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Agitation and Aggression in Dementia Anton P. Porsteinsson MD William B. and Sheila Konar Professor Department of Psychiatry University of Rochester School of Medicine & Dentistry

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Dr. Porsteinsson reports receipt of a grant to his institution from AstraZeneca, Avanir, Baxter, BMS, Eisai, Elan, Eli Lilly, Forum, Genentech/Roche, Janssen Alzheimer Initiative, Merck, Medivation, Pfizer, Toyama, the National Institutes of Health (NIH), the National Institute of Mental Health (NIMH), The National Institute on Aging (NIA), and the Department of Defense; paid consultancy for Elan, Janssen Alzheimer Initiative, Pfizer, and TransTech Pharma; membership on data safety and monitoring boards for Quintiles, Functional Neuromodulation, and the New York State Psychiatric Institute; participation on a speakers bureau for Forest; and development of educational presentations for CME Inc., PRI, and Albert Einstein University.

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The Common View of Dementia

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The Caregivers View of Dementia

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NPS are UNIVERSAL in dementia Cache County Steinberg et al, Int J Ger Psychiatry, 2008

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NPS arebadfor patients & caregivers 'Greater ADL impairment 1 'Worse quality of life 2 'Earlier institutionalization 3 'Major source of caregiver burden 4 '$10,000/year additional care costs 5 'Shorter time to severe dementia 6 'Accelerated mortality 6 1 Lyketsos et al, 1997; 2 Gonzales-Salvador et al, 1999; 3 Steele et al, 1990; 4 Lyketsos et al, 1999; 5 Murman et al, 2002; Peters et al, under review

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NPS severe dementia Cache County Rabins et al, Alzheimers and Dementia, 2012 Steinberg et al, Poster, AAIC 2012

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Provisional research diagnostic criteria for Agitation with cognitive impairment (IPA, 2014) A. Patient meets criteria for a cognitive impairment or dementia syndrome (e.g., Alzheimers dementia, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, other dementia, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment [MCI], or other cognitive disorder) B. Patient exhibits at least one of the following behaviors which are associated with observed or inferred evidence of emotional distress (e.g., rapid changes in mood, irritability, outbursts). The behavior has been sustained or persistent for a minimum of two weeks duration and represents a change from the persons usual behavior. Excessive motor activity (examples include: pacing, rocking, gesticulating, pointing fingers, restlessness, performing repetitious mannerisms) Verbal aggression (e.g., yelling, speaking in an excessively loud voice, using profanity, screaming, shouting) Physical aggression (e.g., grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things and destroying property) ' C. Behaviors are severe enough to produce excess disability which in the clinicians opinion is beyond that due to the cognitive impairment alone including at least one of the following: Significant impairment in interpersonal relationships Significant impairment in other aspects of social functioning Significant impairment in ability to perform or participate in daily living activities D. While co-morbid conditions may be present, the agitation is not attributable solely to another psychiatric disorder, medical condition, or the physiological effects of a substance Cummings et al, International Psychogeriatrics 2015

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Etiologic model for agitation: circuit disruption Agitation phenotype Affective -labile -anxious -irritable Executive -disorganized -disinhibited -overactive AD brain disease Regional effects Affective Circuitry Executive Circuitry Both +

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Hierarchical approach to NPS groups Affective disturbance Psychotic disturbance Dementia-Associated Affective Disorder, depressive Dementia-Associated Affective Disorder, agitated Sleep disturbance Apathetic syndrome Executive dysfunction

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Epidemiology of NPS -1- 'Prevalence: Up to 95% pts at some point during course of dementia 43-59% with MCI Lyketsos et al. Am J Psychiatry 2000; Lyketsos et al. JAMA 2002; Feldman et al. Neurology 2004; Aalten et al. Int J Geriatr Psychiatry 2005

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Epidemiology of NPS -2- 'Most common sxs in DEMENTIA Apathy (27-36%) Depression (24-32%) Agitation/aggression (24-30%) 'Most common sxs in MCI Depression (20%) Apathy (15%) Irritability (15%) Lyketsos et al. Am J Psychiatry 2000; Lyketsos et al. JAMA 2002

