Suicide-related Adverse Events Research Articles

Assessment of suicidality in trials of psychological interventions for depression: a meta-analysis

Psychological interventions that are efficacious as treatments for depression could indirectly affect suicide-related outcomes. We examined suicidal thoughts and behaviours as eligibility criteria, outcomes, and adverse events across trials of psychotherapy for depression. We used a publicly available meta-analytic database developed through systematic searches (updated as of May 1, 2023) to identify randomised controlled trials in which a psychological intervention for depression was compared with an inactive or non-specific control condition in adults with depression and in which any suicide-related outcomes were reported. We also identified studies in which suicide risk was an exclusion criterion. We excluded inpatient studies and trials of unguided digital interventions or collaborative care that included a psychological component. Pairs of reviewers worked independently to select studies and extract data. In a random-effects meta-analysis with robust variance estimation, we assessed the effect of the psychological intervention on suicide outcomes in trials in which suicide was explicitly assessed as an outcome with clinical scales with established psychometric properties. Risk of bias was assessed with the Cochrane risk-of-bias tool (version 2). Of the 469 randomised trials we identified in which a psychological intervention was compared with an inactive control in people with depression, 251 excluded people judged at risk of suicide. Any assessment of suicide was included in only 45 trials, 12 of which assessed suicidal ideation or risk as an outcome. These 12 trials included 3930 participants, 2795 (71%) of whom were female and 1135 (29%) of whom were male; data for age and ethnicity were not consistently reported. Psychological interventions for depression were associated with a small reduction in suicidal ideation and risk in 11 trials (one trial reported only follow-up data) after the intervention (standardised mean difference -0·31 [95% CI -0·60 to -0·03]) but not at follow-up (-0·49 [-1·31 to 0·32]). Suicide-related adverse events were reported in 25 trials, and suicide-related serious adverse events (eg, suicide attempts, deaths by suicide) were reported in 13 trials. Heterogeneity was substantial across all analyses, and prediction intervals crossed zero. Trials of psychological interventions for depression rarely report assessments of suicide. Psychological interventions might reduce suicidal ideation in patients with depression, but more randomised controlled trials are required to clarify this effect. Monitoring and reporting of suicide-related adverse events should be improved in trials of psychological interventions for depression, and future trials should incorporate outcomes related to suicidal thoughts or behaviours. None. For the Spanish translation of the abstract see Supplementary Materials section.

Directionality of change in obsessive compulsive disorder (OCD) and suicidal ideation over six years in a naturalistic clinical sample✰

BackgroundObsessive compulsive disorder (OCD) is associated with elevated suicide risk, but the directionality of the association between OCD severity and suicidal ideation has not been established, which was the goal of this study. MethodsParticipants (n = 325) were adults with either a current or past diagnosis of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) OCD who were assessed annually for suicidal ideation and OCD symptom severity for six years. Cross-lagged panel analyses statistically compared unidirectional and bidirectional models over time. Serious suicide-related adverse events were reported. ResultsThe best-fitting and most parsimonious model included paths predicting suicidal ideation from OCD symptom severity, but not vice versa. These results were confirmed by comparing a model with cross-lagged paths constrained equal to a freely estimated model. Higher OCD symptom severity in a given year was associated with a higher suicidal ideation severity in the subsequent year. Five suicide-related adverse events were reported throughout the duration of the study, including two suicide deaths and three suicide attempts. LimitationsThe study relied on a single-item, annual measure of suicidal ideation in adults, with substantial variability in severity of suicide risk, and missing data increased with later observations in the study. DiscussionOCD symptom severity predicted next year suicidal ideation severity. In contrast, suicidal ideation severity in a given year did not predict next-year OCD symptom severity in this OCD sample. Thus, rather than waiting for suicidal ideation to resolve, clinicians should consider providing empirically supported treatments for OCD.

Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder.

