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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.

Background: Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results., Methods: A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene., Results: Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n=34, 13.6%)., Conclusions: Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P<0.05) could be found between any SNP and neither suicide risk nor personal history of suicide attempts. Interactions between 5HTR1A rs6295 and 5HTR2A rs6313 in suicide risk, and 5HTR1A rs6295 and 5HTR2A rs643627 in a personal history of suicide attempts have been reported (P=0.027 and 0.036, respectively); however, the results did not survive multiple testing correction. In conclusion, our study shows no association between 5HTR1A or 5HTR2A gene polymorphisms and both current suicide risk and personal history of suicide attempts. In addition, epistatic effects of 5HTR1A and 5HTR2A genes on suicidal behaviour were not significant, although sample size limitations do not allow definitive conclusions.

Purpose: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polymorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients., Materials and Methods: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied., Results: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction., Conclusions: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients.

Objectives: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype., Methods: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD., Results: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10⁻⁶. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait., Conclusions: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.

The primary objective of this review is to give an overview of the main findings of the European multicenter project "Patterns of Treatment Resistance and Switching Strategies in Affective Disorder", performed by the Group for the Study of Resistant Depression (GSRD). The aim was to study methodological issues, operational criteria, clinical characteristics, and genetic variables associated with treatment resistant depression (TRD), that is failure to reach response after at least two consecutive adequate antidepressant trials. The primary findings of clinical variables associated with treatment resistance include comorbid anxiety disorders as well as non-response to the first antidepressant received lifetime. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained in case of nonresponse to one medication, the results of the GSRD challenge this notion by demonstrating in retrospective and prospective evaluations that staying on the same antidepressant mechanism of action for a longer time is more beneficial than switching, however, when switching is an option there is no benefit to switch across class. The GSRD candidate gene studies found that metabolism status according to cytochrome P450 gene polymorphisms may not be helpful to predict response and remission rates to antidepressants. Significant associations with MDD and antidepressant treatment response were found for COMT SNPs. Investigating the impact of COMT on suicidal behaviour, we found a significant association with suicide risk in MDD patients not responding to antidepressant treatment, but not in responders. Further significant associations with treatment response phenotypes were found with BDNF, 5HTR2A and CREB1. Additional investigated candidate genes were DTNBP1, 5HT1A, PTGS2, GRIK4 and GNB3., (Copyright © 2012 Elsevier B.V. All rights reserved.)