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NPS Characteristics Often see multiple sxs simultaneously (>40%) Often intermittent/fluctuating NPS that persist over time Approx 65% with sxs over 2 y Associated with dementia stage (mild, mod, severe) Longer: apathy, aberrant motor, agitation Shorter: hallucinations, euphoria, disinhibition Lyketsos et al. JAMA 2002; Aalten et al. Int J Geriatr Psychiatry 2005; Lyketsos et al. Int J Geriatr Psychiatry 2001; Tun et al. Am J Geriatr Psychiatry 2007

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Agitation 'Often stage-specific for AD 'Characterized by: Verbal/physical aggression Repetitive/hyperactive talk, vocalizations, behaviors Disinhibition or inappropriate talk or actions 'Higher risk of disability, distress, injury and nursing home placement Lyketsos et al., Am J Psychiatry 2000; Lyketsos et al., JAMA 2002; Phillips et al., JAGS 2003

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Evaluation of NPS -1- 'Routine surveillance 'ABCs (Antecedants Behavior Consequences) 'Behavioral/Environmental Modifications Define behaviors and symptoms Remove offending triggers Calm reassurance or distraction Address unmet needs, what could make one feel better? Positive reinforcement

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Evaluation of NPS -2- 'Establish/Revisit Medical Diagnoses 'Establish/Revisit Psychiatric Diagnoses 'Evaluate for offending or change in medications Anticholinergic Sedative/hypnotics Drug withdrawal? Drug interactions? 'Consider pain, sensory impairments 'Work-up Delirium

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NPS Rx options disappointing 'Non-pharmacologic promising but unproven, costly, hard to implement 'Many pharmacologic treatments have failed or raised serious safety concerns 'Drug classes assessed: Antipsychotics, SSRI antidepressants, anticonvulsants, benzodiazepines

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Antipsychotics for psychosis or agitation 'Meta-analysis of typical antipsychotics to treat psychosis and agitation 1 Modest effects, significant side effects 'Moderate dose haloperidol (1-2mg) for delusions and hallucinations reduces these symptoms by 60% 2 'Studies utilizing atypical antipsychotics suggest modest efficacy 3,4 Efficacy most evident with risperidone or aripiprazole 4 Higher risk of cerebrovascular incidents and mortality 1 Schneider LS et al. J Am Geriatr Soc. 1990;38:553-563. 2 Devanand DP et al. Am J Psychiatry. 1998;155:1512-1520. 3 Aarsland D, Ballard C. Clin Neurosci Res. 2004;3:397-412. 4 Schneider LS et al. Am J Ger Psychiatry. 2006 14:191-210

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The CATIE-AD Study

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Cerebrovascular Adverse Events: Updated Pooled Analyses of Dementia RCTs Sample Size CVAEsExposure RR (95% CI) (patient years) (D/P) (D/P) Risperidone 1009/712 33/8171.8/118.92.85 (1.297.15) Olanzapine 1175/478 15/2 336.7/134.22.99 (0.726.9) Aripiprazole 598/340 8/2 95.2/54.12.27 (0.4522.0) Quetiapine 355/213 3/4 54.7/32.70.50 (0.112.33) Ziprasidone no available clinical trials data in dementia patients Haloperidol1.27 (0.304.20) Adapted from Schneider L. AAGP; San Diego, CA; March 5, 2005 NB: 95% CI includes 1 for nearly all drugs studied !!

