Lessons Learned: Agitation in Alzheimers Disease International - PowerPoint PPT Presentation

Lessons Learned: Agitation in Alzheimer’s Disease International Society for Clinical Trials in Medicine 9/2/17 Paris, France Paul B. Rosenberg, M.D. Associate Professor of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine

Disclosures • Research support – National Institute on Aging, Alzheimer’s Association, Lilly, Functional Neuromodulation (FNMI), Lilly, Abbvie • Consulting/advisory boards – Lundbeck, Abbvie, GLG, Leerink, Otsuka, Avanir, Astellas • Travel – Avanir, Otsuka • No stock, royalties, patents

Agenda Agitation in Alzheimer’s Disease (AD) • Nosology • Outcome measures • Current state of treatments • Recent trials results • Study design • Potential neurobiological mechanisms • Distinguishing improvement in agitation from improvement in cognition (“pseudospecificity”)

Nosology Agitation: core phenotype • Emotional agitation : distress, upheaval, anger, tension, anxiety, worry, inability to relax Too many adjectives! • Lability : rapid changes in mood, irritability, Need to reduce heterogeneity unexpected outbursts, overreacting, catastrophizing Similar issue to defining psychosis and major depression • Psychomotor agitation : pacing, rocking, restless, gesticulating, pointing fingers, • Verbal aggression : yelling, excessively loud voice, screaming, use of profanity, threats, "in your face" • Physical aggression : grabbing, shoving, pushing, resisting, hitting, kicking, getting in the way

Abridged criteria from International Psychogeriatric Association (2015) A. Cognitive impairment or dementia syndrome B. Patient exhibits at least one of the following behaviors which are associated with observed or inferred evidence of emotional distress sustained or persistent for a minimum of two weeks’ duration and represents a change Phenotypically recognizable from the person’s usual behavior. Reasonably homogenous – Excessive motor activity – Verbal aggression Excludes “minor” agitation – Physical aggression C. Disability greater than cognitive impairment alone – interpersonal relationships – other aspects of social functioning – ability to perform or participate in daily living activities D. not attributable solely to another psychiatric disorder , medical condition, or the physiological effects of a substance Cummings et al, International Psychogeriatrics 2015

NPI: widely used Outcome Measures for Agitation in AD informant report Domains not free-standing CMAI: agitation-specific very detailed description of agitation Broad spectrum Agitation-focused informant report • Neuropsychiatric subscales not widely used (verbal aggression, • Cohen-Mansfield Inventory (NPI) (12 physical aggression, etc.) Agitation Inventory domains) NPI-C: NPI “broadened and deepened” (CMAI) • Neuropsychiatric About twice as many questions • NPI Inventory-Clinician Clinician makes judgment based on informant Agitation/Aggression Version (NPI-C) (16 report and interview of patient domains) • NPI-C Agitation and Domains are free-standing Aggression (separate • Neuropbehavioral Splits up Agitation and Aggression Rating Scale (NBRS) domains) Most studies look at both Agitation and Aggression • Behave-AD and their sum Steinberg & Lyketsos APA Handbook of Psychiatric Measures, 2007

NPI-C (Clinician Rated) Improved NPI • Broad spectrum: NPI with clinician rating • Narrow spectrum: target specific areas • Improved range for early (MCI) and severe disease • Translated into: Spanish, French, Portuguese, Italian, Greek • High inter-rater reliability: ICC= 0.78-0.98 • Strong convergent validity for – Depression (CSDD), Psychosis (BPRS), Apathy (AES), Agitation (CMAI) de Medeiros et al, Int Psychogeriatrics, 2010

Current treatments Disappointing and/or risky • Non-pharmacologic: very few data – Custom Activity Program RCT at Hopkins • Pharmacologic: none approved in US – FDA-approved AD medications (cholinesterase inhibitors; memantine): weak benefit – Antipsychotics: widely used, efficacy dubious, black box warningfor mortality – Anticonvulsants: ineffective risky – Benzodiazepines: ineffective, risky – Antidepressants: many ineffective • Except new data on SSRIs (Kostas’ talk)

CitAD (N=186): Response rate citalopram 40% vs. placebo 26% Porsteinsson et al, JAMA 2014

Placebo response (28%) by week 3 Citalopram (40%) response 9+ weeks Weintraub et al, Am J Geriatric Psych 2015

CitAD: adverse events • Anorexia, diarrhea, fever more common on citalopram (p<0.05) • MMSE decline of 1pt on citalopram (P<0.05) • QTc prolongation on citalopram Porsteinsson et al, JAMA 2014

Conclusion: try s-citalopram (escitalopram, Lexapro) QTc prolongation associated with r- Clinical response associated with s- citalopram levels citalopram levels Response probability MMSE decline associated with r-citalopram levels J Clinical Pharmacology, in press

Escitalopram (S-CitAD) N=589 R01AG052510; PI: Lyketsos

5HT2 antagonists • Pure 5HT2 antagonists (no dopaminergic antagonism) • Pimavanserin=FDA approved for psychosis in Parkinson’s disease Cummings et al., 2014 • Well tolerated in PD with no measurable increase in EPS and only modest sedation • Promising results in 12-week Phase 2 AD agitation trial (U.K., N=181) – At six weeks Participants on PIM had 3.76 point decrease in NPI- NH Psychosis (from baseline of ~ 10) vs. 1.93 points on placebo (p=.045) – Results not statistically significant at 12 weeks though similar – No detriment in cognition • Pimavanserin (Acadia) and ITI-007 (Intracellular Therapeutics) in phase 3 trials for agitation in AD • Nelotanserin (inverse 5HT2 agonist, Axovant) not tested in agitation in AD

THC Rationale Prior studies • Case series (N=40) at McLean • Active ingredient of marijuana Hospital Woodward et al., 2013 • CB1 and CB2 cannabinoid – Dronabinol used for agitation in receptor agonist AD • CB1 = likely associated with – Mean dose ~ 7 mg daily anxiety – Notable reduction in Pittsburgh • CB2 = likely anti-inflammatory Agitation Scale and subdomains effect – AEs: sedation (N=7), delirium • THC = dronabinol, schedule III (N=4) FDA-approved for anorexia • RCT of THC in Netherlands Van den Elsen, 2015 • Being more widely used for – N=50, dose = 4.5 mg daily, behavioral symptoms in AD duration = 3 weeks • Surprisingly benign – Null effect – Probably underdosed

THC-AD Paul B. Rosenberg, M.D (Johns Hopkins) Brent Forester, M.D. (McLean/Harvard) Study experience to date: Krista Lanctot and Nathan Herrmann 7 patients randomized (Sunnybrook, Toronto, CA) No notable AEs 6-week crossover RCT of nabilone vs. High acuity placebo (target dose 2 mg) liberalizing prn lorazepam from .5 Cohen-Mansfield Agitation Inventory = 1 o outcome mg daily to .75 mg daily and allowing intramuscular as well as oral use Still, a hard study to do! One patient had difficulty swallowing overencapsulated medication 4 years to go

Prazosin Postsynaptic α 1 noradrenergic • • 8-week RCT of prazosin for receptors involved with PTSD agitation in 22 AD patients – Although efficacy in PTSD is • Mean dose 5.7 mg daily questionable • Mean NPI decreased from 49 to Prazosin is an α 1 antagonist • 30 on prazosin – FDA approved for – vs. 43 to 41 on placebo hypertension and BPH – Similar results for BPRS • Prazosin improves sleep and and CGI-C reduces nightmares in PTSD • Minimal AEs (including no Raskind et al., 2007 hypotension!) • Why not AD? which frequently • PEACE-AD = multi-site trial involves disrupted sleep and through ADCS (UCSD) (PIs probable circadian rhythm Murray Raskind and Elaine disturbances Peskind)

Study design issues • Duration • Adaptive trial designs – Accounts for sizable placebo – Most studies 12 weeks or less effect – CitAD: placebo response – Need to recruit larger N maxed out at 3 weeks while benefit continued to 9 weeks – For example, S-CitAD will use 3-week psychosocial – Suggests 9 weeks as minimum intervention run-in • Dementia care suppor t • Concomitant medications – Most patients and families get little support for dementia care – Acetylcholinesterase inhibitors and memantine mostly included in the community • only modest effect on agitation, – Psychosocial intervention at best (DIADS, ADMET, CiTAD, S- – Antidepressants and antipsychotics CiTAD) • varied inclusion/exclusion • Enhanced usual care – Trazodone usually allowed for sleep • Ethically important – Benzodiazepines controversial • High retention • We have been using lorazepam up to 0.5 mg daily as prn