Results of the European Group for the Study of Resistant Depression (GSRD) — basis for further research and clinical practice

Abstract

Objectives: The overview outlines two decades of research from the European Group for the Study of Resistant Depression (GSRD) that fundamentally impacted evidence-based algorithms for diagnostics and psychopharmacotherapy of treatment-resistant depression (TRD).

Methods: The GSRD staging model characterising response, non-response and resistance to antidepressant (AD) treatment was applied to 2762 patients in eight European countries.

Results: In case of non-response, dose escalation and switching between different AD classes did not show superiority over continuation of original AD treatment. Predictors for TRD were symptom severity, duration of the current major depressive episode (MDE), suicidality, psychotic and melancholic features, comorbid anxiety and personality disorders, add-on treatment, non-response to the first AD, adverse effects, high occupational level, recurrent disease course, previous hospitalisations, positive family history of MDD, early age of onset and novel associations of single nucleoid polymorphisms (SNPs) within the PPP3CC, ST8SIA2, CHL1, GAP43 and ITGB3 genes and gene pathways associated with neuroplasticity, intracellular signalling and chromatin silencing. A prediction model reaching accuracy of above 0.7 highlighted symptom severity, suicidality, comorbid anxiety and lifetime MDEs as the most informative predictors for TRD. Applying machine-learning algorithms, a signature of three SNPs of the BDNF, PPP3CC and HTR2A genes and lacking melancholia predicted treatment response.

Conclusions: The GSRD findings offer a unique and balanced perspective on TRD representing foundation for further research elaborating on specific clinical and genetic hypotheses and treatment strategies within appropriate study-designs, especially interaction-based models and randomized controlled trials.

Keywords:

• Depression
• psychopharmacotherapy
• response
• treatment resistance
• predictor

Acknowledgments

The authors would like to thank all persons involved in the GSRD project and the patients who participated.

Statement of interest

Dr. Bartova has received travel grants from AOP Orphan, Austroplant, and consultant/speaker honoraria from Janssen, Medizin Medien Austria and Vertretungsnetz. Dr. Dold has received a travel grant from Janssen-Cilag. Dr. Spies has received travel grants from Janssen, AOP Orphan, Austroplant, and Eli Lilly, Workshop participation from Eli Lilly, and speaker honoraria from Austroplant and Janssen. Dr. Serretti is or has been consultant/speaker for Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. Dr. Kasper received grants/research support, consulting fees and/or honoraria within the last 3 years from Angelini, AOP Orphan Pharmaceuticals AG, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. Dr. Souery has received grant/research support from GlaxoSmithKline and Lundbeck; and he has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Janssen and Lundbeck. Dr. Mendlewicz is a member of the faculty of the Lundbeck International Neuroscience Foundation and of the advisory board of Servier. Dr. Zohar has received grant/research support from Lundbeck, Servier and Pfizer; he has served as a consultantor on the advisory boards for Servier, Pfizer, Solvay and Actelion; and he has served on speakers’ bureaus for Lundbeck, GSK, Jazz and Solvay. Dr. Montgomery has been a consultant or served on advisory boards for AstraZeneca, Bionevia, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Grunenthal, Intellect Pharma, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M’s Science, Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Targacept, Transcept, UBC, Xytis and Wyeth. All other authors declare that they have no conflicts of interest.

Author contributions

All authors were actively involved in the selection and review of the scientific content and had full editorial control during the writing and submitting of the manuscript. All authors are entirely responsible for the scientific content.

Additional information

Funding

The Group for the Study of Resistant Depression (GRSD) was supported by an unrestricted grant from Lundbeck, which had no further role in the study design, data collection and analysis and interpretation, as well as in the writing and submitting of the manuscript for publication.