Towards Imaging Biomarkers for Treatment Selection in Major Depressive Disorder

Helen Mayberg, MDEmory University School of Medicine

U Penn Treatment Selection Idea LabJune 3-4, 2016

TINS 2011

Depression Biomarkers Teams

ImagingLab

CallieMcGrathKiSueng Choi

JustinRajendraC.McIntyre(Case)

MaryKelley

DBSGroup

P.HoltzheimerPRivaPosseRobertGross

AndreaCrowellOtis Smart

Vineet TiruvadiAlllison Waters

Ashan Veerakumar

P50MH077083CIDAR(HSM)1RO1MH080880(WEC)R01MH073719-06(HSM)T32GM08695(CLM)K23MH086690(BWD)K23MH077869(PEH)

NARSAD,NIHR29(SBrannan,UTHSCSA)CIHR(Kennedy,Z Segal,Toronto)

NARSAD,WoodruffFund,DanaFoundation,StanleyFoundation,Hope forDepressionResearchFoundation,1R01MH102238(CM),1R01MH106173(CM)

MAPDep Unit

BoadieDunlopWEdCraigheadElizabethBinderMaryKellyTanjaMletzko

Ebrahim HaroonJeffreyRakofskyDylanWintSteveGarlowCoreyBeckSheethal ReddyPatrickSylversLorieRitschelMeredith JonesMaryHeekinMaryrose GerardiJillRosenberg

DrewWestenAndrewMillerMichael OwensJamesRichieDaniel Jaesup YooCharlesNemeroff

Breast Mass

Dx: Mammogram Biopsy: Cell Type

Es+ Receptors è HER2+ètamoxifen Herceptin

Diagnosis: CXR Gram+ Staph Aur.PenVK, MRS

Acid Fast m.TBINH/Rifampin

Cough, Fever è lobar pneumoniaTx Stratification: Smear/Culture/Sensitivity

Goal 1: Get out of episode as fast as possibleGoal 2: match patient to their optimal treatment AND

avoid those that will be unhelpfulGoal 3: if goal 2 met; work to define surrogates of equal reliability

A Treatment Specific Biomarker allows stratificationby definition will NOT define general responsivity (any treatment ok)

Biomarkers in Medicinemodel for MDD?

Neuroimaging Options

Resting CBF/metabolism (PET)Dep

Con

Ligand imaging (PET/SPECT)

Brain

stem

V3"

1

2

3

4

5

6

Con Dep

[123I]β-CIT[SERT]binding

Task-based functionalMRI

DiffusionMRItractographyMRspectroscopy

MEG

EEG

StructuralMRI

hc

Resting state BOLDfMRI

Baxter AmJP 1985 Drevets JNS 1992

dPF

vPF

↓ Activity ↑ ActivityAmg

Thal

Early Indicators of Imaging SubtypesBaseline frontal variability in untreated MDD

UnipolarParkinson’s

F9 F9F9 F9

P40 P40

aCg aCg

Mayberg et al. AJP 1988Ann Neurol 1990

J Nuc Med 1994NeuroReport 1997

MDD, BPD, OCD + dep MDD familial

MedsCg25

PCC

p

Change with SSRI

dPF

ins Cg25

Change w/ CBT

Cg25

vPF

C25

dPF

Cg25

MCC

mF

Change with DBS

PCC

Foundation to Seek Treatment Specific subtypesDifferent changes w/ different treatments

Mayberg Biol Psych 2000, Goldapple ArchGP 2004Kennedy AJP 2007; Mayberg Neuron 2005, Mayberg J Clin Invest 2009

First Clues to Response Subtypes

F9 C24F9 pACC24 pACC24

R>C NR<C

Resp/NonrespBaseline

FDG PET 6 Wk Change with Fluoxetine

Non-Resp

Resp

PF9

SCC25Cg25

PCCF9

p

PCC↑

↓aIns

PF9

25R v 20NR

Mayberg Neuroreport 1997; Mayberg Biol Psych 2000

Theta EEGTCA R>NR

Pizzagalli AJP 2001

Dr.’s choicemedication

Pt vs Controls

Replication, Extension

No findings/patternsthat distinguish within and

across different treatments.Med treatment only

ContNonResp Resp1.30

1.35

1.40

1.45

1.50

1.55

1.60

1

Met

abol

ism

(Reg

iona

l:Glo

bal)

