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Pharmaceutical Considerations in Managing Challenging Behaviors

Pharmaceutical Considerations in Managing Challenging Behaviors. Susan Francis, PharmD, BCPS Durham VA Medical Center. Age Related Changes. Alterations in absorption Changes in serum protein binding Slowed hepatic metabolism Decreased renal clearance

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Pharmaceutical Considerations in Managing Challenging Behaviors

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  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 -> 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 Parkinson’s 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 (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

  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 2006;355:1525-1538

  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 2;293(5):596-608

  15. Systematic Review • Pharmacotherapy resulted in modest improvement of symptoms • However, small improvements may benefit the patient and caregiver. JAMA.  2005;293:596–608.

  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 2;293(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 2;293(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 2;293(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 • Thioridazine (Mellaril) and Thiothixene (Navane) • Less EPS • More sedating • Higher anticholinergic effects • Haloperidol (Haldol) • More EPS • Less sedation • Fewer anticholingeric 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 (< 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 • Delusional disorder: 6 mos, then indefinitely at LED • Psychotic major depression: 6 mos • Mania w/ psychosis: 3 mos • 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

  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 2006;332:756-761

  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 2;293(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 2;293(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

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