Copy number variants and therapeutic response to antidepressant medication in major depressive disorder

Tansey, Katherine E.; Rucker, James; Kavanagh, David; Guipponi, Michel; Perroud, Nader; Bondolfi, Guido; Domenici, Enrico; Evans, David M.; Hauser, Jon C; Henigsberg, Neven; Jerman, Borut; Maier, Wolfgang; Mors, Ole; O'Donovan, Michael Conlon; Peters, Tim J.; Placentino, Anna; Rietschel, Marcella; Souery, Daniel; Aitchison, Katherine J.; Craig, Ian W.; Farmer, Anne; Wendland, Jens R.; Malafosse, Alain; Kapur, Shitij; McGuffin, Peter; Uher, Rudolf

doi:10.1038/tpj.2013.51

Cited by 20 publications

(14 citation statements)

References 31 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36 Additionally, a study investigating the association of CNVs with response to antidepressant medication in major depressive disorder showed no general effect, but the authors noted less response for carriers of CNVs in specific loci, including NRXN1. 37 For therapygenetics, recent studies have mostly used common genetic variants either in selected candidate genes 38 or a hypothesis-free genome-wide approach 39 with no or limited evidence of genetic moderators of treatment response. We used a more refined approach, by investigating rare genic CNVs that are associated with a large risk for ASD as well as other neurodevelopmental and psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Tammimies

Rabkina

et al. 2018

Preprint

View full text Add to dashboard Cite

Challenges in social communication and interaction are core symptoms in autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention.SSGT has shown modest but heterogeneous effects in clinical trials, and therefore identification of effect moderators could enable more precise intervention decisions. One of the major genetic risk factors in ASD are rare copy number variation (CNV). However, limited information exists whether rare CNVs profiles can be used to aid in intervention decisions. Therefore, we conducted the first study to date analyzing rare CNVs as genetic moderators in the outcome of SSGT in ASD. For this, we analyzed rare genic CNV carrier status of 207 children of which 105 received SSGT and 102 standard care as part of a recent randomized clinical trial for 12-weeks SSGT. We used mixed linear models to assess the association of being a CNV carrier, grouped by the effect and size of the CNVs and the primary response to SSGT, the parent-report Social Responsiveness Scale (SRS) measured at post-intervention and 3-months follow-up. Additionally, we analyzed the secondary outcome assessments included parent-rated adaptive behaviors (ABAS-II) and trainer-rated clinical global impression (CGI). We show that being a carrier of any size rare genic CNV did not impact on the SSGT outcome. However, when stratifying the groups by size of the CNVs, we identified that carriers of large CNVs (>500 kb) showed inferior SRS outcomes at post-intervention (β = 15.35, 95% CI 2.86-27.84, P=0.017) and follow-up (β = 14.19, 95% CI 1.68-26.70, P=0.028). Similar results were shown for the parent-rated secondary outcome. In contrast, the carriers of small CNVs had better outcome at post-intervention (β = -1.20, 95 % CI -2.0 --0.4 P = 0.003) but not at follow-up for the trainer-rated secondary outcome CGI. These results remained when we tested the specificity of the effect by including the standard care group and adjusting for IQ levels. While our study suggests that being a carrier of any size rare genic 3 CNV did not impact the outcome, it provides preliminary evidence that carriers of high-riskCNVs might not benefit on SSGT as much as non-carriers. Our results indicate that genetic information eventually might help guide personalized intervention planning in ASD. We additionally highlight that more research is needed to understand the intervention needs of autistic individuals with specified molecular alterations.

show abstract

Section: Discussionmentioning

confidence: 99%

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Tammimies

Rabkina

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…While promising, this result underscores one of the challenges in studying TRD: because the cohorts are diffi cult to collect and characterize, there is a paucity of such samples available, so replication has not been possible. (A second study, using the NEWMEDS cohort, also examined copy number variation, but focused on overall antidepressant response rather than treatment resistance [ 36 ]; evidence of enrichment of duplications was not observed. )…”

Section: Association Studies Of Trdmentioning

confidence: 99%

Genomic Studies of Treatment Resistance in Major Depressive Disorder

Perlis

2016

Genetic Influences on Response to Drug Treatment for Major Psychiatric Disorders

View full text Add to dashboard Cite

Treatment-resistant depression describes the subset of individuals with major depressive disorder who do not reach symptomatic remission despite multiple adequate treatment trials. While treatment resistance has a substantial impact on functioning, quality of life, and healthcare costs, little is known about the underlying neurobiology. While at least some treatment-resistant depression (TRD) risk is likely to be heritable, based primarily on evidence from antidepressant pharmacogenomics, studies to date have failed to reliably identify rare or common genetic variation associated with this phenotype. Challenges in the study of TRD include misclassifi cation arising from medication intolerance or inadequate treatment trials, the heterogeneity of the concept itself, and most notably the absence of well-characterized cohorts with DNA available for study. New strategies to identify large cohorts from biobanks or disease registries and efforts to meta-analyze multiple cohorts may facilitate the identifi cation of risk variants. In addition, further studies to understand the potential utility of pharmacogenomic testing among individuals with TRD or to stratify risk for TRD are needed. Background and MotivationAround 1/3 of individuals who receive initial antidepressant treatment for major depressive disorder will not reach symptomatic remission. A subset of these, perhaps approaching 50 %, will not remit despite additional antidepressant treatment [ 31 ]. Such nonremission in the face of adequate antidepressant trials is referred to as treatment-resistant depression [ 9 ], a concept fi rst characterized more than 40

show abstract

“…They concluded that SVs in drug target genes are important as determinants of individual drug response. Another study conducted in 1,565 patients with MDD revealed association of specific CNVs-including 15q13.3 duplications and exonic neurexin 1 (NRXN1) deletions-with response to serotonergic or noradrenergic antidepressant treatment (Tansey et al 2014). Pharmacogenetic studies targeting CNVs might complement classic pharmacogenetic studies investigating e.g.…”

Section: Future Directions and Clinico-therapeutic Implicationsmentioning

confidence: 99%

Genomic structural variation in affective, anxiety, and stress-related disorders

2014

View full text Add to dashboard Cite

Anxiety and stress-related disorders are common and debilitating mental diseases. Genetic factors as well as environmental factors and life events contribute to their pathogenesis and partly mediate treatment response. However, these disorders are clinically heterogeneous, genetically complex, and the exact genetic causes are still unclear. Recently, some evidence has emerged for structural variation including copy number variants and small deletions/duplications to be associated with mental disorders. Here, the current state of knowledge on the role of genomic structural variation in affective, anxiety and stress-related disorders is reviewed, followed by a critical discussion of present methods to detect structural changes, future directions, and clinical implications including a potential role in personalized medicine.

show abstract

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder

Abstract: General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms

Cited by 20 publications

References 31 publications

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Genomic Studies of Treatment Resistance in Major Depressive Disorder

Genomic structural variation in affective, anxiety, and stress-related disorders

Contact Info

Product

Resources

About