CBT NRs, n=5VEN NRs, n=3

CBT Rs, n=7VEN Rs, n=9

HCs, n=24

C VC V

n=24

31 Randomized: Ven 14, CBT 1727 Tx’ed, 4DO: Ven 13, CBT 1424 Completed: Ven 12, CBT 12Responders: Ven 9/12, CBT 7/12

Kennedy et al. Am J Psych 2007

sgC

Follow-up StudyRandomized 16 weeks Venlafaxine vs CBT

vLF

Tx-specificResponse

Effects

16w Changeindep of Tx or

Outcome

SCC25↑

Ven CBT

↓SCC

vLF

Funded by CIHR Konarski et al. Psych NS 2009

8 NR > 16 R

Baseline Metabolism

SCC 32/24

Clear NR signal in SCCBut no diff CBT/Ven

No crossover/combo Tx

↓↓

ü MDD cohorts• Recurrent Depression (pre-ISLAND) s-CIT, CBT: 12 weeks randomized • Treatment Naïve (PReDICT) sCIT, CBT, dulox; 12 weeks randomized• Treatment Resistant (DBS): 6 months subcallosal cingulate DBS

ü Scans• PET: FDG (pre-ISLAND*); CBF (DBS)• resting-state fMRI: 7 minutes, fixation (PREDICT*, pre-ISLAND, DBS)• Diffusion DTI, structural T1 MRI (DBS*, recurrent, naïve)

ü Analyses• PET: normalized cmrGlc; fMRI: SCC25-seed functional connectivity • ANOVA: Treatment, Response (Rem, NR <30%Δ HDRS)• ANCOVA: Group X %Δ HDRS • ID region that best discriminates R/NR within and across treatments• within cohort now; chronicity, progression, past-Tx future

TSB Development for First Line Optionsfocus on SSRI vs CBT

Recurrent MDD

CBT sCIT

Rem NR NR

FDG PET, resting fMRI

Tx1

Rem2NR2 Rem2 NR2 Tx2

86 randomizedHDRS 18.8+3

12 9 6 11

86 enrolled

12 weeks RxBlinded rating63 completers

12 wk crossoverIn Tx1 nonRem

N=42 N=40

N=33 N=30

RemPhase 1

Tx Specificpattern forCBT/sCIT?

Phase 2Ever better vsnever better?

Rem: HDRS<8NR: HDRS Δ <30%

NIMH 1-R01MH073719-1-48 5 7 7

Experiment 1: Recurrent MDDremission or non-response to CBT vs SSRI

C McGrath et al. JAMA Psychiatry 2013

Rem NR

L Amygdala

R Inf TempBA20

L Precuneus

L PremotorBA 6

R MotorBA4

sCIT

sCIT

CBT

CBT

sCIT

sCIT

CBT

CBT

sCIT

sCIT

CBT

CBT

Rem NR

sCIT

sCIT

CBT

CBT

sCIT

sCIT

CBT

CBT

sCIT

sCIT

CBT

CBT

1.4

1.3

1.2

1.1

.85

.80

.75

.70

1.07

1.02

0.97

0.92

1.3

1.2

1.1

1.0

.81

.76

.71

.66

1.3

1.2

1.1

1.0

2-way ANOVA Treatment (CBT, sCIT) x Outcome (Rem, NR)

R AnteriorInsula

NOTE: many regions discriminate NR not R

Insula discriminates both

Phase 1: Define Candidate Biomarker RegionsRem/Non-Resp within/across CBT or sCIT randomization

Right Anterior Insula

Average Effect size: 1.43Most sign for all grp contrasts

.9.9

51

1.05

1.1

-100 -50 0 50 -100 -50 0 50

cbt escit

Right_Insula

% change phase 1

Graphs by treatment arm

CBT

r=0.55p=0.001

% change HDRS phase 1

r=-0.31p=0.09

sCITLow Insula: Rem to CBT, NR to DrugHigh Insula: Rem to Drug, NR to CBTP2: Remit when matched to brain typeInsula outperformed any multi-region model

DrugType

CBTType

Phase 1 Randomized Tx Phase 2 CBT+sCIT

P2Rem

drug addedto CBT

CBT addedto drug

Test Insula as Best TSB among 6 Candidatesphase 1 and Phase 2

McGrath et al. JAMA Psychiatry 2013Dunlop et al. J Neuropsych Clin NS 2014

Post-Phase 2: Clue to Treatment Resistancewhat baseline pattern predicts failure to combined CBT+med?

