Predictors and Moderators of Time to Remission of Major Depression

with

Interpersonal Psychotherapy and SSRI Pharmacotherapy

Ellen Frank, PhD Distinguished Professor of Psychiatry

University of Pittsburgh School of Medicine

OVERVIEW

• Rationale and Aims of the Depression Phenotypes Study

• The Spectrum Psychopathology Concept• Early Studies of Spectrum Psychopathology as

Predictors of Treatment Response• Depression Phenotypes Study Design and

Outcomes

Rationale and Aims of the Depression Phenotypes Study

Depression: The Search for Treatment Relevant Phenotypes - Study Rationale and Aims

• To define a set of indicators and corresponding assessment instruments that show a strong, consistent and clinically significant association with depression treatment outcome with pharmacotherapy vs. psychotherapy

• Potential indicators studied: 1) type and number of mood spectrum features 2) type and number of anxiety spectrum features 3) treatment exposure – to both SSRI and IPT

4) demographic and clinical characteristics

The Spectrum Psychopathology Concept

Patients who meet criteria for a DSM disorder often manifest a spectrum of related symptoms, behavioral tendencies and temperament traits, not included in the diagnostic criteria.

Recognition of these clinically significant features can improve the doctor-patient relationship, identify clinically meaningful subtypes, and guide treatment decisions.

THE PISA-PITTSBURGH SPECTRUM CONCEPT

EVOLVED FROM CASSANO’S SEMINAL OBSERVATIONS

Cassano GB, et. al. AJP 1997; 154(suppl 6):27-38

We assume that spectrum features may be present over the course of the lifetime, often as isolated phenomena even in those who do not currently meet or have never met the full criteria for the related syndrome.

THE PISA-PITTSBURGH SPECTRUM CONCEPT

SAB

“Atypical “Symptoms(i.e. not included in diagnosticCriteria)

Associated features Typical

Symptoms

BehavioralTendencies

Features ofInterpersonalRelationships

Clinical Observations of patients meeting criteria for a DSM IV Disorder

www.spectrum-project.org

• General description of spectrum concept

• Downloadable copies of all instruments

• Bibliography through 2006

ILLUSTRATING THE SPECTRUM APPROACH: PANIC-AGORAPHOBIC SPECTRUM

• How an instrument was developed

• Confirmation of reliability and validity

• Establishing clinical significance

PANIC-AGORAPHOBIC SPECTRUM

114 symptoms and related behavioral tendencies

and temperament traits

DOMAINSSeparation sensitivityPanic-like symptoms

Stress sensitivityAnxious expectation

Medication/substance sensitivityAgoraphobic symptoms

Illness phobia/hypochondriasisreassurance orientation

DISTRIBUTION OF SCI-PAS SCORES IN PATIENTS WITH DSM IV PANIC DISORDER

0%

5%

10%

15%

20%

25%

30%

0-20 21 -30

31 -40

41 -50

51 -60

61 -70

71 -80 81 -90

91 -100

Per

cen

tag

e o

f su

bje

cts

Total SCI-PAS Score

DISTRIBUTION OF SCI-PAS SCORES IN PATIENTS WITHOUT DSM IV PANIC DISORDER

0%

10%

20%

30%

40%

50%

60%

0-20 21 - 30 31 - 40 41 - 50 51 - 60 61 - 70 71 -80 81 - 90 91 -100

Total SCI-PAS Score

Per

cen

tag

e o

f su

bje

cts

Early Studies of Spectrum Psychopathology as Predictors of

Treatment Response

• improvement of the clinician-patient relationship• identification of clinically meaningful subtypes

• treatment selection

• monitoring course of illness or treatment

• measurement of outcome

• prevention

POTENTIAL UTILITIES OF THE SPECTRUM APPROACH

RELATIONSHIP OF PANIC SPECTRUM TO RESPONSE TO ACUTE TREATMENT OF A

MOOD DISORDER

H1: The presence of panic-agoraphobic spectrum symptomatology is associated with significantly longer times to remission of acute mood episodes.

Survival Functions

WKSREMIT

403020100

Cu

m S

urv

iva

l

1.2

1.0

.8

.6

.4

.2

0.0

PAS score

35+

35+ censored

<35

<35, censored

TIME TO REMISSION AMONG UNIPOLAR PATIENTS WITH HIGH VS. LOW PAS-SR SCORES

Breslow test = 4.50

p < .05

Frank et al., Am. J. Psych., 157(7):1101-1107, 2000.

TIME TO REMISSION AMONG BIPOLAR PATIENTS WITH HIGH vs. LOW PAS-SR SCORES

Frank et al., Arch Gen Psychiatry, 59: 905-912, 2002.

Breslow test = 13.6

P = .0002

Depression Phenotypes Study Design and Outcomes

Depression Phenotypes Study Design

SSRI

IPT

Response?

Add IPT toSSRI

Add SSRITo IPT

Stabilized?Continue

IPT

Response?

Switch to 2nd

Antidepressant

Stabilized?

Stabilized?Continue

SSRI

Stabilized?

