Br J Psychiatry 2010; 196(6); 434-9
FDA Black Box Warning
Net effectiveness
 “For every 100 patients with dementia
treated with an antipsychotic medication,
only 9 to 25 will benefit and 1 will die”
 Drs Avorn, Choudhry & Fishcher, Harvard Medical School
 Dr Scheurer, Medical University of South Carolina
Source: Independent Drug Information Service (IDIS) Restrained Use of
antipsychotic medications: rational management of irrationality. 2012
Adverse Drug Events
Risk vs. Benefit
Risk of Mortality Among individual Antipsychotics in
Patients
Design: Retrospective cohort study (Dept of Veterans Affairs 1999-2006)
with Dementia
Population: Patients with dementia≥ 65 years of age
Sample size: 33,604 patients
Primary outcome
180 day mortality rate
Medications Evaluated
-risperidone
-olanzapine
-Quetiapine
-haloperidol
Results:
1.5 fold increase in
mortality associated
with use of haloperidol
when compared to
atypicals
Current Guidance-Agency on Healthcare Research and Quality
(AHRQ) Comparative Effectiveness Review of
Off label use of Atypical Antipsychotics
Small Statistically
significant effect
AHRQ Publication No 11EHC087-EF
Risperidone, aripiprazole and
olanzapine have some
efficacy in treating behavioral
sx in dementia
Atypical Antipsychotics – Consensus?
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Organization- Year- Country - Recommendations regarding
antipsychotic use in dementia
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ASCP 2011 USA - 2nd Line: “Only for the duration needed, and at the lowest
effective dose”
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APA 2007 USA -2nd Line: “Recommended for the treatment of psychosis and
agitation in dementia”
AGS 2011 USA - 2nd Line: “May be needed for treatment of distressing
delusions and hallucinations”
NICE 2006 UK- 2nd Line: “Risk benefit analysis should occur prior to use”
CCSMH 2006 Canada 2nd Line:“Atypical antipsychotics should only be used if there
is marked risk, disability or suffering associated with the symptoms”
EFNS 2007 Europe- 2nd Line:“Antipsychotics, conventional as well as atypical,
may be associated with significant side effects and
should be used with caution”
American Society of Consultant Pharmacists, position statement, 2011
Aging Res Rev. 2012 Jan;11(1):78-86
Summary and Key Points
 Risperidone has the most evidence
supporting efficacy in BPSD
 THERE ARE NO FDA –APPROVED MEDICATIONS
FOR BEHAVIORAL PROBLEM IN DEMENTIA
 THERE IS NO CONCENSUS AMONG EXPERTS IN THE
FIELD
 Antipsychotics are 2ND LINE!
 Only use drug therapy if behaviors cause severe
distress on immediate risk