In a review published earlier this month in Frontiers in Psychiatry, Daniel Safer and Julie Magno Zito explore and critique the recent increase in antidepressant medication (ADM) for youth diagnosed with major depressive disorder (MDD). They expose methodological limitations of the studies that are popularly cited to rationalize ADM prescriptions as first-line treatment.
At the essence of their paper is the contention that, “If one excludes the placebo substitution maintenance trials because of their serious methodological flaws ([…], then available research support for ADM treatment during maintenance for youth diagnosed with MDD loses its foundation.” Citing resemblances between the natural course of MDD, and MDD across points in treatment with ADM, they make the case that ADM treatment lacks sufficient support.
It wasn’t until the late 20th century that children began receiving depressive disorder diagnoses and corresponding treatments. Now, rates of MDD diagnoses continue to increase, and approximately one in nine adolescents satisfy diagnostic criteria for MDD. Many have called for increased appreciation for systemic contributions to widespread experiences of despair (e.g., environmental factors), yet treating symptoms at an individual level remains the standard approach.
Approximately one out of 15 children will be prescribed antidepressants by the age of 17, yet many recent studies have indicated the limited or minimal benefit of ADM use for children and adolescents. Additional research has challenged the notion that pharmacological interventions enhance the impact of psychotherapy among teens. Despite the abundance of noninvasive behavioral, psychological, and psychosocial therapeutic options available, research surrounding pharmacological interventions is better funded and associated benefits may be exaggerated.
Safer and Zito’s review captures a variety of studies and meta-analyses published between 2000 and 2018. Publications were gathered that reported the impact of ADM use on depressive symptoms in the context of short-term efficacy trials (approximately eight to 12 weeks in duration) and extension and maintenance trials. Other important, related factors, including, “tricyclic ADM efficacy and extended clinical trials before 1997, antidepressant adverse drug events, ADM maintenance treatment for OCD, trial vs. community rates of ADM non-adherence, or ADM outcome findings comparing NIMH vs. industry sponsorship,” warrant consideration but were beyond the scope of the review.
Findings from the review of short-term efficacy trials indicate “increasingly limited” support for ADM, with a trend towards “higher placebo responses.” Short-term trials seem to find larger effects of ADM use among adolescents with MDD diagnoses compared to younger children, but even these effects are “marginal.”
The authors also sought to address the following questions pertaining to extension and maintenance in clinical trials:
“How much is known about the long-term course of MDD in youth? Does the discontinuation of ADM in drug responders create problems? Does including an ADM along with a psycho-social intervention for MDD further improve outcome?”
Results indicate that following often selective eligibility procedures, youth who respond to short-term ADM treatment typically continue to experience benefits in a six- to eight-month extended ADM intervention period. Relapse was not thoroughly accounted for in publications identified, but when accounted for, relapse of symptoms occurred among approximately one-third of subjects receiving ADM treatment.
In extension trials, authors identified that dropout rates were quite high, with just under half of all original participants dropping out on average, and most extension trials were not controlled. Additionally, they noted numerous limitations to placebo maintenance substitution trials (in which participants who “experienced a response during short-term ADM trials […] are then encouraged to enter into a double-blind, placebo-controlled maintenance trial).”
Finally, Safer and Zito describe a few additional limitations to current research such as the exclusion of youth most vulnerable to relapse (e.g., females, individuals who report suicidality, and individuals with substance abuse challenges) from clinical ADM trials limiting the generalizability of results, patterns of bias in ADM efficacy trials, and more. Overall, this review provides an accessible synthesis of the theoretical and methodological issues that call to question the body of research promoting ADM in the context of MDD prescription among youth.
“Continued mental health intervention for youth diagnosed with MDD is usually useful and often necessary. Including ADM (apart from its “placebo impact”) during continued psychosocial treatment of youth with MDD requires far better evidence of benefit than is presently available.”
Safer, D. J., & Zito, J. M. (2019). Short- and Long-Term Antidepressant Clinical Trials for Major Depressive Disorder in Youth: Findings and Concerns. Frontiers in Psychiatry, 10. (Link)