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      A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials

      review-article
      1 , , 1 , 1 , 2 , 3 , 4 , 5 , 6 , 4 , 7 , 8 , 9 , 10 , 1 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 15 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 1 , 11 , 1 , 11 , 38 , 39 , 40 , 38 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 52 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 49 , 50 , 52 , 62 , 63 , 64 , 50 , 65 , 66 , 61 , 67 , 46 , 48 , 62 , 64 , 68 , 1 , 11
      Molecular Psychiatry
      Nature Publishing Group UK
      Diagnostic markers, Depression

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          Abstract

          Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

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          Most cited references78

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          The PHQ-9: validity of a brief depression severity measure.

          While considerable attention has focused on improving the detection of depression, assessment of severity is also important in guiding treatment decisions. Therefore, we examined the validity of a brief, new measure of depression severity. The Patient Health Questionnaire (PHQ) is a self-administered version of the PRIME-MD diagnostic instrument for common mental disorders. The PHQ-9 is the depression module, which scores each of the 9 DSM-IV criteria as "0" (not at all) to "3" (nearly every day). The PHQ-9 was completed by 6,000 patients in 8 primary care clinics and 7 obstetrics-gynecology clinics. Construct validity was assessed using the 20-item Short-Form General Health Survey, self-reported sick days and clinic visits, and symptom-related difficulty. Criterion validity was assessed against an independent structured mental health professional (MHP) interview in a sample of 580 patients. As PHQ-9 depression severity increased, there was a substantial decrease in functional status on all 6 SF-20 subscales. Also, symptom-related difficulty, sick days, and health care utilization increased. Using the MHP reinterview as the criterion standard, a PHQ-9 score > or =10 had a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively. Results were similar in the primary care and obstetrics-gynecology samples. In addition to making criteria-based diagnoses of depressive disorders, the PHQ-9 is also a reliable and valid measure of depression severity. These characteristics plus its brevity make the PHQ-9 a useful clinical and research tool.
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            The PHQ-9

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              A RATING SCALE FOR DEPRESSION

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                Author and article information

