Bifunctional DEGS2 has higher hydroxylase activity toward substrates with very-long-chain fatty acids in the production of phytosphingosine ceramides.

Phytosphingosine (PHS) is a sphingolipid component present mainly in epithelial tissues, including the epidermis and those lining the digestive tract. DEGS2 is a bifunctional enzyme that produces ceramides (CERs) containing PHS (PHS-CERs) via hydroxylation and sphingosine-CERs via desaturation, using dihydrosphingosine-CERs as substrates. Until now, the role of DEGS2 in permeability barrier functioning, its contribution to PHS-CER production, and the mechanism that differentiates between these two activities have been unknown. Here, we analyzed the barrier functioning of the epidermis, esophagus, and anterior stomach of Degs2 KO mice and found that there were no differences between Degs2 KO and WT mice, indicating normal permeability barriers in the KO mice. In the epidermis, esophagus, and anterior stomach of Degs2 KO mice, PHS-CER levels were greatly reduced relative to WT mice, but PHS-CERs were still present. We obtained similar results for DEGS2 KO human keratinocytes. These results indicate that although DEGS2 plays a major role in PHS-CER production, another synthesis pathway exists as well. Next, we examined the fatty acid (FA) composition of PHS-CERs in various mouse tissues and found that PHS-CER species containing very-long-chain FAs (≥C21) were more abundant than those containing long-chain FAs (C11-C20). A cell-based assay system revealed that the desaturase and hydroxylase activities of DEGS2 toward substrates with different FA chain lengths differed and that its hydroxylase activity was higher toward substrates containing very-long-chain FAs. Collectively, our findings contribute to the elucidation of the molecular mechanism of PHS-CER production.

Emergency Visits and Hospitalization After Chat Message, Voice Call, or Video Call for Telehealth in Obstetrics and Gynecology Using Telehealth Service User Data in Japan: Cross-sectional Study.

BACKGROUND: In obstetric and gynecologic practices, synchronous telehealth services via chat message, voice calls, and video calls have been increasingly equipped to improve patients' health care accessibility and clinical outcomes. Nevertheless, differences in clinical outcomes between communication tools remain unknown, especially in terms of safety. OBJECTIVE: This study compared the occurrence of emergency visits and hospitalization after telehealth services through different communication tools, including chat messages, voice calls, and video calls. METHODS: We collected data on obstetric and gynecologic concerns of women who consulted specialized doctors and midwives through a telehealth consulting service in Japan (Sanfujin-ka Online) between January 1, 2019, and December 31, 2020. The outcomes were emergency visits or hospitalizations at night after the consultation. Chi-square test and multivariate logistic regression analysis were performed to compare the clinical outcomes between the groups who received telehealth services via chat message, voice calls, and video calls. RESULTS: This study included 3635 participants. The mean age of the participants was 31.4 (SD 5.7) years, and the largest age group (n=2154, 59.3%) was 30-39 years. The numbers (or proportions) of those who received telehealth services via chat message, voice calls, and video calls were 1584 (43.5%), 1947 (53.6%), and 104 (2.9%), respectively. The overall incidence of the outcome was 0.7% (26/3635), including 10 (0.3%) cases of chat message, 16 (0.5%) cases of voice calls, and no video calls. There were no emergency visits that happened due to inappropriate advice. No significant difference in the proportions of the outcomes was observed between the communication tools (P=.55). The multivariate logistic regression analysis showed no significant differences in the outcome between those who used chat message and those who used voice calls (odds ratio 1.63, 95% CI 0.73-3.65). CONCLUSIONS: The communication tools of telehealth services in obstetrics and gynecology did not show a significant difference in terms of emergency visits or hospitalizations after using the service.

Adjunctive brexpiprazole in patients with major depressive disorder and anxiety symptoms: an exploratory study.

BACKGROUND: Major depressive disorder (MDD) with concurrent anxiety symptoms may signal a difficult-to-treat patient. Brexpiprazole is a serotonin-dopamine activity modulator: a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. The objective of this Phase IIIb study was to explore effectiveness, safety, and tolerability of brexpiprazole adjunctive to antidepressant (ADT) monotherapy in patients with MDD and anxiety symptoms (NCT02013531). METHODS: Patients with MDD, Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 20, and inadequate response to current ADT received open-label brexpiprazole 1-3 mg day-1 (target dose 2 mg day-1) + ADT for 6 weeks. Efficacy endpoints included change from baseline at Week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, HAM-A total score, and Sheehan Disability Scale (SDS). Safety and tolerability assessments included adverse events (AEs). RESULTS: Of 37 participants enrolled, 32 (86.5%) completed the study. Baseline mean (SD) MADRS total score was 30.1 (5.1); mean HAM-A total score was 26.9 (5.0). Improvements from baseline were observed at Week 6 for least squares mean change in MADRS total score (-19.6, p < .0001 vs. baseline), HAM-A total score (-17.8, p < .0001) and mean (SD) SDS mean score [-3.6 (2.6)]. Brexpiprazole was well tolerated. The most frequent treatment-emergent AEs were increased appetite (13.5%) and diarrhea, dry mouth, and dizziness (all 10.8%). CONCLUSIONS: These open-label results support the anxiolytic effects of adjunctive brexpiprazole in the treatment of patients with MDD.

