Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment: A Meta-analysis of Randomized Controlled Trials

Department of Psychiatry, Columbia University, New York, New York, United States
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 05/2007; 297(15):1683-96. DOI: 10.1001/jama.297.15.1683
Source: PubMed

ABSTRACT 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 Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine,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.


Available from: Remy P Barbe, May 30, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Impulsive-aggressive behaviors have been consistently implicated in the phenomenology, neurobiology, and familial aggregation of suicidal behavior. The purpose of this study was to extend previous work by examining laboratory behavioral measures of delayed reward impulsivity and impulsive aggression in adolescent suicide attempters and never-suicidal comparison subjects. Methods: Using the Point Subtraction Aggression Paradigm (PSAP) and the Delay Discounting Task (DDQ), the authors examined delay discounting and impulsive aggression in 40 adolescent suicide attempters, ages 13-18, and 40 never-suicidal, demographically matched psychiatric comparison subjects. Results: Overall, suicide attempters and comparison subjects performed similarly on the PSAP and DDQ. There was a significant group by current psychotropic medication use interaction (p=0.013) for mean aggressive responses on the PSAP. Group comparisons revealed that attempters emitted more aggressive responses per provocation than comparison subjects, only in those not on psychotropic medication (p=0.049), whereas for those currently treated with psychotropic medication, there were no group differences (p>0.05). This interaction effect was specific to current antidepressant use. Among all subjects, family history of suicidal behavior (suicide or suicide attempt) in first degree relatives was significantly correlated with both delay discounting (r=-0.22, p=0.049), and aggressive responding (r=0.27, p=0.015). Family history of suicidal behavior was associated with delay discounting, but not with aggressive responding on the PSAP, after controlling for relevant covariates. Conclusions: In this study, impulsive-aggressive responding was associated with suicide attempt only in those not being treated with antidepressants. Future work to replicate and extend these findings could have important therapeutic implications for the treatment of depressed suicide attempters, many of whom are affected by impulsive aggression.
    Journal of Child and Adolescent Psychopharmacology 03/2015; 25(2). DOI:10.1089/cap.2014.0042 · 3.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several systematic reviews have been published about the relationship of the use of selective serotonin reuptake inhibitors (SSRIs) and risk of suicidal ideation or behavior but there has been no formal assessment of the quality of these reports. Assess the methodological quality of systematic reviews about the relationship of SSRI use and suicidal ideation and behavior; and provide overall conclusions based on this assessment. Systematic reviews of RCTs that compared SSRIs to placebo and used suicidal ideation or behavior as a key outcome variable were identified by searching Pubmed, Embase, The Cochrane Library, EBSCO, PsycINFO, Chinese National Knowledge Infrastructure, Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, and the Chinese Biological Medical Literature Database. The methodological quality of included reviews was independently assessed by two expert raters using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) scale. Twelve systematic reviews and meta-analyses were identified. The inter-rater reliability of the overall AMSTAR quality score was excellent (ICC=0.86) but the inter-rater reliability of 5 of the 11 AMSTAR items was poor (Kappa <0.60). Based on the AMSTAR total score, there was one high-quality review, eight moderate-quality reviews, and three low-quality reviews. The high-quality review and three of the moderate-quality reviews reported a significantly increased risk of suicidal ideation or behavior in the SSRI group compared to the placebo group. Three of the four reviews limited to children and adolescents found a significantly increased risk of suicidal ideation or behavior with SSRI use which was most evident in teenagers taking paroxetine and in teenagers with depressive disorders. The available evidence suggests that adolescents may experience an increase in suicidal ideation and behavior with SSRI use, particularly those who have a depressive disorder and those treated with paroxetine. However, there are few high-quality reviews on this issue, so some doubt about the evidence remains. The AMSTAR scale may be useful in the ongoing efforts to improve the quality of systematic reviews, but further work is needed on tightening the operational criteria for some of the items in the scale.
    10/2014; 26(5):248-258. DOI:10.11919/j.issn.1002-0829.214080
  • [Show abstract] [Hide abstract]
    ABSTRACT: Meta-analysis has increasingly been used to identify adverse effects of drugs and vaccines, but the results have often been controversial. In one respect, meta-analysis is an especially appropriate tool in these settings. Efficacy studies are often too small to reliably assess risks that become important when a medication is in widespread use, so meta-analysis, which is a statistically efficient way to pool evidence from similar studies, seems like a natural approach. But, as the examples in this paper illustrate, different syntheses can come to qualitatively different conclusions, and the results of any one analysis are usually not as precise as they seem to be. There are three reasons for this: the adverse events of interest are rare, standard meta-analysis methods may not be appropriate for the clinical and methodological heterogeneity that is common in these studies, and adverse effects are not always completely or consistently reported. To address these problems, analysts should explore heterogeneity and use random-effects or more complex statistical methods, and use multiple statistical models to see how dependent the results are to the choice of models.
    Drug Safety 02/2015; 38(3). DOI:10.1007/s40264-015-0268-x · 2.62 Impact Factor