Aging Really Matters New Directions in Understanding Late Life Neuropsychiatric Disorders

Transcription

1 Aging Really Matters New Directions in Understanding Late Life Neuropsychiatric Disorders Constantine G. Lyketsos, MD, MHS Chair of Psychiatry, Johns Hopkins Bayview Elizabeth Plank Althouse Professor, Johns Hopkins University 55 th Annual ACP Meeting Geriatric Research Award Lecture Tampa, 24 February 2018 Disclosures (since 1993) Grant support (research or CME) NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo-Smith-Kline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, National Football League, Elan, Functional Neuromodulation Consultant/Advisor Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, Orion, Otsuka, Astellas, Merck Honorarium or travel support Pfizer, Forest, Glaxo-Smith Kline, Health Monitor 1

2 Acknowledgements: epidemiology Johns Hopkins Peter Rabins, MD Paul Rosenberg, MD Laura Gitlin, PhD Hochang Lee, MD Martin Steinberg, MD Adam Rosenblatt, MD Vani Rao, MD Chiadi Onyike, MD Brian Appleby, MD Peter Zandi, PhD Kate de Medeiros, PhD Quincy Samus, PhD Matthew Peters, MD Collaborators John Breitner, MD Joann Tschanz, PhD Helen Kales, MD Kathy Welsh-Bohmer, PhD Fernando Taragano, MD Serge Gauthier, MD Acknowledgements: clinical trials Johns Hopkins Chairman s Office Constantine Lyketsos, MD Peter Rabins, MD Cynthia Munro, PhD Jeannie Leoutsakos Constantine Frangakis, PhD Dimitri Avramopoulos, PhD Coordinating Center Dave Shade, JD Lea Drye, PhD Curt Meinert, PhD Susan Tonascia, ScM Ann Casper, MA Vijay Vadiya, MSc/MPH Johns Hopkins Site Paul Rosenberg, MD Chris Marano, MD U Southern Caifornia Lon Schneider, MD Karen Dagerman, PhD U Toronto Bruce Pollock, MD Zahinoor Ismail, MD Med U South Carolina Jacob Mintzer, MD Columbia U Dev Devanand, MD Gregory Pelton, MD U Rochester Anton Porsteinsson, MD U Pennsylvania Dan Weintraub, MD Stanford U Jerry Yesavage, MD Wes Ashford, MD 2

3 Funding Sources: Thank you! NIA R01AG NIA R01 AG NIA P50 AG NIMH R01 MH60626 NIA R01 AG21136 NIA R01 AG11380 NIMH U01 MH Nosology is ultimately about effective treatment The existing nosology is failing us in later life Our treatments are poorly effective We need new nosology for more efficient & effective treatment development 3

4 Talk overview Case examples Brain changes with age Epidemiology of late life neuropsychiatric disorders (NPD) Focus on NPD in Alzheimer s disease Implications for prevention of dementia A common presentation 72 year old, retired nurse with anxiety, irritability, worry, loss of interest, & social withdrawal of 2-3 years duration. Referred to a psychiatrist who diagnosed major depression and initiated treatment with CBT & sertraline. Later added venlafaxine and buproprion leading to remission. Subsequently began complaining of memory loss and getting lost while driving. Cognitive testing indicated amnestic MCI. Workup revealed POSITIVE Florbetapir (amyloid) PET scan 4

5 Another common presentation 81 year old man diagnosed with AD 3 years ago. Last few months is casily and constantly frustrated with minor matters and takes it out on family. Very agitated when requests made. For example, when hearing its time to eat, he says I will eat when I want, gets up and joins at the table while screaming and yelling. At Thanksgiving he started accusing his daughter of taking his money and not buying her children Christmas gifts. When brother tried to reassure him he raised his fists and threaten to throw him out on the street. What is the common theme? Neuropsychiatric disorders with onset in later life WHEN: (1) The brain is aging (2) Pathological brain changes are common 5

