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Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial

Author/s: 
Sofie Mesens, Andrew D Krystal, Rama Melkote, Haiyan Xu, Gahan Pandina, Jay B Saoud, Remy Luthringer, Adam Savitz, Wayne C Drevets

Importance: Existing pharmacological treatments for insomnia have significant limitations.

Objective: To assess the effective dose range, safety, and tolerability of the novel selective orexin-2 receptor antagonist seltorexant in insomnia disorder.

Design, setting, and participants: This randomized, double-blind, active- and placebo-controlled, dose-finding, polysomnography study was conducted from November 2017 to April 2019 at 55 sites in 6 countries and analyzed in August 2019. The timeline for submission of this data for publication was impacted by internal strategic decision-making. Adults (aged 18-64 years) and older adults (aged 65-85 years) with insomnia (Insomnia Severity Index score ≥15) and no psychiatric comorbidity were included.

Interventions: Participants were randomized 1:1:1:1:1 to receive nightly oral-seltorexant (5 mg, 10 mg, or 20 mg), placebo, or zolpidem (5-10 mg) for 14 days.

Main outcomes and measures: Primary and key secondary outcomes included the dose-response relationship of night 1 latency to persistent sleep (LPS) and wake after sleep onset over the first 6 hours (WASO-6). Other secondary outcomes included night 13 LPS and WASO-6. Due to asymmetrical distributions of LPS and WASO-6 at baseline, log transformation was applied and results were expressed as back-transformed least-squares mean (LSM) ratios for comparisons between groups.

Results: Overall, 364 participants (mean [SD] age, 57.8 [12.4] years; 246 [67.6%] female) received seltorexant, 5 mg (n = 71), 10 mg (n = 74), or 20 mg (n = 71); placebo (n = 75); or zolpidem (n = 73). The night 1 dose-response relationship for LPS was significant (with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models), with greater improvements in seltorexant, 10 mg and 20 mg, vs placebo (10 mg: LSM ratio, 0.64; 90% CI, 0.51-0.81; 20 mg: LSM ratio, 0.51; 90% CI, 0.41-0.64) and in seltorexant, 20 mg, vs zolpidem (LSM ratio, 0.71; 90% CI, 0.57-0.88). The night 1 dose-response relationship for WASO-6 was also significant, with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models (seltorexant, 10 mg: LSM ratio, 0.68; 90% CI, 0.55-0.85; seltorexant, 20 mg: LSM ratio, 0.60; 90% CI, 0.48-0.74). Night 1 LPS and WASO-6 improvements were maintained on night 13 for seltorexant, 10 mg and 20 mg, but diminished for zolpidem. On night 13, compared with zolpidem, seltorexant, 10 mg and 20 mg, improved LPS by 30% and 28%, respectively, and seltorexant, 20 mg, improved WASO-6 by 31%. Treatment-emergent adverse events (TEAEs) were lower across the combined seltorexant doses (73/216 [33.8%]) relative to placebo (37/75 [49.3%]) and zolpidem (31/73 [42.5%]). Two participants experienced serious TEAEs during the double-blind phase (1 in the seltorexant, 20 mg, group and 1 in the zolpidem group). Three participants in the seltorexant, 5 mg, and 1 in the seltorexant, 20 mg, group experienced asymptomatic electrocardiogram-related TEAEs leading to discontinuation.

Conclusions and relevance: Among participants with insomnia in this study, seltorexant, 10 mg and 20 mg, improved sleep initiation and maintenance throughout 14 days of treatment. Seltorexant was generally well tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT03375203.

Keywords 
sleep medicine neurology Psychiatry and Behavioral Health Seltorexant Insomnia medications sleep disorders

Has This Child Experienced Physical Abuse? The Rational Clinical Examination Systematic Review

Author/s: 
Sonal N Shah, Hiu-Fai Fong, Suzanne B Haney, Mary Clyde Pierce, Nancy S Harper, Mark I Neuman

Importance: Nearly 100 000 children experience physical abuse each year in the US. Among approximately 2000 annual deaths related to child maltreatment, more than 40% resulted from physical abuse, and half of those children were younger than 1 year. Many of these young children had unidentified abusive injuries before the fatal event.

Objective: To determine the accuracy of clinical and radiologic findings for identifying physical abuse among children who have sustained an injury.

Data Sources and Study Selection: MEDLINE, PubMed Central, and Embase were searched for articles published from 1970 to September 2024. Three authors identified studies describing clinical and radiologic characteristics in children and adolescents undergoing assessment for physical abuse.

Data Extraction and Synthesis: The number of children with and without each clinical or radiologic finding, and the presence or absence of physical abuse, which had been determined by expert panels, predefined criteria, or standardized scales that quantify the level of concern for abuse, were recorded.

Main Outcomes and Measures: The sensitivity, specificity, and likelihood ratios (LRs) of each finding for the presence of physical abuse were calculated and the range or calculated summary measures were reported when the finding was evaluated in more than 1 study.

Results: Of 7378 unique articles, 18 studies met inclusion criteria. The prevalence of physical abuse in these 18 studies ranged from 5% to 79%. Studies that were focused on skin findings in children evaluated for trauma showed that the presence of oral injury such as a torn frenulum (positive LR, 6.6 [95% CI, 3.2-14.0]), bruising on the buttocks (positive LR range, 15-83) or neck (positive LR range, 2.2-84), patterned bruises (positive LR range, 2.0-66), and subconjunctival hemorrhage (positive LR range, 5.4-130) were associated with increased likelihood of physical abuse. In studies of hospitalized children with head injury, the presence of retinal hemorrhages (positive LR, 11.0 [95% CI, 4.0-32.0]), seizures (positive LR, 3.9 [95% CI, 2.4-6.5]), hypoxic ischemic injury (positive LR, 3.4 [95% CI, 1.8-6.4]), or a subdural hematoma (positive LR, 3.2 [95% CI, 2.6-3.8]) increased the likelihood of physical abuse. In studies examining children who underwent skeletal surveys, a single fracture (positive LR, 5.9 [95% CI, 2.9-12.0]) or multiple fractures (positive LR, 3.8 [95% CI, 2.4-6.0]) increased the likelihood of physical abuse.

Conclusions and Relevance: A detailed physical examination that reveals oral injury, bruises on the buttocks or neck, patterned bruises, and subconjunctival hemorrhage in young children should alert clinicians to the possibility of physical abuse. Findings on neuroimaging and ophthalmologic evaluation in infants and young children with head trauma can help clinicians determine the likelihood of physical abuse.

Keywords 
The Rational Clinical Examination Trauma and Injury child abuse Psychiatry and Behavioral Health Child and Adolescent Psychiatry

What Is Perinatal Depression?

Author/s: 
Rebecca Voelker

Perinatal depression can occur during pregnancy and the first 12 months after childbirth.

Perinatal depression, also called postpartum depression, affects about 1 in 7 perinatal individuals. More than 75% of these individuals receive no treatment for perinatal depression. Onset of perinatal depression may occur prepregnancy or may develop over the course of pregnancy and the postpartum period. Untreated perinatal depression is associated with an increased risk of suicide and has additional negative effects on the perinatal individual, the fetus (preterm birth, low birth weight), and the child (impaired attachment, which may affect neurodevelopment) and may negatively affect relationships with partners and other family members.

Keywords 
Depressive Disorders Psychiatry and Behavioral Health Patient Information Reproductive Health Pregnancy Postpartum Depression Perinatal Depression
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