McGrath et al. JAMA Psychiatry 2013Dunlop et al. J Neuropsych Clin NS 2014McGrath et al. Biol Psych 2014

R Ant InsulaExtracted

from Rem/NRin Phase 1/2

drug addedto CBT

CBT addedto drug

Phase2Phase2RemdualNR

activitythroughcommunicationwithpregenualanddorsalanteriorcingulateanddorsolateralprefrontalcortex(Banksetal.,2007;Carballedoetal.,2011;Costafredaetal.,2008).Thisiscompatible

withthepresentmeta-analysisfindingthatincreasedcingulateactiv-ityresultsinanincreasedlikelihoodoftreatmentresponseandwiththehighlevelofagreementbetweenstudiesthatreducedvolumein

Table2Characteristicsoftheoutcomeandexperimentalmeasuresfromthefunctionalandstructuralstudiesonneuroimagingpredictionoftreatmentresponseindepression.

StudyYearModalityMeasurementMeasureofclinicalresponseFollow-up(weeks)

RespondersAnalysis

FunctionalstudiesBrody1999FDG-PETRestHDRSdecreaseby50%ormoreatendpoint89RvNRand

correlationBrannan2000FDG-PETRestRatingsofclinicalnotesbytwopsychiatrists26RvNRDavidson2003fMRI1.5TViewingemotionalpicturesMASQscore8NACorrelationwithRSaxena2003FDG-PETRestChangeinHDRS8to1255%mean

reductionCorrelationwithR

Little2005FDG-PETRestCGIratingof“much”or“verymuchimproved”

upto811RvNR

Siegle2006fMRI3TRatingpersonalrelevanceofemotionalwords

ChangeinBDIscore1262%meanreduction

CorrelationwithR

Chen2007fMRI1.5TImplicitsadfacesandvoxel-basedmorphometry

ChangeinHDRSscore8NACorrelationwithR

Langenecker2007fMRI3TGo/no-gotaskPercentagedecreaseinHDRS1061%meanreduction

CorrelationwithR

Walsh2007fMRI1.5TVerbalworkingmemoryRemission(HDRSb8)89CorrelationwithRFu2008afMRI1.5TImplicitsadfacesRemission(HDRSb8)88RvNR,PRFu2008bfMRI1.5TImplicitsadfacesRemission(HDRSb8)169CorrelationwithRKonarski2008FDG-PETRestHDRSdecreaseby50%ormoreatendpoint169(Ven.),7(CBT)RvNRMarquand2008fMRI1.5TVerbalworkingmemoryRemission(HDRSb8)169RvNR,PRCostafreda2009cfMRI1.5TImplicitsadfacesRemission(HDRSb8)169RvNR,PRMilak2009FDG-PETRestHDRSdecreaseby50%ormoreatendpoint1211RvNRRoy2010fMRI1.5TEmotionalpicture

recognitionmemorytaskPercentagedecreaseinHDRS8NACorrelationwithR

Wagner2010fMRI1.5TStrooptaskRemission(HDRSb7)64(Reb.),6(Cit.)RvNRandcorrelation

Frodl2011fMRI3TImplicitsadandangryfacesHDRSdecreaseby50%ormoreatendpoint4NARvNRRitchey2011fMRI1.5TEvaluationofemotional

picturesPercentagedecreaseinBDImeanof

3012(A)CorrelationwithR

Samson2011fMRI3TImplicitsadfacesHDRSdecreaseby50%ormoreatendpoint410RvNRandcorrelation