Cariprazine is an atypical antipsychotic currently under investigation as adjunctive therapy in patients with major depressive disorder (MDD) who have inadequate response to standard antidepressant therapy. A randomized, double-blind, placebo-controlled, flexible-dose study was conducted from December 2011 to December 2013 in adults who met DSM-IV-TR criteria for MDD and had an inadequate antidepressant response. Eligible patients were randomized to 8-week adjunctive treatment with placebo (n = 269), cariprazine 1-2 mg/d (n = 274), or cariprazine 2-4.5 mg/d (n = 276). The primary efficacy parameter was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score; P values were adjusted for multiple comparisons. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms (ECGs), and suicidality. Compared with placebo, reduction in MADRS total score at week 8 was significantly greater with adjunctive cariprazine 2-4.5 mg/d (least squares mean difference [LSMD] = -2.2; adjusted P = .0114), but not with cariprazine 1-2 mg/d (LSMD = -0.9; adjusted P = .2404). Significant LSMDs for MADRS total score change were detected at all earlier study visits (weeks 2, 4, 6) in the 2- to 4.5-mg/d group and at weeks 2 and 4 in the 1- to 2-mg/d group (all P values < .05). Treatment-emergent adverse events reported in ≥ 10% of patients in either cariprazine dosage group were akathisia (22.3%), insomnia (13.6%), and nausea (12.8%) (all in 2- to 4.5-mg/d group). Mean changes in metabolic parameters, vital signs, and ECG parameters were generally similar between groups. No suicide-related adverse events were reported. These results show that adjunctive cariprazine 2-4.5 mg/d was effective and generally well tolerated in adults with MDD who had inadequate responses to standard antidepressants. Further clinical studies to confirm these results are warranted. ClinicalTrials.gov identifier: NCT01469377.

Identification of suicide-related events through network analysis of adverse event reports.

In the treatment of depression, it is essential to monitor for early warnings of suicide. The aim of this study was to identify the symptoms that would suggest a high suicide risk by analyzing data obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS) of selective serotonin reuptake inhibitors. Using FAERS reports from 1997 to the second quarter of 2012, we constructed the co-occurrence network of adverse events. From this network, we extracted the events that were strongly connected to suicidal events (suicidal attempts, suicidal ideation, suicidal behavior, and complete suicide) by means of the community detection method. We succeeded in obtaining a list of suicide-related adverse events. Owing to the randomness inherent in the algorithms of community detection, we found that the obtained list differed according to each trial of analysis. However, the lists we derived show considerable efficiency in identifying suicidal events. The network analysis appears to be a promising method for identifying signals of suicide.

Asthma and suicide-related adverse events: a review of observational studies

Suicide is a major public health concern. There are several risk factors associated with suicide. Chronic illnesses, such as asthma, have been linked to an increased risk of suicide-related events. This study reviews the evidence of an association between asthma and suicide using published epidemiological observational studies. An electronic search using PubMed and EMBASE was performed. Studies that investigated the association of asthma with suicide-related behaviour were selected. Studies were examined to form a descriptive analysis. Six observational studies met the selection criteria, of which at least one suicide-related adverse event was studied. Three studies investigated completed suicide, two suicide attempts and four suicide ideation. Two of the studies focused on individuals aged <18 yrs. Evidence from observational data support the hypothesis of an association between asthma and suicide-related behaviour (ideation, attempts and completion); however, epidemiological studies, with more objective measures and larger sample sizes, adjusting for a wider scope of suicide-related confounding factors (e.g. comorbidities), and with a longitudinal design, are needed for a more conclusive answer.

Association between Leukotriene-Modifying Agents and Suicide

The US FDA has issued safety alerts and required manufacturers of leukotriene-modifying agents (LTMAs), including montelukast, zafirlukast and zileuton, to include suicide and neuropsychiatric events as a precaution in the drug label. This paper reviews the existing evidence on the potential association between the LTMAs and suicidal behaviour. We conducted a literature search of MEDLINE, EMBASE and International Pharmaceutical Abstracts from 1995 to 2010 (inclusive) to identify pertinent studies and reports. We also examined data obtained from the FDA adverse event reporting system. To date, there are no well conducted, comparative, observational studies of this association, and the safety alerts are based primarily on case reports. While the FDA safety alerts apply to all three LTMAs, montelukast (known by its trade name Singulair®) is by far the most widely used of these drugs and most of the reports to date regarding suicide pertain to montelukast. From 1998 to 2009 there were 838 suicide-related adverse events associated with leukotrienes reported to the FDA, of which all but five involved montelukast. Nearly all cases were reported in 2008 and 2009 (96.1%) after the FDA warnings. LTMAs are approved for use in asthma and allergic rhinitis, and are effective drugs. Both of these diseases are also associated with suicide, making confirmation of the association more difficult. Given the lack of good evidence, we recommend that a large observational cohort or case-control study be conducted to quantify the association between LTMAs and suicide. Until then, when prescribing LTMAs, clinicians should consider the potential for suicide and monitor patients who may be at elevated risk carefully for suicidal ideation or psychiatric symptoms associated with suicidal behaviour.

