Husseini K ManjiGlobal Therapeutic Head

for NeuroscienceJohnson & Johnson

(previously Director of NIMHMood & Anxiety Disorders

Program)

Bipolar Disorder: Harnessing BrainPlasticity for Improved Overall Outcomes

Neuroscience Therapeutic Area

0 10 20 30 40

Mental Illness*

Injuries, including self-inflicted

Alcohol and drug use

Malignant neoplasms (cancer)

Cardiovascular disease

Respiratorydisease

Musculoskeletal disease

Sense organ disease

Digestive disease

Serious Mental Illnesses are Major Causes of Disability Worldwide: GlobalBurden of Disease (DALYs)

(U.S., Canada, and Western Europe 15-44 years old)Disability-Adjusted Life Year (DALY)

Leading Individual Disease (DALY)

Disability-Adjusted Life Year (DALY)

Leading Disease Categories (DALY)

> 35,000 deathsby suicideannually in theUS

Mental Illness* 1. Unipolar Depression

1

Mood Disease Area Strategy

The unmet need is tremendous: why has thedevelopment of better treatments been so slow?

2

Time

• Sheer complexity ofdiseases

• Higher order brain functiondifficult to modelpreclinically

• * Brain is “inaccessible”

• * Our classification system doesn’tdistinguish between subtypes

Arguably the most challenging field to come up withcompletely novel treatments

Up to 12 years

• Generally don’t know until you are intrials with hundreds of patients if itis going to work

33

Neuroscience (esp Psychiatry) is ready forbreakthroughs…………………………

Method of the year, 2010

Recent advances referredto as “the biggestbreakthroughs in

Psychiatry in 40 years”NIMH Director

4

Major mood disorders are among the mostheritable of ALL ILLNESSES

Tw

inP

rob

an

dw

ise

Con

cord

an

ce

72 44 82 103 268 377 433 629 639 906 45 36 259 424

n/Pairs

*Source data from “The Genetics of Complex Human Behaviors,” Science, Vol. 264, 17 June 1994

***

Parkinson’sDisease

BreastCancer

ChronicObstructivePulmonaryDisorder

Hypertension IschemicHeart Disease

Autism MajorMood

Disorders

4

5

“intervention to bring abouta positive change in

cortico-cortical connectivity”

Tremendous Advances in Neuroscience

MultimodalIntegration

MEG fMRIVisualizing plasticity

Neurogenesis

**

(A)

(B)

(C)

(D)

6

Severe Mood Disorders arise from abnormalities of synapticplasticity: not “too much/too little individual neurotransmitter”

Old Model

From Rick Huganir

Leading to completely novel treatments

7

Can we rapidly regulate synaptic plasticity by targeting AMPA & NMDAreceptor subunits? FASTER ONSET? MORE ROBUST?

Neuroscience Therapeutic Area

• Replicated in multiple studies• Same effects seen in BPD

Replicated with additional distinctmolecules

13%

35%

53%56%

71%

58%53%

62-65%

35%

40Minutes.

80Minutes

110Minutes

230Minutes

1Days

2Days

3Days

7Days

8Weeks

Ketamine Placebo Venlafaxine SSRIBupropion

Acute AntidepressantEffect of very low dose Ketamine*

PBO

Drug

Robust and Rapid Antidepressant Effects of Low Dose NMDAAntagonists in Treatment-Resistant Major Depression

Response rate at 1 day in this extremelyrefractory population > 8 weeks with

current Rx in non-refractory populations

8

*Zarate et al. Arch Gen Psychiatry 2006

9

1DiazGranadose et a.l JCP 2010

Baseline Scale Suicidal Ideation(SSI)

Minutes

-60 0 60 120 180 2400

2

4

6

8

10

12

Scale

for

Su

icid

alId

eati

on

(S

SI)

]

]

]

]

]

]

]

]

]

]

High SSI (>4) (n=10)Low SSI (<3) (n=23)

Acute Effect of very low doseKetamine on Suicidal Ideation1

NMDA Antagonists Exert Robust &Rapid Antisuicidal Effects

9

Tremendous Advances in Biomarkersto identify responders to Rx

Non-Resp

PostKet

PreKet

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

Responders

PostKet

PreKet

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

2Cornwell, Salvadore et al., Biol Psychiatry, In Press

?? Neuroactive cytokines

* *

10

Ketamine also exerts Rapid Antidepressant Effects inBipolar Depression in two independent studies

• Once again, a highlyrefractory population

• Had failed multipleprevious treatments

• Did not trigger manicepisodes

MIND AND BODY:

MOOD DISORDERSAFFECT

MULTIPLE ORGANSYSTEMS

12

CRP

SAAIL-6SAA

CRH

EPI / NE

CortisolNE

Proinflammatory state

Insulin Resistance

Inflammation

Hyperinsulinemia& dyslipidemia

MoodDisorders

?? Neuroactive cytokines

From PW Gold, 2008

13

Plasma levels ofIL-1β (A) and TNFa (B) fromuntreateddepressedsubjects with MDD(N=267) orbipolar disorder(N=166) andhealthy controls(N=207) fromLundbeck-sponsored trials

Jones, K.A., Thomsen, C.,Mol. Cell. Neurosci. (2012)

1414

Targeting Specific Neuroactive Cytokines Exerts Major Effects on Synaptic andNeural Plasticity (Not just Brain Inflammation)

Su

rfa

ce

Glu

R1

(%

Co

ntr

ol)

Untreated TNF

200

150

100

0

50

250TNF TreatedUntreated

Hz

(Fre

q.)