6 Challenges of DSM-5 phenotypes Developed for younger ages: ignore the aging brain Challenged by organic causes of later life New onset late life phenotypes atypical for DSM Brain disease specific phenotypes do no fit DSM DSM-phenotype related Rxs not successful Usual Brain Aging regional atrophy, loss of connectivity Reduced gray volume, mostly frontal & mesial temporal Modest hippocampal volume loss Reduced gray matter thickness, mostly frontal Reduced axonal thickness overall Reduced white matter volume pre-frontal, frontal, and inferior parietal Loss of white matter integrity, mostly frontal & temporal Mild, mostly scattered, white matter hyper-intensities Lockhart and DeCarli

7 Pathological age-related brain changes Vascular disease Large & small infarcts Microhemorrhages Proteinopathies Amyloid Tau Alpha-synuclein TDP-43 Lockhart and DeCarli 2014 HALF of older adults exhibit NPD ~50% fit conventional DSM-5 criteria Persistence/recurrence of early onset disorders ~50% new onset cognitive, mood disorders 2 nd peak of depressive d/o incidence ~55yo New depressive d/o phenotypes 40-60% of all involve cognitive decline Olivera et al 2008; Reynolds et al 2015; Gallo et al 1997; Lyketsos

8 New phenotypes in later life Depression without sadness; Depression of Alzheimer disease Another way to approach late life disorders with an eye toward treatment Combine a top down with a bottom up approach Begin with Alzheimer disease: focus on neuropsychiatric syndromes (NPS) 8

9 August D: hospitalized for delusions and change in personality, not cognitive impairment NPS are UNIVERSAL (97%) & fluctuate Cache County Dementia Progression Study Steinberg et al, Int J Geriatr Psychiatry 2008 Tschanz et al, Am J Geriatr Psychiatry

10 NPS are bad for patients & caregivers Greater ADL impairment 1 Worse quality of life 2 Earlier institutionalization 3 Major source of burden 4 Higher costs 5 Faster 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; 6 Peters et al, 2015 How have we tried to develop Rx for NPS? Based on phenomenology (top down) Apply DSM-like phenotypes 10

11 Outcomes are disappointing few meds have efficacy many have significant risks FDA approved AD meds (cholinesterase inhibitors; memantine): ineffective Anticonvulsants: ineffective, risky Benzodiazepines: ineffective, risky Antipsychotics: small benefit, black box warning Antidepressants: ineffective Antipsychotics for psychosis: small benefit Condition-specific risks: BLACK BOX warning AHRQ Comparative Effectiveness Review 2011 Aripiprazole Olanzapine Quetiapine Risperidone Effect Size (SMD) =

12 Antidepressants for depression: no benefit How should we develop Rx for NPS? COMBINE Disease specific phenotypes (top down) Based on cause (bottom up) 12

13 NPS groupings by phenomenology proposed by the ISTAART NPS-PIA Novel Agitation (IPA, 2014) Apathy (Robert, 2010) Sleep disorder (pending) DSM Legacy Psychosis (Jeste, 2000) Depression (Olin, 2003) Etiologies of NPS Direct Indirect British Medical Journal 2015; NIMH/NIA Panel May

14 Three (overlapping) neurobiological models proposed by the ISTAART NPS-PIA 1. Fronto-subcortical circuit disruption 2. Cortico-cortical circuit disruption 3. Monoamine regulatory imbalance Agitation circuit Apathy circuit 14