Assessments of Suicidality in Double-Blind, Placebo-Controlled Trials of Ziprasidone

A pooled analysis was conducted to identify possibly suicide-related adverse events in Pfizer-sponsored, phases 2-4, placebo-controlled, double-blind, adult and pediatric completed randomized controlled trials of ziprasidone and to evaluate the risk of suicidality with ziprasidone versus placebo. The trials included were initiated as early as June 1992, and the cutoff date for selection of the placebo-controlled trials in the Pfizer database was October 2, 2009. The US Food and Drug Administration (FDA)-defined search methodology was used to identify possibly suicide-related adverse events, and the Columbia Classification Algorithm of Suicide Assessment (primary outcome measure) was used to categorize them. The incidences of possibly suicide-related adverse events were calculated for individual classifications and for the predefined combined categories of suicidality (comprising classification codes 1-4) and suicidal behavior (comprising classification codes 1-3), along with the ziprasidone versus placebo relative risks and corresponding 95% CIs. Exact binomial 95% CIs were calculated for the individual treatment group incidences. Suicidality events were identified in 52 among 5,123 subjects treated with either ziprasidone or placebo in 22 trials. No cases of completed suicide occurred in this analysis. There were no statistically significant differences between ziprasidone and placebo in any of the individual classification categories, combined suicidal behavior category (ziprasidone vs placebo relative risk = 0.67; 95% CI, 0.206-2.201), or combined suicidality risk category (ziprasidone vs placebo relative risk = 0.90; 95% CI, 0.514-1.563). Results of our analyses, performed in accordance with the FDA-specified search strategy, reveal no significant differences in treatment-emergent suicidality risk in ziprasidone versus placebo subjects treated in controlled clinical trials.

Suicidality and divalproex sodium: analysis of controlled studies in multiple indications.

BackgroundRecent analyses of antiepileptic drugs have indicated an increase in the risk of suicidality. The objective of this report was to provide clinical information and an independent meta-analysis of divalproex sodium and suicidality events by analyzing data from 13 placebo-controlled studies and 1 low-dose controlled study.MethodsAdverse events considered to be possibly suicide related were identified using the Columbia Classification Algorithm of Suicide Assessment (C-CASA) methodology. Indications included epilepsy, bipolar disorder, migraine prophylaxis, impulsive aggression, and dementia. Narratives were produced for every event, and suicidality event ratings were performed by a third party blinded to treatment assignment. Statistical analyses were conducted using methodology similar to that reported by the US Food and Drug Administration (FDA).ResultsSuicidality events were identified in 5 of the 13 placebo-controlled studies. Of the 1,327 (0.83%) subjects taking divalproex sodium, 11 had suicidality events: 2 suicide attempts and 9 suicidal ideation. Of 992 (0.91%) subjects taking placebo, 9 had suicidality events: 1 preparatory act toward suicide, 2 suicide attempts, and 6 suicidal ideation. Across placebo-controlled studies, the overall estimated odds ratio (OR) of suicidal behavior or ideation was 0.72 (95% CI 0.29 to 1.84). The OR for suicidal behavior was 0.37 (95% CI 0.04 to 2.58), and the OR for suicidal ideation was 0.90 (95% CI 0.31 to 2.79).ConclusionsIn this meta-analysis, divalproex sodium does not appear to increase the risk of suicide-related adverse events relative to placebo in the populations studied. Clinicians should nonetheless remain vigilant in assessing suicidality, not only in patients treated for mental disorders with inherently high suicide risk, but also in patients taking antiepileptic medications.

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.

