From the American Psychiatric Association’s (2000)Practice Guidelines for Major Depressive Disorder in Adults:

From the American Psychiatric Association’s (2000)Practice Guidelines for Major Depressive Disorder in Adults:

• “Antidepressant medications should be provided for moderate to severe depressive disorders unless ECT is planned.”

• “For example, although some data suggest that cognitive behavioral therapy alone may be effective for patients with moderate to severe major depressive disorder, most such patients will require medication.”

• “Antidepressant medications should be provided for moderate to severe depressive disorders unless ECT is planned.”

• “For example, although some data suggest that cognitive behavioral therapy alone may be effective for patients with moderate to severe major depressive disorder, most such patients will require medication.”

CPT II

Acute Phase (16 weeks) Continuation Phase (12 months) Follow-up Phase (12 months)

CT

ADM

PLACEBO

Prior CT

(N=34)

ADM

(N=34)

PLACEBO

(N=34)

(N= 60)

(N= 120)

(N= 60)

3 booster sessions

Major Entry Criteria Major Entry Criteria• Principal Diagnosis of Major Depressive Disorder

• Two consecutive (at least one week apart) scores of 20 or more on a modified 17-item Hamilton Rating Scale for Depression

• No Psychosis or Bipolar Disorder

• No Borderline, Antisocial, or Schizotypal PD

• No marked Substance Abuse or Dependence in previous 6 months

• Principal Diagnosis of Major Depressive Disorder

• Two consecutive (at least one week apart) scores of 20 or more on a modified 17-item Hamilton Rating Scale for Depression

• No Psychosis or Bipolar Disorder

• No Borderline, Antisocial, or Schizotypal PD

• No marked Substance Abuse or Dependence in previous 6 months

Reasons Interested Patients Were Screened Out of the TrialReasons Interested Patients

Were Screened Out of the Trial

4

83

5

1112

13

19

25

29

38

45

63

67

106

129

240

0 20 40 60 80 100 120 140 160 180 200 220 240

Number of Patients

Primary eating disorder

Imminent suicide risk

Schizotypal PD

Antisocial PD

Borderline PD

Outside age limits

Primary anxiety disorder

Recent paroxetine failure

Would not stop current meds

Psychosis

Refused meds

Medical condition

Substance Abuse or Dependence

Bipolar

No Major Depressive Episode

Low severity

Randomized to Treatment

81

82

33

33

89

75

64

53

0 20 40 60 80 100

Percentage

Employed

Married orCohabiting

Caucasian

Female

PennVanderbilt

Demographic InformationDemographic Information

Depressive Subtype and History InformationDepressive Subtype and History Information

12

209

2933

9786

8267

75

4941

9

5843

2810

0 10 20 30 40 50 60 70 80 90 100

Percentage

Bipolar II

Atypical

Melancholic

Chronic, Dysthymic, or Recurrent

Recurrent

Chronic or Dysthymic

Dysthymic

Chronic

Ever Hospitalized

Penn

Vanderbilt

Comorbidity IComorbidity I

3734

249

24

63

239

197

1313

285

6541

8363

0 10 20 30 40 50 60 70 80 90 100

Percentage

Substance Abuse or Dependence

Eating Disorder

Anxiety Disorder NOS

OCD

Specific Phobia

Panic Disorder

GAD

PTSD

Any Anxiety Disorder

Any Axis I Comorbidity

Penn

Vanderbilt

Comorbidity IIComorbidity II

1318

422

000

444

222

1322

756

3891

76

0 10 20 30 40 50 60 70 80 90 100

Percentage

PD NOS

Narcissistic PD

Histrionic PD

Schizoid PD

Paranoid PD

Dependent PD

Avoidant PD

Obsessive Compulsive PD

Any Personality Disorder

Any Comorbidity (Axis I or II)

Penn

Vanderbilt

Acute Phase

CT(N= 60)

ADM(N= 120)

PLACEBO (N= 60)

0 2 4 6 8 10 12 14 16Weeks

(Triple blind)

Un-blinding for pill patients

R a n d o m i z a t i

o n

(Single blind)

