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

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 Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine,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

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Available from: Remy P Barbe, Sep 29, 2015
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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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    ABSTRACT: Paediatric psychopharmacology holds great promise in two equally important areas of enormous biomedical and social impact, namely the treatment of behavioural abnormalities in children and adolescents, and the prevention of psychiatric disorders with adolescent- or adult-onset. Yet, in striking contrast, pharmacological treatment options presently available in child and adolescent psychiatry are dramatically limited. The most important currently unmet needs in paediatric psychopharmacology are: the frequent off-label prescription of medications to children and adolescents based exclusively on data from randomized controlled studies involving adult patients; the frequent lack of age-specific dose, long-term efficacy and tolerability/safety data; the lack of effective medications for many paediatric psychiatric disorders, most critically autism spectrum disorder; the scarcity and limitations of randomized placebo-controlled trials in paediatric psychopharmacology; the unexplored potential for the prevention of psychiatric disorders with adolescent- and adult-onset; the current lack of biomarkers to predict treatment response and severe adverse effects; the need for better preclinical data to foster the successful development of novel drug therapies; and the effective dissemination of evidence-based treatments to the general public, to better inform patients and families of the benefits and risks of pharmacological interventions during development. Priorities and strategies are proposed to overcome some of these limitations, including the European Child and Adolescent Clinical Psychopharmacology Network, as an overarching Pan-European infrastructure aimed at reliably carrying out much needed psychopharmacological trials in children and adolescents, in order to fill the identified gaps and improve overall outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2015; DOI:10.1016/j.euroneuro.2015.06.009 · 4.37 Impact Factor
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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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    ABSTRACT: First line antidepressants are the so-called SSRI's (selective serotonin reuptake inhibitors), e.g. fluvoxamine, fluoxetine, sertraline, paroxetine and escitalopram. Unfortunately, these drugs mostly do not provide full symptom relief and have a slow onset of action. Therefore also other antidepressants are being prescribed that inhibit the reuptake of norepinephrine (e.g. reboxetine, desipramine) or the reuptake of both serotonin (5-HT) and norepinephrine (e.g. venlafaxine, duloxetine, milnacipran). Nevertheless, many patients encounter residual symptoms such as impaired pleasure, impaired motivation, and lack of energy. It is hypothesized that an impaired brain reward system may underlie these residual symptoms. In agreement, there is some evidence that reuptake inhibitors of both norepinephrine and dopamine (e.g. methylphenidate, bupropion, nomifensine) affect these residual symptoms. In the pipeline are new drugs that block all three monoamine transporters for the reuptake of 5-HT, norepinephrine and dopamine, the so-called triple reuptake inhibitors (TRI). The working mechanisms of the above-mentioned antidepressants are discussed, and it is speculated whether depressed patients with different symptoms, sometimes even opposite ones due to atypical or melancholic features, can be matched with the different drug treatments available. In other words, is personalized medicine for major depression an option in the near future? Copyright © 2015. Published by Elsevier B.V.
    European Journal of Pharmacology 01/2015; 753. DOI:10.1016/j.ejphar.2014.11.045 · 2.53 Impact Factor
    • "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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    ABSTRACT: Major depressive disorder is a highly prevalent and debilitating condition in youth, so developing efficient treatments is a priority for mental health professionals. Psychotherapy (i.e., cognitive behavioral therapy/CBT), pharmacotherapy (i.e., SSRI medication), and their combination have been shown to be effective in treating youth depression; however, the results are still mixed and there are few studies engaging multi-level analyses (i.e., subjective, cognitive, and biological). Therefore, the aims of this randomized control study (RCT) were both theoretical - integrating psychological and biological markers of depression in a multi-level outcome analysis - and practical - testing the generalizability of previous results on depressed Romanian youth population. Eighty-eight (N=88) depressed Romanian youths were randomly allocated to one of the three treatment arms: group Rational Emotive Behavior Therapy (REBT)/CBT (i.e., a form of CBT), pharmacotherapy (i.e., sertraline), and group REBT/CBT plus pharmacotherapy. The results showed that all outcomes (i.e., subjective, cognitive, and biological) significantly change from pre to post-treatment under all treatment conditions at a similar rate and there were no significant differences among conditions at post-test. In case of categorical analysis of the clinical response rate, we found a non-significant trend favoring group REBT/CBT therapy. Results of analyses concerning outcome interrelations are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research 11/2014; 225(3). DOI:10.1016/j.psychres.2014.11.021 · 2.47 Impact Factor
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