Milnacipran: recent findings in depression

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) which was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed for this indication (as Ixel®, Toledomin®, Tivanyl® or Dalcipran®) in over 45 countries worldwide including Japan. It was approved for the management of fibromyalgia in the US in 2009. This supplement, which is based on a symposium at the International Forum on Mood and Anxiety (IFMAD) held in Monaco in November 2009, highlights several recent clinical studies with milnacipran in depression. The World Health Organization (WHO) classes suicide as one of the ten leading causes of death for all ages with more than 1.5 million deaths per year estimated for 2020.1 Reports of higher rates of suicide-related adverse events during treatment with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants2 prompted regulatory bodies in the US and Europe to issue suicide risk warnings during the first weeks of antidepressant treatment. More recent evidence, however, suggests a favorable benefit – risk ratio for treating depressed patients with antidepressants with the possible exception of those less than 25 years of age.3 In the first paper in this supplement, Philippe Courtet presents recent research on suicidal behavior and specifically a study of the effects of milnacipran on suicidal behavior in depression patients. This study showed that suicidality decreased progressively in parallel with other depressive symptoms and was essentially absent at the end of the study. At no time during treatment was there any increase of suicidal risk. Depression is common in patients with diabetes and the co-morbidity has a serious negative impact on self-care, adherence to treatment and the general prognostic of diabetes. In particular co-morbid depression is associated with decreased metabolic control, a higher incidence of angiopathic complications and decreased quality of life for diabetes sufferers.4 In the second paper, Peter Hofmann discusses the treatment of co-morbid depression in diabetes patients and in particular the question as to whether antidepressant treatment can improve diabetes symptoms. SSRIs appear to treat the depression effectively but there is no evidence of any major effect on metabolic control. A recent study of milnacipran in diabetes patients with co-morbid depression showed, however, that a wide range of diabetes parameters were all significantly improved in patients with an antidepressant response but not in patients whose depressive symptoms had not responded to milnacipran. Milnacipran and venlafaxine are both SNRIs but with differing selectivities for the two monoamines. Milnacipran has a balanced ratio of potency (1:1.16) for the inhibition of reuptake of the two neurotransmitters.5 One study has shown it to inhibit norepinephrine uptake with greater potency than serotonin (2.22:1).6 In contrast, venlafaxine has a 30-fold greater potency for the serotonin transporter than for the norepinephrine transporter.5 At low doses venlafaxine acts essentially as a SSRI, with significant noradrenergic activity occurring only at higher doses. Thus the choice of dose is critical for any meaningful comparison with venlafaxine. In the third paper, Lucilla Mansuy discusses the various indirect comparisons that have been made between the two SNRIs. She then presents the first direct head-to-head comparison between venlafaxine and milnacipran with both drugs flexibly titrated to 150 to 200 mg/day and which shows the two SNRIs to have similar efficacy and tolerability. In the fourth and final paper, Siegfried Kasper presents an updated overview of milnacipran in depression. He concludes that its distinct combination of favorable characteristics, namely its wide efficacy, good tolerability, low risk of pharmacokinetic drug – drug interactions, minimal, if any, sexual dysfunction or withdrawal effects, and safety in overdose, qualifies milnacipran as a first-line antidepressant treatment for any depressed patient. It may be particularly well-suited for low-energy, slowed-down patients.

A Pooled Analysis of Suicidality in Double-Blind, Placebo-Controlled Studies of Sertraline in Adults

The analyses were conducted to identify possibly suicide-related adverse events in Pfizer-sponsored, phases 2 through 4, placebo-controlled, completed studies of sertraline in adult patients and evaluate the risk of suicidality with sertraline versus placebo. U.S. Food and Drug Administration (FDA)-defined search methodology was used to identify possibly suicide-related adverse events in short-term, all-duration/all-indication, and psychiatric studies of sertraline. Categorization of possibly suicide-related adverse events was based on the approach developed by the Columbia group for the FDA's analysis of pediatric suicide risk with antidepressants. The incidences of possibly suicide-related adverse events were calculated for individual classifications and for the predefined combined category of suicidality along with the sertraline versus placebo relative risks and corresponding 95% CI limits. Exact binomial CI limits were calculated for the individual treatment group incidences. Age group analyses were also performed using the age limits defined by the FDA. Ninety-nine suicidality events were identified among 19,923 sertraline- and placebo-treated subjects participating in 126 studies conducted between the mid-1980s and the mid-2000s. Four cases of completed suicides among 10,917 sertraline-treated subjects yielded an incidence of 0.04% (95% CI = 0.01 to 0.09) and 3 cases among 9,006 placebo treated subjects yielded an incidence of 0.03% (95% CI = 0.01 to 0.10). There were no statistically significant differences between sertraline and placebo in any of the individual categories or combined suicidality risk category across all performed analyses. Results of short-term, all-duration, and psychiatric studies analyses, as well as age-group analyses, performed in accordance with the FDA-specified search strategy, show no significant increase in suicidality risk in adult sertraline- versus placebo-treated patients.

