Alternatives to Antipsychotics for the Treatment of Dementia-Related Behavioral Symptoms Lori A. Daiello Pharm.D, ScM

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 Antipsychotics Alternatives of BPSD 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 1 Schneider LS et al. NEJM 2006;355:1525-1538. 2 Sultzer 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 agents 1 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+ years 1 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 where other psychotropic medications are unsafe, e.g. hepatic failure (lorazepam, oxazepam), severe Parkinson s disease, Dementia with Lewy bodies, status post myocardial infarction, severe cardiac arrhythmias, alcohol or benzodiazepine withdrawal 2 1 Tampi RR, et al. Am J Alzheimers Dis Other Demen. 2014 Mar 6.(epub). 2 Stonnington CM, et al. J Clin Psychiatry 2009;70:1379-84.

Antidepressants for BPSD Agitation, Irritability, Anxiety RCTs: 20 trials of serotonergic agents (SSRIs citalopram, sertraline, paroxetine) and trazodone. 1 Advantages: SSRIs -little sedative effect, cognition neutral? High Risk: Drug interactions with CYP450 inhibitors, serotonin syndrome (multiple serotonergic drugs) Adverse effects: (SSRIs) GI adverse effects, activation, falls?, d bleeding risk? (trazodone) Sedation and hypotension, SIADH, (citalopram) QTc prolongation? Notes: Withdrawal syndrome with some SSRIs and SNRIs; SSRIs are treatment of choice for frontotemporal dementia (FTD) behavioral symptoms? 2 1 Henry G, et al. Am J Alzheimers Dis Other Demen. 201;26:169-83. 2 Nardell M et al. Am J Alzheimers Dis Other Demen. 2014;29:123-32

Antidepressant Treatment of BPSD Citalopram vs Perphenazine or Placebo (Pollock et al 2002) 1 Citalopram vs. Perphenazine vs Placebo x 17 days Results Citalopram - more effective than placebo on total Neurobehavioral Rating Scale (NBRS) (p=0.002) & improvement from baseline in agitation/aggression, psychosis, lability/tension, cognition, and retardation Perphenazine No more effective than placebo on NBRS; improvement from baseline in agitation/aggression, psychosis, lability/tension Citalopram vs. Risperidone (Pollock et al 2007) 2 Citalopram (20-40mg/d) vs. Risperidone (1-2mg/d) x 12 weeks Results Citalopram more effective and better tolerated than risperidone No difference in efficacy of citalopram and risperidone for psychotic symptoms Citalopram vs. Placebo (Porsteinsson et al 2014) 3 Psychosocial intervention + citalopram (titrated to 30mg/d) or placebo x 12 weeks Results Citalopram > placebo for agitation and overall behavioral symptoms on the NPI Greater QTc prolongation and cognitive decline with citalopram 1 Pollock BG et al. Am J Psychiatry 2002:460-465. 2 Pollock BG, et al. Am J Geriatr Psychiatry 2007;50:942-952. 3 Porsteinsson et al. JAMA 2014;311:682-691.

Mood Stabilizers for BPSD Controlled Trials: carbamazepine (CBZ), valproate (VPA), oxcarbazepine Advantages:? Agitation, Aggressive Behavior High Risk: Adverse effect burden outweighs potential for benefits in AD? Drug interactions (CBZ) Adverse effects: (All) sedation, cognitive impairment, falls, idiosyncratic toxicities. GI adverse effects, thrombocytopenia (VPA). Hyponatremia (CBZ) DBPC trial (VPA) in mild-moderate AD; no effect on emergence of agitation/psychosis, but VPA associated with sedation, gait disturbance, tremor, and greater loss of hippocampus and whole brain volumes (p<0.001) compared to placebo 1 Notes: Gait and cognitive ADE may occur within effective dose range. Routine monitoring of serum levels usually unnecessary. 1 Fleisher A, et al. Neurology 2011;77:1263-1271.

