Susan Francis, PharmD, BCPS
Durham VA Medical Center
• Alterations in absorption
• Changes in serum protein binding
• Slowed hepatic metabolism
• Decreased renal clearance
• Multiple comorbidities and multiple
medications
• Drug-disease and drug-drug interactions
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New behaviors may be triggered by delirium
Concomitant medical illness
– UTI, pneumonia, constipation
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Pain
Medication toxicity
– Anticholinergic side effects -> confusion, urinary retention or
constipation
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Best treatment may be to treat underlying condition or
discontinue offending medication
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The classic principles apply
Low starting doses
Conservative dose titration
Extended intervals between dose increases
Continual reassessment of target symptoms and
screening for medication side effects
Avoid adding another medication to treat a side effect
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Psychosis and agitation may wax and wane or may
change in character
Continued use of any intervention for behavioral
disturbances or psychosis must be evaluated and
justified on an ongoing basis
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Important to involve family/caregivers
Identify and quantify target symptoms prior to
treatment
Reassess behaviors and reprioritize goals as part of an
ongoing management plan
Symptom reduction may be more safe and attainable
than symptom free
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Important to consider medication for more severe
behaviors
Not a “cure” but can lessen the frequency and severity
of agitated behavior
Treatment may reduce caregiver burn-out
Biggest limitation: potential for serious side effects and
increased mortality
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Sedation, confusion
◦ Sleep apnea or COPD may be at increased risk for respiratory
depression
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Anticholinergic effects
◦ Confusion, constipation, urinary retention, dry mouth
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Falls, fractures
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Movement disorders (antipsychotics)
Metabolic effects (atypical antipsychotics)
Mortality (antipsychotics)
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Antipsychotics
◦ Reduced with atypicals, still dose-related
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Extrapyramidal symptoms
◦ Worse in the elderly, and patients with Parkinson’s disease or
Lewy Body Dementia
◦ Monitor quarterly (AIMs, DISCUS)
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Tardive dyskinesia
◦ Often irreversible
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Akathisia
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Limited data to guide choice or sequencing and
combining treatments
Expert consensus guidelines offer some framework for
directing therapy
Consider secondary to non-pharmacologic
interventions unless acute/severe
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No significant benefit (p=0.22) with modest treatment
using atypical antipsychotics for behaviors related to
dementia
Olanzapine, risperidone, and quetiapine had
marginally higher response rates (32%, 29%, and 26%,
respectively) than placebo (21%)
NEJM 2006;355:1525-1538
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Increased side effects in the treatment groups:
◦ EPS, sedation, and confusion
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Evidence of metabolic side effects
Weight gain, particularly in women treated with
olanzapine and quetiapine
Olanzapine associated with decreased HDL cholesterol
NEJM 2006;355:1525-1538
English-language, from 1966 to 7/2004
 MEDLINE, Cochrane Database, and a manual search of
bibliographies
 Double-blind, placebo-controlled RCTs or metaanalyses
 Any drugs for patients with dementia that included
neuropsychiatric outcomes
 Trials with depression outcomes only were excluded.
JAMA 2005 Feb 2;293(5):596-608
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Pharmacotherapy resulted in modest improvement of
symptoms
However, small improvements may benefit the patient
and caregiver.
JAMA. 2005;293:596–608.
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A systemic review of conventional antipsychotics:
haloperidol, thioridazine, thiothixene, chlorpromazine,
trifluoperazine and acetophenazine
Two meta-analyses of 12 trials plus two additional
studies included
Aggregate data: there was no clear evidence of benefit
in patients with dementia
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Extensively used for hallucinations and delusions
Not been extensively studied in randomized controlled
clinical trials
Most evidence for risperidone and olanzapine
JAMA 2005 Feb 2;293(5):596-608
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Studies often of short duration, e.g. 6 to 12 weeks
Clinical use often much longer
Methodological limitations
JAMA 2005 Feb 2;293(5):596-608
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Six RCTs showed modest, statistically significant
efficacy of olanzapine and risperidone
Usually well tolerated at lower doses.
Atypical antipsychotics are associated with an
increased risk of stroke.
No trials to directly compare conventional and atypical
antipsychotics.
