TreatmentofMajorDepressionInAdolescents

IanMGoodyerOBEMDFRCPsychFMedSciUniversityofCambridge

Depressedmood

Irritability/anger

Anhedonia

Weight/appetitedisturbanceSleepdisturbance

PsychomotordisturbanceFatigue,lackofenergy,tiredness

Self-perceptionsCognitivedisturbance

Suicide

DSM:UnipolarMajorDepression

mood+4(ormore)others

Psychoticfeatures

3-4symptoms(mild);5-6symptoms(moderate);7+symptoms(severe)plusimpairment

RandomisedControlledTrials:

•  TreatmentofAdolescentdepressionStudy(TADS):2004.

•  AdolescentDepressionandPsychotherapyTrial(ADAPT):2007.

•  TreatmentofResistantDepressioninAdolescents(TORDIA):2008.

•  Improvingmoodwithpsychotherapyandcognitivetherapy(IMPACT):2017.

TADS:RCTDesign

2084screened1008interviewed

549Baselineassessment

Fluoxetine+CBT107(92)

FluoxetineOnlyN=109(91)

CBTOnlyN=111(87)

MedicationPlacebo

N=112(89)

MarchetalJAMA2004;292:807-820

TADS: Adjusted Mean (SE) Scale Scores

MarchetalJAMA2004;292:807-820

% of patients in remission by treatment group

0

1020

3040

5060

7080

comb flux CBT Pillplacebo

% response CDRS-R

N439adolescentswithMD,12weekoutcomes

TADSOutcomes1YearofNaturalisticFollow-Up

MarchJetalAmericanJournalofPsychiatry2009;166:1141-1149

TADS: Summary

•  TreatmentwithfluoxetinealoneorincombinationwithCBTacceleratestheresponse.

•  AddingCBTtomedicationenhancesthesafetyofmedication.

•  Takingbenefitsandharmsintoaccount,combinedtreatmentadvisedformajordepressioninadolescents

MarchJSetalArchGenPsychiatry.200764(10):1132-43.

ADAPT: Adolescent Depression and Psychotherapy Trial

510 NHS outpatients assessed

261excluded(109notdepressed,48DNA,39drugconcerns,38refused,6tooill,1previoustreatment,20other)

249:164hadabriefpsychosocialintervention2/3sessions

126 BII non-responders

211 research interview

208 randomised

85bypassedBII(34inCAMHS,29onSSRI,22urgentmedsrequired)

34improved,4refused

2 refused, 1 improved

104specialistclinicalcare+Fluoxetine20mg-60mg

104specialistclinicalcare+Fluoxetine20mg-60mg+CBT

Clinician Rated Depression Scale 55

6065

7075

0 6 12 28Weeks

SSRI CBT+SSRI

Averagetreatmenteffect=1.43,95%CI-0.71,+3.52,p=0.19

GoodyeretelBMJ.2007Jul21;335(7611):142

CDRS-R

Self Report Depression Symptoms- MFQ

1020

3040

0 6 12 28Weeks

SSRI CBT+SSRI

Averagetreatmenteffect=1.27,95%CI-1.26,+3.80,p=0.32

GoodyeretelBMJ.2007Jul21;335(7611):142

Clinical Global Impression Over Study Period

weeks

Maximumclinicalbenefitsmaynotbeseenuntil28weeksaftertreatmentbegins

GoodyerIMetal(2008)HealthTechnolAssess.12(14):iii-iv,ix-60

ADAPTSummary

•  NoaddedvalueforCBTintreatingunipolardepressionoverandabovethatofspecialistclinicalcareandfluoxetine.

•  Overalltreatmenteffectivenessat28weeksaround60%.

•  Treatmentresistance–10%-20%

•  PatientsintheTrialweremoderate-severelyill.

•  Notaneffectivenesstrialforfluoxetine

Treatment resistant depressions

Brent DA et al: The TORDIA Study JAMA. 2008 February 27; 299(8):

901–913

TORDIA: RCT Design

334treatmentresistantpatientsnoresponseto

SSRIs@12weeks

DifferentSSRIparoxetine,citalopram,fluoxetine,20–40mgN=85

DifferentSSRI+CBTN=83

Venlafaxine(150–225mg)

N=83

Venlafaxine+CBTN=83

Clinical response 12 weeks post new treatment

42

44

46

48

50

52

54

56

New SSRI NS+CBT Venlaf Ven + CBT

CGI %

N=334@entry;N=223completion;ITTanalysis(LR):CBTp=0.03qualifiedbyasitexCBTinteractionp=0.003

Clickonimagetomagnify.

