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

OBJECTIVE: Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective. METHODS: Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26. CONCLUSION: Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.

Effects of Long-Term Sertraline Use on Pediatric Growth and Development: The Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES).

Objective: To describe the results of the Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES) outcome measures of cognitive, emotional, and physical development following long-term treatment with sertraline (for up to 3 years) in children and adolescents aged 6-16 years. Methods: SPRITES was a long-term, multicenter, open-label, prospective observational study designed to compare physical and psychological development in pediatric patients exposed to sertraline (with or without psychotherapy) or psychotherapy alone in usual care settings. Data were summarized descriptively, and outcomes were evaluated using a marginal structural model. Results: Between April 2012 and September 2020, 941 patients across 44 U.S. sites participated in the study. At baseline, 695 participants were exposed to sertraline (physician prescribed) with or without psychotherapy, and 245 participants were exposed to psychotherapy alone. Of these, 432 participants (46.0%) completed the full 3-year study follow-up. No significant changes across time were found in standardized height, BRIEF (Behavior Rating Inventory of Executive Function), Trails B, and Tanner stage based on cumulative sertraline exposure or exposure since the last visit. Change in mean standardized weight across time was positively associated with both cumulative sertraline exposure (p = 0.02) and exposure since the last visit (p = 0.029). The mean changes from baseline across time in standardized weight were standard deviations of 0.02, 0.03, 0.16, and 0.17 at months 3, 6, 30, and 36, respectively. However, this finding was not observed in the mean change across time in standardized body mass index, which was not statistically significant. Conclusions: Results are consistent with normal development. Although a statistically significant finding for standardized weight was observed in comparative analyses, the magnitude of the change is small and observed at higher doses of sertraline only. No other significant differences were observed between the "sertraline" group and the "no pharmacological therapy" group on other primary outcome measures. ClinicalTrials.gov identifier: NCT01302080.

Sertraline Pediatric Registry for the Evaluation of Safety: Design and Clinical Characteristics of Pediatric Patients Prescribed Sertraline.

Objectives: To describe the study design and clinical characteristics of patients in the Sertraline Pediatric RegIstry for The Evaluation of Safety (SPRITES). Methods: SPRITES is an open-label postmarketing study of development and safety outcomes in patients aged 6 to 16 years treated with sertraline (with or without psychotherapy) compared with psychotherapy alone for up to 3 years in the United States. Baseline data included demographics and psychiatric history. Primary outcomes included measures of cognitive and emotional development (Trails B, Behavior Rating Inventory of Executive Function [BRIEF]), physical development (height and weight), and pubertal status (Tanner Stage). Data were also collected on present/lifetime risk of suicide-related events using the Columbia-Suicide Severity Rating Scale. Results: SPRITES enrolled 941 patients between the ages of 6 and 16 years. Patients' baseline mean age was 11.9 years (2.9), 57.2% were female, and 84.8% were white. Most patients (78.4%) had an anxiety disorder, and 15.6% were diagnosed with obsessive-compulsive disorder. The mean age at onset of first mental illness was 7.9 years. A higher percentage of sertraline-treated patients compared with patients who received no pharmacological treatment received prior psychotherapy (59.0% vs. 34.4%, p < 0.001), psychotropic medications for a psychiatric disorder (14.1% vs. 3.3%, p < 0.001), and other non-sertraline selective serotonin reuptake inhibitors (8.6% vs. 1.2%, p < 0.001). Most patients were moderately ill on the Clinical Global Impressions-Severity scale, and a higher (p < 0.001) percentage of sertraline-treated patients had a moderate-to-severe mental illness score compared with the no pharmacological treatment group (73.0% vs. 57.8%, respectively). Although patients at high and imminent risk of a suicidal event were excluded at study entry, the sertraline-treated patients reported higher levels of lifetime suicidal behavior compared with patients treated with no pharmacological treatment (5.8% vs. 2.5%, p = 0.039). Conclusions: Baseline data from this nonrandomized observational study suggest that patients prescribed sertraline are reflective of a more mentally ill study population compared with patients receiving psychotherapy. ClinicalTrials.gov identifier: NCT01302080.