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Mortality in dementia RCTs: Pooled analyses Relative Risk 95% CI Olanzapine2.311.00-5.35 Risperidone1.350.85-2.14 Aripiprazole1.990.86-4.62 Quetiapine1.350.85-2.14 OVERALL1.651.19-2.29 Schneider L et al JAMA, 2005 Antipsychotics have BLACK BOX warning for use in dementia

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Divalproex or carbamazepine for agitation Tariot P 2001172 dementia nursing home and secondary mania Valproate 20- 30mg/kg/d BRMS CMAI CGI 6 weeksDVS=PBO Porsteinsson A 2001 56 nursing home dementia & agitation Valproate individualized vs. PBO BPRS-agitation6 weeksDVS>PBO ? Sival RC 200242 dementia hospitalized ValproateSADS-9 target aggression 3 weeksDVS=PBO Tariot P 2005153 nursing home pAD with agitation Valproate target 750/d vs. placebo BPRS CMAI 6 weeksDVS=PBO Hermann N 200714 ADMMSE below 10 ValproateNPI CMAI 6 weeksDVSPBO Cooney C 19966 AD outpatientsCarbamazepine up to 600mg/d vs. PBO RAGE- aggression 8 weeksCRB>PBO Tariot PN 199851 nursing home dementia Carbamazepine vs. PBO BPRS CGIC 6 weeksCRB>PBO Olin JT 200121 AD failed antipsychotics CarbamazepineCGIC BPRS 6 weeksCRB>PBO

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Antidepressants for agitation ( placebo controlled ) Lawlor BA 199410 AD with agitation Trazodone vs. Buspirone vs. PBO BPRS DMAS 12 weeksTRA>PBO Auchus AP 199715 AD outpatients Fluoxetine vs. Haloperidol vs. PBO Agitation4 weeksFLU=PBO Teri L 2001149 AD agitation Haloperidol vs. trazodone, vs. behavior mgmt vs. PBO ADCS-CGIC16 weeksTRA=PBO Lanctot K 200222 non- depressed AD w/ behavioral disturbance Sertraline 100mg/d vs. PBO NPI4 weeksSER=PBO Pollock BG 200285 hospital dementia Citalopram vs. perphenezine vs. PBO NBRS17 daysCIT>PBO Finkel SI 200424 pAD outpatients Sertraline (24) vs. PBO (120) after open donepezil NPI CGI-I 8 weeks then 12 weeks SER=PBO

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Antidepressants for agitation (active comparator) Sultzer DL 199728 dementiaTrazodone vs. haloperidol Agitation9 weeksTRA=HAL Gaber S 200123 nursing home dementia and agitation Sertraline vs. haloperidol CMAI10 weeksSER=HAL Pollock B 2007103 hospitalized, moderate+ NPS Citalopram vs. risperidone Neurobehavior Rating Scale (NBRS) 12 weeksCIT=RIS in efficacy but CIT>RIS in tolerability

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CITAD: a multi-center trial 1 ' Study Chair Johns Hopkins University (Lyketsos) ' Coordinating Center Johns Hopkins Center for Clinical Trials (Meinert) ' Clinical Centers Columbia University (Devanand) Johns Hopkins University (Rosenberg) Medical University of South Carolina (Mintzer) Stanford University (Yesavage) University of Pennsylvania/VA (Weintraub) University of Rochester (Porsteinsson) University of Southern California (Schneider) University of Toronto (Pollock) 1 R01AG031348

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Agitation & Aggression as Clinical Entity targeted for treatment development 'A reasonably homogeneous patient group: Clinical diagnosis of AD per accepted NIA-AA criteria Focus on Moderate/Severe to increase homogeneity in underlying biology 'Clinically significant agitation/aggression (operationalized): Accepted and widely used NPI criteria for significant severity: NPI- agitation/aggression domain 4 'Relevance to clinical/academic community: Antipsychotics widely used despite black box safety warnings Alzheimer Association - NPS expert roundtable (2010) emphasized the importance of NPS in AD and need for safe and effective treatments Same experts endorsed utility of NPI-C for clinical trials Formation of NPS-PIA as part of ISTAART 27

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Support This work was supported by: 'NIA and NIMH R01AG031348 and in part by NIH P50 AG05142 'William B. and Sheila Konar Endowed Professorship

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CitAD Study Importance 'Agitation is common, persistent and associated with adverse consequences for patients with AD. 'Pharmacological treatment options are not satisfactory 'CitAD study evaluated the efficacy and safety of citalopram for agitation in patients with AD without depression.

