Cited by 509Treatment of Major DepressionPsychotherapy Techniques and ApplicationsStatistical Methods in Clinical Trials

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The Personalized Advantage Index: Translating Research on Prediction into Individualized Treatment Recommendations. A Demonstration

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DeRubeis, Robert J., Cohen, Zachary D., Forand, Nicholas R., Fournier, Jay C., Gelfand, Lois A., Lorenzo-Luaces, Lorenzo·2014·PLoS ONE

DOI 10.1371/journal.pone.0083875PMC PMC3885521

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Abstract

BACKGROUND: Advances in personalized medicine require the identification of variables that predict differential response to treatments as well as the development and refinement of methods to transform predictive information into actionable recommendations. OBJECTIVE: To illustrate and test a new method for integrating predictive information to aid in treatment selection, using data from a randomized treatment comparison. METHOD: Data from a trial of antidepressant medications (N = 104) versus cognitive behavioral therapy (N = 50) for Major Depressive Disorder were used to produce predictions of post-treatment scores on the Hamilton Rating Scale for Depression (HRSD) in each of the two treatments for each of the 154 patients. The patient's own data were not used in the models that yielded these predictions. Five pre-randomization variables that predicted differential response (marital status, employment status, life events, comorbid personality disorder, and prior medication trials) were included in regression models, permitting the calculation of each patient's Personalized Advantage Index (PAI), in HRSD units. RESULTS: For 60% of the sample a clinically meaningful advantage (PAI≥3) was predicted for one of the treatments, relative to the other. When these patients were divided into those randomly assigned to their "Optimal" treatment versus those assigned to their "Non-optimal" treatment, outcomes in the former group were superior (d = 0.58, 95% CI .17-1.01). CONCLUSIONS: This approach to treatment selection, implemented in the context of two equally effective treatments, yielded effects that, if obtained prospectively, would rival those routinely observed in comparisons of active versus control treatments.

