Treatment-emergent Suicidal Ideation Research Articles

Polymorphisms of stress pathway genes and emergence of suicidal ideation at antidepressant treatment onset

The prescription of antidepressant drugs is one of the most frequently used strategies to prevent suicide and suicidal behavior. However, some patients develop suicidal ideation at antidepressant treatment onset, a phenomenon known as treatment-emergent suicidal ideation (TESI). Few studies have explored TESI pharmacogenomics. As the Hypothalamic-Pituitary-Adrenal (HPA) axis might be implicated in suicidal behavior, we assessed the relationship between TESI and single nucleotide polymorphisms (SNPs) in the HPA axis-implicated NR3C1 (n = 7 SNPs), FKBP5 (n = 5 SNPs), AVPR1B (n = 1 SNPs), CRHR1 (n = 1 SNPs), and SKA2 (n = 1 SNPs) genes, in a sample of 3566 adult outpatients with depression for whom an antidepressant treatment was introduced. General practitioners and psychiatrists throughout France followed participants for 6 weeks after the initial prescription of tianeptine, an antidepressant molecule showing mu agonism. Suicidal ideation was assessed with item 10 of the Montgomery-Åsberg Depression Rating Scale (item dedicated to suicidal ideation) at baseline, and at week 2, 4, and 6 of treatment. Within the informative sample, 112 patients reported TESI and 384 did not. TESI was significantly associated with the TT genotype of the SNP rs6902321 in FKBP5 (OR = 1.76, 95% CI = [1.07; 2.90]; p-value = 0.03) and the GG/AG genotype of the SNP rs7208505 in SKA2 (OR = 1.85, 95% CI = [1.03;3.33]; p-value = 0.04). These associations were not significant after multiple test correction. Nevertheless, our results suggest a possible involvement of HPA axis elements in treatment-emergent suicidal ideation (TESI).

Suicidality and other severe psychiatric events with duloxetine: Re-analysis of safety data from a placebo-controlled trial for juvenile fibromyalgia.

In antidepressant trials for pediatric patients with depression or anxiety disorders, the risk of suicidal events and other severe psychiatric adverse events such as aggression and agitation is increased with antidepressants relative to placebo. To examine whether largely mentally healthy adolescents treated for a non-psychiatric condition are also at increased risk of suicidality and other severe psychiatric disorders. This is a re-analysis of a placebo-controlled duloxetine trial for juvenile fibromyalgia based on the main journal article and additional data published in the online supplementary material and on ClinicalTrials.gov. Both serious adverse events related to psychiatric disorders and adverse events leading to treatment discontinuation were defined as severe treatment-emergent psychiatric adverse events. We found that a significant portion of adolescents had treatment-emergent suicidal ideation and behaviour as well as other severe psychiatric adverse events with duloxetine, but no such events were recorded on placebo. The incidence of severe treatment-emergent psychiatric adverse events was statistically significantly higher with duloxetine as compared to placebo. Antidepressants may put adolescents at risk of suicidality and other severe psychiatric disorders even when the treatment indication is not depression or anxiety.

Activation syndrome induced by the antidepressant tianeptine and suicidal ideation: Evidence from a large depressed outpatient sample

ObjectiveTo determine the characteristics of the activation syndrome (AS) that predict the emergence or worsening of suicidal ideation (SI) in the first month of antidepressant treatment with tianeptine, as well as the temporal relationship between both conditions. MethodA naturalistic sample of 2422 depressed outpatients starting a new antidepressant treatment with tianeptine was assessed at 2, 4 and 6 weeks of follow-up using validated questionnaires. Four main dimensions of AS were examined: impulsivity, sleep problems, anxiety and agitation. ResultsThe emergence of an AS was more likely in long-lasting depressive episodes, but less likely if the patient responded to the antidepressant or benzodiazepines were added as an add-on treatment. Treatment-emergent SI was strongly associated to the presence of an AS, particularly in case of sleep problems (OR = 8.42) or impulsivity upsurges (OR = 3.89), even after adjustment for all relevant confounding factors. ConclusionsOur findings suggest a dose-effect mechanism modulating the relationship between treatment-related SI and AS. AS symptoms may need to be monitored closely in the weeks that follow the introduction of an antidepressant treatment.