Diagnosis and Treatment Options for Preschoolers with Attention-Deficit/Hyperactivity Disorder.

Objective: The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), classifies attention-deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder, with symptoms becoming apparent as early as the preschool years. Early recognition can lead to interventions such as parent/teacher-administered behavior therapy, the recommended first-line treatment for preschool patients. There are few data, however, to inform the use of second-line, pharmacotherapy options in this population. In this review, we identified recent literature on the diagnosis and treatment of ADHD in preschool children. Methods: A PubMed and clinicaltrials.gov search was conducted for trials assessing efficacy or safety of ADHD medications in children aged <6 years. Diagnostic methods and criteria focusing on recognition of ADHD in preschool children were also surveyed. Results: The DSM-5 describes different manifestations of ADHD in preschool versus school-aged children, but does not list separate criteria by age group. Importantly, behaviors indicative of ADHD in older children may be developmentally appropriate in preschool children. Several behavioral rating scales have been validated in children younger than 6 years of age for assessing ADHD. The Preschool ADHD Treatment Study (PATS) has provided the most extensive efficacy and safety data on methylphenidate (MPH) for ADHD in preschoolers to date, with significant improvement in ADHD symptoms observed with MPH compared with placebo, although adverse event-related discontinuation was higher in PATS compared with studies of MPH for ADHD in school-aged children. Since PATS was conducted, few studies designed to assess ADHD medication effectiveness in preschool children have been published. One article reported significant improvement in ADHD symptoms with MPH (immediate release) versus placebo, two studies showed no difference between MPH and risperidone or MPH plus risperidone in relief of ADHD symptoms, and one study demonstrated the efficacy of atomoxetine versus placebo for ADHD symptoms in preschoolers. Conclusions: Further research is needed on pharmacotherapy for preschool children with ADHD.

Desvenlafaxine Versus Placebo in the Treatment of Children and Adolescents with Major Depressive Disorder.

OBJECTIVE: To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of 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 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). 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 assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale. RESULTS: The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence of adverse events was similar among groups. CONCLUSION: Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20-50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.

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

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.

Pharmacokinetics and Tolerability of Single-Ascending Doses of Desvenlafaxine Administered to Children and Adolescents with Major Depressive Disorder.

OBJECTIVE: To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory. METHODS: The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents. CONCLUSIONS: Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

Safety and tolerability of desvenlafaxine in children and adolescents with major depressive disorder.

OBJECTIVE: The purpose of this study was to assess long-term safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in children and adolescents with major depressive disorder (MDD). METHODS: An 8 week, multicenter, open-label, fixed-dose study of children (ages 7-11 years) and adolescents (ages 12-17 years) with MDD was followed by a 6 month, flexible-dose extension study. Patients were administered desvenlafaxine 10-100 mg/day (children) or 25-200 mg/day (adolescents) for a total of 8 months. Treatment-emergent adverse events (AEs), withdrawals because of AEs, laboratory tests, vital signs, and the Columbia Suicide-Severity Rating Scale (C-SSRS) were collected. Eight month safety results from the lead-in plus extension studies are reported for extension study participants, using lead-in study day -1 as baseline. RESULTS: Forty patients were enrolled in both studies (20 children; 20 adolescents). Of those, four children and three adolescents withdrew because of AEs. Treatment-emergent AEs reported by three or more patients were upper abdominal pain (15%) and headache (15%) in children, and somnolence (30%), nausea (20%), upper abdominal pain (15%), and headache (15%) in adolescents. Negativism (oppositional behavior) in a child was the single serious AE reported. No deaths occurred during the lead-in or extension studies. Mean pulse rates demonstrated statistically significant increases from lead-in study baseline to final evaluation (children, +5.2 bpm; adolescents, +5.9 bpm; p≤0.05). No statistically significant change in blood pressure was observed at final evaluation. Two adolescents (0 children) reported suicidal ideation on the C-SSRS at screening assessment and during the lead-in and/or extension trials; one adolescent reported suicidal ideation after screening only. CONCLUSIONS: Long-term (8 month) treatment with desvenlafaxine was generally safe and well tolerated in depressed children and adolescents.