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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 • • 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 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 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 dementiarelated 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 dose J 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 function JAMA 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