TORDIA:Clinicalresponse72weekspostnewtreatment

Responseapparentby6weeks.~30%-noremissionand25%relapse.

VitielloB,etalJClinPsychiatry.2011Mar;72(3):388-96

TordiaSummary

•  TreatmentresistancetoanSSRIcanrespondtocombinationtherapysuchasanotherSSRI+CBT.

•  Venlafaxinenotamedicationofchoice.

•  Responsebyabout6weekswithlittlegainfromthen.

TreatmentofDepressedAdolescents2000-2018

•  Severedepressionsoccurin1%-2%

•  Nonremissionby12months~30%

•  Treatmentnonresponserate~10%-20%

•  Norobustclinicalorpsychosocialpredictorsoftreatmentresponse,resistanceorrecurrencerisk

•  Lessgoodresponseinthosewith–  ahistoryofchildhoodmaltreatment,–  mildmaniaatpresentation,–  currentdepressioninmothers.

ImprovingMoodWithPsychoanalyticPsychotherapyAndCognitiveBehaviour

Therapy:THEIMPACTSTUDY

TheIMPACTConsortiumIanMGoodyer

ChiefInvestigatorUniversityofCambridge

Whatwereourobjectives

•  Whetherpsychologicaltreatmentwas‘goodenough’tomaintainreduceddepressivesymptoms12monthsaftertreatment.

•  Ifsowouldthisbecosteffectiveaswellasclinicallyeffective.

•  WouldspecialisttreatmentofCBTbesuperiortoshorttermpsychoanalytictherapy(STPP)inachievingtheobjectives.•  WouldCBTand/orSTPPbesuperiortothereferencetreatmentofbriefpsychosocialintervention(BPI)

PrinciplesofBriefPsychosocialIntervention

•  Collaborativecare.

•  Informationexchange.

•  Selectedbehaviouralactivation

•  Rehabilitationandrecovery.

•  Improvingandmaintainingmentalandphysicalhygiene,engaginginpleasurableactivities,maintainingschoolworkandpeerrelationsanddiminishingsolitariness.

ShortTermPsychoanalyticPsychotherapy

•  Aimstoincreasethecoherenceoftheyoungperson’smentalmodelsofattachmentrelationships•  Therebyimprovecapacityforaffectregulationandtherebythemakingandmaintainingofpositiverelationships.•  Techniquesbasedontherelationshipwiththetherapist.

•  Explorationofthe'internalworld’experiences:currentpreoccupations,memories,day-dreams,nocturnaldreamsandphantasies.

•  Attendingtounconsciousphenomenaisspecifictopsychoanalyticpsychotherapy.

•  Thepatient’sexperienceofthetherapistreceiving,holdinginmind,andthinkingaboutprojectedmaterialisacentralfeatureofthetherapy.

CognitiveBehaviourTherapy

•  CognitiveBehaviourTherapy(CBT)isbasedontheclassicalformoriginallydevelopedforadultswithdepression.•  Pervasiveinformationprocessingbiaseswhichincreasevulnerabilitytodepressioninthecontextofenvironmentalstress.•  Thesebiasesmaintainandamplifycoremoodsymptomsofdepression.

•  ThefocusofCBTistoidentifytheinformationprocessingbiasesthatmaintaindepressionandlowmoodandtoamendthesethroughaprocessofcollaborativeempiricismbetweenthetherapistandclient.•  CBTwasadaptedforthisstudybyincreasingfocusonengagement,useofbehaviouraltechniquesandparentalinvolvement,

TherapyDuration

•  BPI:12sessions,(8individual+4family/parent),over20weeks.

•  STPP:28sessions(+7parentsessions)over28weeks.

•  CBT:Upto20sessionsover30weeks(parentinvolvementifindicated).

ProfessionalsDeliveringTherapy

BPI:ChildandAdolescentPsychiatrists(80%)includingFellowsandChildandAdolescentMentalHealthNurses(20%).CBT:Clinicalpsychologistsorotherprofessionalswithpostqualification

traininginCBTSTPP:Child/AdolescentPsychotherapistsandtraineesintheirlastyear.