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Aim in Depression and Anxiety
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Preface
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Construct and Data-Evaluation Validity
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.004
Single-Case Experimental Research Designs
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Control and Comparison Groups
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Cautions, Negative Effects, and Replication
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Selecting Measures for Research
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.011
Glossary
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.021
Special Topics of Assessment
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.013
References
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.022
Ideas that Begin the Research Process
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.005
Methodology
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.020
Subject Index
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.025
Presenting and Analyzing the Data
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.015
Name Index
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.024
Scientific Integrity
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.018
Introduction
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.002
Assessment: Types of Measures and Their Use
Kazdin, A. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108993647.012
Experimental Research Using Group Designs
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“Much more work is needed, however, particularly regarding personalization; that is, for whom do which interventions work best (e.g., DeRubeis et al., 2014; Young et al., 2021).”
Background
Precision therapeutics—personalizing psychological therapy for depression in adolescents
Aitken, M., Durber, C. M., & Goodyer, I. M. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91709-4.00006-8
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“…of such characteristics/aptitudes as part of a systematic treat-ment selection process (Beutler et al., 2006; Beutler & Clarkin, 1990) in service of more personalized psychotherapy (Barber & Solomonov, 2019; DeRubeis et al., 2014; Lorenzo-Luaces et al., 2020; Zilcha-Mano et al., 2021).”
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Background
Insights in Public Mental Health: 2022
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“However, if strongly beneficial ITRs do not exist, further efforts aimed at finding the right predictors would be a futile enterprise.”
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Chapter 10. Latent Variable–Based Predictive And Explanatory Disease Models
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Back Matter
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Chapter 6. Using Inflammatory Biomarkers To Identify And Treat Transdiagnostic Subtypes In Psychiatric Disorders
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Front Matter
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Chapter 7. Pharmacogenetic Testing: A Tool for Precision Prescribing in Psychiatry
Bousman, C., Forbes, M., & Dunlop, B. W. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615379118.lg07
Chapter 8. Treatment Prediction Biomarkers For Major Depressive Disorder
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Chapter 3. Neural Mechanisms Of Bipolar Disorder: Toward Personalized Markers of Future Illness Risk
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Chapter 11. Computational Cognitive Methods For Precision Psychiatry
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Chapter 4. Information Processing Impairments As Transdiagnostic Treatment Targets In Psychiatric Disorders
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Index
(2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615379118.index
Chapter 13. Moving From Precision to Personalized Psychiatry: Clinical Perspectives on the New Era
Perna, G., & Nemeroff, C. B. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615379118.lg13
Chapter 1. A Neural Circuit–Informed Taxonomy For Precision Psychiatry
Hack, L. M., Ball, T. M., & Williams, L. M. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615379118.lg01
Chapter 14. Preparing For The Future Of Precision Psychiatry: The Critical Role of Neuroscience Education
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“50 For the trees for treatment-subgroup interactions, we will use the R package quint.”
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“Identifying the most predictive variables —such as a patient’s demographic and clinical characteristics — plays a pivotal role in tailoring individualized treatment plans[14].”
Additional file 2 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432305
Additional file 1 of The importance of transdiagnostic symptom level assessment to understanding prognosis for depressed adults: analysis of data from six randomised control trials
O’Driscoll, C., Buckman, J. E. J., Fried, E. I., Saunders, R., Cohen, Z. D., Ambler, G., DeRubeis, R. J., Gilbody, S., Hollon, S. D., Kendrick, T., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14545012
Self-citation
Additional file 6 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432329
Additional file 1 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432293
Additional file 1 of Design of an RCT on cost-effectiveness of group schema therapy versus individual schema therapy for patients with Cluster-C personality disorder: the QUEST-CLC study protocol
Groot, I. Z., Venhuizen, A. S. M., Bachrach, N., Walhout, S., de Moor, B., Nikkels, K., Dalmeijer, S., Maarschalkerweerd, M., van Aalderen, J. R., de Lange, H., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303227
Additional file 9 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432350
Additional file 11 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432290
Additional file 1 of Explainable AI enables clinical trial patient selection to retrospectively improve treatment effects in schizophrenia
Mellem, M. S., Kollada, M., Tiller, J. M., & Lauritzen, T. Z. (2021) · Figshare · doi:10.6084/m9.figshare.14633688
Additional file 8 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432344
Additional file 5 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432323
Additional file 2 of Towards optimal treatment selection for borderline personality disorder patients (BOOTS): a study protocol for a multicenter randomized clinical trial comparing schema therapy and dialectical behavior therapy
Wibbelink, C. J. M., Arntz, A. R., Grasman, R. P. P. P., Sinnaeve, R., Boog, M., Bremer, O. M. C., Dek, E. C. P., Alkan, S. G., James, C., Koppeschaar, A. M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19129058
Additional file 3 of Towards optimal treatment selection for borderline personality disorder patients (BOOTS): a study protocol for a multicenter randomized clinical trial comparing schema therapy and dialectical behavior therapy
Wibbelink, C. J. M., Arntz, A. R., Grasman, R. P. P. P., Sinnaeve, R., Boog, M., Bremer, O. M. C., Dek, E. C. P., Alkan, S. G., James, C., Koppeschaar, A. M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19129061
Additional file 3 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432308
Additional file 4 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432317
Additional file 1 of Patient characteristics associated with retrospectively self-reported treatment outcomes following psychological therapy for anxiety or depressive disorders - a cohort of GLAD study participants
Rayner, C., Coleman, J. R. I., Skelton, M., Armour, C., Bradley, J. R., Buckman, J. E. J., Davies, M. R., Hirsch, C. R., Hotopf, M. H., Hübel, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21602068
