• Document: Alternatives to Antipsychotics for the Treatment of Dementia-Related Behavioral Symptoms Lori A. Daiello Pharm.D, ScM
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Alternatives to Antipsychotics for the Treatment of Dementia-Related Behavioral Symptoms Lori A. Daiello Pharm.D, ScM Assistant Professor of Neurology (Research) and Health Services, Policy, & Practice (Research) Warren Alpert Medical School of Brown University Research Scientist, Alzheimer's Disease and Memory Disorders Center Rhode Island Hospital “Normal” Behaviors Associated with Degenerative Dementias Generally Unresponsive to Psychoactive Medications • Wandering* • Disrobing • Persistent disruptive vocalization (swearing, offensive comments, yelling/screaming)* • Restlessness/ repeated attempts to unsafely arise from chair or climb out of bed* • Inappropriate urination/defecation • Hiding/hoarding • Eating inedibles • Annoying repetitive activities, including “exit seeking” • Climbing into bed with other residents • Sleep disturbance, diurnal reversal* • Pushing wheelchair-bound residents * may be related to pain or discomfort Behavioral Symptoms that May Respond to Pharmacologic Intervention • Anxiety • Depressive symptoms • Persistent physical aggression • Manic-like symptoms • Persistent and distressing delusions or hallucinations • Sleep disturbance, initial or middle insomnia • Sexually inappropriate behavior Pharmacologic Treatment of BPSD • Antipsychotics • “Alternatives” –Benzodiazepines –Antidepressants –Anticonvulsant Mood Stabilizers –Cholinesterase Inhibitors (CHEI) and Memantine –Miscellaneous agents Antipsychotics for BPSD • Modest benefit may be offset by adverse effects • CATIE-AD (2006)1 – No significant difference between risperidone, olanzapine, quetiapine, or placebo in time to discontinuation for lack of efficacy – Adverse effects > potential benefits • CATIE-AD (2008)2 – Risperidone and olanzapine more effective for particular symptoms, such as anger, aggression, and paranoid ideas than placebo. – Functional abilities, care needs, and QOL were not improved over 12 weeks 1Schneider LS et al. NEJM 2006;355:1525-1538. 2Sultzer DL et al. Am J Psychiatry 2008;165:844-854. Safety of Antipsychotics for BPSD • Documentation of monitoring in nursing home settings • Extrapyramidal Adverse Effects – Highest risk with risperidone; lowest with quetiapine, clozapine – Comparative risk of tardive dyskinesia in dementia is similar between atypical and conventional agents1 • Falls • Metabolic adverse effects (atypicals) – Little or no effect on weight gain or DM in NH settings in most studies – No effect on BP or triglycerides • Cerebrovascular Adverse Effects • Pneumonia • Mortality 1 Lee PE et al. J Am Geriatr Soc.2005;53:1374-1379. Steinberg M, et al. Am J Psychiatry 2012;169:900-906. Bias in Non-Randomized Studies of Antipsychotics and Mortality Risk • Are results of observational studies biased by unmeasured patient characteristics?? • Analyze mortality in elderly users of conventional antipsychotics in Medicare dataset • Adjust for BMI, smoking, cognitive impairment, physical impairment, and ADL level • Results – Don’t adjust for cognitive impairment - >50% overestimation of mortality in antipsychotic users vs nonusers – Don’t adjust for ADL impairment – 13% underestimation of mortality in conventional vs atypical antipsychotic users Schneeweiss S, et al. CNS Drugs 2009;23(2):171-180. Risk of Mortality Among Individual Antipsychotics and Valproate in Dementia Kales HC et al. Am J Psychiatry 2012;169:71-79. Interpreting the Evidence for Antipsychotic Alternatives to Treat BPSD • Considerations • Non-uniform diagnostic criteria across trials • Diverse outcomes and measurement • Varying duration of follow-up • Variable inclusion/exclusion criteria for trial entry – Other psychotropics allowed? – Cholinesterase inhibitors (CHEI) and memantine allowed? • Systematic reviews are helpful, but interpretation is challenging due to these limitations Benzodiazepines for BPSD Severe Acute or Episodic Behavioral Symptoms • RCTs: Only 5 published trials in the past 50+ years1 • Advantages: rapid onset of effect; multiple dosage forms • High Risk: chronic use • Adverse effects: cognitive dysfunction, gait changes, falls, disinhibition • Note: Pharmacogenetic determinants of cognitive adverse effects? • Utility: Situations

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