Anti-Dementia Medications for BPSD Agitation, Restlessness, Anxiety/Depressive Sx, Psychosis? Advantages: May also benefit cognition and/or function in some patients with AD. First-line treatment in DLB. High Risk: (CHEI) May worsen BPSD in behavioral variant FTD and precipitate mania in BPAD Adverse effects: (CHEI) GI adverse effects - nausea, vomiting, diarrhea, anorexia, weight loss, dizziness, leg cramps, urinary incontinence, bradycardia. Drug interactions with anticholinergics. (Memantine) dizziness, agitation, confusion, headache, constipation. Potential drug interactions with other NMDA receptor antagonists (amantadine, dextromethorphan) Notes: Delay emergence of behavioral symptoms? Behavioral effects may occur in the absence of cognitive benefits Gauthier S, et al. Int Psychogeriatr 2010;22:346-372. Kerchner G, et al. Expert Rev Neurother 2011;11:709-17. Bentué-Ferrer D, et al. CNS Drugs. 2003;17:947-963

Behavioral Effects of CHEI in Lewy Body Dementia 12-week DBPC Trial of Donepezil (N=140) Mori E, et al. Ann Neurol 2012;72:41-52.

CHEI vs Atypical Antipsychotics in Moderate-Severe Dementia with BPSD Ballard C, et al. BMJ 2005 26-wk DBPC trial of Rivastigmine ( 9mg) vs Quetiapine (100mg) vs Placebo; (N=93) Quetiapine associated with > cognitive decline than placebo Neither quetiapine nor rivastigmine more effective than placebo for agitated behavior Holmes C, et al. Int J Geriatr Psychiatry 2007 6 wk DB trial of Rivastigmine (6mg) vs Risperidone (1mg); (N=28) Risperidone more effective than rivastigmine for agitated behavior

Memantine for BPSD Associated with d emergence of BPSD: agitation/aggression (p=0.002), irritability/lability (p=0.004), & night-time behavior (p=0.05) in post hoc analysis of pooled clinical trial data 1 Most robust effects on behavioral symptoms in combination with CHEI in moderate-severe AD 2 Comparison Groups 2 Behavioral Symptoms Between Group Mean Difference NPI Total Score 99% Confidence Interval p Active Memantine vs. Placebo Memantine Continue Donepezil vs. Placebo Donepezil Donepezil + Active Memantine vs. Donepezil + Placebo Memantine - 4.0-0.6 to - 7.4 0.002-2.3-1.1 to -5.7 0.08-5.1-0.3 to 9.8 0.006 1 Gauthier S, et al. Int J Geriatr Psychiatry 2008;23: 537 545. 2 Howard R, et al. NEJM 2012;366:893-903.

Dextromethorphan/Quinidine (DM/Q) for BPSD First approved treatment for pseudobulbar affect No evidence for effectiveness in BPSD Rapid improvement of agitated behavior in a middleage patient with acute exacerbation of cerebellum cognitive affective syndrome (N=1) Safety Adverse effects - dizziness, diarrhea, falls, headache, nausea, fatigue, constipation, and dysphagia CYP450 2D6 inhibitors increase levels of DM and Q No interaction with memantine in middle-aged adults Schoedel KA et al. Clin Drug Investig. 2012;32(3):157-69.

Prazosin for BPSD in Moderate-Severe AD Up-regulation of post-synaptic alpha-1 receptors associated with aggressive behavior in post-mortem AD studies 1 Prazosin is a well-tolerated alpha-1 antagonist used in the treatment of HTN and BPH DBPC pilot study of 22 patients with probable or possible AD 2 Compared to placebo, prazosin (mean dose 5.6mg/d) was associated with robust reductions in agitation and aggression on the NPI and BPRS after 8 weeks of treatment Low dose prazosin was well tolerated 1 Sharp SI, et al. Am J Geriatr Psychiatry. 2007;15:435-7. 2 Wang LY, et al. Am J Geriatr Psychiatry 2009;17:744-751.

Yokukansan/Yi-Gan San for BPSD Hallucinations, Delusions, Agitation and Aggression Traditional Asian medicine (Kampo); combination of 7 herbs 1 Antagonist at 5-HT 2A receptors, modulator of excitotoxicity? Four RDBPC trials in AD with BPSD; open label studies FTD, dementia with Lewy bodies, Parkinson s disease, TBI 2013 study - yokukansan, fluvoxamine and risperidone were efficacious for BPSD Yokukansan demonstrated excellent safety and tolerability 2 Serious adverse events are uncommon; monitor for hypokalemia, hypertension (Glycyrrhizae constituent) 1 Matsuda, Y et al. Hum Psychopharmacol 2013;28:80-6.: 2 Teranishi et al. J Clin Psychopharmacol 2013;33:600-7..