JAMA 2005 Feb 2;293(5):596-608
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Worsening cognitive impairment
Oversedation
Falls
Neuroleptic Malignant Syndrome
• Haloperidol (Haldol)
• More EPS
• Less sedation
• Fewer anticholingeric
effects
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Thioridazine (Mellaril)
and Thiothixene
(Navane)
Less EPS
More sedating
Higher anticholinergic
effects
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Aripiprazole (Abilify), olanzapine (Zyprexa)
quetiapine (Seroquel), risperidone (Risperidal)
Minimally anticholinergic
Cause fewer extrapyramidal symptoms than
conventional antipsychotics
EPS dose related
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Increased risk of hyperglycemia and all-cause mortality
May increase risk of stroke in elderly patients who
have dementia-related psychosis
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PRN “as-needed” basis should be discouraged once
symptoms are controlled in LTC setting
Improvement in behavior often occurs more quickly
and at lower dosages of these agents than reduction of
psychotic symptoms
Use lowest effective doses to minimize adverse effects
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Most studied for behaviors related to dementia
Most commonly used in clinical practice
Use has declined since black box warning
Better tolerated than conventional (1st generation)
antipsychotics
Lower risk of EPS but there is still a dose-dependent
risk
Metabolic syndrome (wt gain, DM, Lipids)
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Data is conflicting
Greatest concern with risperidone
A large population based cohort study of adults aged
≥65 years found a similar risk of ischemic stroke among
atypical and conventional antipsychotics
◦ same among a subgroup with atrial fibrillation or prior stroke
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Meta-analysis of 15 studies (9 unpublished) in patients
with dementia
Increased risk compared with controls (3.5 versus 2.3
percent, OR 1.54)
Most deaths cardiovascular or infectious
Risks did not differ among agents studied (aripiprazole,
olanzapine, quetiapine, risperidone)
Most studies were short-term (< 3 months)
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Large retrospective cohort study
22,890 elderly patients receiving antipsychotic
medications
Compared risks with conventional vs atypical
Significantly higher mortality was seen in patients
taking conventional agents (OR 1.37)
Increase in risk greatest early in therapy and with
higher doses of conventional agents
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Retrospective study
Increased mortality risk at 30 days for patients
receiving atypical antipsychotics, compared to no
antipsychotics
Both community-dwelling and LTC patients (HR 1.31
and 1.55, respectively)
Conventional antipsychotics increased 30-day mortality
more than atypicals
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A randomized trial compared mortality for 165 patients
with Alzheimer disease
Continue their antipsychotic medication or switch to
placebo
Survival at 12 and 24 months was significantly greater
for the group assigned to placebo
◦ Survival 24 months, 71 placebo vs 46 percent for antipsychotic
continuance.
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Antipsychotic medications have been associated with
increased mortality in the elderly with dementiarelated behavior
Both atypical and conventional agents
Risk should be discussed with patients, families, and
other caregivers
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The medication must be necessary
◦ Behavior poses danger to self, others or interfere with ability
to provide care
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In residents with dementia, must document specific
behaviors and number of episodes
Lowest Effective Dose
Drug should be discontinued if not needed
Close monitoring for significant side effects
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A trial at dose reduction or elimination of agents may
be appropriate
6 mo. reassessment and stepwise reduction in LTC
mandated by OBRA guidelines
Recognize that behavior may vary over time
Safety of patient and others is primary
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Delirium: 1 week
Agitated Dementia:
Taper w/in 3-6 months
to find LED
Schizophrenia:
Indefinite at LED
Not a substitute for clinical
judgment
LED = Lowest effective maintenance dose
J Clin Psychiatry. 2004;65 Suppl 2:5-99
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Delusional disorder: 6
mos, then indefinitely
at LED
Psychotic major
depression: 6 mos
Mania w/ psychosis: 3
mos
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Supported by expert consensus when used judiciously
and with proper documentation
Document risk vs. benefit
Reassess need for continued therapy, potential for
dose reduction
Monitor for adverse effects
Try nonpharmacologic interventions first unless danger
present and continue with Rx
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Staff training on alternatives to drug use for
management of agitated behavior
Reduced antipsychotic therapy 19%
No significant differences in the level of agitated or
disruptive behavior between intervention and control
homes
BMJ 2006;332:756-761
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Other psychotropic classes should be considered
particularly in patients without psychosis
Mood stabilizers/Anticonvulsants
Antidepressants
Anxiolytics
Cognitive enhancers: Acetylcholinesterase inhibitors,
memantine
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Most commonly used to target aggression
Most commonly see Divalproex (Depakote) or
Carbamazepine (Tegretol) in patients with dementia
Sometimes used second-line in patients with poor
response to antipsychotic agents
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3 RCTs investigating valproate showed no efficacy
2 small RCTs of carbamazepine had conflicting results
Effective and well-tolerate in multiple small, relatively
short term studies
Clinical use often limited by side effects, drug
interactions, and a narrow therapeutic window
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Depression with psychotic features vs. psychotic
symptoms of dementia
SSRIs used most often due to favorable side effect
profile
Five trials showed no efficacy for treating
neuropsychiatric symptoms other than depression,
with the exception of 1 study of citalopram.