StructuralstudiesVakili2000sMRI1.5TManualhippocampalvolumeHDRSdecreaseby50%ormoreatendpoint821RvNRFrodl2004sMRI1.5TManualhippocampalvolumeRemission(HDRSb7)5218RvNRMacQueen2008sMRI1.5/

3TManualhippocampalvolumeRemission(HDRSb7)814RvNR

Costafreda2009asMRI1.5TVoxel-basedmorphometryRemission(HDRSb8)89RvNR,PRLi2010sMRI1.5TVoxel-basedmorphometryRemission(HDRSb8)619RvNRGong2011sMRI3TVoxel-basedmorphometryRefractoryvsnon-refractorydepression6to1223RvNR,PR

HDRS:HamiltonDepressionratingscale;BDI:BeckDepressionInventory.MASQ:MoodandAnxietySymptomQuestionnaire.CGI:Clinicalglobalimpressionscale.InGongetal.(2011)refractorydepressionwasdefinedaslessthan50%decrHRSDaftertwodrugtrialsfromtwodifferentpsychopharmclasses.Ven:venlafaxine.Reb:reboxetine;Cit:citalopram.RvNR:Respondersversusnon-respondersanalysis.PRPatternrecognitionanalysis.NA:notavailable.

Fig.1.Meta-analysisoffunctionalpredictorsoftreatmentresponseindepression.In-creasedactivationinanteriorcingulateispredictiveofpositiveresponsetotreatment(inred),whileincreasedactivationintherightamygdala,striatumandinsulaincreasesthelikelihoodofpoorresponse(inblue).ResultsarePb0.05(withFDRmultiplecom-parisonscorrection).(Forinterpretationofthereferencestocolorinthisfigurelegend,thereaderisreferredtothewebversionofthisarticle.)

Fig.2.Plotofindividualstudyfindingsinanteriorcingulate.Studiesthatreportedin-creasedactivationassociatedwithpositiveresponsetotreatmentarerepresentedbyredcrosses,whiletheoppositefindingofincreasedactivationassociatedtopoorre-sponsearerepresentedbybluecrosses.(Forinterpretationofthereferencestocolorinthisfigurelegend,thereaderisreferredtothewebversionofthisarticle.)

5 C.HY.Fuetal./NeurobiologyofDiseasexxx(2012)xxx–xxx

Pleasecitethisarticleas:Fu,C.HY.,etal.,Predictiveneuralbiomarkersofclinicalresponseindepression:Ameta-analysisoffunctionalandstructuralneuroimagingstudiesofpharmacologicalandpsychologicaltherapies,Neurobiol.Dis.(2012),doi:10.1016/j.nbd.2012.05.008

Fu et al 2012 Neurobiol Dis.

éNR

éR

imaging meta-analysis

Next Steps:prospective testing of

insula biomarker.Better than

flipping a coin?

NIMH2-R01MH073719-5InSuLa AssessedNeeds for

Depression:TheISLANDStudy

DualAllHealthyfailureRemControls

Dual Failureversus Ever

Better 2 phases

SCC

Imaging done within 1 week of screening and enrollment MRI/PET same day; analysis within 24 hrs

define brain type for treatment; patient and raters blinded

Figure8.

InSuLa Assessed Needs for Depression: ISLAND studytreat by brain type

NIMH 5R01MH073719-06

Goal: prospective replication of insula finding.

same scanner, same team, same patient criteria

go-no-go for future larger trial (stratified/randomize)if positive; focus on non-imaging surrogates

opportunity to see change by brain typeopportunity to enlarge dual failure pool

considered 1-sample or 2-sample comparison of proportions

Use historic remission rates (35% published)or Control group (randomized or usual care)-1 sample: 50% remission target: 100/77completers -2 sample: 340/170 per grp; > 3x the cost

intent: pragmatic, cost effective, before ramping up

Tx Naïve MDD

CBT DUL

Rem NR NR

resting fMRI

17 10 8 22 6 19 Rem

sCIT

NR Rem

Experiment 2: Treatment Naïve MDDCBT – escitalopram – duloxetine

PReDICT: P50MH077083 (CIDAR), 1RO1MH080880

SCC25 seed WB FCn=344 randomized

HDRS 19.8+3.8

ANCOVA HDRS % ΔANOVA subset Rem-NR3 groups: candidates regions37 48 37

putative clinical algorithmCBT v Drug; CIT v DUL, TRD

7 min rs-fMRI

12 weeks Tx; Blinded ratings 234 Completers 1

2

n=122 with usable scans

n=82 unambiguous

outcomes(58R, 24 NR)

