REVIEW OF: Mossman S et al, J Child Adolesc Psychopharmacol 2021;31(4):259–267

STUDY TYPE: Meta-analysis

Many research studies report a 30%–60% placebo response rate in pediatric selective serotonin reuptake inhibitor (SSRI) research, rendering the trial “negative” despite a 55%–60% response from the SSRI. We know that different SSRIs are equally effective in adults with major depressive disorder (MDD), so why does fluoxetine fare better than other SSRIs in pediatric MDD meta-analyses? Is it a true difference or research error? This study explored some of the complex factors that influence research outcomes in children and adolescents with anxiety and depression, and the results can help our patients.

After careful screening, the authors analyzed 49 randomized, double-blinded, placebo-controlled trials of the effectiveness of antidepressants for the treatment of depression or anxiety in youth. They examined demographics, funding sources, disorders targeted, and dosing schedules. More studies received industry funding than federal funding (57% vs 33%), more targeted depression than anxiety (74% vs 27%), and more used flexible dosing than fixed dosing (57% vs 33%). The trials covered 19 antidepressants from five classes, most commonly fluoxetine (κ=7). The mean enrollment was 176 patients per study, and the median treatment duration was eight weeks.

Surprisingly, federally funded antidepressant research trials had a 25% greater chance of showing efficacy as compared to industry-funded trials. While medication response was similar irrespective of funding, industry-funded trials had higher placebo response rates (p<0.001), leading to more frequent trial “failures” despite their incentive to report positive findings (recall the infamous Study 329, where industry researchers misrepresented data to create a treatment effect for paroxetine).

Greater placebo response in industry-funded trials was associated with fewer patients per site and larger numbers of sites. The authors argue that the 1997 FDA Modernization Act and the 2003 Pediatric Research Equity Act prefer research completion over outcomes, thus incentivizing low-quality, underpowered, hastily implemented research studies over higher-quality ones.

Fluoxetine was the only SSRI to have a federally funded study, and the better-quality research design may account for its relative superiority to other SSRIs in children and adolescents. Fluoxetine’s long half-life may be another factor, making it more forgiving with fewer withdrawal problems when there are lapses in compliance.

Carlat Take

Higher placebo rate in pediatric antidepressant trials may be related to poorly designed industry-funded studies, which might be excluded from future meta-analyses to improve accuracy. Step back and deploy a range of lifestyle interventions and therapies, and keep an open mind for trying other medications if fluoxetine fails.