Dataset Information

Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study.

ABSTRACT: 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.A subsample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression 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.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).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.

SUBMITTER: Brent D

PROVIDER: S-EPMC2887294 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study.

Brent David D Melhem Nadine N Ferrell Robert R Emslie Graham G Wagner Karen Dineen KD Ryan Neal N Vitiello Benedetto B Birmaher Boris B Mayes Taryn T Zelazny Jamie J Onorato Matthew M Devlin Bernie B Clarke Greg G DeBar Lynn L Keller Marty M

The American journal of psychiatry 20091215 2

<h4>Objective</h4>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.<h4>Method</h4>A subsample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial, 155 of whom were of European origin, were genotyped with respect to 21 polymorphisms on 12 genes that have a repor ...[more]

PMID: 20008943

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Project description:ImportanceSuicide prevention is an important component of depression management. Knowledge about depressed adolescents with increased risk for suicide can inform suicide prevention efforts.ObjectiveTo describe the risk of documented suicidal ideation within a year following a diagnosis of depression and to examine how the risk of documented suicidal ideation differed by recent violence encounter status among adolescents with new depression diagnoses.Design, setting, and participantsRetrospective cohort study in clinical settings including outpatient facilities, emergency departments, and hospitals. Using IBM's Explorys database containing electronic health records from 26 US health care networks, this study observed a cohort of adolescents with new depression diagnoses from 2017 to 2018 for up to 1 year. Data were analyzed from July 2020 to July 2021.ExposuresRecent violence encounter was defined by a diagnosis of child maltreatment (physical, sexual, or psychological abuse or neglect) or physical assault within 1 year before depression diagnosis.Main outcomes and measuresThe main outcome was diagnosis of suicidal ideation within 1 year following depression diagnosis. Multivariable adjusted risk ratios of suicidal ideation were calculated for overall recent violence encounters and for individual forms of violence.ResultsAmong a total of 24 047 adolescents with depression, 16 106 (67.0%) were female and 13 437 (55.9%) were White. A total of 378 had experienceda violence (hereafter, encounter group) and 23 669 had not (hereafter, nonencounter group). Following the diagnosis of depression, 104 adolescents with any past-year violence encounter (27.5%) documented suicidal ideation within 1 year. In contrast, 3185 adolescents in the nonencounter group (13.5%) experienced thoughts of suicide following the diagnosis of depression. In multivariable analyses, those with any violence encounter had 1.7 times (95% CI 1.4-2.0) higher risk of documented suicidal ideation compared with those in the nonencounter group (P < .001). Among different forms of violence, sexual abuse (risk ratio, 2.1; 95% CI, 1.6-2.8) and physical assault (risk ratio, 1.7; 95% CI, 1.3-2.2) were associated with significantly increased risk of suicidal ideation.Conclusions and relevanceAmong adolescents with depression, persons who experienced past-year violence encounters showed a higher rate of suicidal ideation than those who had not. These findings highlight the importance of identifying and accounting for past violence encounters when treating adolescents with depression to reduce risk of suicide. Public health approaches to prevent violence may help to avert morbidity associated with depression and suicidal ideation.

Project description:Therapeutic seizures may work for treatment-resistant depression (TRD) by producing neuroplasticity. We evaluated whether magnetic seizure therapy (MST) produces changes in suicidal ideation and neuroplasticity as indexed through transcranial magnetic stimulation and electroencephalography (TMS-EEG) of the dorsolateral prefrontal cortex (DLPFC). Twenty-three patients with TRD were treated with MST. Changes in suicidal ideation was assessed through the Scale for Suicidal Ideation (SSI). Before and after the treatment course, neuroplasticity in excitatory and inhibitory circuits was assessed with TMS-EEG measures of cortical-evoked activity (CEA) and long-interval cortical inhibition (LICI) from the left DLPFC, and the left motor cortex as a control condition. As in our previous report, the relationship between TMS-EEG measures and suicidal ideation was examined with the SSI. Results show that 44.4% of patients experienced resolution of suicidal ideation. Based on DLPFC assessment, MST produced significant CEA increase over the frontal central electrodes (cluster p < 0.05), but did not change LICI on a group level. MST also reduced the SSI scores (p < 0.005) and the amount of reduction correlated with the decrease in LICI over the right frontal central electrodes (cluster p < 0.05; rho = 0.73 for Cz). LICI change identified patients who were resolved of suicidal ideation with 90% sensitivity and 88% specificity (AUC = 0.9, p = 0.004). There was no significant finding with motor cortex assessment. Overall, MST produced significant rates of resolution of suicidal ideation. MST also produced neuroplasticity in the frontal cortex, likely through long-term potentiation (LTP)-like mechanisms. The largest reduction in suicidal ideation was demonstrated in patients showing concomitant decreases in cortical inhibition-a mechanism linked to enhanced LTP-like plasticity. These findings provide insights into the mechanisms through which patients experience resolution of suicidal ideation following seizure treatments in depression.

Project description:Objective: To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Methods: Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ2 tests. Results: In adolescents with treatment-resistant MDD (N = 97), aged 12-21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5-31.9) to 14.8 (range: 1.8-31.7) to 19.5 (range: 2.5-36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased (p = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ2 = 17, p < 0.001). Conclusions: This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.

Dataset Information

Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study.

Publications

Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study.

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