Towards Imaging Biomarkers for Treatment Selection in ... · PR NR, v R 9 16 8) b (HDRS Remission...
Transcript of Towards Imaging Biomarkers for Treatment Selection in ... · PR NR, v R 9 16 8) b (HDRS Remission...
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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
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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
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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?
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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
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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
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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
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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
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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
↓↓
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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
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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
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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
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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
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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
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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
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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
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−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
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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
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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
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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