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Hi! David Rosenberg here for the Psychopharmacology Institute. I am professor and Chair of the Department of Psychiatry and Behavioral Neurosciences at Wayne State University. I have also served as Chief of Child Psychiatry at the Children’s Hospital of Michigan. I first authored the first textbook on pediatric psychopharmacology, which is now in its third edition. So, I am very passionate about psychopharmacology.
Currently, there are only 2 FDA-approved antidepressants for youth with major depressive disorder (MDD)—fluoxetine and escitalopram. Moreover, only fluoxetine is FDA approved for preadolescents. So, the need for additional medication options in youth with depression is clear. High placebo response rates in depressed youth have further complicated this matter and made it challenging to discriminate between medication vs placebo differences. However, there is no question for clinicians in the trenches treating depressed youth; there is a huge need.
In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will look at a 6-week randomized, double-blind, placebo-controlled trial of duloxetine in 148 children and adolescents 9-17 years with MDD in Japan, which was followed by a longer-term open-label extension trial of about 1 year to evaluate longer-term safety of duloxetine. Moreover, this was a study conducted at 36 medical institutions in Japan. Consistent with studies of duloxetine in children and adolescents with major depressive disorder in the United States, no significant difference was found between duloxetine vs placebo in children and adolescents with MDD in Japan. Because of this, the open-label extension trial was terminated early. Like many other industry-supported studies, the trial’s placebo response rate was also high. Overall, duloxetine was well tolerated with no new safety signals noted.
What is the bottom line? Duloxetine is not ready for primetime use in children and adolescents with MDD. It is not surprising that duloxetine did not separate from placebo in depressed youth in Japan, considering the evidence of prior controlled studies in youth in the United States. So, duloxetine cannot be recommended for treating MDD in children and adolescents.
The bottom line is that SSRIs remain the safest and most effective treatment of choice in terms of medication in depressed youth. The safety profile for nonselective serotonin reuptake inhibitors, like duloxetine, is not as good, and the evidence for its efficacy in depression and anxiety in youth is mixed. So, more often than not, the best and most evidence-based practice is to go with an SSRI—particularly fluoxetine or escitalopram—when medication is indicated for children and adolescents with depression. These negative findings in many antidepressants tested in youth, which have been successful and effective in adults with MDD, underscore the importance of brain and pharmacogenetic research to identify predictors and biomarkers of treatment response or lack thereof.
So, the quest for novel approaches to treat better child and adolescent depression is vital and has to go on. We still do not fully understand the developmental, genetic, or other factors that account for the aids of the switch from adolescence to adulthood, where there is this broader and more significant response to non-SSRIs. So, duloxetine is not recommended as a treatment for child and adolescent depression.
Abstract
Efficacy and Safety of Duloxetine in Children and Adolescents with Major Depressive Disorder in Japan: A Randomized Double-Blind Placebo-Controlled Clinical Trial Followed by an Open-Label Long-Term Extension Trial
Takuya Saito, Mitsuhiro Ishida, Atsushi Nishiyori, Toshimitsu Ochiai, Hideaki Katagiri, Hideo Matsumoto
Objective: The goal of this study was to evaluate the efficacy and safety of duloxetine in children and adolescents (9-17 years of age) with major depressive disorder (MDD) in Japan.
Methods: This study consists of two clinical trials. First, a 6-week, randomized double-blind placebo-controlled clinical trial (RCT) was conducted. The primary endpoint of RCT was the change in Children’s Depression Rating Scale-Revised (CDRS-R) total scores from baseline. Following RCT, an open-label long-term extension trial (OLE) was conducted to investigate the longer-term safety of duloxetine for ∼1 year.
Results: In RCT, CDRS-R total score changes from baseline to 6 weeks after the start of administration (primary endpoint) were -21.03 in the duloxetine group (n= 74) and -22.42 in the placebo group (n= 74). No significant difference was observed in the primary endpoint between the groups (p= 0.5587). In addition, no significant difference was observed in secondary endpoints such as CDRS-R response rates. The proportion of patients with ≥1 treatment-emergent adverse event (TEAE) in RCT was significantly higher in the duloxetine group (78.7%) than in the placebo group (62.2%), and most were mild or moderate in severity. Changes in CDRS-R total scores during OLE, in consecutive patients from the duloxetine group in RCT (n= 63), or placebo group (n= 59) in RCT, and newly enrolled patients (n= 28), were -12.1, -11.3, and -17.8, respectively. The proportion of patients with ≥1 TEAE in OLE was 90.5%, 88.1%, and 89.3% in the respective groups, and most of them were mild or moderate in severity.
Conclusions: Duloxetine did not show superiority to placebo in efficacy in children and adolescents with MDD in Japan. Overall reported TEAEs were consistent with the currently available duloxetine safety profile and no new safety finding was observed in the two clinical trials.
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Reference
Saito, T., Ishida, M., Nishiyori, A., Ochiai, T., Katagiri, H., & Matsumoto, H. (2022). Efficacy and safety of duloxetine in children and adolescents with major depressive disorder in Japan: A randomized double-blind placebo-controlled clinical trial followed by an open-label long-term extension trial. Journal of Child and Adolescent Psychopharmacology, 32(3), 132-142.