Design

ReassessmentsAtthenominal6,12,3652and86week

MDDN=470

BPI12sessions/20weeks

N=155Endofstudy=132

CognitiveBehaviourTherapy20sessions/20weeks

N=154Endofstudy=130

STPP28sessions/30weeks

N=156Endofstudy=119

RandomisedtoOneof3Treatmentarms

MR-IMPACTME-IMPACTGeneticAssayCognitiveAssayCortisolAssay

GoodyerIMetalTrials.2011Jul13;12:175

ParticipantCharacteristics

Characteristic BPI(n=155)Freq.(%)

CBT(n=154)Freq.(%)

STPP(n=156)Freq.(%)

MeanAgeinyrs15.6(1.4) 15.6(1.4) 15.6(1.5)

Females115(74) 114(74) 119(76)

White121(82) 131(86) 130(86)

SSRIbeforetrialentry29(19) 32(21) 28(18)

Mean(MFQ)depressionscore 46.2(10.6) 46.2(10.3) 45.4(10.8)

Interviewerratedsymptoms8.4(2.5) 8.7(2.3) 3.  (2.5)

PsychosocialimpairmentScale18.9(6.0) 18.4(6.0) 18.3(6.3)

ParticipantCharacteristicsatBaseline

Characteristic BPI(n=155)Freq.(%)

CBT(n=154)Freq.(%)

STPP(n=156)Freq.(%)

RecentSelfharm26(17) 25(16) 34(22)

LifetimeSelfHarm87(56) 75(49) 84(54)

RecentSuicidalAttempts3(2) 2(1) 7(5)

LifetimeSuicideAttempts57(37) 48(31) 55(35)

Comorbidity(1+)71(46) 80(52) 74(47)

DisruptiveBehaviourDisorders20(13) 20(13) 16(10)

MedianTime(weeks)FromRandomisationToStartingTherapy

BPI CBT STPP

Region Median (95% c.i.) Median (95% c.i.) Median (95% CI)

East Anglia 4.3 (3.3 to 5.6) 7.3 (5.1 to 10.1) 4.7 (3.9 to 5.7)

North London 2.9 (2.0 to 3.7) 4.0 (3.0 to 4.7) 3.9 (2.7 to 4.4)

North West 4.0 (3.1 to 4.6) 4.0 (2.9 to 4.9) 4.4 (3.1 to 6.1)

DurationOfTherapyInWeeks

Treatment Med Max Mean SD N

BPI 22.1 111.9 27.5 21.5 130

CBT 23.1 99.6 24.9 17.7 130

STPP 30.1 97.0 27.9 16.8 131

BPI CBT STPPMedian(IQR)a 6 (4,11) 9 (5,14) 11 (5,23)

Planned 12 20 28

Numberoftherapysessionsattended

Treatmentdifferentiation0

12

34

5BPI CBT STTP

CB Domain PI Domain

CPPS

Doma

in Sc

ore

Graphs by Trial Arm

Measurestakenby2ratersindependentlylisteningtoafixedtimeseriesfrom279audiotapesrandomlyselectedfromthe3armsstratifiedbyage,centreandphaseoftherapy(early,2-4,later>4sessions).MeasuredusingtheCPPSreliability=0.82&0.8perscale.•  CBT>STPPon(CB)sub-scalescore(95%CI1·73to2·09,p<0·0001).•  STPP>CBTmeanon(PI)sub-scalescore(95%CI1·01to1·3,p<0·0001).•  BPI<CBTonCBsub-scale(meandiff.=-0·93,95%CI-1·12to-0·75,p<0·0001)•  BPI<STPPonthePIsub-scale(meandiff.=-1·30,95%CI-1·48to-1·11,p<0·0001).•  81%ofBPI,80%ofSTPPand74%ofCBTsessionsmetcriteria

