Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

Abstract

Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25–50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD).Methods: Outpatient children (7–11 years) and adolescents (12–17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale–Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions–Severity, Clinical Global Impressions–Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale.Results: The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, −22.6 [1.17]) or fluoxetine (−24.8 [1.17]; placebo, −23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%).Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25–50 mg/d was generally safe and well tolerated in children and adolescents in this study.

Duty to Warn: Antidepressant Black Box Suicidality Warning Is Empirically Justified

“…We also examined two recent desvenlafaxine trials for youth depression, neither of which demonstrated efficacy for desvenlafaxine (52,53). Across the two trials, we did not observe clear trends in suicidality as reported via adverse events or on the C-SSRS.…”

Safety, Tolerability, and Efficacy of Desvenlafaxine in Children and Adolescents with Major Depressive Disorder: Results from Two Open-Label Extension Trials

“…Principal investigators were child and adolescent or general psychiatrists with experience in the diagnosis and treatment of pediatric depression and in conducting industry-sponsored studies; evaluator qualifications and training were previously described. 27,28 Lead-in studies were similarly designed phase 3, multicenter, randomized, double-blind, placebo-controlled trials. Participants enrolled in the lead-in for study 1030 were randomly assigned (1:1:1) to placebo, desvenlafaxine low exposure (20-35 mg/d), or desvenlafaxine higher exposure (25-50 mg/d), with desvenlafaxine dose based on body weight at baseline (Supplemental Table 1).…”

“…Enrollment criteria for the lead-in studies are described in detail in separate publications. 27,28 Briefly, those enrolled included male and female outpatients, aged 7 years to less than 18 years who at time of enrollment met Diagnostic and Statistical Manual of Mental Disorders (4th ed., Text Revision) criteria for MDD as the primary diagnosis, as assessed by the KIDDIE Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version 30 (K-SADS-PL) and clinical interview. A comprehensive diagnostic psychiatric evaluation, including collection of psychiatric history and treatments and confirmation of the MDD diagnosis, was performed by a psychiatrist at screening of the lead-in study.…”

“…Patients with a history or presence of MDD with psychotic features or any psychotic disorder, bipolar disorder (or first-degree relative with bipolar disorder) or manic episodes, or comorbid primary psychiatric condition other than MDD, based on comprehensive psychiatric interview and evaluation supported by the K-SADS-PL, were excluded from the lead-in studies. 27,31 The extension studies included patients who completed one of the 8-week lead-in studies and who would benefit from long-term treatment, in the investigator's opinion. The investigator's determination was based on the results of efficacy and tolerability assessments and overall clinical presentation during the lead-in study and was intended to allow the investigator flexibility in considering the range of factors that may impact patient participation in a longer-term study.…”

“…Neither desvenlafaxine nor fluoxetine groups separated statistically from placebo on the primary efficacy outcome in these short-term, phase 3 studies. 27,28 Thus, the two double-blind, placebo-controlled studies failed to demonstrate efficacy of desvenlafaxine for treating MDD in children and adolescent patients. This paper presents the results of two 6-month extension trials that enrolled patients who had completed one of the phase 3, shortterm studies.…”