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: 35.29). 05/2007; 297(15):1683-96. DOI: 10.1001/jama.297.15.1683
Source: PubMed


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 Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine,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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    • "Potential explanations for these results include age-related differences in the neurobiological and psychosocial underpinnings of depression and inadequate study design (i.e., inclusion criteria not sufficiently selective for severity or comorbidity, questionnaires and outcome measures inappropriate for age, lack of a placebo run-in phase before placebo randomization) (Moreno et al., 2007; Usala et al., 2008; Tsapakis et al., 2008). Importantly, in youngsters the efficacy of SSRIs is significantly higher for obsessive–compulsive disorder (OCD) (NNT=6) and, especially, for generalized anxiety disorder (NNT=3) than for juvenile depression (NNT=10) (Bridge et al., 2007), and very comparable to the efficacy recorded for OCD and anxiety in adults (Huhn et al., 2014). Not all off-label prescriptions are supported by sufficient evidence, which is very concerning. "
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    • "Patients should never suddenly stop SSRImedication , without consulting his/her general practitioner, because this may cause severe negative withdrawal side effects. Results of a comprehensive review of pediatric trials conducted between 1988 and 2006 suggested that the benefits of SSRI medications likely outweigh the increased suicide risk in children and adolescents with major depression and anxiety disorders (Bridge et al., 2007). "
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    • "Therefore, conducting more RCTs investigating pharmacotherapy , CBT, and their combination in treating youth depression is extremely important, as many clinical aspects (e.g., multi-level analyses of the outcomes) related to treatment response (e.g., efficacy/effectiveness) and its mechanisms of change still remain to be clarified. In this sense, investigating new CBT approaches would be a promising direction given the fact that current treatments still elicit only a moderate success rate, with between one third and one half of youths still not responding to treatment (Bridge et al., 2007; Weisz et al., 2006). For instance, REBT, rational emotive behavior therapy/REBT – a form of CBT – which assumes that core irrational beliefs generate distorted automatic thoughts that further generate dysfunctional consequences (e.g., dysfunctional feelings, maladaptive behaviors) – has been found (see David et al., 2008) effective in treating major depressive disorder in adult population when compared to pharmacotherapy (being included in the NICE Guidelines; see NICE, 2010), but no such results have yet been reported for a youth population. "
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