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CitAD Study - Design 'Randomized, placebo-controlled, double- blind, parallel group 9 week trial 'All participants received psychosocial intervention 'Participants assigned to citalopram (target dose of 30 mg/d) or placebo in 1:1 ratio 'Primary objective was evaluating efficacy of citalopram for agitation in patients with AD 'Secondary objectives examined effects on function, caregiver distress, safety, cognitive safety, and tolerability

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CitAD Study outcome measures 'Primary NBRS-A and mADCS-CGIC 'Secondary NPI total; NPI individual domains; NPI-CD; CMAI; ADCS-ADL; cumulative lorazepam rescue dose 'Secondary safety MMSE; GUG; AEs assessed through checklist and open ended questions; ECG added.

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CitAD Study results 'N = 186 (cit=94 and pla=92) 'Age = 78 'Women = 46% 'Caucasian = 65% 'Community dwelling 89% 'AchEI use in 69%, memantine use in 42% 'MMSE = 15.7 (cit=17.0 and pla=14.4) 'NPI total 37.3 'At week 9, 78% on 30 mg/d and 15% on 20 mg/d 'No between-group difference in adherence (80% remained on treatment) and >90% completion rates

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CitAD Study results 'Citalopram showed significant improvement over placebo on both primary outcome measures (NBRS-A and mADCS-CGIC) and on the secondary outcome measures of CMAI, NPI total, NPI-CD but not on NPI-A, ADCS- ADL or rescue lorazepam 'Anorexia, diarrhea, URTI, fever and falls were more common with citalopram while weight loss and insomnia were more common on placebo. Worsening of cognition was seen it cit group.

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Citalopram FDA warning 'Dose dependent risk of QT prolongation 'Due to post-marketing reports and unpublished FDA study '119 healthy, non-depressed 1945 year olds 'QTc prolongation: 8.5 msec for 20 mg/d 18.5 msec for 60 mg/d 'Recc daily maximum dose of 40 mg/d in adults and 20 mg/d in >60 y.o. 'Avoid use in congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent MI or uncompensated CHF

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CitAD Study - Design 'Subjects were recruited from 09/2009 01/2013 'FDA safety communication regarding citalopram and QTc prolongation in 08/2011 'Dose maintained at 30 mg/d 'Modifications made to entry criteria 'ECGs were added to required study procedures 'Magnesium added to existing electrolyte monitoring 'Patients with prolonged QTc excluded >450 msec for men >470 msec for women

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CitAD Study ECG 'Initiated after 138 patients were randomized 'ECG at screening, wk 3 and first visit at 30 mg/d if on slow titration 'Available for 48 patients (cit=24; pla=24) 'No difference in cardiovascular burden between the two groups. 'BL QTc cit 419 msec; pla 416 msec

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CitAD study - ECG 'Of 24 subjects assigned to citalopram at week 3: 16 on 30 mg/d 3 on 20 mg 2 on 10 mg 1 on 0 mg 2 missed the week 3 visit

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QTc changes BL-wk3

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CitAD QT findings

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Summary 'Mean QTc at enrollment was similar to other studies of older adults 'Compared to placebo, citalopram was associated with 18.1 msec lengthening of QTc 'This increase is higher than anticipated based on the FDA safety communication 'The increase was close to FDA guidance of proarrythmic properties (20 msec) 'Our findings support the FDA warning against use of citalopram >20 mg in patients over 60 years of age

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CitAD study clinical AE 'At week 3, one patient on citalopram developed ventricular bigeminy alongside a 48 msec lengthening of QTc (444 msec to 492 msec) and study drug was discontinued. He was taking one other medication known to prolong QT (alfuzosin) 'For the full study, no cardiovascular related deaths. 'For the full study, two cit subjects had syncope and one pla subject fell and broke her hip.

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DM/Q Sequential Parallel Comparison Design

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DM/Q Safety and Tolerability

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DM/Q

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Scyllo-inositol