Polymorphism A118G of opioid receptor mu 1 (OPRM1) is associated with emergence of suicidal ideation at antidepressant onset in a large naturalistic cohort of depressed outpatients

Antidepressants have been the object of an international controversy for about thirty years. Some patients are inclined to develop suicidal ideation (SI) at antidepressant onset; this phenomenon is known as Treatment Emergent Suicidal Ideation (TESI), and it has conducted regulatory bodies to prompt warnings on antidepressants. Since, few studies have explored the pharmacogenomics of TESI. Given the growing body of evidence connecting the opioidergic system with suicidal behavior (particularly mu opioid receptor (MOR)), we decided to examine the relationship between two genetic polymorphisms (SNPs) in the opioidergic system and TESI in a sample of 3566 adult depressed outpatients. General practitioners and psychiatrists throughout France followed participants for 6 weeks after an initial prescription of tianeptine, an antidepressant treatment with mu agonism. Suicidal ideation was assessed with the item 10 of the Montgomery-Asberg Depression Rating Scale (item dedicated to SI) at baseline, and after 2 weeks, 4 weeks and 6 weeks. We analysed rs1799971 from the OPRM1 gene and rs105660 from the OPRK1 gene. Within the sample, 112 patients reported TESI while 384 did not. We found a significant association between AA genotype of rs1799971 and TESI even after adjustment for potential cofounders (OR = 1.93, 95% CI = [1.07; 3.49]; p-value = 0.03). On the other hand there were no significant association between rs1799971 and rs105560 with worsening of suicidal ideation or lifetime suicide attempts. Nevertheless, our results suggest a possible involvement of opioidergic system in TESI.

SA7 - GENOME-WIDE ASSOCIATION STUDIES OF SUICIDAL IDEATION DURING PSYCHOTROPIC MEDICATION

Background Suicidal behaviour can be a serious symptom of psychiatric disorder and may change during the course of psychotropic medication treatment. There have been a number of published Genome-Wide Association Studies (GWASs) of treatment-emergent suicidal ideation, but there has not been GWAS of resolution of suicidal ideation during drug treatment. Here we report on two such GWASs. Methods From the STEP-BD study, we have 450 patients with bipolar disorder assessed on the MADRS. We analyzed the change in suicidality from baseline to six months. From the IMPACT study (Individualized Medicine: Pharmacogenetic Assessment & Clinical Treatment), we have 118 participants suffering from anxiety, depression, bipolar disorder, and/or attention-deficit hyperactivity disorder. They were genotyped on the Illumina Omni 2.5 M chip and were followed for eight weeks on the Beck Depression Inventory. Of these participants, 69 experienced suicidal ideation at baseline, and 23 of them did not experience suicidal ideation at their eight-week study visit. Conversely, 49 participants did not have suicidal ideation at baseline, of which six reported suicidal ideation at the eight-week visit. We analyzed the change in suicidal ideation during these studies, including baseline suicidality scores, age, and sex as covariates. Results We did not observe genome-wide significant findings from either GWAS. We observed a possible genetic overlap between suicidal ideation in the STEP-BD bipolar disorder sample and suicidal ideation in the IMPACT sample (p=0.047). Discussion Suicide is a clinically important phenotype in clinical studies. Investigating the increases as well as decreases in suicidal ideation during psychotropic medication may be an interesting avenue for further genetic investigations.

Safety, Tolerability, and Efficacy of Desvenlafaxine in Children and Adolescents with Major Depressive Disorder: Results from Two Open-Label Extension Trials.

Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective. Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R). A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26. Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.