&p

A(A

mp

)

20

15

100

5

0

Untreated

TNFR1

Frequency Amplitude

*

*

Targeting Specific Neuroactive Cytokines Reverses DepressivePhenotype in Several Different Robust Models

REVERSAL OF DEPRESSIVE Sx

(C) IL6

Control

0.8

0.6

0.4

0.0

0.2

10

lL6 abs

*

REVERSAL OF DEPRESSIVE SYMPTOMS(A) IL 1b

Pre-1Ra

Pre-PBS

4030

20

010

90

50607080

Pre-Severe Stress Post-Severe Stress

CUS+1Ra

CUS+PBS

**##

DEPRESSIVE SYMPTOMS(B) NFkB

0

50

300

100

150

200

250

CTRL

*

CUS

#

SC+CUS

Malenka et al

Duman, Russo and Nestler

15

Preliminary evidence suggests that targeting cytokines may bebeneficial in the treatment of mood disorders

Etanercept for depressive sx in psoriasis(Tyring et al, Lancet, 2006)

Infliximab in MDD (Change in CRP byresponder status; Raison et al 2013)

Genes

Manic-Depressive Illness (Bipolar Disorder and RecurrentDepression): targeting the Biology of Recurrence

EnvironmentalFactors

Pe

rce

nta

ge

of

Tim

eIll

Mania Depression0

5

10

15

20

25

30

35

(4.53x) (2.47x)

Before Li+

After Li+

~6X reduction insuicide

Molecules whose “job” it is to helpnerve cells grow & survive

17

Nestler et al, Nature NeuroscienceDrevets et al Nature, 1997

Recurrent Mood Disorders are Not Classical NeurodegenerativeDisease, but Have Atrophic Changes in Discrete Brain Regions

Mood Disorders

Control

PFC

volu

me

(m

m3

)

Control Bipolar Unipolar

300

200

100

0

*

*

~40%reduced grey

matter insubgen PFCx

17

Neuroscience Therapeutic Area

Control

Chronic lithium robustly regulates regional Bcl-2 levels

Lithium

Anterior Cingulate

Dentate Gyrus

Striatum

In animal studies,increasing Bcl-2protects against:

StrokeAlzheimer’s toxinsParkinson’s toxinsStress-induced damageFree radicals

?? Human data

19

A genetic variant associated with Bipolar Susceptibility &Antidepressant Response has major effects on Bcl-2 ProteinLevels, Susceptibility to “cell death” & Gray Matter Volumes

GG >> AA VentralStriatum Gray Matter

Gray Matter VolumeBcl-2 Protein Levels

**

Bcl-

2P

rote

inLevel

(%

of

GG

)

AA AG GG

200

150

100

0

50

Apoptosis

THAPS

Ap

op

toti

cC

ell

s(%

)

45

0

40

35

30

25

20

15

10

5

AA0 1 5

AG0 1 5

*

**

GG0 1 5

Neuroscience Therapeutic Area

Atrophic neurons

Reversal ofatrophy

Lithium – via its effects on “neurotrophic molecules”appears to enhance neuronal resilience

20

Hippocampal volume PFCx volume: in px only

21

Increasing levels of keyneurotrophic molecules increases

resilience & enhances recovery

Reducing levels of key neurotrophicmolecules reduces resilience &

increases susceptibility

Mice Developing Depressive Symptoms (%)

Normal Bcl-2

Lower Bcl-2

Normal BAG-1 levels

High BAG-1 levels

Dep

ressiv

eP

hen

oty

pe

30

20

10

0

Day1

Day3

Day8

Day2

RapidRecovery

RemainDepressed

*

21

100

Depressed

*Non-

Depressed

40

10

0

60

50

30

20

70

90

80

22

tBid Bcl-2

Dep

ressiv

eP

hen

oty

pe

Similar effects seen in5 different models

without toxicity

*

InducedPhenotype

LL44 Bl-2A7

60

0

50

40

30

20

10

Saline

Scrambled

Active

22

Does enhancing neurotrophic function enhanceresilience and recovery?

We need holistic solutions not just pills: we are dealingwith individuals with ‘real lives ’, not isolated neurons!

Software basedcognitive remediation

Patient ManagementPrograms

Treat underlyingBiology plus….

Remote monitoring topre-empt relapses

Y Interventions toengage appropriateexperiential circuitry

Neuroscience Therapeutic Area

Severe Mood Disorders: Unique Challenges

• Serious mental illnesses are the most disabling and costlydisorders globally; mood disorders the highest

• Targeting synaptic plasticity and cellular resilience hasthe potential for markedly improved treatments

• Move the paradigm to “pre-emption” – prevent theravages of the illness

• We need to move beyond the notion of single magicbullets and develop holistic, integrated solutions thatmake a real difference in patients’ lives

• This is a shared societal responsibility – we are only goingto succeed by working together

“There is no health without mental health”