15 Monoamine regulatory imbalance serotonergic agents for Agitation in AD 15

16 Big benefit: 26% placebo vs. 40% citalopram R01AG031348; PI: Lyketsos Benefit to psychotic symptoms Table 2 Neuropsychiatric Inventory (NPI) domains at week 9 All participants* Participants reporting symptom** Citalopram Placebo Citalopram Placebo n (%) n (%) OR* (95% CI) p-value Median (IQR)** Median (IQR)** p-value Number with week 9 NPI data Individual domains Delusions 22 (26 %) 35 (42 %) 0.40 (0.18, 0.91) (2, 8) 4 (3, 8) 0.46 Hallucinations 11 (13 %) 13 (16 %) 1.53 (0.50, 4.71) (1, 3) 6 (4, 6) <0.01 Agitation/aggression 66 (77 %) 70 (84 %) 0.63 (0.28, 1.41) (2, 8) 6 (3, 8) 0.05 Depression/dysphoria 24 (28 %) 30 (36 %) 0.69 (0.34, 1.39) (1, 6) 3 (2, 6) 0.35 Anxiety 36 (42 %) 54 (65 %) 0.43 (0.22, 0.84) (2.5, 8) 4 (3, 6) 0.78 Elation/euphoria 3 (3 %) 5 (6 %) 0.45 (0.09, 2.21) (1, 8) 3 (2, 6) 0.55 Apathy/indifference 41 (48 %) 42 (51 %) 0.92 (0.47, 1.80) (3, 8) 6 (4, 8) 0.36 Disinhibition 27 (31 %) 34 (41 %) 0.71 (0.35, 1.46) (2, 8) 4 (2, 6) 0.73 Irritability/lability 49 (57 %) 61 (73 %) 0.38 (0.19, 0.76) (2, 6) 6 (3, 8) 0.13 Aberrant motor behavior 34 (40 %) 47 (57 %) 0.49 (0.24, 0.99) (3, 8) 4 (3, 8) 0.96 Sleep and nighttime behavior 21 (24 %) 30 (36 %) 0.56 (0.27, 1.16) (3, 12) 3 (2, 6) 0.03 Appetite and eating disorders 22 (26 %) 18 (22 %) 1.32 (0.62, 2.82) (4, 8) 4 (3, 8) 0.84 Summary scores Non-mood score 78 (91%) 79 (95%) 0.48 (0.10, 2.00) (5, 17) 14 (8, 24) <0.01 Affective score 72 (84%) 78 (94%) 0.33 (0.11, 1.03) (4, 14.5) 12 (6, 20) 0.04 Psychotic score 28 (33%) 37 (45%) 0.67 (0.31, 1.44) (2, 6) 6 (4, 9) 0.02 Leonpacher et al, Am J Psychiatry

17 Response limited to a subgroup Schneider et al, Am J Psychiatry 2016 Response depends on Agitation phenotype Affective vs. Dysexecutive Charu et al, Int J Biostat

18 Linking Top Down to Bottom up etiologic model for agitation Agitation phenotype Affective -labile -anxious -irritable Executive -disorganized -disinhibited -overactive Affective Circuitry Serotonergic regulation Executive Circuitry AD brain disease Circuit disruption What s next? S-CitAD (1) test the Affective Agitation hypothesis (2) reduce heterogeneity by identifying subgroups N=589 R01AG052510; PI: Lyketsos 18

19 Novel medications for agitation in study or under development Citalopram and S-citalopram Brexpiprazole D -dextromethorphan Dronabinol Prazosin Several other compounds being considered But wait! Alzheimer s begins in the brain decades before cognitive symptoms MCI is a cognitive syndrome that seems to precede dementia Could there be an NPS syndrome that might afford a different prevention opportunity? 19

20 NPS in MCI: faster conversion to dementia NPS in cognitive normals faster conversion to MCI N=1587 NPS higher risk of MCI Agitation HR=3.06 Anxiety HR= 1.87 Irritability HR=1.84 Depression HR=

21 Mild Behavioral Impairment (MBI) greater risk of dementia than MCI alone Type of dementia matters: MCI alone (n=154) 28 (18%) dementia: 27 AD MCI with NPS (n=85) 54 (63%): 37 AD and 15 FTD MBI with abnormal cognition (n=59) 41 (69%): 25 AD and 12 FTD MBI normal cognition (n=60) 44 (73%): 41 FTD and 3 AD 358 patients at CEMIC Buenos Aires, Argentina Referred to the memory clinic (collaborative) Followed for five years Taragano et al, J Clinical Psychiatry,

22 The theory about Mild Behavioral Impairment Usual Aging MCI MBI Dementia Cognitive & behavioral disorders: PARALLEL manifestations of Alzheimer s SMC MCI Dementia Amyloid Tau Neurons impaired Neuron & system loss Behavior change MBI NPS 22

23 Dementia prevention with an SSRI in persons with MBI? Nosology is ultimately about effective treatment A new nosology is emerging accounting for the aging brain and brain diseases of later life Study of NPS and MBI portend novel therapies Dementia prevention might be possible by targeting and treating MBI 23

24 Thank you! Eucaristw! 24