Augmented (41%)

Not Augmented (59%)

2%3%

0%0%

1%0%0%

1%0%0%

1%0%

7%1%

0%7%

3%3%

0%0%

7%0%

1%3%

15%10%

13%

0% 2% 4% 6% 8% 10% 12% 14% 16%

Percentage

Unknown

Suicide

Suicide Risk

Hospitalized

Too busy

SEs / Did not like treatment

Dissatisfied w/progress

Refused Tx

All reasons

PlaceboADMCT

Dropouts in First 8 WeeksDropouts in First 8 Weeks

13%

23%

5%12%

26%

35%

75%

51%

60%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Pe

rce

nta

ge

Remission (0-7) Response (8-12) Nonresponse (13 and up)

HRSD Score Categories

PlaceboADMCT

Degrees of Response at 8 WeeksDegrees of Response at 8 Weeks

16.0

14.4

13.4

12

14

16

18

20

22

24

26

Intake 0 2 4 6 8

Week

Mo

dif

ied

17-

item

Ham

ilto

n R

atin

g S

cale

fo

r D

epre

ssio

n

PlaceboCTADM

Mean HRSD Scores Over 8 WeeksMean HRSD Scores Over 8 Weeks

Change in Depressive Symptomsfrom Intake to Week 8 (HRSD)

Change in Depressive Symptomsfrom Intake to Week 8 (HRSD)

Contrast Mean HRSD Difference Effect Size (d)

Effect Size Descriptora

ADM vs. Placebo

2.3 .73** medium

CT vs. Placebo

1.7 .54# medium

ADM vs. CT

0.6 .19 --

**p < .01 #p < .10 a From Cohen

Contrast Mean HRSD Difference Effect Size (d)

Effect Size Descriptora

ADM vs. Placebo

2.3 .73** medium

CT vs. Placebo

1.7 .54# medium

ADM vs. CT

0.6 .19 --

**p < .01 #p < .10 a From Cohen

Dropouts in ADM and CTover 16 Weeks

Dropouts in ADM and CTover 16 Weeks

2%3%

0%1%

0%1%

0%1%

7%2%

7%8%

0%0%

0%1%

15%16%

0% 2% 4% 6% 8% 10% 12% 14% 16% 18%

Percentage

Unknown

Suicide

Suicide Risk

Hospitalized

Too busy

SEs / Did not like treatment

Dissatisfied w/progress

Refused Tx

All reasons

ADM

CT

25%

49%

40%

57% 58%

0%

10%

20%

30%

40%

50%

60%

Pe

rce

nta

ge

8 Weeks 16 Weeks

Placebo (n=60)

ADM (n=120)

CT (n=60)

Percent Responders (HRSD < 12) amongAll Assigned, Across Sites

Percent Responders (HRSD < 12) amongAll Assigned, Across Sites

Degrees of Response after 16 WeeksDegrees of Response after 16 Weeks

45%

37%

12%

21%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Per

cen

tag

e

Remission (HRSD = 0 -- 7) Response (HRSD = 8 -- 12)

ADM CT

Percent Response (HRSD < 12) by Site (16 Weeks)

Percent Response (HRSD < 12) by Site (16 Weeks)

47%

63%67%

53%

0%

10%

20%

30%

40%

50%

60%

70%

Pe

rce

nta

ge

ADM CT ADM CT

Penn Vanderbilt

Sample Characteristics on Potential Predictors of Response

Demographics History/SubtypeAge 40+12 Ever Hospitalized 19%Female 59% Chronic 50%Minority 18% Recurrent 75%Married 33% Melancholic 31%Employed 82% Atypical 15%

Axis I Comorbidity (73%) Axis II Comorbidity (47%)PTSD 17% Cluster A 3%GAD 13% Cluster B 4%Panic Dis. 13% Avoidant 18%Eating Dis. 17% OCPD 15%Subs. Use 36% PD NOS 16%

Predicts response across ADM and CT (Prognostic)

Predicts differential response to ADM vs. CT (Prescriptive)

Chronicity Predicts Poor Response (Prognostic)

Chronicity Predicts Poor Response (Prognostic)

