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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 THE PISA-PITTSBURGH SPECTRUM CONCEPT EVOLVED FROM CASSANO’S SEMINAL OBSERVATIONS 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. Cassano GB, et. al. AJP 1997; 154(suppl 6):27-38 THE PISA-PITTSBURGH SPECTRUM CONCEPT 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. Associated features Typical Symptoms “Atypical “ Symptoms (i.e. not included in diagnostic Criteria) Behavioral Tendencies Features of Interpersonal Relationships SAB 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 DOMAINS Separation sensitivity Panic-like symptoms Stress sensitivity Anxious expectation Medication/substance sensitivity Agoraphobic symptoms Illness phobia/hypochondriasis reassurance orientation Percentage of subjects DISTRIBUTION OF SCI-PAS SCORES IN PATIENTS WITH DSM IV PANIC DISORDER 30% 25% 20% 15% 10% 5% 0% 0-20 21 30 31 40 41 50 51 60 61 70 Total SCI-PAS Score 71 -80 81 90 91 100 Percentage of subjects 60% DISTRIBUTION OF SCI-PAS SCORES IN PATIENTS WITHOUT DSM IV PANIC DISORDER 50% 40% 30% 20% 10% 0% 0-20 21 - 30 31 - 40 41 - 50 51 - 60 61 - 70 71 -80 81 - 90 Total SCI-PAS Score 91 100 Early Studies of Spectrum Psychopathology as Predictors of Treatment Response POTENTIAL UTILITIES OF THE SPECTRUM APPROACH • improvement of the clinician-patient relationship • identification of clinically meaningful subtypes • treatment selection • monitoring course of illness or treatment • measurement of outcome • prevention 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. TIME TO REMISSION AMONG UNIPOLAR PATIENTS WITH HIGH VS. LOW PAS-SR SCORES Survival Functions 1.2 1.0 Breslow test = 4.50 p < .05 .8 .6 PAS score .4 35+ 35+ censored .2 <35 0.0 <35, censored 0 10 20 30 40 WKSREMIT Frank et al., Am. J. Psych., 157(7):1101-1107, 2000. TIME TO REMISSION AMONG BIPOLAR PATIENTS WITH HIGH vs. LOW PAS-SR SCORES Breslow test = 13.6 P = .0002 Frank et al., Arch Gen Psychiatry, 59: 905-912, 2002. Depression Phenotypes Study Design and Outcomes Depression Phenotypes Study Design YES SSRI Stabilized? Add IPT to SSRI Stabilized? NO YES IPT Continue IPT Response? NO YES Switch to 2nd Antidepressant Stabilized? Continue TX monthly YES Continue TX monthly Continue TX monthly NO Add SSRI To IPT Stabilized? NO Random Assignment YES NO Response? NO 291 Patients Continue SSRI YES Switch to 2nd Antidepressant Acute Phase: 12 weeks or until stabilization Continue TX monthly Continuation Phase: 24 weeks (can begin any time after 12 weeks) 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 6.Drug sensitivity and phob 2.Agoraphobia 7.Medical reassurance 3.Claustrophobia 8.Rescue object 4.Separation anxiety 9.Loss sensitivity 5.Fear of losing control 10.Family reassurance Rucci et al., Psychiatric Res, 2009 Rucci et Jal., JAD, 2009 Lifetime MOODS Factors Depressive Factors 1. 2. 3. 4. Depressive Mood Psychomotor retardation Suicidality Drug/Illness related depression 5. Psychotic symptoms 6. Neurovegetative sx Manic Factors 1. Psychomotor activation 2. Mixed Instability 3. Spirituality/Mysticism/Psychoticism 4. Mixed Irritability 5. Euphoria Cassano et al., JAD, 2008a;2008b 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. Patient Flow- First 12 Weeks of Acute Phase PISA N=138 Mean age 40 85% F PITTSBURGH N=153 Mean age 39 61% F Randomization IPT N=70 SSRI N=68 IPT N=79 SSRI N=74 Remission at Week 12 N=49 (70%) 47 IPT 2 IPT+SSRI N=45 (66%) 44 SSRI 1 SSRI+IPT N=30 (38%) 21 IPT 9 IPT+SSRI N=34 (46%) 31 SSRI 3 SSRI+IPT 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 Patient Flow – Full Acute Phase PISA N=138 Mean age 40 85% F PITTSBURGH N=153 Mean age 39 61% F Randomization IPT N=70 SSRI N=68 IPT N=79 SSRI N=74 Total Remissions N=61 (87.1%) 51 IPT 10 IPT+SSRI N=58 (85.3%) 44 SSRI 14 SSRI+IPT N=63 (79.7%) 23 IPT 40 IPT+SSRI N=56 (75.7%) 32 SSRI 24 SSRI+IPT Cumulative Percentage of Remission Over Full Acute Phase IPT N=149 SSRI N=142 100 100 SSRI+IPT 80 34.2 60 8.7 40 45.8 20 49 % remission % remission 80 IPT+SSRI IPT SSRI 28.2 60 2.8 40 20 19.5 52.8 53.5 3 months 3-9 months 28.9 0 0 6 weeks 3 months 3-9 months 6 weeks •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. 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-fornon-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 Pittsburgh Joan Buttenfield Andrea Fagiolini Victoria J. Grochocinski Patty Houck Helena C. Kraemer David J. Kupfer M. Katherine Shear Wesley K. Thompson Pisa Giovanni B. Cassano Simona Calugi Rocco Nicola Forgione Luca Maggi Paola Rucci Paolo Scocco Study Clinicians Pittsburgh Andrea Fagiolini Dana Fleming Debra Frankel Cathy Maihoefer Kim McCaskey Lee Dorothy Parks Holly A. Swartz Kelly Wells Pisa Susanna Banti Antonella Benvenuti Luca Maggi Mario Miniati Marco Saettoni Alessandra Papasogli Gitana 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