                Contributors
                luca.sforzini@kcl.ac.uk
                Journal
                Mol Psychiatry
                Mol Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                15 December 2021
                15 December 2021
                2022
                : 27
                : 3
                : 1286-1299
                Affiliations
                [1 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, ; London, UK
                [2 ]GRID grid.5379.8, ISNI 0000000121662407, Neuroscience and Psychiatry Unit, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biological, Medical and Human Sciences, , The University of Manchester and Manchester Academic Health Sciences Centre, ; Manchester, UK
                [3 ]GRID grid.412041.2, ISNI 0000 0001 2106 639X, Department of General and Academic Psychiatry, Centre Hospitalier Charles Perrens, Laboratory of Nutrition and Integrative Neurobiology (UMR INRAE 1286), , University of Bordeaux, ; Bordeaux, France
                [4 ]GRID grid.5949.1, ISNI 0000 0001 2172 9288, Department of Psychiatry and Psychotherapy, , University of Münster, ; Münster, Germany
                [5 ]GRID grid.5949.1, ISNI 0000 0001 2172 9288, Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, , University of Münster, ; Münster, Germany
                [6 ]GRID grid.412282.f, ISNI 0000 0001 1091 2917, Department of Psychiatry and Psychotherapy, , University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, ; Dresden, Germany
                [7 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Psychiatry, Melbourne Medical School and The Florey Institute of Neuroscience and Mental Health, , The University of Melbourne, ; Parkville, VIC Australia
                [8 ]Mood Disorders Research Unit, The Royal’s Institute of Mental Health Research, Ottawa, ON Canada
                [9 ]GRID grid.28046.38, ISNI 0000 0001 2182 2255, Department of Psychiatry, , University of Ottawa, ; Ottawa, ON Canada
                [10 ]GRID grid.28046.38, ISNI 0000 0001 2182 2255, Department of Cellular and Molecular Medicine, University of Ottawa, ; Ottawa, ON Canada
                [11 ]GRID grid.451056.3, ISNI 0000 0001 2116 3923, National Institute for Health Research Mental Health Biomedical Research Centre, South London and Maudsley NHS Foundation Trust and King’s College London, ; London, UK
                [12 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Medical Sciences Division, Department of Psychiatry, , University of Oxford, ; Oxford, UK
                [13 ]GRID grid.7872.a, ISNI 0000000123318773, APC Microbiome Ireland, Cork, Ireland; Department of Psychiatry and Neurobehavioral Sciences, , University College Cork, ; Cork, Ireland
                [14 ]GRID grid.9024.f, ISNI 0000 0004 1757 4641, Department of Molecular Medicine, Division of Psychiatry, , University of Siena, ; Siena, Italy
                [15 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Translational and Clinical Research Institute, , Newcastle University, ; Newcastle upon Tyne, UK
                [16 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Depression Research Center of the German Depression Foundation and Department of Psychiatry, Psychosomatics and Psychotherapy, , Goethe University, ; Frankfurt, Germany
                [17 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Psychiatry, , University of California, San Francisco, ; San Francisco, CA USA
                [18 ]GRID grid.26009.3d, ISNI 0000 0004 1936 7961, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, ; Durham, NC USA
                [19 ]GRID grid.412116.1, ISNI 0000 0001 2292 1474, Université Paris Est Creteil (UPEC), AP-HP, Hôpitaux Universitaires Henri Mondor, Département Médico-Universitaire d’Addictologie et Psychiatrie (DMU IMPACT), INSERM U955, IMRB, translational Neuropsychiatry lab, Fondation FondaMental, ; F-94010 Creteil, France
                [20 ]Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle, UK
                [21 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Psychiatry, , University of Toronto, ; Toronto, ON Canada
                [22 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Pharmacology and Toxicology, , University of Toronto, ; Toronto, ON Canada
                [23 ]GRID grid.231844.8, ISNI 0000 0004 0474 0428, Mood Disorders Psychopharmacology Unit, , University Health Network, ; Toronto, ON Canada
                [24 ]GRID grid.490755.a, Brain and Cognition Discovery Foundation, ; Toronto, ON Canada
                [25 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, , Heidelberg University, ; Square J5, 68159 Mannheim, Germany
                [26 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Department of Psychiatry and Behavioral Sciences, , Emory University School of Medicine, ; Atlanta, GA 30322 USA
                [27 ]GRID grid.89336.37, ISNI 0000 0004 1936 9924, Department of Psychiatry, , University of Texas at Austin, Dell Medical School, ; Austin, TX USA
                [28 ]GRID grid.5963.9, Department for Psychiatry and Psychotherapy, , Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, ; Hauptstrasse 5, 79104 Freiburg, Germany
                [29 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Centre for Neuropsychopharmacology, Division of Psychiatry, , Imperial College, London, ; London, UK
                [30 ]GRID grid.251993.5, ISNI 0000000121791997, Istituto di Neuroscience, , University of Florence, Italy; Albert Einstein College of Medicine, ; New York, USA
                [31 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Department of Psychiatry and Behavioral Sciences, , Psychiatry University of Miami, ; Miami, FL USA
                [32 ]GRID grid.7548.e, ISNI 0000000121697570, Department of Biomedical, Metabolic & Neural Sciences, , University of Modena, ; Modena, Italy
                [33 ]GRID grid.504900.8, VeraSci, ; Durham, NC USA
                [34 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Department of Psychiatry, Amsterdam UMC, , Vrije Universiteit and GGZinGeest, ; Amsterdam, the Netherlands
                [35 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Psychiatry and Behavioral Sciences, , Stanford University, ; Stanford, CA USA
                [36 ]GRID grid.265892.2, ISNI 0000000106344187, Department of Psychiatry, , University of Alabama at Birmingham, ; Birmingham, AL USA
                [37 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Department of Psychiatry, , University of British Columbia, ; Vancouver, British Columbia Canada
                [38 ]GRID grid.414802.b, ISNI 0000 0000 9599 0422, Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM), ; Bonn, Germany
