Fluoxetine alone or paired with cognitive behavioral therapy (CBT) was the most effective treatment for children and adolescents with depressive disorders, according to a systematic review and meta-analysis published in Lancet Psychiatry.

Researchers searched publication databases through January 1, 2019. Studies with data on placebo-controlled or head-to-head trials of 16 antidepressants, 7 psychotherapies, and 5 combinatory therapies for the treatment of patients aged ≤18 years were included. Criteria involved having at least 10 patients diagnosed according to standard operationalized criteria and treatment lasting 4 weeks or longer.

Of the 20,366 publications, 71 studies were included, with a total of 9510 patients, largely with moderate to severe depression. The final data were published between 1986 and 2018. The primary outcomes were efficacy, or change in depressive symptoms, and acceptability, which related to treatment discontinuation. Overall, the mean study sample size was 136 patients, and the mean age was 14.0 years.

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Only fluoxetine with CBT (standardized mean difference [SMD], -0.73; 95% credible interval [CrI], -1.39 to -0.07) or fluoxetine alone (SMD, -0.51; 95% CrI, -0.84 to -0.18) were more effective than a placebo or psychological controls (SMD range, -1.73 to -0.83). They were also more effective than CBT (SMD, -0.78; 95% CrI, -1.55 to -0.01) or psychodynamic therapy (SMD, -1.14; 95% CrI, -2.20 to -0.08). Overall, no pharmacotherapy alone was more effective than psychotherapy alone.

Venlafaxine significantly increased the risk for suicidal behavior or ideation when compared with a placebo (odds ratio [OR], 8.31; 95% CrI, 1.92-343.17). Nefazodone and fluoxetine had fewer dropouts than sertraline, imipramine, or desipramine (OR range, 0.17-0.50). The investigators reported that any active intervention, except for nortriptyline (SMD range, 1.04-2.22), had a better outcome than waiting lists (SMD range, 0.67-2.08).

A significant limitation for this study was the result of the Confidence In Network Meta-Analysis test, which categorized the efficacy and acceptability of the evidence presented in the underlying studies. Of the 72 comparisons, the efficacy of 9 studies was rated as low and 63 as very low, and the acceptability was very low for 58 studies. These data indicated that overall, there was a scarcity of high quality evidence.

The study authors concluded that fluoxetine with or without CBT may be the best acute therapy for adolescents with moderate to severe depressive disorders. However, outcomes of these interventions may vary, and the researchers emphasized that patients, their caregivers, and clinicians should carefully monitor any active intervention.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Zhou X, Teng T, Zhang Y, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7:581-601. doi:10.1016/S2215-0366(20)30137-1.