9.8 10.511.8

13.0

0

2

4

6

8

10

12

14

Ter

min

atio

n H

amil

ton

Sco

re

ADM(N=63)

CT(N=28)

ADM(N=57)

CT(N=32)

Non Chronic Patients Chronic patients

Being Unemployed Predicts Poor Response (Prognostic)

Being Unemployed Predicts Poor Response (Prognostic)

8.69.8

11.4 11.6

0

2

4

6

8

10

12

Ter

min

atio

n H

amil

ton

Sco

re

ADM(N=103)

CT(N=47)

ADM(N=17)

CT(N=13)

Employed Unemployed

Cluster A Predicts Poor Response (Prognostic)

Cluster A Predicts Poor Response (Prognostic)

10.8 11.1

16.318.2

02468

101214161820

Ter

min

atio

n H

amil

ton

Sco

re

ADM(N=116)

CT(N=58)

ADM(N=4)

CT (N=2)

No Cluster A Cluster A

PTSD Predicts Poor Response(Prognostic)

PTSD Predicts Poor Response(Prognostic)

9.811.4

14.9

12.5

0

2

4

6

8

10

12

14

16

Ter

min

atio

n H

amil

ton

Sco

re

ADM(N=104)

CT(N=47)

ADM(N=16)

CT(N=13)

Non PTSD Patients PTSD Patients

GAD Predicts Differential Response (Prescriptive)

GAD Predicts Differential Response (Prescriptive)

11.4 11.2

7.5

15.7

0

2

4

6

8

10

12

14

16

Ter

min

atio

n H

amil

ton

Sco

re

ADM(N=105)

CT(N=54)

ADM(N=15)

CT (N=6)

Non GAD Patients GAD Patients

CPT II

Acute Phase (16 weeks) Continuation Phase (12 months) Follow-up Phase (12 months)

CT

ADM

PLACEBO

Prior CT

(N=34)

ADM

(N=34)

PLACEBO

(N=34)

(N= 60)

(N= 120)

(N= 60)

3 booster sessions

75%

60%

19%

Sample Characteristics on Potential Predictors of Relapse

Demographics History/SubtypeAge: 40+12 Early Onset: 49%Female: 58% Dysthymic: 34%Minority: 13% Recurrent: 75%Married: 37% Melancholic: 34%Employed: 89% Atypical: 24%

Axis I Comorbidity (69%) Axis II Comorbidity (49%)PTSD:10% Cluster A: 1%GAD: 11% Cluster B: 1%Panic Dis. 12% Avoidant: 18%Eating Dis. 18% OCPD: 13%Subs. Use 31% PD NOS: 19%

Predicts risk for relapse

16%

30%

39%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

ADM followed byPlacebo

ADM followed by ADM CT followed by 3additional sessions

Sustained Improvementfor All Assigned to Treatment

Sustained Improvementfor All Assigned to Treatment

0

500

1000

1500

2000

2500

3000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Months in Treatment

Co

st

in D

olla

rs

CT

ADM

Cumulative Direct Costs of ADM and CT

16% 15%

31%29%

47%

31%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

ADM followed byPlacebo

ADM followed by ADM CT followed by 3additional sessions

Penn Vandy

Sustained Improvement Rates by SiteSustained Improvement Rates by Site

Treatment Response as a Function of Site and GenderTreatment Response as a Function of Site and Gender

64%

40%

60%

67%

76%71%

37%

57%

0

10

20

30

40

50

60

70

80

% R

es

po

ns

e

Vandy Penn Vandy Penn

CT ADM

male

female

Response to CT as a Function of PTSD by SiteResponse to CT as a Function of PTSD by Site

60%

53%

63% 62%

33% 33%

0

10

20

30

40

50

60

70

% R

esp

on

se

Overall No PTSD PTSD

Penn (10%)

Vandy (29%)

Therapist Competence as a Function of Experience in the Trial (Vandy)

Therapist Competence as a Function of Experience in the Trial (Vandy)