Vilazodone May Be Safer Option to Treat Adult MDD

Back to table of contents Previous article Next article PsychopharmacologyFull AccessVilazodone May Be Safer Option to Treat Adult MDDJoAnn BlakeJoAnn BlakeSearch for more papers by this authorPublished Online:26 Dec 2017https://doi.org/10.1176/appi.pn.2018.pp11b2AbstractThe FDA requires clinical trials of new psychotropic drugs include a prospective assessment of suicidal ideation and behavior.Vilazodone appears to pose little or no risk of treatment-emergent suicidal ideation or behavior in adults with major depressive disorder (MDD) or generalized anxiety disorder (GAD), according to a study in the journal International Clinical Psychopharmacology.Treatment-emergent suicidal ideation and behavior remain ongoing concerns with antidepressants, says Michael Thase, M.D.Data pooled from four double-blind, placebo-controlled vilazodone trials for MDD (including 2,233 patients) and three for GAD (including 1,475 patients) revealed that suicide-related adverse events occurred in less than 1 percent of patients treated with vilazodone and placebo. Vilazodone, which is approved for the treatment of MDD in adults, has also been evaluated as a possible treatment for adults with GAD. “We found this result reassuring, and it might steer us to picking this drug more often,” said lead author Michael Thase, M.D., a professor of psychiatry at Perelman School of Medicine at the University of Pennsylvania. For other types of antidepressants, the risk of suicide ideation may be as high as 4 percent compared with 2 percent for placebo, he said. The Food and Drug Administration (FDA) requires clinical trials of new psychotropic drugs to include a prospective assessment of suicidal ideation and behavior. “The FDA’s duty is to warn when there is evidence of some risk of initiating treatment,” Thase said. “In the previous decade, comprehensive reviews suggested a small, but real increase—not due to chance—in suicidal thoughts compared with placebo.” For the vilazodone meta-analysis, Thase and colleagues evaluated treatment-emergent suicidal ideation using adverse event reporting and Columbia Suicide Severity Rating Scale (C-SSRS) monitoring. They analyzed treatment-emergent suicide by C-SSRS category shift from no suicidal ideation (C-SSRS=0) at baseline to suicidal ideation (C-SSRS=1-5). Studies in the meta-analysis included MDD patients with 17-item Hamilton Depression Rating Scale (HAMD17) total score ≥22 and item 1 (depressed mood) score ≥2 or HAMD17 total score ≥18; and Montgomery-Åsberg Depression Rating Scale total score ≥26. Key eligibility criteria for GAD studies included patients with Hamilton Anxiety Rating Scale total score ≥20, item 1 (anxious mood) score ≥2, and item 2 (tension) score ≥2; Clinical Global Impressions-Severity of Illness score ≥4; and HAMD17 total score ≤17.Incidences of suicidal ideation/behavior were as follows: MDD (vilazodone=19.9 percent, placebo=24.7 percent); GAD (vilazodone=7.7 percent, placebo=9.4 percent). Shifts from no suicidal ideation/behavior at baseline to suicidal ideation during treatment are as follows: MDD (vilazodone=9.4 percent, placebo=10.3 percent); GAD (vilazodone=4.4 percent, placebo=6.1 percent). The difference between any suicidal ideation during vilazodone treatment and any suicidal ideation during placebo treatment is statistically significant, Thase said. Among patients who entered these studies with no recent suicidal ideation or behavior at baseline, more than 85 percent continued to have no suicidality during treatment. “I think the Thase data showing a favorable profile with respect to treatment-emergent suicidal features in the manufacturer’s pooled trials are compelling, credible, and useful,” said Joseph Goldberg, M.D., a clinical professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York. Goldberg said he has prescribed the medication extensively with success for patients with major depression and depression with prominent anxiety. Vilazodone, a serotonin partial agonist-reuptake inhibitor (SPARI), was introduced in the United States in 2011. SPARI medications have the potential for faster onset of action, greater efficacy, and better tolerability, according to a 2014 study.This medication also could have benefits for subgroups of people with depression, including those with anxiety disorders, and might have fewer sexual side effects than selective serotonin reuptake inhibitors (SSRIs), according to a 2015 study on vilazodone.Thase told Psychiatric News that treatment-emergent suicidal ideation and behavior remain ongoing concerns with antidepressants. He cautioned that all patients be monitored for suicidal thoughts and behaviors during antidepressant treatment. The study was funded by Forest Research Institute Inc., an Allergan affiliate, makers of vilazodone (Viibryd). Thase reported a potential conflict of interest in his role as an advisor or consultant for Allergan and Forest Laboratories. The other authors on the study acknowledged a potential conflict of interest as full-time employees of Allergan or Forest Research Institute at time of study. ■Back to Psychopharmacology Newsletter Table of Contents ISSUES NewArchived

Effects of vilazodone on suicidal ideation and behavior in adults with major depressive disorder or generalized anxiety disorder: post-hoc analysis of randomized, double-blind, placebo-controlled trials.

