Hiroki Fukuju

This article relates to Response to Durability of zuranolone in postpartum depression versus major depressive disorder.

Aim: To evaluate the safety and tolerability of repeating 14‐day treatment with zuranolone (30 mg) followed by a 6‐week follow‐up period (one treatment cycle) for a maximum of six treatment cycles in Japanese participants with major depressive disorder. Methods: This multicenter Phase 3 study was conducted in two parts (70 sites; Japan). Part B was an open‐label study for participants who completed the initial double‐blind study (Part A; zuranolone vs. placebo) in which all eligible participants received zuranolone regardless of their assignments in Part A. Endpoints included treatment‐emergent adverse events (TEAEs) and efficacy using the 17‐item Hamilton Depression Rating Scale (HAMD‐17). Results: A total of 271, 213, 170, 147, 126, and 99 participants were evaluated in Cycles 1–6, respectively. TEAEs occurring in ≥5% of participants were somnolence and dizziness during the treatment period and nasopharyngitis during the follow‐up period, and no new safety signals were observed with increased numbers of treatment cycles. Additionally, no TEAEs suggestive of drug dependence or withdrawal symptoms were identified. The HAMD‐17 total score decreased by 8 and 15 days after the initiation of zuranolone in all six cycles, and there were no meaningful differences in the HAMD‐17 total score reduction across treatment cycles. Conclusion: In this open‐label part of the Phase 3 study in Japan, zuranolone decreased the HAMD‐17 total scores from baseline over 15 days during repeated treatment cycles in patients with major depressive disorder, without any new safety signals.

Aim: To evaluate the efficacy and safety of oral zuranolone for 14 days, compared with placebo, in Japanese patients with major depressive disorder (MDD). Methods: This multicenter, Phase 3 study was conducted in two parts (70 sites; Japan) including a randomized, double‐blind, placebo‐controlled, parallel‐group part presented herein. Participants aged 18–75 years with the 17‐item Hamilton Rating Scale for Depression (HAMD‐17) total score ≥ 22 were randomized (1:1) ratio to receive either zuranolone (30 mg once daily) or placebo for 14 days with follow‐up on Days 3, 8, and 15 and then weekly for 6 weeks (57 days) thereafter. The primary endpoint was change from baseline in the HAMD‐17 total score at Day 15. Results: Overall, 412 participants were randomized to receive either zuranolone 30 mg ( n = 207) or placebo ( n = 205). The difference in the least‐squares mean (95% confidence interval [CI]) change from baseline in the HAMD‐17 total score between groups (−1.20; 95% CI: −2.32, −0.08; P = 0.0365) was statistically significant on Day 15. A significant improvement in the HAMD‐17 total score was observed with zuranolone 30 mg during the early treatment period on Days 3 and 8 compared with placebo; however, no significant differences were observed between the groups at later time points, from Day 22 to Day 57. The frequency of adverse events was higher in the zuranolone group (55.1%) than in the placebo group (40.7%); however, no serious adverse events were reported. Conclusion: Zuranolone improved depressive symptoms on Day 15, compared with placebo, in Japanese patients with MDD. No new safety signals were observed. Clinical Trial Registration: jRCT2031210577.

Background/Objectives: Dysregulated gamma oscillations are associated with cognitive dysfunction. Auditory stimulation at 40 Hz enhances neural activity in brain regions associated with learning, attention, and memory. This study assessed the safety and acceptability of 40 Hz amplitude-modulated auditory stimulation in healthy older people. Auditory stimuli were created using popular songs, where vocals and background music were separated and independently amplitude-modulated at 40 Hz with different modulation depths to generate periodic 40 Hz gamma waveforms. Methods: In this open-label, single-arm study, healthy participants aged ