1
 Pharmaceutical Considerations in Managing
Challenging Behaviors

• Susan Francis, PharmD, BCPS
• Durham VA Medical Center

2
Age Related Changes

• 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

3
Importance of Evaluation Before Rx

• New behaviors may be triggered by delirium
• Concomitant medical illness
• UTI, pneumonia, constipation
• Pain
• Medication toxicity
• Anticholinergic side effects -gt confusion,
  urinary retention or constipation
• Best treatment may be to treat underlying
  condition or discontinue offending medication

4
Geriatric Dosing Principles

• 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

5
Course of Dementia

• 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

6
Setting Reasonable Expectations

• 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

7
Role of Medications in Behavior Management

• 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

8
Common Adverse Effects of Psychotropics

• Sedation, confusion
• Sleep apnea or COPD may be at increased risk for
  respiratory depression
• Anticholinergic effects
• Confusion, constipation, urinary retention, dry
  mouth
• Falls, fractures

9
Common Adverse Effects of Psychotropics

• Movement disorders (antipsychotics)
• Metabolic effects (atypical antipsychotics)
• Mortality (antipsychotics)

10
Movement Disorders

• Antipsychotics
• Reduced with atypicals, still dose-related
• Extrapyramidal symptoms
• Worse in the elderly, and patients with
  Parkinsons disease or Lewy Body Dementia
• Monitor quarterly (AIMs, DISCUS)
• Tardive dyskinesia
• Often irreversible
• Akathisia

11
Pharmacotherapy for Behaviors Related to Dementia

• 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

12
CATIE-AD Trial

• No significant benefit (p0.22) 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 20063551525-1538

13
CATIE-AD Trial

• Increased side effects in the treatment groups
• EPS, sedation, and confusion
• Evidence of metabolic side effects
• Weight gain, particularly in women treated with
  olanzapine and quetiapine
• Olanzapine associated with decreased HDL
  cholesterol
• NEJM 20063551525-1538

14
Systematic Review

• English-language, from 1966 to 7/2004
• MEDLINE, Cochrane Database, and a manual search
  of bibliographies
• Double-blind, placebo-controlled RCTs or
  meta-analyses
• Any drugs for patients with dementia that
  included neuropsychiatric outcomes
• Trials with depression outcomes only were
  excluded.
• JAMA 2005 Feb 2293(5)596-608

15
Systematic Review

• Pharmacotherapy resulted in modest improvement of
  symptoms
• However, small improvements may benefit the
  patient and caregiver.
• JAMA.  2005293596608.
•  

16
Efficacy of Conventional Antipsychotics

• 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

17
Efficacy of Atypical Antipsychotics

• Extensively used for hallucinations and delusions
• Not been extensively studied in randomized
  controlled clinical trials
• Most evidence for risperidone and olanzapine
• JAMA 2005 Feb 2293(5)596-608

18
Efficacy of Atypical Antipsychotics

• Studies often of short duration, e.g. 6 to 12
  weeks
• Clinical use often much longer
• Methodological limitations
• JAMA 2005 Feb 2293(5)596-608

19
Efficacy of Atypical Antipsychotics

• 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 2293(5)596-608

20
Common Adverse Effects of Antipsychotics

• Worsening cognitive impairment
• Oversedation
• Falls
• Neuroleptic Malignant Syndrome

21
Adverse Effects of Antipsychotics Conventional
(1st) Generation

• Haloperidol (Haldol)
• More EPS
• Less sedation
• Fewer anticholingeric effects

• Thioridazine (Mellaril) and Thiothixene (Navane)
• Less EPS
• More sedating
• Higher anticholinergic effects

22
Adverse Effects of Antipsychotics Atypical (2nd
Generation)

• Aripiprazole (Abilify), olanzapine
  (Zyprexa)quetiapine (Seroquel), risperidone
  (Risperidal)
• Minimally anticholinergic
• Cause fewer extrapyramidal symptoms than
  conventional antipsychotics
• EPS dose related

23
Adverse Effects of Antipsychotics Atypical (2nd
Generation)

• Increased risk of hyperglycemia and all-cause
  mortality
• May increase risk of stroke in elderly patients
  who have dementia-related psychosis

24
Considerations for Antipsychotics

• 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

25
Atypical Antipsychotics

• 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)

26
Stroke Risk with Atypical Antipsychotics

• 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

27
Mortality Atypical Antipsychotics

• 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 (lt 3 months)

28
Mortality Conventional Antipsychotics

• 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

29
Mortality Canada

• 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

30
Mortality UK

• 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.

31
Mortality

• Antipsychotic medications have been associated
  with increased mortality in the elderly with
  dementia-related behavior
• Both atypical and conventional agents
• Risk should be discussed with patients, families,
  and other caregivers

32
Considerations in LTC OBRA

• The medication must be necessary
• Behavior poses danger to self, others or
  interfere with ability to provide care
• 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

33
To Taper or Not To Taper That is the Question

• 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

34
Expert Consensus Duration of Tx Before Taper

• 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. 200465 Suppl 25-99

• Delusional disorder 6 mos, then indefinitely at
  LED
• Psychotic major depression 6 mos
• Mania w/ psychosis 3 mos

35
Role of Antipsychotics in Dementia

• 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

36
Impact of Staff Training on Non-Pharmacologic
Approaches

• 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 2006332756-761

37
Beyond Antipsychotics Alternatives

• Other psychotropic classes should be considered
  particularly in patients without psychosis
• Mood stabilizers/Anticonvulsants
• Antidepressants
• Anxiolytics
• Cognitive enhancers Acetylcholinesterase
  inhibitors, memantine

38
Anticonvulsants

• 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

39
Anticonvulsants

• 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

40
Antidepressants

• 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 2293(5)596-608

41
Anxiolytics

• 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

42
Anxiolytics

• 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

43
Acetylcholinesterase Inhibitors

• 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 2293(5)596-608

44
Acetylcholinesterase Inhibitors

• May reduce problem behaviors, considered an
  adjunctive treatment.
• Even small gains or stabilization of symptoms may
  lower caregiver burden

45
Memantine

• Only neuropeptide-modifying agent
• Regulates glutamate
• Common side effects Nausea, dizziness, diarrhea
• Requires dose reduction for renal impairment
• VA Criteria for Use

46
Memantine

• May decrease agitation/aggression, irritability
  and other behavioral disturbances
• Post-hoc analyses of clinical trial
• Systematic reviews to date have not demonstrated
  a statistically significant effect
• 2 RCTs had conflicting results
• Results may be clinically meaningful for
  individual patients

47
Pyschosis in Dementia

• 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.

48
Intractable symptoms

• 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

49
Hallucinations in Dementia

• 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

50
Agitation or Combativeness

• Antipsychotics are often used even in the absence
  of psychosis
• Use is supported in the literature
• Weigh benefit to potential risk of increased
  mortality

51
Agitation, Delusions and Aggression

• 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

52
Sexually Inappropriate Behavior

• Behavioral interventions
• Redirection, distraction
• Avoid stimulants
• Review current medications for side effects
• Consider UTI
• SSRIs
• Medroxyprogesterone acetate, Leuprolide,
  Estradiol, Cimetidine

53
Sleep disorders

• Sleep hygiene first line
• Limit caffeine, avoid daytime naps
• 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

54
Alternative Therapies

• 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

55
Future of Pharmacotherapy in Dementia

• 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

56
Practical Considerations to Promote Adherence

• 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

57
Practical Considerations to Promote Adherence

• 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

58
Questions