Additional file 10 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432281
Additional file 7 of Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry
Kappelmann, N., Rein, M., Fietz, J., Mayberg, H. S., Craighead, W. E., Dunlop, B. W., Nemeroff, C. B., Keller, M., Klein, D. N., Arnow, B. A., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12432338
Additional file 4 of Towards optimal treatment selection for borderline personality disorder patients (BOOTS): a study protocol for a multicenter randomized clinical trial comparing schema therapy and dialectical behavior therapy
Wibbelink, C. J. M., Arntz, A. R., Grasman, R. P. P. P., Sinnaeve, R., Boog, M., Bremer, O. M. C., Dek, E. C. P., Alkan, S. G., James, C., Koppeschaar, A. M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19129064
Additional file 1 of Schema therapy versus cognitive behavioral therapy versus individual supportive therapy for depression in an inpatient and day clinic setting: study protocol of the OPTIMA-RCT
Kopf‐Beck, J., Zimmermann, P., Egli, S., Rein, M., Kappelmann, N., Fietz, J., Tamm, J., Rek, K., Lucae, S., Brem, A.-K., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13093877
Additional file 1 of Towards optimal treatment selection for borderline personality disorder patients (BOOTS): a study protocol for a multicenter randomized clinical trial comparing schema therapy and dialectical behavior therapy
Wibbelink, C. J. M., Arntz, A. R., Grasman, R. P. P. P., Sinnaeve, R., Boog, M., Bremer, O. M. C., Dek, E. C. P., Alkan, S. G., James, C., Koppeschaar, A. M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19129055
Üstbilişsel faktörlerin travma sonrası stres bozukluğu belirtileri ile ilişkisinde duygu düzenleme stratejilerinin aracı rolü
Arslan, H., & Yılmaz, A. E. (2026) · Klinik Psikoloji Dergisi · doi:10.57127/kpd.26024438.1744806
Predictors of the Effectiveness of Psychedelics in Treating Depression—A Scoping Review
Chmiel, J., & Rybakowski, F. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052202 · Cited by 1
“Identifying robust predictors allows clinicians to tailor interventions to individual patient needs [39].”
The effectiveness of an adapted modular CBT training for youth with depressive symptoms: a study protocol for an n-of-1 trial
de Lange, J., Telman, L. G. E., van den Heuvel, M. W. H., Vroegindeweij, A., & Bodden, D. H. M. (2026) · BMC Psychology · doi:10.1186/s40359-026-04252-8
“Based on several characteristics of a client, the PAI can predict what sequences of modules would most likely lead to the most optimal treatment outcome for an individual [22].”
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What Happens After Intensive Treatment? Post-Discharge Skill Use and Affect as Predictors of Depression Outcomes
McGhie, S. F., Forgeard, M., Fan, K., McNally, R. J., & Beard, C. (2026) · Cognitive Therapy and Research · doi:10.1007/s10608-026-10727-0
Development of a baseline battery to optimize depression treatment assignment in primary care: Balancing breadth and brevity
Pozuelo, J. R., Kessler, R. C., Patel, V., Lahiri, A., Parashar, Y., Herzallah, M. M., Khanduri, M., O’Neill, K., Martinez, A., Bhan, A., et al. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.121674
Practice-Based Evidence and Data-Informed Psychological Therapy
Lutz, W., Hehlmann, M. I., Deisenhofer, A., Moggia, D., Schaffrath, J., Vehlen, A., Eberhardt, S. T., & Schwartz, B. (2026) · Oxford University Press eBooks · doi:10.1093/9780197748336.003.0003
Uncovering latent trajectories of daily tinnitus symptoms through app-based monitoring during treatment
Engelke, M., Langguth, B., Probst, T., Pryss, R., Schoisswohl, S., Simões, J. P., ten Klooster, P. M., Tödtli, B., Vogel, C., & Schlee, W. (2026) · Internet Interventions · doi:10.1016/j.invent.2026.100943
“Precision matching approaches, such as the Personalized Advantage Index (PAI), may help optimize treatment allocation using prescriptive predictors (DeRubeis et al., 2014).”
An Interpersonal, Context-Responsive, and Evidence-Based Approach to Psychotherapy
Constantino, M. J. (2026) · Journal of Contemporary Psychotherapy · doi:10.1007/s10879-026-09730-z
Toward Personalized Psychoeducational Interventions for Psychophysical Health: A Systematic Review and Meta-Analysis for Tailored Intervention Selection
Gkintoni, E., & Vantarakis, A. (2026) · Journal of Personalized Medicine · doi:10.3390/jpm16040215
Protocol for a randomized trial to predict the efficacy of cognitive and behavioral interventions for symptoms of depression
Ding, J., Chiu, J. C., Moon, S., Ren, Y., Turner, D., Shoval, G., Niv, Y., & Berwian, I. M. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1774560
“Following the approach of the personalized advantage index (PAI; 88, 89), we will use the model to predict for each participant the outcome for the intervention they received (using models trained on data not including this participant) and for the one they did not receive (counterfactual outcome).”
Personalized Treatment Selection for Digital Eating Disorder Interventions: A Proof‐of‐Concept for the Personalized Advantage Index
McClure, Z., Fuller‐Tyszkiewicz, M., Messer, M., & Linardon, J. (2026) · International Journal of Eating Disorders · doi:10.1002/eat.70112
“…models that estimate individual-level outcomes under each treatment condition based on baseline characteristics, and then comparing these predicted outcomes to determine which treat-ment is expected to yield the superior result for a given person (DeRubeis et al. 2014; Meinke et al. 2024).”
Influential
Effectiveness and mechanisms of Intensive Short-Term Dynamic Psychotherapy for treatment-resistant depression: a reanalysis of a randomized controlled trial
Johansson, R., & Lilliengren, P. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1815946
“Modern precision medicine approaches in psychotherapy emphasize such moderation effects (53, 54), recognizing that “ one size ﬁ ts all ” models fail to capture the complexity of therapeutic change.”
Epilogue
Sunzeri, F. (2026) · Springer eBooks · doi:10.1007/978-3-032-14465-2_26
Large Language Models in Mental Health Research and Treatment
Mesquiti, S., & Nook, E. C. (2026) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-092524-113527 · Cited by 2
Domain adaptive uplift modeling across heterogeneous mental health cohorts
Emran, A., & Islam, A. A. A. (2026) · iScience · doi:10.1016/j.isci.2026.116027
“18 In practice, stepped-care models reflect the same underlying principle: that monitoring intensity and support level should be matched to predicted individual need rather than applied uniformly.”
Adherence to Interventions in Integrative Treatment: Associations With Therapeutic Alliance and Early Outcomes
Manubens, R. T., Babl, A., Martínez, D., Roussos, A., & Penedo, J. M. G. (2026) · Counselling and Psychotherapy Research · doi:10.1002/capr.70167
Identifying distinct trajectories of change in anhedonia during psychological treatment for depression
Pugh, D., Saunders, R., Jones, A., Dunn, B., Suh, J. W., Stott, J. C. H., Wheatley, J., Pilling, S., & Buckman, J. E. J. (2026) · Psychological Medicine · doi:10.1017/s0033291726104875
“…additional characteristics linked with treat-ment prognosis were unavailable, including level of previous treat-ment/therapy experience, depression chronicity, marital status, social support, and personality disorder comorbidity (Buckman et al., 2021a, 2021b, 2021c, 2022; DeRubeis et al., 2014).”
Personalized and optimal treatment estimated by a value search method in a randomized clinical trial with psychodynamic versus cognitive behavioral therapy for depression
Klungsøyr, O., Røssberg, J. I., Papageorgiou, C., Evensen, J. H., Løvgren, A., Malkomsen, A., Osnes, K., Ulberg, R., Wilberg, T., & Dammen, T. (2026) · Psychotherapy Research · doi:10.1080/10503307.2026.2682995
Personalized Medicine for the Treatment of Depression
Roh, D., & Kim, M.-D. (2026) · Springer eBooks · doi:10.1007/978-981-92-1331-3_14