The effect of brexpiprazole in adult outpatients with early-episode schizophrenia: an exploratory study.

The aim of this study was to evaluate flexibly dosed brexpiprazole for early-episode schizophrenia through the assessment of efficacy, social functioning, and tolerability. This was an exploratory, 16-week, open-label, flexible-dose (1, 2, 3, or 4 mg/day; target dose 3 mg/day) study in outpatients with early-episode schizophrenia (18-35 years old, ≤5 years' duration of illness). Efficacy was assessed by the Positive and Negative Syndrome Scale score (PANSS) and social functioning was assessed by changes from baseline in PANSS modified prosocial subscale, personal and social performance (PSP), and specific levels of functioning (SLOF) scales. Safety and tolerability were also evaluated. Overall, 25/49 patients completed the study. Symptoms of schizophrenia improved over the entire treatment period, as evidenced by reductions in PANSS total score from baseline (least squares mean change at week 16: -10.2). Improvements in social functioning were shown by least squares mean changes from baseline at week 16 in the PANSS prosocial subscale (-2.0), PSP (6.6), and SLOF (13.1). Brexpiprazole was generally well tolerated; the most common adverse events were insomnia (7/49 patients), somnolence (4/49), sedation, weight increase, and nausea (each 3/49). Brexpiprazole may represent a novel and effective treatment strategy for patients with early-episode schizophrenia and may be effective for improving social function.

Brexpiprazole as an adjunctive treatment in young adults with major depressive disorder who are in a school or work environment.

BACKGROUND: Major depressive disorder (MDD) is a common, debilitating disorder with substantial socioeconomic burden. Many patients with MDD experience symptoms that impair functioning and productivity, often negatively affecting work or educational pursuits. This Phase 3b open-label study evaluated adjunctive brexpiprazole in young adults with MDD, who were in work or study. METHODS: Young patients (18-35 years) with MDD (inadequate responders to 1-3 antidepressant treatments [ADT] for their current episode) received brexpiprazole 1-3mg/day (target dose, 2mg/day) adjunctive to the same stable dose of ADT for 12 weeks. RESULTS: Depressive symptoms improved during treatment with adjunctive brexpiprazole (primary endpoint, least squares [LS] mean change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score, -18.1 [p<0.0001]). Reductions from baseline in Sheehan Disability Scale Score (SDS; LS mean change -11.2 [p<0.0001]) and Work Limitations Questionnaire (WLQ; p<0.0001) indicated improvements in the effects of patients' symptoms on functioning (work/school, social life, and home responsibilities). Changes from baseline in additional measures supported improvements in patient functioning and depression symptoms. The most common adverse events were headache (21.3%), weight increase (17.0%), and somnolence (17.0%); reported rates of akathisia were low (6.4%). Clinically relevant increases in weight (≥7%) occurred in 10.5% of patients. LIMITATIONS: Open-label design; absence of comparator. CONCLUSIONS: Brexpiprazole may represent an effective therapy for adjunctive treatment strategy of young adults with MDD who are working or studying. The observed improvements in work/school functioning in patients with MDD, whose depression was treated with ADT+brexpiprazole, suggests potential to reduce socioeconomic burden.

The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study.

The aim of this study was to explore the effects of brexpiprazole and aripiprazole on efficacy, cognitive functioning, and safety in patients with acute schizophrenia. Patients who would benefit from hospitalization/continued hospitalization for acute relapse of schizophrenia were enrolled and randomized (2 : 1) to target doses of open-label brexpiprazole 3 mg/day or aripiprazole 15 mg/day for 6 weeks. Outcomes included change from baseline to week 6 in the Positive and Negative Syndrome Scale total score, Barratt Impulsiveness Scale 11-item score, and Cogstate computerized cognitive test battery scores. Patients treated with brexpiprazole (n=64) or aripiprazole (n=33) showed reductions in symptoms of schizophrenia as assessed by Positive and Negative Syndrome Scale total score (-22.9 and -19.4, respectively). A modest reduction in impulsivity was observed with brexpiprazole, but not aripiprazole (mean change in the Barratt Impulsiveness Scale 11-item total score: -2.7 and 0.1, respectively). No change in Cogstate scores was observed for either treatment. Brexpiprazole was well tolerated and the incidence of akathisia was lower in patients treated with brexpiprazole (9.4%) than aripiprazole (21.2%). Clinically relevant improvements in psychopathology were observed in patients with acute schizophrenia treated with brexpiprazole or aripiprazole. Brexpiprazole was well tolerated, with a lower incidence of akathisia than aripiprazole.