Safety and Efficacy of Levomilnacipran Extended Release in Pediatric Patients Aged 7-17 Years with Major Depressive Disorder: Results of Two Phase 3, Randomized, Double-Blind Studies.

Objective: Major depressive disorder (MDD) presents a significant psychosocial burden, and there is an unmet need for additional treatment options in pediatric patients. Here, we report the results of two phase 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group studies evaluating the efficacy and safety of levomilnacipran extended release in children and adolescents with MDD. Methods: In the first study, LVM-MD-11, patients aged 12-17 years received daily doses of levomilnacipran 40 mg (n = 134), levomilnacipran 80 mg (n = 138), fluoxetine 20 mg (n = 134), or placebo (n = 141). In the second study, LVM-MD-14, patients aged 7-17 years received levomilnacipran 40 to 80 mg (n = 166), fluoxetine 20 mg (n = 166), or placebo (n = 160) daily. Primary and secondary efficacy endpoints were changes in Children's Depression Rating Scale-Revised (CDRS-R) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively. Results: In LVM-MD-11, there were no significant differences in change in CDRS-R total score between patients treated daily with placebo (least squares mean [LSM] change in CDRS-R total score -22.9) versus levomilnacipran 40 mg (-23.3; p = 0.8035) or 80 mg (-22.6; p = 0.8681). Similarly, in LVM-MD-14, there were no significant differences in LSM change in CDRS-R total score with placebo (-21.3) versus levomilnacipran 40 to 80 mg daily (-23.0; p = 0.2215). There were also no significant differences between the fluoxetine and placebo groups in either study for changes in CDRS-R total score. Changes in CGI-S score were not significant between placebo and levomilnacipran 40 to 80 mg daily or between placebo and fluoxetine. Levomilnacipran was generally well tolerated. Conclusions: The high placebo response in this study prevented the detection of an effect of levomilnacipran in children and adolescents. Clinical Trial Registration numbers: NCT02431806 and NCT03569475.

A Multicenter Double-Blind, Placebo-Controlled Trial of Escitalopram in Children and Adolescents with Generalized Anxiety Disorder.

Objective: Generalized anxiety disorder (GAD) in children and adolescents is associated with substantial morbidity and increases the risk of future psychopathology. However, relatively few psychopharmacologic studies have examined treatments for GAD in pediatric populations, especially in prepubertal youth. Methods: Children and adolescents aged 7-17 years of age with a primary diagnosis of GAD were treated with flexibly dosed escitalopram (10-20 mg daily, n = 138) or placebo (n = 137) for 8 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS) for GAD, Clinical Global Impression of Severity (CGI-S) scale, Children's Global Assessment Scale (CGAS); safety measures included the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as adverse events (AEs), vital signs, and electrocardiographic and laboratory monitoring. Results: Escitalopram was superior to placebo in reducing anxiety symptoms of GAD, as seen in the difference in mean change from baseline to week 8 on the PARS severity for GAD score (least squares mean difference = -1.42; p = 0.028). Functional improvement, as reflected by CGAS score, was numerically greater in escitalopram-treated patients compared with those receiving placebo (p = 0.286), and discontinuation owing to AEs did not differ between the two groups. Vital signs, weight, laboratory, and electrocardiographic results were consistent with previous pediatric studies of escitalopram. Conclusions: Escitalopram reduced anxiety symptoms and was well tolerated in pediatric patients with GAD. These findings confirm earlier reports of escitalopram efficacy in adolescents aged 12-17 years and extend the safety and tolerability data to children with GAD aged 7-11 years. ClinicalTrials.gov Identifier: NCT03924323.