47 45

36

45

36

45

0

10

20

30

40

50

CT

Sco

re

Therapist 1 Therapist 2 Therapist 3

1st half

2nd half

Response to Treatmentas a Function of Time in Trial

Response to Treatmentas a Function of Time in Trial

57%63%

47%

60% 57% 57%

0%

10%

20%

30%

40%

50%

60%

70%

% R

es

po

ns

e

Penn CT Vandy CT ADM

1st half

2nd half

0

5

10

15

20

25

30

35

40

45

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Week

Do

sag

e (m

g)

Vandy

Penn

Weekly Paxil Dosage By Site

0

5

10

15

20

25

30

35

40

45

50

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Week

Do

sag

e (m

g)

Vandy (Aug)

Vandy (No Aug)

Penn (Aug)

Penn (No Aug)

Weekly Paroxetine Dosage by Site and Augmentation

-10

-5

0

5

10

15

20

25

30

Least to Most Responsive Patients

HR

SD

Ch

ang

e

PlaceboADMCT

Response to Treatment as a Function of Ordinal Rank within Group (Vandy)

Response to Treatment as a Function of Ordinal Rank within Group (Vandy)

-10

-5

0

5

10

15

20

25

30

Least to Most Responsive Patients

HR

SD

Ch

an

ge

PlaceboADMCT

Response to Treatment as a Function of Ordinal Rank within Group (Penn)

Response to Treatment as a Function of Ordinal Rank within Group (Penn)

‘Normalcy’

Symptoms

Syndrome

Treatment phases

progression

to disorder

RelapseRelapseRelapseRelapse RecurrenceRecurrenceRecurrenceRecurrence

RemissionRemissionRemissionRemission RecoveryRecoveryRecoveryRecovery

Acute Continuation Maintenance

X

Incompleterecovery

Chronicity

Response, Remission, Recovery, Relapse, Recurrence & Chronicity

adapted from Kupfer & Frank 2001

ResponseResponseResponseResponse

Time

Sev

erit

y

RX

16 wks 12 mo 12 mo

Prevention of Relapse Following Successful Treatment

0

0.2

0.4

0.6

0.8

1

0 1 2 3 4 5 6 7 8 9 10 11 12

Months (following active treatment)

% S

urv

ival Placebo (n=35)

Drug (n=34)

Compliant (n=30)

Prior CT (n=35)

Prevention of Recurrence in Recovered Patients Following Successful Treatment

0

0.2

0.4

0.6

0.8

1

Months (following end of continuation)

% S

urv

ival

Drug (n=14)CT (n=20)

25% ITT25% ITT

Prevention of Relapse and Recurrence Following Successful Treatment

0

0.2

0.4

0.6

0.8

1

Months (following active treatment)

% S

urv

ival

Placebo (n=35)

Drug (n=34)

Compliant (n=30)

Prior CT (n=35)

ContinuationContinuation FollowupFollowup

ADM and CT

(N=225)

ADM(N=225)

ADM(N=90+)

No ADM(N=90+)

1st

R a n d o

m i z a t i o n

Acute Treatment(3-12 months)

Continuation (6-18 months)

Maintenance/Follow-up(36 months)

CPT III

No ADM(N=90+)

ADM(N=90+)

2nd

R a n d o m i z a t i o n

Remission Recovery

Response Relapse Recurrence

(twice weekly/weekly)

(monthly)

(weekly/biweekly) (monthly)

(monthly/quarterly)

(monthly/quarterly)

Medication SequenceMedication Sequence

SNRI MAOITCA

SNRI or SSRI

Augment Augment Augment Augment

Acute Remission Recovery Normal

Symptoms Elevated Normal Normal Normal

Mechanisms Elevated Elevated Normal Normal

Traits Elevated Elevated Elevated Normal

Acute Remission Recovery Normal

Symptoms Elevated Normal Normal Normal

Mechanisms Elevated Elevated Normal Normal

Traits Elevated Elevated Elevated Normal

Using Longitudinal Data to Disentangle Cause from Consequence

Using Longitudinal Data to Disentangle Cause from Consequence

0%

10%

20%

30%

40%

50%

60%

Psychotherapy and Medications in the Treatment of Unipolar Depression

(AHCPR)

