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      Antidepressant Utilization and Suicide in Europe: An Ecological Multi-National Study

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          Abstract

          Background

          Research concerning the association between use of antidepressants and incidence of suicide has yielded inconsistent results and is the subject of considerable controversy. The first aim is to describe trends in the use of antidepressants and rates of suicide in Europe, adjusted for gross domestic product, alcohol consumption, unemployment, and divorce. The second aim is to explore if any observed reduction in the rate of suicide in different European countries preceded the trend for increased use of antidepressants.

          Methods

          Data were obtained for 29 European countries between 1980 and 2009. Pearson correlations were used to explore the direction and magnitude of associations. Generalized linear mixed models and Poisson regression distribution were used to clarify the effects of antidepressants on suicide rates, while an autoregressive adjusted model was used to test the interaction between antidepressant utilization and suicide over two time periods: 1980–1994 and 1995–2009.

          Findings

          An inverse correlation was observed in all countries between recorded Standardised Death Rate (SDR) for suicide and antidepressant Defined Daily Dosage (DDD), with the exception of Portugal. Variability was marked in the association between suicide and alcohol, unemployment and divorce, with countries depicting either a positive or a negative correlation with the SDR for suicide. Every unit increase in DDD of an antidepressant per 1000 people per day, adjusted for these confounding factors, reduces the SDR by 0.088. The correlation between DDD and suicide related SDR was negative in both time periods considered, albeit more pronounced between 1980 and 1994.

          Conclusions

          Suicide rates have tended to decrease more in European countries where there has been a greater increase in the use of antidepressants. These findings underline the importance of the appropriate use of antidepressants as part of routine care for people diagnosed with depression, therefore reducing the risk of suicide.

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          Most cited references61

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          The fallacy of the ecological fallacy: the potential misuse of a concept and the consequences.

          Ecological studies have been evaluated in epidemiological contexts in terms of the "ecological fallacy." Although the empirical evidence for a lack of comparability between correlations derived from ecological- and individual-level analyses is compelling, the conceptual meaning of the ecological fallacy remains problematic. This paper argues that issues in cross-level inference can be usefully conceptualized as validity problems, problems not peculiar to ecological-level analyses. Such an approach increases the recognition of both potential inference problems in individual-level studies and the unique contributions of ecological variables. This, in turn, expands the terrain for the location of causes for disease and interventions to improve the public's health.
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            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.
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              Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials.

              The US Food and Drug Administration (FDA) has issued warnings that use of antidepressant medications poses a small but significantly increased risk of suicidal ideation/suicide attempt for children and adolescents. To assess the efficacy and risk of reported suicidal ideation/suicide attempt of antidepressants for treatment of pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders. PubMed (1988 to July 2006), relevant US and British regulatory agency reports, published abstracts of important scientific meetings (1998-2006), clinical trial registries, and information from authors. Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine) in participants younger than 19 years with MDD, OCD, or non-OCD anxiety disorders. Information was extracted on study characteristics, efficacy outcomes, and spontaneously reported suicidal ideation/suicide attempt. Twenty-seven trials of pediatric MDD (n = 15), OCD (n = 6), and non-OCD anxiety disorders (n = 6) were selected, and risk differences for response and for suicidal ideation/suicide attempt estimated by random-effects methods. Pooled risk differences in rates of primary study-defined measures of responder status significantly favored antidepressants for MDD (11.0%; [95% confidence interval {CI}, 7.1% to 14.9%]), OCD (19.8% [95% CI, 13.0% to 26.6%), and non-OCD anxiety disorders (37.1% [22.5% to 51.7%]), corresponding to a number needed to treat (NNT) of 10 (95% CI, 7 to 15), 6 (4 to 8), and 3 (2 to 5), respectively. While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs placebo (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 [95% CI, 77 to 1000]), the pooled risk differences within each indication were not statistically significant: 0.9% (95% CI, -0.1% to 1.9%) for MDD, 0.5% (-1.2% to 2.2%) for OCD, and 0.7% (-0.4% to 1.8%) for non-OCD anxiety disorders. There were no completed suicides. Age-stratified analyses showed that for children younger than 12 years with MDD, only fluoxetine showed benefit over placebo. In MDD trials, efficacy was moderated by age, duration of depression, and number of sites in the treatment trial. Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                19 June 2013
                : 8
                : 6
                : e66455
                Affiliations
                [1 ]CEDOC, Departamento de Saúde Mental, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
                [2 ]Departamento de Psiquiatria e Saúde Mental, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal
                [3 ]Personal Social Services Research Unit, LSE Health and Social Care, London School of Economics and Political Science, London, United Kingdom
                [4 ]National Suicide Research Foundation, Cork, Ireland
                [5 ]Katholieke Universiteit Leuven, LUCAS, Leuven, Belgium
                [6 ]Estonian-Swedish Mental Health and Suicidology Institute (ERSI), Tallinn, Estonia
                [7 ]Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [8 ]Health Psychology Section, Department of Health Sciences, University Medical Center, University of Groningen, Groningen, The Netherlands
                [9 ]Department of Psychiatry, University of Leipzig, Leipzig, Germany
                Nathan Kline Institute for Psychiatric Research and New York School of Medicine, United States of America
                Author notes

                Competing Interests: Ricardo Gusmão, Sónia Quintão, David McDaid, Ella Arensman, Chantal Van Audenhove, Claire Coffey, Airi Varnik, Peeter Varnik and James Coyne have declared that no competing interests exist. Ulrich Hegerl read the journal’s policy and has the following conflicts: Dr. Hegerl is an advisory board member for Lilly and Lundbeck, a consultant for Nycomed and a speaker for Bristol-Myers Squibb. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: RG SQ. Performed the experiments: RG SQ JC. Analyzed the data: RG SQ DM EA CVA CC AV PV JC UH. Contributed reagents/materials/analysis tools: RG SQ DM EA CVA CC AV PV JC UH. Wrote the paper: RG SQ DM EA CVA CC AV PV JC UH. Obtained permission for use of cell line: RG SQ.

                Article
                PONE-D-13-09418
                10.1371/journal.pone.0066455
                3686718
                23840475
                963e4194-b39b-494b-a7c4-7016f1853b53
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 March 2013
                : 29 April 2013
                Page count
                Pages: 15
                Funding
                The OSPI project has received funding from the European Community’s Seventh Framework Programme, FP7/2007–2013 ( http://ec.europa.eu/research/fp7/index_en.cfm) under grant agreement n° 223138. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Clinical Research Design
                Epidemiology
                Epidemiology
                Pharmacoepidemiology
                Mental Health
                Psychiatry
                Mood Disorders
                Therapies
                Drug Psychotherapy
                Public Health
                Drug Policy
                Social and Behavioral Sciences
                Sociology
                Suicide

                Uncategorized
                Uncategorized

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