Benefits and risks of using antidepressants in children and adolescents

The present controversy about the use of selective serotonin re-uptake inhibitors in paediatric patients has been the subject of many publications. This article summarises the available data on the efficacy and safety of selective serotonin re-uptake inhibitors and other non-tricyclic antidepressants in children and adolescents with mental disorders. These data are compared with those related to the efficacy and safety of tricyclic antidepressants. If selective serotonin re-uptake inhibitors appear to be the drugs of choice in depressive and anxiety disorders, their effects are strongest in non-obsessive-compulsive anxiety disorders, intermediate in obsessive-compulsive disorders and more modest in major depressive disorders. All antidepressants may induce psychiatric and suicide-related adverse events. In this respect, the balance of benefit and risk seems to favour fluoxetine as the first-choice antidepressant. Above all, this review emphasises research questions that need to be answered fully about the potential role of antidepressants in the management of children and adolescents with psychiatric disorders. Given these unanswered questions, the use of antidepressant medications in children and adolescents should remain cautious and well monitored.

Evaluating suicide-related adverse events in clinical trials of fluoxetine treatment in adults for indications other than major depressive disorder

The association between treatment-emergent suicidality as an adverse event and fluoxetine treatment was examined using a fluoxetine double-blind placebo-controlled database of clinical trials for indications other than major depressive disorder. The database consisted of 53 trials for 16 different indications (14 psychiatric, two non-psychiatric). Within each study, patient adverse event reports and narratives were searched extensively for treatment-emergent thoughts and behaviors associated with suicide. The incidence of adverse events was classified using Food and Drug Administration (FDA) codes for completed suicide, preparatory acts, suicidal ideation and the summary category of 'all suicidality.' The risk difference and risk ratios between fluoxetine and placebo treatment arms were compared using Mantel-Haenszel methods. Within this large database, patients were randomly assigned to receive treatment with either fluoxetine (n = 7066) or placebo (n = 4382). Treatment groups did not differ in their risk for the emergence of suicidality for any FDA code; the risk ratio for 'all suicidality' was 0.82 (p = 0.406), and there were no completed suicides in either group. Analyses based on treatment indication (bulimia, obsessive-compulsive disorder, other psychiatric and non-psychiatric illness) also showed no significant difference in risk between treatment groups. When examined by age categories (18-24, 25-30, 31-65, and 65 years), fluoxetine and placebo treatments did not result in significant risk difference for the emergence of suicidality. The risk of treatment-emergent suicidality does not appear to be associated with fluoxetine treatment for adults with various non-MDD conditions.

Suicide-related adverse events and antipsychotic use: An analysis of data from the WHO and FDA AERS database

Suicide-related adverse events and antipsychotic use: An analysis of data from the WHO and FDA AERS database

Lilly Agrees to Add Warning On Strattera Labeling

Lilly Agrees to Add Warning On Strattera Labeling

Clinical review of mania, hostility and suicide-related events in children and adolescents treated with antidepressants

Recent controversy surrounding the use of non-tricyclic antidepressants and the emergence of suicide-related events, hostility/behavioural activation and mania in youth with depression warrants an exploration of the results from randomized controlled trials (RCTs) and published case reports for the emergence of these adverse events. To provide a clinical review of the available evidence from RCTs and case reports regarding the safety of nontricyclic anti-depressants in youth with depression. Seven RCTs of antidepressant use in youth with depression, four case reports of suicide-related adverse events, three case reports of hostility/behavioural activation, and 12 case reports of precipitation of mania were reviewed. The majority of patients with suicide-related adverse events from both RCTs and published case reports were suicidal before the start of antidepressant treatment. Hostility/behavioural activation generally developed within days to weeks after the start of antidepressant treatment; in the majority of cases, symptoms resolved within four weeks of dosage lowering or discontinuation of the medication alone. Rates for precipitation of mania from RCTs ranged from 0% to 6%. In approximately 60% of published case reports, manic symptoms resolved with the discontinuation or lowering of the dosage of medication alone. Several trends were observed in the association between adverse events and the use of nontricyclic antidepressants in youth. When prescribing antidepressants to youth, clinicians should closely monitor patients and fully inform them and their families of the risks and benefits of treatment with antidepressants.