Pharmaceutical Considerations in Managing Challenging Behaviors
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Transcript of Pharmaceutical Considerations in Managing Challenging Behaviors
Susan Francis, PharmD, BCPSDurham 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
• New behaviors may be triggered by delirium• Concomitant medical illness – UTI, pneumonia, constipation
• Pain• Medication toxicity– Anticholinergic side effects -> confusion, urinary retention or
constipation• Best treatment may be to treat underlying condition or
discontinue offending medication
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
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
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
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
Sedation, confusion◦ Sleep apnea or COPD may be at increased risk for respiratory
depression Anticholinergic effects◦ Confusion, constipation, urinary retention, dry mouth
Falls, fractures
Movement disorders (antipsychotics) Metabolic effects (atypical antipsychotics) Mortality (antipsychotics)
Antipsychotics◦ Reduced with atypicals, still dose-related
Extrapyramidal symptoms◦Worse in the elderly, and patients with Parkinson’s disease or
Lewy Body Dementia◦Monitor quarterly (AIMs, DISCUS)
Tardive dyskinesia◦Often irreversible
Akathisia
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
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
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 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 meta-
analyses 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
Pharmacotherapy resulted in modest improvement of symptoms
However, small improvements may benefit the patient and caregiver.
JAMA. 2005;293:596–608.
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
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
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
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
Worsening cognitive impairment Oversedation Falls Neuroleptic Malignant Syndrome
• Haloperidol (Haldol)• More EPS• Less sedation• Fewer anticholingeric
effects
Thioridazine (Mellaril) and Thiothixene (Navane)
Less EPS More sedating Higher anticholinergic
effects
Aripiprazole (Abilify), olanzapine (Zyprexa)quetiapine (Seroquel), risperidone (Risperidal)
Minimally anticholinergic Cause fewer extrapyramidal symptoms than
conventional antipsychotics EPS dose related
Increased risk of hyperglycemia and all-cause mortality May increase risk of stroke in elderly patients who
have dementia-related psychosis
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
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)
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
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)
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
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
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.
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
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
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
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
doseJ Clin Psychiatry. 2004;65 Suppl 2:5-99
Delusional disorder: 6 mos, then indefinitely at LED
Psychotic major depression: 6 mos
Mania w/ psychosis: 3 mos
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
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
Other psychotropic classes should be considered particularly in patients without psychosis
Mood stabilizers/Anticonvulsants Antidepressants Anxiolytics Cognitive enhancers: Acetylcholinesterase inhibitors,
memantine
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
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
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
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
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
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 functionJAMA 2005 Feb 2;293(5):596-608
May reduce problem behaviors, considered an adjunctive treatment.
Even small gains or stabilization of symptoms may lower caregiver burden
Only neuropeptide-modifying agent Regulates glutamate Common side effects: Nausea, dizziness, diarrhea Requires dose reduction for renal impairment VA Criteria for Use
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
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.
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
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
Antipsychotics are often used even in the absence of psychosis
Use is supported in the literature Weigh benefit to potential risk of increased mortality
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
Behavioral interventions◦ Redirection, distraction◦ Avoid stimulants
Review current medications for side effects Consider UTI SSRIs Medroxyprogesterone acetate, Leuprolide, Estradiol,
Cimetidine
• 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
• 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
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
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
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