Evidence of Efficacy Antidepressant for depression in children

Evidence of Efficacy Antidepressant Medication for depression
Both the single largest placebo-controlled comparison study of tricyclic antidepressants (TCAs) and placebo, and a subsequent metaanalysis showed no difference between drug and placebo, while several studies have demonstrated efficacy with selective serotonin reuptake inhibitors (SSRI) antidepressants, especially using fluoxetine.

This may be reflective of an overall developmental difference insofar as adolescents and younger adults may respond better to serotonergic agents, whereas older adults respond equally as well to serotonergic and to noradrenergic agents -risk factor for depression in children, onset and recurrence-.

Fluoxetine is the best-studied antidepressant with the strongest efficacy data, and consequently is the only antidepressant to receive FDA and MHRA approval for use for the treatment of depression in children and adolescents. In these three studies of fluoxetine, a higher proportion of those treated with fluoxetine were much or very much improved compared to those treated with placebo (52-61% vs. 33-37%), for a median number needed to treat (NNT) of five. In the TADS study, fluoxetine was more efficacious than both placebo and cognitive behavior therapy (proportion significantly improved, 61% vs. 43% vs. 35%, respectively). However, combined treatment resulted in the highest rate of symptomatic remission (37% vs. 20% on fluoxetine alone).

A metaanalysis of all available clinical trials, both published and unpublished, shows that SSRIs are superior to placebo, with the average response rate for antidepressant vs. placebo of 60% vs. 49%, for an overall NNT of 9 (95% confidence interval, 7 to 14). The relatively low effect size of SSRIs vs. placebo for child and adolescent mood depressed is due to the high placebo response rate. The drug-placebo difference was inversely proportional to the number of study sites involved in the trial, suggesting that some studies with large numbers of sites may have been less selective in recruitment. Other explanations for the relative modest effects of antidepressants include use of inadequate dosage, duration of antidepressant medication too short to achieve the full effect, and aggregation of results of children and adolescents, when, in some studies there were significant effects for adolescents, but not for children.

Besides fluoxetine, other drugs for which there are published studies that have demonstrated efficacy are citalopram, paroxetine, and sertraline, although the effect sizes were relatively small and there are other negative studies for these agents that have not yet been published. A review of the published and unpublished studies indicates that, for paroxetine, and for venlafaxine, the response to antidepressants medication was superior to placebo for adolescents, but not for children. In some studies, such as those for venlafaxine, the doses used appeared to be substantially below those recommended for clinical practice.

Adverse Events in Antidepressant Treatment
The FDA conducted a metaanalysis that found a higher rate of suicide-related, spontaneously reported adverse events on drug than on placebo (4% vs. 2%). There were relatively few suicide attempts, no completions, and most suicidal events occurred early in treatment. The increased risk for suicidality was found regardless of indication, in subjects with depression, OCD, and anxiety. A more recent metaanalysis that included additional studies not included in the FDA and using random rather than fixed effects models reported rates of suicidal adverse events for drug and placebo of 2.5% vs. 1.7%, respectively, for a risk difference of 0.8%, and a number needed to harm (NNH) of 125 (95% confidence interval 56 to ∞). Thus, the number of those who benefit from SSRIs (NNT = 9) to those who become suicidal (NNH = 125) is around 14 times higher, which seems to be an acceptable risk benefit ratio.

In addition to the concern over suicide and self-injurious behavior, antidepressants are associated with increased incidence of sleep disruption, vivid dreams, nausea and gastrointestinal distress, increase in agitation, akathisia, anxiety, headache, serotonin syndrome (particularly in combination with other serotonergic agents) and bruising (due to a prolongation of clotting time). The latter side effect is usually not clinically significant, but can become so in patients with intrinsic coagulation disorders or who are undergoing surgery. One pharmaco-epidemiological study found that the risk of SSRI-treatment-associated mania was greatest in patients under the age of 14.