REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial.

Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.

Patterns of Smoking Behaviour in Low-Income Pregnant Women: A Cohort Study of Differential Effects on Infant Birth Weight.

Maternal smoking accounts for 20%-30% of low birth weight (BW). Second-Hand Smoke (SHS) also negatively affects BW. This cohort study explored the differential effect of smoking patterns during pregnancy on infant BW. Smoking status for 652 self-reported smokers attending public ante-natal clinics was assessed at baseline (V1 first ante-natal visit), 28-32 weeks (V2) and one week after birth (V3). Multivariable generalised linear regression models tested smoking patterns (continuing to smoke, sustained quitting, partial quitting) on BW adjusting for household smoking and other co-variates. Total quitting showed a median increase of 288 g in BW (95% CI (confidence intervals): 153.1-423 g, p < 0.001), compared to partial quitting (147 g, (95% CI: 50-244 g), p < 0.003). In partial quitters, increased BW was observed only in females 218 g, (95% CI: 81-355 g), p = 0.002). Household SHS showed a specific negative influence on pre-term but not term BW. This study suggests that, for low-income women, quitting or partial quitting during pregnancy both have a positive influence on infant BW. Whether others in the household smoke is also important.

Altered Platelet Function in Intrauterine Growth Restriction: A Cause or a Consequence of Uteroplacental Disease?

Objective A limited number of platelet function studies in intrauterine growth restriction (IUGR) have yielded conflicting results. We sought to evaluate platelet reactivity in IUGR using a novel platelet aggregation assay. Study Design Pregnancies with IUGR were recruited from 24 weeks' gestation (estimated fetal weight < 10th centile) and had platelet function testing performed after diagnosis. A modification of light transmission aggregometry created dose-response curves of platelet reactivity in response to multiple agonists at differing concentrations. Findings were compared with healthy third trimester controls. IUGR cases with a subsequent normal birth weight were analyzed separately. Results In this study, 33 pregnancies retained their IUGR diagnosis at birth, demonstrating significantly reduced platelet reactivity in response to all agonists (arachidonic acid, adenosine diphosphate, collagen, thrombin receptor-activating peptide, and epinephrine) when compared with 36 healthy pregnancy controls (p < 0.0001). Similar results were obtained for cases demonstrating an increasing in utero growth trajectory. When IUGR preceded preeclampsia or gestational hypertension, platelet function was significantly reduced compared with normotensive IUGR. Conclusion Using this comprehensive platelet assay, we have demonstrated a functional impairment of platelets in IUGR. This may reflect platelet-derived placental growth factor release. Further evaluation of platelet function may aid in the development of future platelet-targeted therapies for uteroplacental disease.

Extreme Obesity and Postcesarean Wound Complications in the Maternal-Fetal Medicine Unit Cesarean Registry.

OBJECTIVE: The objective of this study was to estimate the association between obesity and wound complications after cesarean delivery. METHODS: A secondary cohort analysis of the Maternal-Fetal Medicine Unit Cesarean Registry. We stratified the exposure, maternal body mass index (BMI) at delivery, as not obese (BMI < 30), obese (BMI 30-45), and extremely obese (BMI > 45). Our primary outcome was wound complication composite of wound infection, endometritis, wound opening, seroma/hematoma, and hospital readmission. Our secondary outcomes included infection composite (wound infection and endometritis) and each individual outcome included in the primary composite. We performed unadjusted and multivariable logistic regression analyses. RESULTS: We included 38,229 women who underwent cesarean; 39% were not obese, 55% were obese, and 6% were extremely obese. In our cohort, 40% of women underwent repeat cesarean and 57% underwent cesarean after labor. Extremely obese women had increased risk for any wound complication (14%, adjusted odds ratio [AOR], 1.65; 95% confidence interval [CI], 1.44-1.89), endometritis (8.3%, AOR, 1.26; 95% CI, 1.07-1.49), wound infection (2.0%, AOR, 3.77; 95% CI, 2.60-5.46), wound opening (0.8%, AOR, 5.47; 95% CI, 2.79-10.71), and wound infection-related hospital readmission (3.6%, AOR, 2.97; 95% CI, 2.26-3.91) compared with nonobese women. Obese women had increased risk for any wound complication (9.6%, AOR, 1.14; 95% CI, 1.06-1.23) and postcesarean infection (7.7%, AOR, 1.12; 95% CI, 1.03-1.22) but not other outcomes. CONCLUSION: In a large multicenter cohort study, we found that extreme obesity was associated with substantial increase in maternal postcesarean complications, and the association between obesity and postcesarean complications appears dose related. These findings validate associations found in single-center studies.