                [39 ]GRID grid.452397.e, Office of Therapies for Neurological and Psychiatric disorders, Human Medicines Division, , European Medicines Agency, ; Amsterdam, the Netherlands
                [40 ]GRID grid.418236.a, ISNI 0000 0001 2162 0389, Biostatistics, GlaxoSmithKline, ; London, UK
                [41 ]Laughren Psychopharm Consulting, LLC, Rockville, MD USA
                [42 ]GRID grid.434485.a, GAMIAN-Europe (Global Alliance of Mental Illness Advocacy Networks-Europe), ; Brussels, Belgium
                [43 ]GRID grid.412966.e, ISNI 0000 0004 0480 1382, Department of Psychiatry and Psychology, School for Mental Health and Neuroscience, EURON, , Maastricht University Medical Centre, ; Maastricht, the Netherlands
                [44 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Faculty of Psychology, Center for Experimental and Learning Psychology, , University of Leuven, ; Leuven, Belgium
                [45 ]GRID grid.452397.e, Data, Analytics and Methodology Taskforce, , European Medicines Agency, ; Amsterdam, the Netherlands
                [46 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Department of Psychiatry, , Hospital Universitari Vall d’Hebron (HUVH), ; Barcelona, Catalonia Spain
                [47 ]GRID grid.469673.9, ISNI 0000 0004 5901 7501, Biomedical Network Research Centre on Mental Health (CIBERSAM), ; Madrid, Spain
                [48 ]GRID grid.7080.f, ISNI 0000 0001 2296 0625, Department of Psychiatry and Forensic Medicine, , Universitat Autònoma de Barcelona, ; Barcelona, Catalonia Spain
                [49 ]GRID grid.15496.3f, ISNI 0000 0001 0439 0892, Vita-Salute San Raffaele University, ; Milan, Italy
                [50 ]GRID grid.18887.3e, ISNI 0000000417581884, Division of Neuroscience, Psychiatry and Clinical Psychobiology, , IRCCS Scientific Institute Ospedale San Raffaele, ; Milan, Italy
                [51 ]GRID grid.430994.3, ISNI 0000 0004 1763 0287, Strategic Projects Unit, Vall d ‘Hebron Research Institute (VHIR), , Vall d’Hebron Barcelona Hospital Campus, ; Barcelona, Spain
                [52 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, ; Berlin, Germany
                [53 ]GRID grid.419619.2, ISNI 0000 0004 0623 0341, Janssen Research & Development, ; Beerse, Belgium
                [54 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Charité – Universitätsmedizin Berlin, Department of Psychosomatic Medicine, Campus Benjamin Franklin, ; Berlin, Germany
                [55 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, University Medical Center Hamburg-Eppendorf, Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Center for Molecular Neurobiology, ; Hamburg, Germany
                [56 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Psychiatry, Erasmus University Medical Centre, ; Rotterdam, the Netherlands
                [57 ]GRID grid.419481.1, ISNI 0000 0001 1515 9979, Medical Director Neuroscience for Region Europe at Novartis Pharma, ; Basel, Switzerland
                [58 ]GRID grid.10939.32, ISNI 0000 0001 0943 7661, Department of Psychiatry, , University of Tartu, ; Tartu, Estonia
                [59 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Faculty of Medicine, Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences, , Imperial College London, ; London, UK
                [60 ]Documental Ltd, Tallin, Estonia; West Tallinn Central Hospital, Tallinn, Estonia
                [61 ]GRID grid.497530.c, ISNI 0000 0004 0389 4927, Department of Global Regulatory Affairs, Neuroscience, , Janssen Research & Development, LLC, ; Titusville, NJ USA
                [62 ]GRID grid.430994.3, ISNI 0000 0004 1763 0287, Group of Psychiatry, Mental Health and Addictions, , Vall d’Hebron Research Institute (VHIR), ; Barcelona, Catalonia Spain
                [63 ]GRID grid.7080.f, ISNI 0000 0001 2296 0625, Universidad Autónoma de Barcelona, ; Barcelona, Spain
                [64 ]GRID grid.469673.9, ISNI 0000 0004 5901 7501, Biomedical Network Research Centre on Mental Health (CIBERSAM), ; Barcelona, Catalonia Spain
                [65 ]GRID grid.419619.2, ISNI 0000 0004 0623 0341, Experimental Medicine, Janssen Research & Development, , Janssen Pharmaceutica NV, ; Beerse, Belgium
                [66 ]European Infrastructure for Translational Medicine (EATRIS), Amsterdam, Netherlands
                [67 ]GRID grid.419481.1, ISNI 0000 0001 1515 9979, Neuroscience, Global Drug Development, , Novartis Pharma AG, ; Basel, Switzerland
                [68 ]GRID grid.497530.c, ISNI 0000 0004 0389 4927, Department of Neuroscience, Janssen Research & Development, LLC, ; Titusville, NJ USA
                Author information
                http://orcid.org/0000-0001-6795-0391
                http://orcid.org/0000-0003-0539-2376
                http://orcid.org/0000-0002-2666-859X
                http://orcid.org/0000-0002-6990-939X
                http://orcid.org/0000-0001-5518-6138
                http://orcid.org/0000-0002-2316-7220
                http://orcid.org/0000-0002-6702-781X
                http://orcid.org/0000-0001-5473-3697
                http://orcid.org/0000-0001-8260-7997
                http://orcid.org/0000-0001-7867-1160
                http://orcid.org/0000-0001-5693-8936
                http://orcid.org/0000-0002-1286-1401
                http://orcid.org/0000-0003-2291-6952
                http://orcid.org/0000-0003-4949-856X
                http://orcid.org/0000-0002-6326-8333
                http://orcid.org/0000-0001-5188-4799
                http://orcid.org/0000-0002-4051-997X
                http://orcid.org/0000-0001-9594-0246
                http://orcid.org/0000-0001-5332-3549
                http://orcid.org/0000-0003-1622-0350
                http://orcid.org/0000-0002-9132-5091
                Article
                1381
                10.1038/s41380-021-01381-x
                9095475
                34907394
                c3c93aec-0316-4b26-87ba-b9688d79eaa4
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 August 2021
                : 11 October 2021
                : 26 October 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100010767, Innovative Medicines Initiative (IMI);
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                Categories
                Review Article
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                © The Author(s), under exclusive licence to Springer Nature Limited 2022

                Molecular medicine
                diagnostic markers,depression
                Molecular medicine
                diagnostic markers, depression

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