Treatment-emergent suicidal ideation and behavior are ongoing concerns with antidepressants. Vilazodone, currently approved for the treatment of major depressive disorder (MDD) in adults, has also been evaluated in generalized anxiety disorder (GAD). Post-hoc analyses of vilazodone trials were carried out to examine its effects on suicidal ideation and behavior in adults with MDD or GAD. Data were pooled from vilazodone trials in MDD (four studies) and GAD (three studies). The incidence of suicide-related events was analyzed on the basis of treatment-emergent adverse event reporting and Columbia-Suicide Severity Rating Scale (C-SSRS) monitoring. Treatment-emergent suicidal ideation was analyzed on the basis of a C-SSRS category shift from no suicidal ideation/behavior (C-SSRS=0) at baseline to suicide ideation (C-SSRS=1–5) during treatment. In pooled safety populations (MDD, n=2233; GAD, n=1475), suicide-related treatment-emergent adverse events occurred in less than 1% of vilazodone-treated and placebo-treated patients. Incidences of C-SSRS suicidal ideation were as follows: MDD (vilazodone=19.9%, placebo=24.7%); GAD (vilazodone=7.7%, placebo=9.4%). Shifts from no suicidal ideation/behavior at baseline to suicidal ideation during treatment were as follows: MDD (vilazodone=9.4%, placebo=10.3%); GAD (vilazodone=4.4%, placebo=6.1%). Data from placebo-controlled studies indicate little or no risk of treatment-emergent suicidal ideation or behavior with vilazodone in adults with MDD or GAD. Nevertheless, all patients should be monitored for suicidal thoughts and behaviors during antidepressant treatment.

Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial

BackgroundAt least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. MethodsThe current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. ResultsThere was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: −13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: −5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. LimitationsOpen-label, proof-of-concept design. ConclusionsHerein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.

Treatment Emergent Suicidal Ideation in depressed older adults.

Treatment-Emergent Suicidal Ideation (TESI) in older adults is poorly understood. We characterized TESI in older depressed adults during treatment with venlafaxine and explored whether TESI is related to antidepressant exposure versus dimensions of the psychiatric illness. We examined the relationship among medication exposure, onset of TESI, and clinical characteristics. We analyzed data on 233 clinical trial participants with major depression and no baseline suicidal ideation who were treated for up to 12 weeks with venlafaxine XR (target dose: 150-300 mg/day). Suicidal ideation was assessed weekly with the Scale for Suicide Ideation. A Kaplan-Meier curve displayed the time course of TESI. Differences in baseline demographic and clinical variables between the TESI and Non-TESI groups were assessed with analyses of covariance or logistic regression. A final multivariate logistic regression model indicated baseline predictors of TESI. Depression treatment outcomes in subjects developing TESI versus those who did not were examined with a mixed effects model. TESI occurred in 10% of participants, typically with onset within 4 weeks of the start of treatment. Anxiety, and depression severity at baseline were predictors of TESI. Most TESI was mild and transient, with 6/233 participants having TESI considered clinically meaningful. TESI was not associated with venlafaxine blood levels or side effects. In older depressed adults, TESI is relatively uncommon and it is likely related to the underlying illness rather than to a medication adverse effect. This suggests that TESI requires continuing rather than discontinuing antidepressant treatment. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Sheehan Suicidality Tracking Scale (S-STS): Reliability, convergent and discriminative validity in young Italian adults

Background and purposeThe Sheehan Suicidality Tracking Scale (S-STS) is a patient self-report or clinician-administered rating scale that tracks spontaneous and treatment-emergent suicidal ideation and behaviors. This study set out to evaluate the reliability, convergent and divergent validity of the S-STS in a sample of college students, a population with a high risk of completed and attempted suicide. MethodsCross-sectional, survey design. Participants (303 undergraduate students; males: 42%) completed several measures assessing psychological distress (General Health Questionnaire; GHQ); self-esteem (Rosenberg Self Esteem Scale; RSES); social support (Modified Social Support Survey; MOSSS); and suicidal behavior, including ideation and attempts (S-STS). ResultsBoth internal consistency and test–retest stability were excellent for the S-STS-global score. The S-STS subscale on suicide ideation also showed good reliability, while the subscale on suicidal behavior showed some inconsistency at retest. Convergent and divergent validity of S-STS was confirmed. All S-STS items loaded on a single factor, which had an excellent fit for the unidimensional model, thus justifying the use of the S-STS as a screening tool. In a mediation model, self-esteem and social support explained 45% of the effects of psychological distress on suicide ideation and behavior as measured by the S-STS-global score. ConclusionsThis study provided promising evidence on the convergent, divergent, internal consistency and test–retest stability of the Sheehan Suicidality Tracking Scale. The cross-sectional design and lack of measures of hopelessness and helplessness prevent any conclusion about the links of suicidal behavior with self-esteem and social support.