Authors: DeRubeis, R. J., Cohen, Z. D., Forand, N. R., Fournier, J. C., Gelfand, L. A., & Lorenzo-Luaces, L.
Affiliations: University of Pennsylvania (US)
The Ohio State University (US)
University of Pittsburgh (US)
Corresponding author: DeRubeis, Robert J.
ORCID: DeRubeis, Robert J.
Cohen, Zachary D.
Forand, Nicholas R.
Fournier, Jay C.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2014-01-08
Volume: 9
Issue: 1
Pages: e83875
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0083875
PMC: PMC3885521
OpenAlex: W2079702662
Cited by: 509
References: 42
Citations by year: 2026: 36 · 2025: 25 · 2024: 33 · 2023: 41 · 2022: 52 · 2021: 99 · 2020: 46 · 2019: 51 · 2018: 34 · 2017: 35 · 2016: 26 · 2015: 23 · 2014: 8
FWCI: 22.60
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute of Mental Health (2-R01-MH-060998-06, R01MH060998)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords: personalized medicine, treatment selection, differential treatment response, prediction of treatment outcome, major depressive disorder, antidepressants, cognitive behavioral therapy, Hamilton Depression Rating Scale, treatment response prediction
MeSH terms: Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Health Planning Guidelines, Humans, Prognosis, Psychiatric Status Rating Scales, Cognitive Behavioral Therapy, Translational Research, Biomedical, Precision Medicine

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The Personalized Advantage Index: Translating Research on Prediction into Individualized Treatment Recommendations. A Demonstration

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