Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial

Perroud, Nader; Uher, Rudolf; Marušič, Andrej; Rietschel, Marcella; Mors, Ole; Henigsberg, Neven; Hauser, Joanna; Maier, Wolfgang; Souery, Daniel; Placentino, Anna; Szczepankiewicz, Aleksandra; Jørgensen, Lisbeth Flindt; Strohmaier, Jana; Zobel, Astrid; Giovannini, C; Elkin, Amanda; Gunasinghe, Cerisse; Gray, Joanna; Campbell, Desmond; Gupta, Bhanu; Farmer, Anne; McGuffin, Peter; Aitchison, Katherine J.

doi:10.1186/1741-7015-7-60

Cited by 51 publications

(56 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings of a significant association between increasing suicidal ideation during treatment and the ADRA2A gene implies that dysregulation of noradrenergic transmission through alpha-2A adrenergic receptors may have an impact on aggressive and impulsive behaviors, especially in men taking nortriptyline. Our results therefore support the hypothesis that hypersensitivity or enhanced activity of these receptors could, in part, explain why some individuals have an increase in suicidal ideation during treatment with a noradrenergic antidepressant (Perroud et al, 2009). Our results also suggest that this sensitivity is explained by a genetic polymorphism within the relevant gene (ADRA2A).…”

Section: Discussionsupporting

confidence: 85%

“…Decreased BDNF levels have been reported in the plasma and CSF of subjects with SB, so that it could be postulated that SB would be most pronounced in the acute phase of treatment. In our study, however, the risk of an increase in total suicidal ideation (combining treatment-emergent and treatmentworsening) was approximately evenly distributed through the assessment period (Perroud et al, 2009). It is therefore possible that the reduction in BDNF level is more persistent in suicidal subjects than in non-suicidal ones.…”

Section: Discussionmentioning

confidence: 54%

“…Second, to check that the detected associations were not due to confounding by specific individual or center-ofrecruitment effects, significant SNPs were reanalyzed using a generalized linear latent and mixed model (GLLAMM) in STATA as previously described (Perroud et al, 2009). Using this method, we were able to include all individuals, that is, those who switched and those who did not switch medication, by relaxing the assumption of conditional independence in the responses of the same person and for the same center of recruitment by including a subjectspecific random intercept nested in a center-specific random intercept (Rabe-Hesketh and Skrondal, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…A composite score was calculated using item response theory (IRT), which allowed the use of all available data and provided us with unbiased estimates in the presence of missing values (Perroud et al, 2009;Uher et al, 2008).…”

Section: Suicidal Ideationsmentioning

confidence: 99%

“…A previous analysis of this dataset showed that individuals with treatment-emergent suicidal ideation and those with treatment-worsening suicidal ideation shared similar risk factors (Perroud et al, 2009). We therefore designated individuals with either emergence or worsening of suicidal ideation at any time point in the 12-week follow-up period (254) as 'cases' and those without any increase of suicidal ideation (542) as 'controls'.…”

Section: Suicidal Ideationsmentioning

confidence: 99%

See 4 more Smart Citations

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

Perroud

Aitchison

Uher

et al. 2009

Neuropsychopharmacol

Self Cite

104

View full text Add to dashboard Cite

The aim of this study was to investigate genetic predictors of an increase in suicidal ideation during treatment with a selective serotonin reuptake inhibitor or a tricyclic antidepressant. A total of 796 adult patients with major depressive disorder who were treated with a flexible dosage of escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP) were included in the sample and provided data on suicidal ideation. Nine candidate genes involved in neurotrophic, serotonergic, and noradrenergic pathways were selected based on previous association studies with suicidal ideation or behavior. Using a logistic regression model, 123 polymorphisms in these genes were compared between subjects with an increase in suicidal ideation and those without any increase in suicidal ideation. Polymorphisms in BDNF, the gene encoding the brain-derived neurotrophic factor, were significantly associated with an increase in suicidal ideation. The strongest association was observed for rs962369 in BDNF (p ¼ 0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p ¼ 0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha 2A -adrenergic receptor gene (ADRA2A) (p ¼ 0.007). The associations observed with polymorphisms in BDNF suggest the involvement of the neurotrophic system in vulnerability to suicidality. Epistasis between BDNF and NTRK2 suggests that genetic variations in the two genes are involved in the same causal mechanisms leading to suicidality during antidepressant treatment. Among men, genetic variation in noradrenergic signaling may interact with norepinephrine reuptake-inhibiting antidepressants, thereby contributing to suicidality.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Suicidal Ideationsmentioning

confidence: 99%

Section: Suicidal Ideationsmentioning

confidence: 99%

See 3 more Smart Citations

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

Perroud

Aitchison

Uher

et al. 2009

Neuropsychopharmacol

Self Cite

104

View full text Add to dashboard Cite

show abstract

Antidepressant Dosage and Suicidal Ideation

et al. 2014

View full text Add to dashboard Cite

The respondents used 61 distinct EMR systems (Q4) and came from a broad range of practice types (Q1). Nine EMRs were used by 20 or more respondents, accounted for 324 (78.8%) of all users, and users of each of these lost free time (P < .05 for all). Of these 9, the Veterans Affairs' Computer Patient Record System (CPRS) was associated with the least free time loss (−20 minutes) (P = .04). Respondents were experienced EMR users. Most (70.6%) used all of the EMR functions listed in Q4, and 82.5% had EMRs in their practice for more than a year (Q7). Among all respondents, 89.8% reported that at least 1 data management function was slower post-EMR adoption, and 63.9% reported that note writing took longer. Surprisingly, a third (33.9%) reported that it took longer to find and review medical record data with the EMR than without, and a similar proportion, 32.2%, that it was slower to read other clinicians' notes.The mean time loss for attending physicians was −48 minutes per clinic day (P < .001), or 4 hours per 5-day clinic week. The mean loss for trainees was −18 minutes per day, less than that of attending physicians (P < .001). For the 59.4% of all respondents who did lose time, the mean loss was −78 minutes per clinic day, or 6.5 hours per 5-day clinic week.

show abstract

Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: A genome‐wide association and polygenic scoring study

Mullins

Perroud

Uher

et al. 2014

American J of Med Genetics Pt B

Self Cite

111

115

View full text Add to dashboard Cite

Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.

show abstract

Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial

Cited by 51 publications

References 41 publications

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

Antidepressant Dosage and Suicidal Ideation

Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: A genome‐wide association and polygenic scoring study

Contact Info

Product

Resources

About