Rule Out Pharmacologic Triggers Anticholinergic medications (Delirium) Pharmacologic disinhibition Benzodiazepines O'Sullivan GH, et al. Br J Psychiatry 1994 Jul;165(2):79-86. Rothschild AJ. J Clin Psychiatry 1992;53:69-79. Fava M, Borofsky GF. Int J Psychiatry Med 1991; 21:99-104. Kalachnik JE, et al. J Autism Dev Disord. 2003;33(3):349-54. Testosterone Orengo C, et al. J Neuropsychiatry Clin Neurosci 2002;14(2):161-6. Orengo C, et al. J Nerv Ment Dis. 1997 May;185(5):349-51. Dopaminergic Agents Uitti RJ, et al.clin Neuropharmacol 1989 Oct;12(5):375-83. Cummings JL. JAGS 1991;39:708-716.

Off-Label Prescribing and BPSD

Risk Management for Off-Label Prescribing 1 Be aware of research literature and guidelines that may support the indication Document the reason why off-label use is indicated Could non-pharmacologic management suffice? Document ineffective medication trials Document risks and benefits Monitor for adverse events Consider obtaining a second opinion Obtain informed consent from the patient or proxy 1 Adapted from Recupero PR, et al. J Psychiatr Pract. 2007;13(3):143-152.

Maine Regulations Governing the Licensing and Functioning of SNFs and Nursing Facilities Chapter 11: Physical and chemical restraints Physical examination to rule out physical cause Gradual dose reduction for antipsychotics, unless clinically contraindicated Documentation of less restrictive measures to treat or manage behavioral symptoms Resident, family or legal guardian is made aware of potential side effects and agrees with treatment www.maine.gov/sos/cec/rules/10/ch110.htm Accessed 4/14/14.

Maine Regulations Governing the Licensing and Functioning of SNFs and Nursing Facilities Psychoactive drugs may not be used: In quantities that interfere with level of alertness and ability to participate in rehabilitation programs; or On an as needed basis exceeding five (5) times in a seven (7) day period; Use of chemical restraints will be part of the care plan, which will address the medical reason for which the medication is used, with a succession of approaches and interventions to be utilized prior to the administration of chemical restraints. Close monitoring at regular intervals, determined by the physician and multidisciplinary team, of all residents receiving psychoactive drugs. www.maine.gov/sos/cec/rules/10/ch110.htm Accessed 4/14/14.

The New War on Drugs

. [CMS] is considering reviving the specific citation for antipsychotic use to encourage more scrutiny, but is concerned that homes will instead use other sedating drugs that can also be harmful. One of the things we want to do is to make sure that surveyors are looking out for a prescribing shift. Did a person get taken off of an antipsychotic and simply put on an antidepressant or antianxiety agent instead? Alice Bonner PhD, RN CMS Director, Division of Nursing Homes Lazar K, Carrol M. A rampant prescription, hidden peril"; The Boston Globe, 4/29/12.

Pharmacologic Management of BPSD Expert Panel Recommendations 2014 Psychotropic drugs should be used only after behavioral and environmental modifications, and medical interventions Three exceptions Major depression with or without suicidal ideation Psychosis causing harm or with great potential of harm Aggression causing risk to self or others Close follow-up to monitor for adverse effects of psychotropic medications is necessary Use should be time-limited, because behaviors and symptoms may resolve over time with or without drug treatment. Kales HC, et al. J Am Geriatr Soc 2014; March 17 (epub)

Summary Eliminate potential pharmacologic triggers Adequate trial of cholinesterase inhibitor and/or memantine in AD or DLB Trial of serotonergic antidepressant for agitated or aggressive behavior with mood component Role of mood stabilizer anticonvulsants is not well defined; use of CBZ or VPA not recommended for patients with behavioral symptoms related to AD

Resources American Health Care Association website: www.ahcancal.org/quality_improvement/qualityinitiative/pages/resourcesbygoal.aspx#4 Dementia Beyond Drugs (book) www.healthpropress.com/store/power-29562/ Improving Antipsychotic Appropriateness in Dementia Patients (IA-ADAPT) www.healthcare.uiowa.edu/igec/iaadapt Quality of Life Outcomes for People with Alzheimer s Disease and Related Dementia www.healthcare.uiowa.edu/igec/iaadapt/