USING ANTIPSYCHOTICS TO TREAT THE BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD)- WHAT IS THE EVIDENCE? Mugdha Thakur, MD Associate Professor of Psychiatry and Behavioral Sciences Duke University School of Medicine
PHARMACOLOGIC MANAGEMENT OF BPSD What is the evidence? Placebo controlled trials A priori defined primary outcome measure
ANTIPSYCHOTICS Positive efficacy studies: Haloperidol Risperidone Olanzapine Aripiprazole (quetiapine) Maglione (AHRQ) 2011
ATYPICAL ANTIPSYCHOTICS- EFFICACY Risperidone Olanzapine Quetiapine Aripiprazole Overall ++ + + ++ Psychosis ++ +/- +/- + Agitation ++ ++ +/- + ++ : moderate or high evidence of efficacy + : low or very low evidence of efficacy +/- : mixed results Schneider 2006, Maglione (AHRQ) 2011
ATYPICAL ANTIPSYCHOTICS- EFFICACY Maglione (AHRQ) 2011
ATYPICAL ANTIPSYCHOTICS: EFFICACY 15 trials, n = 3353 (drug) vs. 1757 (placebo) Modest benefit Better results for patients in nursing homes Patients without psychotic symptoms Patients who were more severely cognitively impaired 1/3 dropped out Schneider 2006
TYPICAL ANTIPSYCHOTICS- EFFICACY Haldol Equivalent to atypical antipsychotics Maglione (AHRQ) 2011
ATYPICAL ANTIPSYCHOTICS: RISKS 2003: FDA warning CVAEs 2004: FDA warning all cause mortality 1.6 to 1.7 times placebo 10 week trial: 4.5% (drug) vs. 2.6% (placebo) NNT and NNH: For every 9 to 25 persons helped with these medications, there would be one death Other risks: Sedation, urinary symptoms, EPS, worsening cognition Jeste 2007
ATYPICAL ANTIPSYCHOTICS: RISKS CATIE- AD: No difference in time to discontinuation between risperidone, olanzapine, quetiapine, placebo Risperidone and Olanzapine better efficacy Quetiapine and Placebo better tolerability Schneider 2006
TYPICAL ANTIPSYCHOTICS: RISKS 6 large cohort studies comparing mortality for typical and atypical antipsychotics 4 found higher mortality with typical antipsychotics 2 found no difference FDA warning 2008 Maglione (AHRQ) 2011
ANTIPSYCHOTICS RISK Kales, 2012
ANTIPSYCHOTICS: DISCONTINUATION DART-AD: RCT probability of survival 12 m 24m 36m Antipsychotic 70% 46% 30% Placebo 77% 71% 59% No overall detrimental effect of stopping antipsychotic medication Deterioration in those with worse baseline BPSD (NPI > 15) Ballard 2008, 2009
ANTIPSYCHOTICS: DISCONTINUATION ADAD (Antipsychotic Discontinuation in AD) Trial 180 patients with probable AD, psychosis/ agitationaggression Outpatients and nursing homes 16 weeks of open label treatment with Risperidone: 62% response rate Responders randomized to continuation vs. placebo Devanand 2012
ANTIPSYCHOTICS: DISCONTINUATION Relapse rate at 16 weeks Placebo: 60% Risperidone: 33% Devanand 2012
ANTIPSYCHOTICS: DISCONTINUATION Relapse Rate at 32 weeks Placebo: 48% Risperidone: 15% Devanand 2012
CHOLINESTERASE INHIBITORS CALM-AD Donepezil = Placebo Systematic review 14 studies (9 with Donepezil), median 24 weeks Low NPI scores at baseline BPSD was secondary outcome in most studies 3 studies found modest statistical difference in NPI scores between drug and placebo Lewy Body Disease Rivastigmine > Placebo Howard 2007, Rodda 2009, McKeith 2000
MEMANTINE No prospective placebo controlled trials for treatment of BPSD Pooled retrospective analysis of 3 trials 6 months 60% patients had agitation/ aggression (NPI) Memantine > Placebo Wilcock 2008
SELECTIVE SEROTONIN REUPTAKE INHIBITORS Cochrane Review 5 studies comparing SSRIs to placebo 2 studies showing some benefit (sertraline, citalopram) No difference in rates of withdrawal between SSRIs and placebo Seitz 2011
MOOD STABILIZERS Carbamazepine (300-400mg) > Placebo More ataxia, disorientation, hallucinations Tariot 1998, Olin 2001 Divalproex/ Valproate (480-826mg) = Placebo Porsteinsson 2001, Sival 2002, Tariot 2001, Tariot 2005 Tariot 2001 trial (secondary mania) discontinued due to excessive dropouts in drug group compared to placebo
MOOD STABLILIZERS- SAFETY Mortality data Prophylaxis with VPA to prevent behavioral symptoms not effective VPA causes increased brain atrophy and hippocampal atrophy over 1 year of treatment Kales 2012, Fleisher 2011, Tariot 2011, Sandson 2006
Lebert 2004, Teri 2000, Sultzer 1997 TRAZODONE Trazodone > Placebo in 26 FTD patients Trazodone (200mg) = Placebo = Haloperidol (1.8mg) = Behavior Management Training 34% subjects improved (N =147) Trazodone = Haloperidol in dementia
PROPRANOLOL Propranolol augmentation (106 mg) > Placebo (Peskind 2005) gains lost at 6 months Aggression/ agitation Case series (Shankle 1995) Case reports (Pauszek 1991, Gadbaw 1989, Weiler 1988) Peskind 2005
PAIN MANAGEMENT 8 weeks of pain protocol management > usual care 352 NH patients with moderate to severe dementia and behavioral disturbance Tylenol, morphine, buprenorphine patch, pregabalin Husebo 2011
PRAZOSIN Prazosin > Placebo 22 subjects, 8 weeks 6 mg daily (2mg qam + 4 mg qpm) Starting dose of 1 mg, titrated up by 1-2 mg q 3-7 days Excluded SBP < 110 mm Hg, orthostatic Almost 50% dropout rate Post mortem studies of AD patients show aggressive behavior significantly correlated with alpha1 adrenoreceptor count Wang 2009, Sharp 2007
BENZODIAZEPINES No placebo controlled trials in BPSD Active comparator trials IM Olanzapine = IM Lorazepam > Placebo for acute agitation (Meehan 2002) Oxazepam = Haloperidol = Diphenhydramine (Coccaro 1990) Lorazepam = Alprazolam (Ancill 1991)
HORMONE THERAPY Transdermal estrogen 100 mcg/ d = Placebo 8 weeks, n = 27 Rebound increase in aggression on removal of patches Hall 2005
SUMMARY OF EVIDENCE Evidence for efficacy in the short term exists for: Antipsychotics Pain Management SSRIs Trazodone (FTD) Propranolol Prazosin Carbamazepine Cholinesterase Inhibitors (LBD) All drug treatments are off label, No FDA approved treatments
LIMITATIONS OF EVIDENCE Subtypes of dementia lumped together Behavioral symptoms lumped together What is placebo effect?
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