Dynamic

IPT

CT

BT

Medications

Placebos

0%

10%

20%

30%

40%

50%

60%

70%

MAOIs TCAs SSRIs Heteros

Response to Different Medication Classes and Placebo Controls (AHCPR)

% Response

Comp Drug

Placebo

0%

10%

20%

30%

40%

50%

60%

Jarrett (Atypical) DeRubeis (8weeks)

DeRubeis (16weeks)

CT in Placebo-controlled Trials

CBTDrugPlacebo

0%

10%

20%

30%

40%

50%

60%

70%

80%

Kovacs Blackb Simons Evans Shea

Relapse Following Treatment Termination: CT versus Medications

CT

Drug

Comb

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Evans Hollon

Relapse following Successful Treatment: Prior CT versus Medications

CTDrugDrug-CComb

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Paykel Fava #1 Fava #2 Teasdale

Relapse/Recurrence Following CT for Residual Symptoms

CBTDrug

0%

10%

20%

30%

40%

50%

60%

70%

80%

Blackbrn Murphy Hollon Keller

Response to Combined Treatment with CT and Medications in Adult Outpatients

CBTDrugComb

Combined Treatment with CBASP and Nefazodone (Keller et al., 2000)

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 10 11 12

Weeks in Treatment

HR

SD

DrugCBASPComb

0%

10%

20%

30%

40%

50%

60%

Post HRSD 6 or below

Less Severe More Severe

Pre HRSD 20 or above

Patients in Full Remission at Posttreatment in TDCRP (ITT)

CBTIPTTCAPlacebo

0

2

4

6

8

10

12

14

16

Post HRSD

Treatment Condition (CT by Site)

Site Differences in the TDCRP (High Severity Completers N=42)

Placebo (n=13)

Drug (n=15)

CT (n=14)

CT by Site:

Site 1 (n=3)

Site 2 (n=6)

Site 3 (n=5)

Post-treatment HRSD Scores forSeverely Depressed Patients (Intake HRSD > 20)

Post-treatment HRSD Scores forSeverely Depressed Patients (Intake HRSD > 20)

10.79.9

11.5

15.2

12.714.0

4.5

12.113.1

12.1

02468

1012141618

Elkin (N=53)

Rush (N=26)

Murphy (N=22)

Hollon (N=68)

Pooled (N=169)

Po

sttr

ea

tme

nt H

RS

D (

lea

st s

qu

are

s m

ea

n)

ADM CT

10.79.9

11.5

15.2

12.714.0

4.5

12.113.1

12.1

02468

1012141618

Elkin (N=53)

Rush (N=26)

Murphy (N=22)

Hollon (N=68)

Pooled (N=169)

Po

sttr

ea

tme

nt H

RS

D (

lea

st s

qu

are

s m

ea

n)

ADM CT

(From DeRubeis et al., 1999, Am J of Psychiatry)

Attributional Styles as a Function of Treatment Condition (CPT II)

Attributional Styles as a Function of Treatment Condition (CPT II)

-1

-0.5

0

0.5

1

1.5

2

0 2 4 6 8 10 12 14 16

Weeks in Treatment

AS

Q P

os-

Neg

(ad

j)

Placebo

Drug

CBT

-1

-0.5

0

0.5

1

1.5

2

0 2 4 6 8 10 12 14 16

Weeks in Treatment

AS

Q P

os-

Neg

(ad

j)

Placebo

Drug

CBT** **

ASQ and Relapse as a Function of Treatment Condition

ASQ and Relapse as a Function of Treatment Condition

ASQ and Relapse

-4

-2

0

2

4

6

8

10

0 2 4 6 8 10 12 14

Months Survived without Relapse Following Successful Treatment

AS

Q P

os-

Neg

(ad

j)

Drug

CBT

ASQ and Relapse

-4

-2

0

2

4

6

8

10

0 2 4 6 8 10 12 14

Months Survived without Relapse Following Successful Treatment

AS

Q P

os-

Neg

(ad

j)

Drug

CBT

R2=.18R2=.18

R2=.05R2=.05