Antidepressant Efficacy in Teens Clouded by Poor- Quality Industry Trials?

Megan Brooks

March 23, 2017

The inclusion of a large number of industry-sponsored antidepressant trials in meta-analyses has distorted the picture of antidepressant efficacy for child and adolescent depression, says a leading child psychiatrist with expertise in clinical trials.

John T. Walkup, MD, vice chair of child and adolescent psychiatry at Weill Cornell Medicine and New York–Presbyterian Hospital in New York City, urges clinicians to look more closely at the strengths and weaknesses of the studies included in pooled analyses when making decisions about prescribing selective serotonin reuptake inhibitors (SSRIs) to young people.

"To truly understand the evidence base for the treatment of teen depression, one should focus on the federally funded studies of teen depression, not the large number of failed industry-sponsored pediatric depression trials," Dr Walkup told Medscape Medical News.

The efficacy and safety of SSRIs for children and adolescents with depression have been the subject of "great controversy" in the scientific and clinical arena and have received much attention in the media, Dr Walkup notes in a review article published online March 3 in the American Journal of Psychiatry.

Poor Quality Research Dominates

The controversy spiked in 2016 with the publication of a meta-analysis in the Lancet that suggested that antidepressants are minimally effective, not effective, or are no more effective than placebo in children and adolescents.

One problem, said Dr Walkup, is that there are two "high-quality" studies of pediatric depression, funded by the National Institute of Mental Health (NIMH), and more than 16 "poor-quality" industry-funded studies.

"In modern comprehensive meta-analyses, the sheer number of poor-quality studies overwhelm the few high-quality positive studies that demonstrate the efficacy of antidepressants for teen depression," he said.

In industry-sponsored trials, placebo response rates have been consistently high (>50%), or the differences between active drug and placebo have been small (roughly 10%), or both, Dr Walkup points out in his article.

These trials are most often considered negative trials (ie, trials that did not demonstrate efficacy). However, the methodologic and implementation challenges inherent to these studies suggest that they should be considered failed trials, "and thus largely uninformative regarding efficacy and ineligible for inclusion in meta-analyses," Dr Walkup writes.

In contrast to the industry-sponsored trials, the NIMH-funded depression trials have many "methodological strengths, lower placebo response rates (30% to 35%), and meaningful between-group differences (25% to 30%) that support antidepressant efficacy," he notes.

A possible reason for the differences in results is that the number of study sites was higher in the industry-funded trials, which may make it tough for investigators to maintain study quality.

The NIMH-funded trials, in contrast, used fewer sites, which may have led to research of higher quality. This may account for findings of larger clinical effects. In addition, the investigators received more extensive training, Dr Walkup suggests.

"The NIMH-funded trials," he concludes, "taken together with the demonstrated efficacy of the serotonin reuptake inhibitors for childhood-onset obsessive-compulsive disorder [OCD] and the anxiety disorders, suggest a broad and important role for antidepressant medications in pediatric internalizing conditions," he writes.

"The positive public health message regarding antidepressant efficacy should reflect the high-quality studies, not the large number of poor-quality studies," said Dr Walkup.

A More Balanced Perspective

In an accompanying editorial, Daniel Pine, MD, of the NIMH Intramural Research Program, and Robert Freedman, MD, of the University of Colorado School of Medicine in Aurora, note that some clinicians working with children and adolescents might have hesitated before recommending an SSRI, because of continued questioning in the media of the evidence for their effectiveness.

This review "helps to generate a more balanced perspective, which promises to reduce the burden facing these clinicians," they write.

The review provides evidence that government-supported and industry-supported studies yield different conclusions: independent studies supported by the NIMH yield stronger evidence of efficacy than do the initial industry-funded trials.

"It is these NIMH trials that families and clinicians can turn to when considering whether or not to use an SSRI as part of a comprehensive treatment plan for the adolescent or child with depression," write Dr Pine and Dr Freedman.

"Clearly, SSRIs can have adverse effects on behavior in children and adolescents. Moreover, even in government-funded studies of the highest quality, the magnitude of the clinical effect in major depression is not large," they point out.

Nevertheless, this review "reminds us that the efficacy data clearly do support the use of SSRIs in pediatric major depression, anxiety disorders, and OCD and that the benefits outweigh the risks in many clinical scenarios," Dr Pine and Dr Freedman write.

"Most importantly, when clinicians look beyond controversy to their patients' clinical burden, Walkup's perspective helps us carefully evaluate the efficacy data to choose the best treatment for children and adolescents with major depression, anxiety disorders, and OCD, and in particular, to consider the SSRIs as a reasonable therapeutic option for many of our patients," they conclude.

Dr Walkup was an investigator in the Treatment for Adolescents With Depression Study, the Treatment of Adolescent Suicide Attempters study, and studies conducted by the Sertraline Pediatric Depression Study Group; he was also involved in a number of NIMH-funded and industry-funded studies of OCD, the non-OCD anxiety disorders, bipolar disorder, and attention-deficit/hyperactivity disorder between 1997 and 2009. The authors of the editorial have disclosed no relevant financial relationships.

Am J Psychiatry. Published online March 3, 2017. Abstract, Editorial

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