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