JAMA 2005 Feb 2;293(5):596-608
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Benzodiazepines should not be considered first-line
therapy, even in patients with prominent anxiety
No published studies to support use in dementia
Community surveys suggest frequent use
May worsen behavior: amnestic and disinhibitory
effects
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High risk for falls
Limit to management of otherwise unresponsive acute
symptoms
Discontinue as soon as symptoms can be controlled
with other agents.
Limit to agents with short half-lives, no active
metabolites, and little potential for drug interaction.
◦ LOT: Lorazepam, Oxazepam, Temazepam
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2 meta-analyses and 6 RCTs
Small but statistically significant efficacy
Data on primary endpoints of cognitive function show
a delay in time to institutionalization
◦ May reflect improved behavior, a delay in onset of behavior
symptoms, or retention of function
JAMA 2005 Feb 2;293(5):596-608
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May reduce problem behaviors, considered an
adjunctive treatment.
Even small gains or stabilization of symptoms may
lower caregiver burden
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Only neuropeptide-modifying agent
Regulates glutamate
Common side effects: Nausea, dizziness, diarrhea
Requires dose reduction for renal impairment
VA Criteria for Use
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May decrease agitation/aggression, irritability and
other behavioral disturbances
◦ Post-hoc analyses of clinical trial
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Systematic reviews to date have not demonstrated a
statistically significant effect
2 RCTs had conflicting results
Results may be clinically meaningful for individual
patients
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May cause significant distress
Associated with behavior that may place the patient or
others at risk
Treatment with low doses of antipsychotic medication
is indicated
Should include nonpharmacological interventions.
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May require hospitalization in a geriatric psychiatry
unit for medication adjustment
Patients with Lewy body disease often present with
hallucinations and may be particularly resistant to
antipsychotics-may worsen with treatment
Behavior problems are dynamic and variable; may
resolve spontaneously
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If minimal or no distress to the patient and not linked
to agitation or combativeness, preferred not to treat
with medication
Provide reassurance and redirection
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Antipsychotics are often used even in the absence of
psychosis
Use is supported in the literature
Weigh benefit to potential risk of increased mortality
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Mood stabilizers and SSRIs are commonly used in
clinical practice
They have not been consistently shown to be effective
in treating these symptoms
Limited evidence for safety in patients with behaviors
related to dementia
No comparative data with atypical antipsychotics
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Behavioral interventions
◦ Redirection, distraction
◦ Avoid stimulants
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Review current medications for side effects
Consider UTI
SSRIs
Medroxyprogesterone acetate, Leuprolide, Estradiol,
Cimetidine
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Sleep hygiene first line
– Limit caffeine, avoid daytime naps
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Review timing and side effects of current medications
Avoid benzodiazepines and anticholinergics
Consider trazodone 25 mg PO at bedtime
Alternative Rx: Quetiapine or zolpidem
OTC: Melatonin, light therapy
– No convincing evidence
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Aromatherapy for patients with dementia and
agitation
Lavender oil or lemon balm
Inhalation or skin application
Mechanism remains unclear
Conducive to home-like environment
Low cost
Minimal risk
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More research is needed to direct the pharmacologic
management of behavior problems
Clinical trials with a stepwise, multiple-agent design
would provide a stronger basis for recommendations
and a better understanding of impact of medications
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Establish routine for taking medications to help reduce
resistance and arguments
Streamline medications/reduce pill burden to promote
acceptance of treatment
Consider rapidly dissolving tabs for persistent refusals
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Ask pharmacist for assistance if pt has difficulty
swallowing pills
Monitor for cheeking
Pill boxes can be a useful memory aid for both the
person with dementia and the caregiver