PrevalenceofDepressiveSymptomsAtEntry

0

10

20

30

40

50

60

70

80

90

100

BPI

CBT

STPP

DepressionScoresOverTheStudy

0

5

10

15

20

25

30

35

40

45

50

Baseline 6week 12week 36week 52week 86week

BPI

CBT

STPP

Endoftreatment

MeanMFQ

Score

DepressionSumScoresOverTheStudy20

3040

50Sc

ore

0 20 40 60 80 100Weeks

BPI CBT STPP

ns

IndividualDifferencesinSymptomChange

AverageSymptomChangeovertime

IndividualSymptomChangeovertime

Individualdifferencesinsymptomchangeisevident

020

4060

MFQ

0 20 40 60 80Weeks

20

30

40

0 25 50 75Weeks

MFQ

Female Male

SuicideAttempts&NSSI

0

2

4

6

8

10

12

14

16

18

20

Baseline 6 12 36 52 86

SuicAtmpt

NSSI

Nobetweentreatmentgroupdifferences

SSRIPrescribingOverTheStudy

0

5

10

15

20

25

30

35

40

45

<36wk >=36wk

BPI

CBT

STPP

CostEffectivenessinUKPounds

0

500

1000

1500

2000

2500

3000

3500

Treatment FollowUp Total

BPI(n=90)

CBT(n=92)

STPP(n=91)

UKPo

unds

Summary

•  TherearenosuperiorityeffectsofCBToverSTP.

•  All3treatmentsarestatisticallyaseffectiveaseachother.

•  Allthreetherapiesshowreducedsymptomsayearaftertreatment.

•  BPIoffersanadditionalpatientchoiceforpsychologicaltherapy.

•  Nocosteffectivenessadvantagebetweenthe3treatmentgroups.

Causality

•  Cannotfullydiscountthepossibilitythatalltheobserveddeclineinsymptomsandimprovementinwell-beingwasafunctionoftime.

•  Fluoxetinemayacceleratethedeclineinsymptomsacrossthecohortindependentofpsychologicaltreatment.

•  Theabsenceofanotreatmentcontrolgrouplimitstheassertionthatanytherapywascausallyeffective.

ConfirmClinicallyDepressedAscertaindiagnosis,obtainselfreportsymptomscores

AssessPredictors/ModeratorsofLikelyTreatmentResponse1.Historyofchildhoodmaltreatment.2.Currentdepressioninaparent.3.Comorbiditiesatpresentation4.Expectationsoftreatment5.Complianceandresponsetopasttreatments.

CollaborativeDiscussion1.Entercollaborativediscussionwithpatientandfamilyaboutdepressionandtreatmentoptions.2.Explainaboutdepressionandanswerallrelevantquestions.3.Explaintreatmentoptionsincludingassociatedrisks.4.Getaplannedtherapeuticsprotocolagreedwithadolescent.5.Offeratimelineforfirstlinetreatment.

TherapeuticActivation1.Firstlinemonotherapycanbepsychological.2.Canbecombinationpsychosocial+fluoxetine.3.Complexcasesmayneedcombinationtherapywithfluoxetineasapriority+psychosocialtreatment.

Therapeuticreview:3-4weeks1.  Ispatientalliedwiththerapistandtreatment2.  Assessforsideeffects:considertreatment

reluctance,non-complianceandnon-attendanceaspossiblesignsofadverseeffectstotreatment.

3.  Furthercollaborativediscussionaboutprogress.

4.  Continueorrevisitcurrenttreatmentplan.

TreatmentProgress1.  Someimprovementswithanytreatmentby6

weeks.2.  12-18weeksexpectremissioninabout50%

ofcases.3.  By24-36weeksexpectremissioninafurther

20-30%.4.  Expect10%-20%dropoutby12weeks.5.  Expect10%-20%treatmentresistance.6.  Noimprovementby6-12weeks-repeatboxD.

A

B

C

D

E

ClinicalAssessment,TreatmentandMonitoring

FutureResearch

•  Treatmentresponse.

•  Themaintenanceofpositiveeffects.

•  Non-response.

•  WhetherBPIisofutilityincommunityandprimarycaresettings.

•  Fluoxetineeffects.

Acknowledgements

•  ThisresearchwasfundedbytheNationalInstituteforHealthResearchHealthTechnologyAssessment(NIHRHTA)programme(projectnumber:06/05/01).

•  TheviewsexpressedinthispublicationarethoseoftheauthorsanddonotnecessarilyreflectthoseoftheHTAprogramme,NIHR,NHS,ortheDepartmentofHealth.

•  TheongoingresearchisfundedbytheWellcomeTrust,RoyalSocietyandFriendsofPeterhouse.