Switch to 2nd

Antidepressant

Continue TXmonthly

YES

NO

YES

NO

NO

YES

YES

NO

291Patients

Random Assignment

Acute Phase: 12 weeks or until stabilizationContinuation Phase: 24 weeks (can begin any time after 12 weeks)

Continue TXmonthly

Continue TXmonthly

Continue TXmonthly

YES

YES

NO

NO

Predictors/Moderators Examined

• Lifetime and last-month MOODS, PAS, OBS and SHY total scores

• Lifetime MOODS factor scores• Lifetime PAS factor scores• Demographic and traditional clinical characteristics• Site

Lifetime PAS Factors

1.Panic symptoms 2.Agoraphobia

3.Claustrophobia

4.Separation anxiety

5.Fear of losing control

Rucci et al., JAD, 2009Rucci et al., JAD, 2009Rucci et al., J Psychiatric Res, 2009Rucci et al., J Psychiatric Res, 2009

6.Drug sensitivity and phobia

7.Medical reassurance

8.Rescue object

9.Loss sensitivity

10.Family reassurance

Lifetime MOODS Factors

1. Depressive Mood2. Psychomotor retardation3. Suicidality4. Drug/Illness related

depression5. Psychotic symptoms

6. Neurovegetative sx

Cassano et al., JAD, 2008a;2008bCassano et al., JAD, 2008a;2008b

1. Psychomotor activation2. Mixed Instability3. Spirituality/Mysticism/Psy-

choticism4. Mixed Irritability5. Euphoria

Depressive FactorsDepressive Factors Manic FactorsManic Factors

Prediction and Moderation Analyses

Cox regression models were used to analyze the effects of each potential spectrum or other predictor/moderator, site, treatment and their interactions on time to remission truncated at 12 weeks.

N=30 (38%)21 IPT9 IPT+SSRI

N=45 (66%)44 SSRI1 SSRI+IPT

N=34 (46%)31 SSRI3 SSRI+IPT

N=49 (70%)47 IPT2 IPT+SSRI

PISAN=138

Mean age 4085% F

PITTSBURGHN=153

Mean age 3961% F

IPTN=70

SSRIN=68

IPTN=79

SSRIN=74

Randomization

Remission at Week 12

Patient Flow- First 12 Weeks of Acute Phase

Predictors of Time to Remission over 12 Weeks

Frank et al, Psychological Medicine, in press

Predictors of Time to Remission over 12 Weeks

Frank et al, Psychological Medicine, in press

Moderators of Time to Remission over 12 Weeks - I MOODS Psychomotor Activation Factor

Frank et al, Psychological Medicine, in press

Moderators of Time to Remission over 12 Weeks – II PAS Medical Reassurance Factor

Frank et al, Psychological Medicine, in press

N=63 (79.7%)23 IPT40 IPT+SSRI

N=58 (85.3%)44 SSRI14 SSRI+IPT

N=56 (75.7%)32 SSRI24 SSRI+IPT

N=61 (87.1%)51 IPT10 IPT+SSRI

PISAN=138

Mean age 4085% F

PITTSBURGHN=153

Mean age 3961% F

IPTN=70

SSRIN=68

IPTN=79

SSRIN=74

Randomization

Total Remissions

Patient Flow – Full Acute Phase

Cumulative Percentage of Remission Over Full Acute Phase

19.5

45.8 49

8.7

34.2

0

20

40

60

80

100

6 weeks 3 months 3-9 months

% r

emis

sio

n

IPT+SSRI

IPT

IPT N=149 SSRI N=142

•Across both study sites, the strategy of initial IPT or SSRI monotherapy, followed by augmentation for non-remitters was associated with very high remission rates.

•One-third of patients ultimately received combination treatment.

28.9

52.8 53.5

2.8

28.2

0

20

40

60

80

100

6 weeks 3 months 3-9 months%

rem

issi

on

SSRI+IPT

SSRI

Summary

•The MOODS and PAS factors provided good prediction of time to remission for both IPT and SSRI treatment.

•A only one MOODS and one PAS factor moderated treatment response both study sites.

•A monotherapy-followed-by-combination-for- non-remitters sequence leads to a high remission rate among outpatients with unipolar depression regardless of whether the sequence is begun with medication or psychotherapy.

.

Collaborators

PittsburghJoan ButtenfieldAndrea FagioliniVictoria J. GrochocinskiPatty HouckHelena C. KraemerDavid J. KupferM. Katherine ShearWesley K. Thompson

PisaGiovanni B. CassanoSimona CalugiRocco Nicola ForgioneLuca MaggiPaola RucciPaolo Scocco

Study Clinicians

PittsburghAndrea FagioliniDana FlemingDebra FrankelCathy MaihoeferKim McCaskey LeeDorothy ParksHolly A. SwartzKelly Wells

PisaSusanna BantiAntonella BenvenutiLuca MaggiMario MiniatiMarco SaettoniAlessandra PapasogliGitana Giorgi

Other Key Personnel

Pittsburgh

Joel Anderton

Debbie Stapf

Gail Kepple

Teresa Pagano

Pisa

Giulia Gray

Giuseppina Pica

Riccardo Rolla

Spectrum Advisory Board – 1997

Pittsburgh Depression Phenotypes Team - 2010