Selective Serotonin Reuptake Inhibitor and Venlafaxine Use in Children and Adolescents with Major Depressive Disorder: A Systematic Review of Published Randomized Controlled Trials

Abstract

Objective: This review critiques published randomized placebo-controlled trials pertaining to the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in the treatment of major depressive disorder in children and adolescents. Method:Medline was searched for articles meeting defined inclusion criteria. The following key terms were used: depressive disorders, antidepressive agents, fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, venlafaxine, child, and adolescent.Results: Six articles met inclusion criteria. Only 2 studies claim efficacy by significant results in primary outcomes; both have since been contested in further analysis. Not one study adequately examines safety, particularly with respect to whether a link exists between antidepressant use and induction of suicidal ideation or attempts. Conclusion:Published studies on SSRI or venlafaxine use in children and adolescents are inconclusive with respect to safety and efficacy, owing to inappropriate claims of efficacy, lack of improvement in global functioning scores, nonstandardized data collection regarding adverse effects, exclusion of suicidal subjects in the recruitment process, grouping of children and adolescents together, small sample sizes, conflict of interest posed by pharmaceutical company sponsorship, and publishing bias. Future investigators should consider these factors when developing study designs. (Can J Psychiatry 2004;49:557-563) Information on author affiliations appears at the end of the article. Clinical Implications· Published evidence regarding the efficacy of selective serotonin reuptake inhibitor (SSRI) and venlafaxine use in children and adolescents with major depression is inconclusive. · Published evidence regarding the safety of SSRI and venlafaxine use in children and adolescents with major depression is also inconclusive. · For future studies of this issue to be clinically relevant, researchers should base claims of efficacy on primary outcomes, should adequately measure suicidal ideation and behaviours, and should have nonindustry funding. Limitations· Unpublished studies were not included in the review.

Perspectives on the Efficacy of Antidepressants for Child and Adolescent Depression

“…They concluded that a large benefit from newer antidepressant drugs is unlikely. Reviewing the same studies, another report judged the efficacy data to be inconclusive [53]. …”

“…Since the above reviews [52,53] included in their analysis a negative study of fluoxetine which involved a small (n = 30), clinically heterogeneous (mixed inpatients and outpatients) participant group [39], some later reviews opted to exclude this negative study from their analyses. For example, one study analyzed five of the six published papers addressed in the above-mentioned reviews [52,53], as well as data from six unpublished studies accessed through collaboration with the UK's MHRA [50].…”

Childhood and Adolescent Depression

“…18,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] Tricyclic antidepressants are ineffective in children and have limited effectiveness in adolescents, with safety concerns in both groups. 18,40,41 There also is limited evidence for the effectiveness of selective serotonin reuptake inhibitors (SSRIs).…”

“…Furthermore, there are high placebo response rates and methodologic flaws in studies supporting SSRI use. 43,52 For example, although one study indicated that fluoxetine plus cognitive behavior therapy was the best choice, the success of fluoxetine was found only in the unblinded arms of the study: the blinded arms showed no better response than with placebo. 39 Finally, most studies are underpowered to address the outcome of suicide.…”

Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats

“…However, not only adults suffer from depression: estimations of the prevalence of depression amongst adolescents range between 1% and 25% (Kessler et al, 2001;van Dulmen et al, 2002). Consequently, SSRIs are often prescribed to children and adolescents, despite a lack of demonstrated efficacy and safety data in this subgroup (Courtney, 2004;Lynch et al, 2001;Murray et al, 2004;Rushton et al, 2000). Besides the risk of side effects caused by SSRIs during treatment in adolescents (Wilnes et al, 2003), SSRIs might also disturb the development of the central nervous system that is still proceeding during adolescence (Spear, 2000).…”