Fluoxetine, either alone or in combination with CBT, appears to be the most effective treatment for children and adolescents with moderate to severe depression, a systematic review and network meta-analysis has concluded.

Placebo-controlled and head to head trials of 16 antidepressants, seven psychotherapies and five combinations of antidepressant and psychotherapy were identified from databases and trial registers. Double-blind randomised controlled trials (RCTs) of antidepressant monotherapy and observer-blind or self-rated trials of psychotherapy or combination therapy were included.

Trials involving participants with bipolar disorder or subthreshold, treatment-resistant or psychotic depression were excluded.

Overall, 71 trials with a total of 9,510 participants were analysed. Patients ranged in age from 3 to 20, mean 14 years, and 57.2% were female.

Three quarters (75.5%) had moderate to severe depression.

The primary outcomes were efficacy and acceptability, defined respectively as the change in the depression symptom score and the all-cause discontinuation rate.

Only two treatments were significantly more effective than pill placebo, namely fluoxetine; effect size i.e. standardised mean difference (SMD) -0.51 (95% CI: -0.84 to -0.18) and fluoxetine plus CBT SMD -0.73, (95% CI: -1.39 to -0.07). Fluoxetine plus CBT was significantly more effective than both CBT alone SMD -0.78 (95% CI: -1.55 to -0.01) and psychodynamic therapy SMD -1.14 (95% CI: -2.20 to -0.08), but not more effective than fluoxetine alone SMD -0.22 (95% CI: -0.86 to 0.42). Fluoxetine, fluoxetine plus CBT and interpersonal therapy were all significantly more effective than psychological placebo.

Fluoxetine was associated with fewer dropouts than sertraline, imipramine, and desipramine.

The non-significant findings for other antidepressant monotherapies may in part simply reflect that there were more fluoxetine trials compared with trials for other antidepressants.

The authors highlight a number of limitations. Most of the included studies were of low or very low quality, and there was some evidence of publication bias. A further difficulty is the high placebo response rate in children.

Psychological placebo usually involves a non-directional and neutral discussion so satisfactory blinding may not be possible.

The authors conclude: ‘The findings suggest that fluoxetine (alone or in combination with CBT) might be considered the best option to treat acute symptoms in children and adolescents with major depression.’

The NICE guideline currently recommends a psychological intervention for initial management of moderate to severe depression in children and adolescents,1 and this may now need to be reviewed.

NICE recommends that antidepressant treatment should not be initiated in primary care.¹ Children and adolescents with moderate to severe depression should be referred to child and adolescent mental health services (CAMHS).

Dr Phillip Bland