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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