78
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective To examine the risk of suicidal behaviour within clinical trials of antidepressants in adults.

          Design Meta-analysis of 372 double blind randomised placebo controlled trials.

          Setting Drug development programmes for any indication in adults.

          Participants 99 231 adults assigned to antidepressants or placebo. Median age was 42 and 63.1% were women. Indications for treatment were major depression (45.6%), other depression (4.6%), other psychiatric disorders (27.6%), and non-psychiatric disorders (22.2%).

          Main outcome measures Suicidal behaviour (completed suicide, attempted suicide, or preparatory acts) and ideation.

          Results For participants with non-psychiatric indications, suicidal behaviour and ideation were extremely rare. For those with psychiatric indications, risk was associated with age. For suicidal behaviour or ideation and for suicidal behaviour only, the respective odds ratios were 1.62 (95% confidence interval 0.97 to 2.71) and 2.30 (1.04 to 5.09) for participants aged <25, 0.79 (0.64 to 0.98) and 0.87 (0.58 to 1.29) for those aged 25-64, and 0.37 (0.18 to 0.76) and 0.06 (0.01 to 0.58) for those aged ≥65. When age was modelled as a continuous variable, the odds ratio for suicidal behaviour or ideation declined at a rate of 2.6% per year of age (−3.9% to −1.3%, P=0.0001) and the odds ratio for suicidal behaviour declined at a rate of 4.6% per year of age (−7.4% to −1.8%, P=0.001).

          Conclusions Risk of suicidality associated with use of antidepressants is strongly age dependent. Compared with placebo, the increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents. The net effect seems to be neutral on suicidal behaviour but possibly protective for suicidal ideation in adults aged 25-64 and to reduce the risk of both suicidality and suicidal behaviour in those aged ≥65.

          Related collections

          Most cited references13

          • Record: found
          • Abstract: found
          • Article: not found

          Suicidality in pediatric patients treated with antidepressant drugs.

          There has been concern that widely used antidepressant agents might be associated with an increased risk of suicidal ideation and behavior (suicidality) in pediatric patients. To investigate the relationship between antidepressant drugs and suicidality in pediatric patients participating in randomized, placebo-controlled trials. Data were derived from 23 trials conducted in 9 drug company-supported programs evaluating the effectiveness of antidepressants in pediatric patients and 1 multicenter trial (the Treatment for Adolescents With Depression Study) that evaluated fluoxetine hydrochloride. All placebo-controlled trials submitted to the Food and Drug Administration were eligible for inclusion. Evaluable data were derived from 4582 patients in 24 trials. Sixteen trials studied patients with major depressive disorder, and the remaining 8 studied obsessive-compulsive disorder (n = 4), generalized anxiety disorder (n = 2), attention-deficit/hyperactivity disorder (n = 1), and social anxiety disorder (n = 1). Only 20 trials were included in the risk ratio analysis of suicidality because 4 trials had no events in the drug or placebo groups. Individual patient data were available for all the trials. A meta-analysis was conducted to obtain overall suicidality risk estimates for each drug individually, for selective serotonin reuptake inhibitors in depression trials as a group, and for all evaluable trials combined. There were no completed suicides in any of these trials. The multicenter trial was the only individual trial to show a statistically significant risk ratio (4.62; 95% confidence interval [CI], 1.02-20.92). The overall risk ratio for selective serotonin reuptake inhibitors in depression trials was 1.66 (95% CI, 1.02-2.68) and for all drugs across all indications was 1.95 (95% CI, 1.28-2.98). The overall risk difference for all drugs across all indications was 0.02 (95% CI, 0.01-0.03). Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials.

            To establish whether an association exists between use of selective serotonin reuptake inhibitors (SSRIs) and suicide attempts. Systematic review of randomised controlled trials. Medline and the Cochrane Collaboration's register of controlled trials (November 2004) for trials produced by the Cochrane depression, anxiety, and neurosis group. Studies had to be randomised controlled trials comparing an SSRI with either placebo or an active non-SSRI control. We included clinical trials that evaluated SSRIs for any clinical condition. We excluded abstracts, crossover trials, and all trials whose follow up was less than one week. Seven hundred and two trials met our inclusion criteria. A significant increase in the odds of suicide attempts (odds ratio 2.28, 95% confidence 1.14 to 4.55, number needed to treat to harm 684) was observed for patients receiving SSRIs compared with placebo. An increase in the odds ratio of suicide attempts was also observed in comparing SSRIs with therapeutic interventions other than tricyclic antidepressants (1.94, 1.06 to 3.57, 239). In the pooled analysis of SSRIs versus tricyclic antidepressants, we did not detect a difference in the odds ratio of suicide attempts (0.88, 0.54 to 1.42). Our systematic review, which included a total of 87 650 patients, documented an association between suicide attempts and the use of SSRIs. We also observed several major methodological limitations in the published trials. A more accurate estimation of risks of suicide could be garnered from investigators fully disclosing all events.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Why add anything to nothing? The arcsine difference as a measure of treatment effect in meta-analysis with zero cells.

              For clinical trials with binary endpoints there are a variety of effect measures, for example risk difference, risk ratio and odds ratio (OR). The choice of metric is not always straightforward and should reflect the clinical question. Additional issues arise if the event of interest is rare. In systematic reviews, trials with zero events in both arms are encountered and often excluded from the meta-analysis.The arcsine difference (AS) is a measure which is rarely considered in the medical literature. It appears to have considerable promise, because it handles zeros naturally, and its asymptotic variance does not depend on the event probability.This paper investigates the pros and cons of using the AS as a measure of intervention effect. We give a pictorial representation of its meaning and explore its properties in relation to other measures. Based on analytical calculation of the variance of the arcsine transformation, a more conservative variance estimate for the rare event setting is proposed. Motivated by a published meta-analysis in cardiac surgery, we examine the statistical properties of the various metrics in the rare event setting.We find the variance estimate of the AS to be more stable than that of the log-OR, even if events are rare. However, parameter estimation is biased if the groups are markedly unbalanced. Though, from a theoretical viewpoint, the AS is a natural choice, its practical use is likely to continue to be limited by its less direct interpretation. Copyright (c) 2008 John Wiley & Sons, Ltd.
                Bookmark

                Author and article information

                Contributors
                Role: medical officer
                Role: director, division of psychiatry products
                Role: medical officer
                Role: mathematical statistician
                Role: mathematical statistician
                Role: associate director for safety, division of neurology products
                Role: associate director, division of epidemiology
                Role: associate director for medical policy
                Role: mathematical statistics team leader
                Journal
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1468-5833
                2009
                2009
                11 August 2009
                : 339
                : b2880
                Affiliations
                [1 ]Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002, USA
                Author notes
                Correspondence to: Marc Stone marc.stone@ 123456fda.hhs.gov
                Article
                stom616250
                10.1136/bmj.b2880
                2725270
                19671933
                fa97981c-3461-4c36-b4bf-0a2488dd72ca

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 1 May 2009
                Categories
                Research
                Clinical trials (epidemiology)
                Child and adolescent psychiatry (paedatrics)
                Medicines regulation
                Child and adolescent psychiatry
                Mood disorders (including depression)
                Suicide (psychiatry)
                Drugs: musculoskeletal and joint diseases
                Suicide (public health)

                Medicine
                Medicine

                Comments

                Comment on this article