Association of FKBP5 Polymorphisms With Suicidal Events in the Treatment of Resistant Depression in Adolescents (TORDIA) Study

Abstract

Objective-The authors sought to assess the relationship between candidate genes and two clinical outcomes, namely, symptomatic improvement and the occurrence of suicidal events, in a sample of treatment-resistant depressed adolescents. Method-A subsample of depressed adolescents participating in the Treatment of SSRI-ResistantDepression in Adolescents (TORDIA) trial, 155 of whom were of European origin, were genotyped with respect to 21 polymorphisms on 12 genes that have a reported association with depression, treatment response, or suicidal events. Participants had not responded to a previous adequate trial with an antidepressant and were randomized to receive either another selective serotonin reuptake inhibitor or venlafaxine, with or without cognitive-behavioral therapy (CBT). Single-nucleotide polymorphism (SNP) analyses were conducted using PLINK with permutation procedures.Results-No relationship was observed between any polymorphism and response to treatment. The FKBP5 (which codes for a protein causing subsensitivity of the glucocorticoid receptor) rs1360780TT and rs3800373GG genotypes were associated with suicidal events (N=18), even after controlling for treatment effects and relevant covariates. These two SNPs were in significant linkage disequilibrium (r=0.91).Conclusions-The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity. These results are consistent with those of other studies linking alterations in the hypothalamic-pituitary-adrenal axis with suicidal behavior. The small number of events and lack of a placebo condition make these results preliminary. Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment.Clinical guidelines recommend the use of antidepressants for moderate to severe adolescent depression (1). However, even under the controlled conditions of clinical trials, only around 60% of depressed adolescents respond to an initial trial with a selective serotonin reuptake inhibitor (SSRI) (2). The high rate of nonresponse and the occurrence of suicidal events in depressed adolescents are both important clinical concerns (2). In this context, efforts to NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript personalize treatment by identifying which patients are most likely to respond to antidepressants and least likely to experience a suicidal event are of high public health significance. Pharmacogenetics, which examines the relationship between genetic variation and clinical response to a given medication, holds promise for personalizing and optimizing pharmacotherapy.Pharmacogenetic predictors of antidepressant response have primarily focused on the impact of genetic variations in the serotonin transporter promoter gene (SLC64A) and on other serotonin-related receptors because of the mechanisms of action of SSRIs (3). Antidepressant treatment response has been associated with the l...

Genome-Wide Association Study of Antidepressant Treatment-Emergent Suicidal Ideation

“…However, we found one SNP within GDA, which was associated in the GENDEP GWAS approach, significantly associated with TESI. Moreover, we found further evidence for FKBP5 and ABCB1 to be implicated in TESI, which were previously reported in two other candidate gene approaches on emerging or worsening of suicidal ideation (Brent et al, 2010a;Perroud, 2011).…”

“…In candidate gene studies, associations with suicidal ideation were found with genetic markers within the genes encoding the glutamate receptors GRIK2 and GRIA3 (Laje et al, 2007), and the cyclic adenosine response-element binding protein (CREB1) (Perlis et al, 2007b) in the STAR*D cohort and the genes encoding brain-derived neurotrophic factor (BDNF), the neurotrophic tyrosine kinase receptor type 2 (NTRK2), and a-2 adrenergic receptor (ADRA2A) (Perroud et al, 2009) in GENDEP. Further candidate gene approaches revealed associations of markers within FK506-binding protein 5 (FKBP5) in the Treatment of Resistant Depression in Adolescents (TORDIA) study (Brent et al, 2010a) and in FKBP5 and ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1) in a sample of depressed outpatients . Previously, markers of the two glutamatergic receptor genes could be partly replicated in our Munich Antidepressant Response Signature (MARS) project (http://www.mars-depression.de), an independent sample consisting mainly of individuals of German origin (Menke et al, 2008).…”

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

“…Indeed, T homozygotes were found to exhibit elevated cortisol levels during recovery after stress (Ising et al 2008). In line with this, rs1360780 has been associated with psychopathology such as mood disorders (Binder et al 2004;Lavebratt et al 2010;Lekman et al 2008;Zobel et al 2010) and suicidality (Brent et al 2010). Moreover, this SNP has been shown to interact with childhood abuse in predicting PTSD symptoms (Binder et al 2008) and susceptibility to depression (Appel et al 2011), with an increased risk in the TT genotype following childhood abuse.…”

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

“…In humans, healthy adults homozygous for these alleles show a greater and more prolonged cortisol response during the Trier Social Stress Test compared with those who have complementary genotypes (Ising et al, 2008). These SNPs, as well as rs9296158 and rs9470080, have been associated with a higher FKBP5 expression and a stronger induction of FKBP5 mRNA by cortisol (Binder et al, 2004;Tatro et al, 2010), and subsequently have been correlated with depression (Binder et al, 2004;Tatro et al, 2010) and suicide (Brent et al, 2010;Perez-Ortiz et al, 2013). They also affect cortisol responses and result in diminished dexamethasone suppression (Binder et al, 2008).…”