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55th Annual ACP Meeting

Geriatric Research Award Lecture

Tampa, 24 February 2018

Constantine G. Lyketsos, MD, MHS

Chair of Psychiatry, Johns Hopkins Bayview

Elizabeth Plank Althouse Professor, Johns Hopkins University

kostas@jhmi.edu

Aging Really Matters New Directions in Understanding Late

Life Neuropsychiatric Disorders

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

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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

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Funding Sources: Thank you!

• NIA R01AG052510

• NIA R01 AG031348

• NIA P50 AG005146

• NIMH R01 MH60626

• NIA R01 AG21136

• NIA R01 AG11380

• NIMH U01 MH066136

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

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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

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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

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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 Agingregional 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 2014

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Pathological age-related brain changes

Vascular disease

• Large & small

infarcts

• Microhemorrhages

Lockhart and DeCarli 2014

Proteinopathies

• Amyloid

• Tau

• Alpha-synuclein

• TDP-43

HALF of older adults exhibit NPD

• ~50% fit conventional DSM-5 criteria

– Persistence/recurrence of early onset disorders

• ~50% new onset cognitive, mood disorders

– 2nd 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 2007

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“New” phenotypes in later lifeDepression 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)

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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 2012

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NPS are “bad” for patients & caregivers

• Greater ADL impairment1

• Worse quality of life2

• Earlier institutionalization3

• Major source of burden4

• Higher costs5

• Faster to severe dementia6

• Accelerated mortality6

1Lyketsos et al, 1997; 2Gonzales-Salvador et al, 1999; 3Steele et al, 1990;

4Lyketsos et al, 1999; 5 Murman et al, 2002; 6 Peters et al, 2015

• Based on phenomenology (top down)

– Apply DSM-like phenotypes

How have we tried to develop Rx for NPS?

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Outcomes are disappointingfew 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

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Antipsychotics for psychosis: small benefit

Condition-specific risks: BLACK BOX warning

Aripiprazole

Olanzapine

Quetiapine

Risperidone

Effect Size

(SMD) = 0.20

AHRQ Comparative Effectiveness Review 2011

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Antidepressants for depression: no benefit

How should we develop Rx for NPS?

COMBINE

• Disease specific phenotypes (top down)

• Based on cause (bottom up)

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NPS groupings by phenomenologyproposed by the ISTAART NPS-PIA

Novel

• Agitation (IPA, 2014)

• Apathy (Robert, 2010)

• Sleep disorder (pending)

DSM Legacy

• Psychosis (Jeste, 2000)

• Depression (Olin, 2003)

British Medical Journal 2015; NIMH/NIA Panel May 2017

Etiologies of NPS

Direct

Indirect

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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

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Monoamine regulatory imbalance

serotonergic agents for “Agitation in AD”

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R01AG031348; PI: Lyketsos

Big benefit: 26% placebo vs. 40% citalopram

Benefit to “psychotic” symptomsTable 2 Neuropsychiatric Inventory (NPI) domains at week 9

All participants* Participants reporting symptom**

Citalopram Placebo

OR* (95% CI) p-value

Citalopram Placebo

p-valuen† (%) n† (%) Median (IQR)** Median (IQR)**

Number with week 9 NPI data 86 83

Individual domains

Delusions 22 (26 %) 35 (42 %) 0.40 (0.18, 0.91) 0.03 4 (2, 8) 4 (3, 8) 0.46

Hallucinations 11 (13 %) 13 (16 %) 1.53 (0.50, 4.71) 0.46 1 (1, 3) 6 (4, 6) <0.01

Agitation/aggression 66 (77 %) 70 (84 %) 0.63 (0.28, 1.41) 0.26 3 (2, 8) 6 (3, 8) 0.05

Depression/dysphoria 24 (28 %) 30 (36 %) 0.69 (0.34, 1.39) 0.30 3 (1, 6) 3 (2, 6) 0.35

Anxiety 36 (42 %) 54 (65 %) 0.43 (0.22, 0.84) 0.01 4 (2.5, 8) 4 (3, 6) 0.78

Elation/euphoria 3 (3 %) 5 (6 %) 0.45 (0.09, 2.21) 0.32 1 (1, 8) 3 (2, 6) 0.55

Apathy/indifference 41 (48 %) 42 (51 %) 0.92 (0.47, 1.80) 0.82 4 (3, 8) 6 (4, 8) 0.36

Disinhibition 27 (31 %) 34 (41 %) 0.71 (0.35, 1.46) 0.35 4 (2, 8) 4 (2, 6) 0.73

Irritability/lability 49 (57 %) 61 (73 %) 0.38 (0.19, 0.76) 0.01 4 (2, 6) 6 (3, 8) 0.13

Aberrant motor behavior 34 (40 %) 47 (57 %) 0.49 (0.24, 0.99) 0.05 4 (3, 8) 4 (3, 8) 0.96

Sleep and nighttime behavior 21 (24 %) 30 (36 %) 0.56 (0.27, 1.16) 0.12 4 (3, 12) 3 (2, 6) 0.03

Appetite and eating disorders 22 (26 %) 18 (22 %) 1.32 (0.62, 2.82) 0.47 4 (4, 8) 4 (3, 8) 0.84

Summary scores

Non-mood score 78 (91%) 79 (95%) ††0.48 (0.10, 2.00) 0.41 8.5 (5, 17) 14 (8, 24) <0.01

Affective score 72 (84%) 78 (94%) 0.33 (0.11, 1.03) 0.06 7 (4, 14.5) 12 (6, 20) 0.04

Psychotic score 28 (33%) 37 (45%) 0.67 (0.31, 1.44) 0.30 4 (2, 6) 6 (4, 9) 0.02

Leonpacher et al, Am J Psychiatry 2016

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Response limited to a subgroup

Schneider et al, Am J Psychiatry 2016

Charu et al, Int J Biostat 2017

Response depends on Agitation phenotype

Affective vs. Dysexecutive

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Linking Top Down to Bottom up etiologic model for agitation

Agitation

phenotype

Affective

-labile

-anxious

-irritable

Executive

-disorganized

-disinhibited

-overactive

AD brain

disease

Circuit

disruption

Affective

Circuitry

Executive

Circuitry

Serotonergic regulation

What’s next? S-CitAD(1) test the “Affective Agitation” hypothesis

(2) reduce heterogeneity by identifying subgroups

N=589

R01AG052510; PI: Lyketsos

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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?

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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=1.63

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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, 2009

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The theory about “Mild Behavioral Impairment”

Usual

Aging

MCI

MBI

Dementia

Amyloid Tau Neurons

impairedNeuron &

system loss

SMC MCIDementia

Behavior

change MBI NPS

Cognitive & behavioral disorders:

PARALLEL manifestations of Alzheimer’s

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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

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Thank you!

Eucaristw!