The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives

Fabbri, Chiara; Corponi, Filippo; Souery, Daniel; Kasper, Siegfried; Montgomery, Stuart; Zohar, Joseph; Rujescu, Dan; Mendlewicz, Julien; Serretti, Alessandro

doi:10.1093/ijnp/pyy024

Cited by 45 publications

(40 citation statements)

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“…Possible ways by which this could be achieved include: (1) identifying genetic predictors of non-response to specific antidepressant classes; (2) prescribing treatments with increased efficacy but limited availability because of costs constraints to patients having genetic risk for TRD. However, most existing pharmacogenomic studies were focused on measures of response to the last treatment without taking into account previous treatments, leaving the genetics of TRD largely unexplored 7 . Another issue was the investigation of common variants only, while the possible role of rare variants was overlooked, despite they were suggested as one of the factors contributing to missing heritability of common traits 8 .…”

Section: Introductionmentioning

confidence: 99%

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

et al. 2020

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Treatment-resistant depression (TRD) occurs in~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.

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Section: Introductionmentioning

confidence: 99%

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

et al. 2020

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“…Arguably, it is possible that genetic mechanisms could partly contribute to the emergence of tolerance to antidepressants in specific subsets of patients.The genetics of molecules putatively implicated in treatment loss of response or treatment-resistant depression included BDNF, GRIK4, KCNK2, SLC6A4, however, most studies have been based on candidate gene approach, and only for few genes replication supported associations with treatmentresistant depression. Among serotonin receptor, the GG variant for the rs7333412 SNP of the 5HT2A has shown association with less proneness to antidepressant response compared to the AA/AG variant.In the preclinical study, it has been demonstrated that the 5-HT2A receptors may have an inhibitory effect on the neuronal activity of the serotonergic neurons after acute administration of SSRIs GWAS (Genome-Wide Association Studies) did not detect any genome-wide significant association at the variant level, however, signal transduction including genes regulating synaptic plasticity, cytoskeleton architecture, and neurogenesis could be associated with treatment-resistant depression, according to the results by genome-wide association studies of antidepressant response[68].…”

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The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications

Fornaro

Anastasia²,

Novello

et al. 2019

Pharmacological Research

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“…29,30 Enrichment was also identified in gene sets involved in cytoskeleton regulation and regulation of second messenger cascades, in line with previous findings. 4 Another encouraging finding was the observation of a significant higher expression of the genes of interest in some brain regions compared with other tissues (supplementary Figure 4).…”

Section: Key Findings and Interpretationmentioning

confidence: 79%

“…4 Another GWAS investigated the role of rare variants in TRD and again the most interesting results were obtained at the gene-set level, showing enrichment of rare variants in genes regulating actin cytoskeleton, although the finding did not survive multiple-testing correction. 4 The present paper reports a GWAS of common variants and a meta-analysis at the polymorphism, gene and gene-set (pathway) level, with the aim of contributing to filling the gap in our knowledge about TRD genetics.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples

et al. 2018

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BackgroundTreatment-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.MethodA 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.ResultsNo 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).ConclusionsThe 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.

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The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives

Abstract: Genetic biomarkers to identify patients with higher risk of treatment-resistant depression or to guide treatment in these patients are not available yet. Methodological improvements of future studies could lead to the identification of genetic biomarkers with clinical validity.

Cited by 45 publications

References 78 publications

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications

Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples

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