Dunlop et al Trials 13:106, 2012

−100 −50 0 50

−0.4

−0.2

0.0

0.2

0.4

Left Midbrain ADM

HDRS−17 % Change

Bila

tera

l cg2

5 rs

FC (z−s

core

)

R = 0.12 (0.276)RemittersPartial ResponseNon Response

−100 −50 0 50

−0.4

−0.2

0.0

0.2

0.4

Left Midbrain CBT

HDRS−17 % Change

Bila

tera

l cg2

5 rs

FC (z−s

core

)

R = −0.39 (0.017)RemittersPartial ResponseNon Response

−100 −50 0 50

−0.4

−0.2

0.0

0.2

0.4

Left IFG ADM

HDRS−17 % Change

Bila

tera

l cg2

5 rs

FC (z−s

core

)

R = 0.16 (0.137)

−100 −50 0 50

−0.4

−0.2

0.0

0.2

0.4

Left IFG CBT

HDRS−17 % Change

Bila

tera

l cg2

5 rs

FC (z−s

core

)

R = −0.43 (0.009)

−100 −50 0 50

−0.4

−0.2

0.0

0.2

0.4

Left BA10 ADM

HDRS−17 % Change

Bila

tera

l cg2

5 rs

FC (z−s

core

)

R = 0.21 (0.052)

−100 −50 0 50

−0.4

−0.2

0.0

0.2

0.4

Left BA10 CBT

HDRS−17 % Change

Bila

tera

l cg2

5 rs

FC (z−s

core

)

R = −0.5 (0.002)

ADM

vlpf47-ins

midbrainPAG-DR

mF10

CBT

HDRS17change HDRS17changeNRRNRRNRCBT ADM

RestingStateFunctionalConnectivityprediction of ADM (cit=dul) & CBT outcomes

UNPUBLISHEDDunlop et alin review

Forcepsminor

uncinatef.

Cingulum

mF10 aTh

pMCC

SCC25vSt

mF10Ctx-St

Structural ConnectivitypMCC/SMA

.

C25

mF10aIns

aIns

p10

UF

Findings Across Methods and Groups within Target MapPET, Seed SCC-fMRI, DTI-FA

.

pMCC/SMACingulum b.

vmF10-p10uF/Fm

ant ThalCtx-thalamic fs.

HC CBT MED TRD HC CBT MED DBS HC CBT MED DBS

*** * * ****

++

thFA

-DTI

FMCB+

Differentiate R and TR in Recurrent MDD?evidence for cummulative, progessive pathology in TRD?

Towards a Map of Treatment Resistancecombined rs-fMRI, PET, DTI-FA in DBS Cohort

Common DTI mapin DBS Responders

Riva Posse and Choi Biol Psych 2014UNPUBLISHED comparisons right

Predict %change in HDRS depending on PRS and treatment and identify best-fit PRS

Build high resolution polygenic scores (PRS) with PRSice for each endophenotypein the Second Dataset

Neuroimaging endophenotypeassociated SNPs

Genome-wide association studyfor each PET biomarker (n=6)

3

42

1

Cohort 2 Tx Naive MDD

N=218(141)N=71(35)

Cohort 1 Recurent MDD

CBTsCITDUL

T Carrillo and EB BinderMax Planck Munich

Imaging-informed Polygenic Predictors

SummaryTSB for First-line Treatment Selection

Proof-of-Concept

ü PET now: test Insula biomarker prospectively in individuals (ISLAND)

ü Future: Stratified randomization, multicenter, surrogate

ü fMRI now: Phase 2 Tx PReDICT cohort, dual mailures

ü test reliability of candidates: PET vs fMRI

ü Combine/Model other markers in conjunction with imaging

ü test nonimaging surrogates (genetic, immune, psychophysical)

ü available cohorts for modeling