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Susan Francis, PharmD, BCPS Durham VA Medical Center.

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1 Susan Francis, PharmD, BCPS Durham VA Medical Center

2 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 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  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  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  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  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  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  Movement disorders (antipsychotics)  Metabolic effects (atypical antipsychotics)  Mortality (antipsychotics)

10  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  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  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:

13  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:

14  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):

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

16  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  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):

18  Studies often of short duration, e.g. 6 to 12 weeks  Clinical use often much longer  Methodological limitations JAMA 2005 Feb 2;293(5):

19  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):

20  Worsening cognitive impairment  Oversedation  Falls  Neuroleptic Malignant Syndrome

21 Haloperidol (Haldol) More EPS Less sedation Fewer anticholingeric effects  Thioridazine (Mellaril) and Thiothixene (Navane)  Less EPS  More sedating  Higher anticholinergic effects

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

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

24  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  Most studied for behaviors related to dementia  Most commonly used in clinical practice  Use has declined since black box warning  Better tolerated than conventional (1 st generation) antipsychotics  Lower risk of EPS but there is still a dose-dependent risk  Metabolic syndrome (wt gain, DM, Lipids)

26  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  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  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  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  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  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  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  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  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

35  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  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:

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

38  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  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  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):

41  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  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  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):

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

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

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

53 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 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  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  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  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

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