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

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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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          Most cited references22

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          The path to personalized medicine.

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            Prevention of relapse following cognitive therapy vs medications in moderate to severe depression.

            Antidepressant medication prevents the return of depressive symptoms, but only as long as treatment is continued. To determine whether cognitive therapy (CT) has an enduring effect and to compare this effect against the effect produced by continued antidepressant medication. Patients who responded to CT in a randomized controlled trial were withdrawn from treatment and compared during a 12-month period with medication responders who had been randomly assigned to either continuation medication or placebo withdrawal. Patients who survived the continuation phase without relapse were withdrawn from all treatment and observed across a subsequent 12-month naturalistic follow-up. Outpatient clinics at the University of Pennsylvania and Vanderbilt University. A total of 104 patients responded to treatment (57.8% of those initially assigned) and were enrolled in the subsequent continuation phase; patients were initially selected to represent those with moderate to severe depression. Patients withdrawn from CT were allowed no more than 3 booster sessions during continuation; patients assigned to continuation medication were kept at full dosage levels. Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression or Hamilton Depression Rating Scale scores of 14 or higher during the continuation phase. Recurrence was defined in a comparable fashion during the subsequent naturalistic follow-up. Patients withdrawn from CT were significantly less likely to relapse during continuation than patients withdrawn from medications (30.8% vs 76.2%; P = .004), and no more likely to relapse than patients who kept taking continuation medication (30.8% vs 47.2%; P = .20). There were also indications that the effect of CT extends to the prevention of recurrence. Cognitive therapy has an enduring effect that extends beyond the end of treatment. It seems to be as effective as keeping patients on medication.
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              A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.

              The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome. To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression. Genomewide pharmacogenetic association study with 2 independent replication samples. We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample). We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome. Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome. These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                8 January 2014
                : 9
                : 1
                : e83875
                Affiliations
                [1 ]Department of Psychology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [2 ]Department of Psychiatry, The Ohio State University, Columbus, Ohio, United States of America
                [3 ]Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
                Queen Elizabeth Hospital, Hong Kong
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RJD ZDC NRF JCF LG LLL. Analyzed the data: ZDC. Wrote the paper: RJD ZDC NRF JCF LG LLL.

                Article
                PONE-D-13-33641
                10.1371/journal.pone.0083875
                3885521
                24416178
                21ca527f-8c0d-4000-ade5-c991d1b9e267
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 August 2013
                : 9 November 2013
                Page count
                Pages: 8
                Funding
                Support provided by NIMH grant 2-R01-MH-060998-06, “Prevention of Recurrence in Depression with Drugs and CT” ( http://www.nimh.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Clinical Genetics
                Personalized Medicine
                Clinical Research Design
                Clinical Trials
                Statistical Methods
                Mental Health
                Psychiatry
                Mood Disorders
                Psychology
                Clinical Psychology
                Therapies
                Drug Psychotherapy
                Psychotherapy
                Social and Behavioral Sciences
                Psychology
                Therapies
                Drug Psychotherapy
                Psychotherapy
                Clinical Psychology

                Uncategorized
                Uncategorized

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