Chiara Fabbri1, Siegfried Kasper2, Alexander Kautzky3, Lucie Bartova3, Markus Dold4, Joseph Zohar5, Daniel Souery6, Stuart Montgomery7, Diego Albani8, Ilaria Raimondi9, Dimitris Dikeos10, Dan Rujescu11, Rudolf Uher12, Cathryn M Lewis13, Julien Mendlewicz14, Alessandro Serretti15. 1. Research Fellow,Department of Biomedical and NeuroMotor Sciences,University of Bologna,ItalyandInstitute of Psychiatry, Psychology and Neuroscience,King's College London,UK. 2. Professor,Department of Psychiatry and Psychotherapy,Medical University Vienna,Austria. 3. PhD Student,Department of Psychiatry and Psychotherapy,Medical University Vienna,Austria. 4. Associate Professor,Department of Psychiatry and Psychotherapy,Medical University Vienna,Austria. 5. Professor,Department of Psychiatry,Sheba Medical Center and Sackler School of Medicine,Tel Aviv University,Israel. 6. Director,Laboratoire de Psychologie Medicale,Universitè Libre de Bruxelles and Psy Pluriel,Centre Européen de Psychologie Medicale,Brussels,Belgium. 7. Professor,Imperial College, University of London,UK. 8. Director,Unità Genetica delle Malattie Neurodegenerative, Istituto di Ricerche Farmacologiche Mario Negri IRCCS,Italy. 9. Research Fellow,Unità Genetica delle Malattie Neurodegenerative, Istituto di Ricerche Farmacologiche Mario Negri IRCCS,Italy. 10. Professor,Department of Psychiatry,Athens University Medical School,Greece. 11. Professor,University Clinic for Psychiatry, Psychotherapy and Psychosomatic, Martin-Luther-University Halle-Wittenberg,Germany. 12. Professor,Department of Psychiatry,Dalhousie University,Canada. 13. Professor,Institute of Psychiatry, Psychology and Neuroscience,King's College London,UK. 14. Professor,School of Medicine, Free University of Brussels,Belgium. 15. Professor,Department of Biomedical and NeuroMotor Sciences,University of Bologna,Italy.
Abstract
BACKGROUND: Treatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine. METHOD: A sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants. RESULTS: No individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027). CONCLUSIONS: The identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.
BACKGROUND: Treatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine. METHOD: A sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants. RESULTS: No individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027). CONCLUSIONS: The identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.
Authors: Oliver Pain; Karen Hodgson; Vassily Trubetskoy; Stephan Ripke; Victoria S Marshe; Mark J Adams; Enda M Byrne; Adrian I Campos; Tania Carrillo-Roa; Annamaria Cattaneo; Thomas D Als; Daniel Souery; Mojca Z Dernovsek; Chiara Fabbri; Caroline Hayward; Neven Henigsberg; Joanna Hauser; James L Kennedy; Eric J Lenze; Glyn Lewis; Daniel J Müller; Nicholas G Martin; Benoit H Mulsant; Ole Mors; Nader Perroud; David J Porteous; Miguel E Rentería; Charles F Reynolds; Marcella Rietschel; Rudolf Uher; Eleanor M Wigmore; Wolfgang Maier; Naomi R Wray; Katherine J Aitchison; Volker Arolt; Bernhard T Baune; Joanna M Biernacka; Guido Bondolfi; Katharina Domschke; Masaki Kato; Qingqin S Li; Yu-Li Liu; Alessandro Serretti; Shih-Jen Tsai; Gustavo Turecki; Richard Weinshilboum; Andrew M McIntosh; Cathryn M Lewis Journal: Biol Psychiatry Glob Open Sci Date: 2022-04
Authors: Chiara Fabbri; Siegfried Kasper; Alexander Kautzky; Joseph Zohar; Daniel Souery; Stuart Montgomery; Diego Albani; Gianluigi Forloni; Panagiotis Ferentinos; Dan Rujescu; Julien Mendlewicz; Rudolf Uher; Cathryn M Lewis; Alessandro Serretti Journal: Transl Psychiatry Date: 2020-02-03 Impact factor: 6.222