Genetics of emergent suicidality during antidepressive treatment—Data from a naturalistic study on a large sample of inpatients with a major depressive episode

Factors contributing to treatment-emergent suicidal ideation (TESI) using antidepressants have been in the focus of recent research strategies. We investigated previously established clinical predictors of TESI and combined these with several polymorphisms of candidate genes in patients with major depressive disorder. Common polymorphisms involved in the tryptophan hydroxylase 1 (TPH1) and 2 (TPH2), serotonin transporter, monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) were investigated in a naturalistic inpatient study of the German research network on depression. We compared patients showing TESI with non-TESI suicidal patients and with non-suicidal patients using univariate tests to detect relevant factors, which were further tested in logistic regression and CART (Classification and Regression Trees) analyses. Of the 269 patients, TESI occurred in 22 patients (17 female), 117 patients were defined as non-TESI suicidal patients, and 130 patients were classified as non-suicidal. When comparing cases with both control groups we found the TPH2 rs1386494 (C/T) polymorphism to be moderately associated with TESI (Univariate tests: TESI vs. non-suicidality: p=0.005; adjusted: p=0.09; TESI vs. non-TESI suicidal patients: p=0.0024; adjusted: p=0.086). This polymorphism remained the only significant genetic factor in addition to clinical predictors in logistic regression and CART analyses. CART analyses suggested interactions with several clinical predictors. Haplotype analyses further supported a contribution of this polymorphism in TESI. The TPH2 rs1386494 (C/T) polymorphism might contribute to the genetic background of TESI. This polymorphism has been previously associated with committed suicide and major depressive disorder. The small number of cases warrants replication in larger patient samples. Lack of a placebo control group hampers definite conclusions on an association with antidepressive treatment.

Genome-wide association study of antidepressant treatment-emergent suicidal ideation.

Emergence of suicidal ideation (TESI) during treatment with antidepressants in major depression led to a black box warning. We performed a genome-wide association study to identify genetic markers, which increase the risk for this serious side effect. TESI was evaluated in depressed in-patients (N=397) and defined by an emergence of suicidal thoughts during hospitalization without suicidal thoughts at admission using the suicide item (3) of the Hamilton Depression Rating Scale. Genotype distribution of 405.383 single-nucleotide polymorphisms (SNPs) in patients with TESI (N=32/8.1%) was compared to patients without increase in suicidal ideation (N=329/82.9%) and to a subgroup never reported suicidal ideation (N=79/19.9%). Top results were analyzed in an independent sample (N=501). None variant reached genome-wide significance, the best associated SNP was rs1630535 (p-value=1.3 × 10(-7)). The top 79 SNPs could be analyzed in an independent sample, and 14 variants showed nominal significant association with the same risk allele in the replication sample. A discriminant analysis classifying patients using these 79 SNPs revealed a 91% probability to classify TESI vs non-TESI cases correctly in the replication sample. Although our data need to be interpreted carefully owing to the small numbers in both cohorts, they suggest that a combination of genetic markers might indeed be used to identify patients at risk for TESI.

FC04-06 - Candidate gene association study of suicidality in treatment resistant MDD

Suicidal behaviour runs in families and the existence of genetic vulnerability to suicidality is well-established. Mental disorders, especially depression, are present in more of 90% of suicides. The incidence of treatment emergent suicidal ideation in major depression (MDD) varies from 4% to 20%, depending on the definition of suicidal ideation and sample characteristics.In the present study, we further elucidated the impact of depression candidate genes in treatment emergent suicidal ideation in MDD. One hundred-seventy MDD patients were collected in the context of a resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. MDD subjects were genotyped for SNPs within the COMT gene, BDNF, DTNBP1, 5HT1A, 5HT2A, GNB3, GRIK4, PTGS1, PTGS2, CREB, and cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene. Response, remission and treatment resistance, as well as suicidality information derived from Mini International Neuropsychiatric Interview (MINI) and Hamilton Rating Scale for Depression (HAM-D) were recorded.A quantitative and measure of suicidal behaviour was defined using the Hamilton rating scale (score 0 to 4) and the MINI-item (yes/no) on suicidality in a large cohort of depression cases. In addition, we tested for association with ‘serious suicidal attempts’ corresponding to a HAMD score of 4 (discrete trait analyses). Results of this candidate gene approach in treatment emergent suicidal ideation in MDD will be presented and discussed.

Treatment-emergent suicidal ideation during 4 months of acute management of unipolar major depression with SSRI pharmacotherapy or interpersonal psychotherapy in a randomized clinical trial

To date, few randomized controlled trials (RCTs) of major depression have examined suicidal ideation as an outcome measure. Our aim is to determine the incidence of treatment-emergent suicidal ideation (ESI) and behaviors during the acute phase of treatment with an SSRI antidepressant or interpersonal psychotherapy (IPT) in patients with unipolar major depression. In a two-site RCT, 291 adult outpatients with nonpsychotic major depression and a Hamilton Depression Rating Scale (HDRS) score ≥15 were randomly allocated to IPT or SSRI. Participants who did not remit with monotherapy received augmentation with the other treatment. ESI was defined as a post-baseline HDRS suicidality item score ≥2 or a post-baseline Quick Inventory of Depressive Symptomatology (QIDS) score ≥2 in patients with a baseline score ≤1. Of the 231 participants who had no suicidal ideation at baseline, 32 (13.8%) subsequently exhibited ESI on at least one post-baseline visit. Time to suicidal ideation was significantly longer in patients allocated to SSRI compared to those allocated to IPT (HR = 2.21, 95% CI 1.04-4.66, P = .038), even after controlling for treatment augmentation, benzodiazepine use, and comorbidity with anxiety disorders. Worsening of suicidal ideation occurred in 7/60 patients who had suicidal ideation at baseline. In the large majority of cases, suicidal ideation was successfully managed with the study protocol. In the context of careful monitoring and frequent contact, selective serotonin reuptake inhibitor (SSRI) was associated with a lower risk of ESI than IPT and both SSRI and IPT appeared to be safe treatments for patients with past suicide attempts, none of whom exhibited ESI during the study.

Analysis of Suicidality in Pooled Data From 2 Double-Blind, Placebo-Controlled Aripiprazole Adjunctive Therapy Trials in Major Depressive Disorder

To assess the impact of adjunctive aripiprazole versus adjunctive placebo treatment on suicidality in patients with major depressive disorder. Data were pooled from 2 identical aripiprazole augmentation studies. Patients with DSM-IV-TR-diagnosed major depressive disorder with an inadequate response to 8 weeks of prospective antidepressant treatment were randomly assigned to adjunctive placebo or adjunctive aripiprazole (2-20 mg/d) treatment for 6 weeks. Adverse events related to suicidality were identified in the adverse event database using the Medical Dictionary for Regulatory Activities-preferred term. Treatment-emergent suicidal ideation was defined using item 10 (suicidality) of the Montgomery-Åsberg Depression Rating Scale (MADRS) and item 18 (suicidality) of the Inventory of Depressive Symptomatology (IDS). In total, 737 patients were included in the safety database (aripiprazole n = 371; placebo n = 366). No suicides were reported. There were no treatment-emergent, suicide-related adverse events in the aripiprazole group; 2 patients in the placebo group had ≥ 1 adverse event related to suicide (both suicidal ideation). More placebo than aripiprazole patients > 25 years old experienced a 2-point (P < .01) or 1-point (P < .05) worsening of MADRS item 10 scores. For this age group, 2-point improvement in MADRS item 10 scores and 1-point improvement of IDS item 18 scores were significantly more common in aripiprazole patients than placebo patients (both P < .05). This post hoc analysis demonstrated that adjunctive aripiprazole treatment in patients with depression with a history of an inadequate response to antidepressant medication is associated with a decreased rate of suicidality in a group of subjects not at significant risk. Prospective trials directly assessing suicidality are needed to further understand the benefits of an adjunctive antipsychotic in an at-risk population. clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

Suicidal Ideation and Early Response to Antidepressants

Treatment-emergent suicidal ideation is more common early than later in antidepressant treatment. To examine whether early antidepressant response is

Suicidality and Risk of Suicide—Definition, Drug Safety Concerns, and a Necessary Target for Drug Development

To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies of major depression, bipolar disorder, schizophrenia, substance abuse/dependence, and other psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this scholarly article, which has been developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement have been noted. The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's effort to promote standard definitions and definable expectations for investigators and industry sponsors by endorsing the terminology in the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to build upon its new authority to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk within informative large health care-related databases in the United States and abroad. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the current Agency requirement that all CNS clinical drug trials must include a C-CASA-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed, and they need to be included to enable premarket assessments of the risks and benefits of medications related to suicidal ideation, suicidal behavior, and suicide in such patients.

Suicidality and Risk of Suicide—Definition, Drug Safety Concerns, and a Necessary Target for Drug Development

To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies in studies of psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this brief report and the accompanying full article from which it is distilled. The full article was developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement at the conference have been noted in the text. The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's encouragement of standard definitions and definable expectations for investigators and industry sponsors. Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the requirement that all central nervous system clinical drug trials must include a Columbia Classification Algorithm of Suicide Assessment (C-CASA)-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed.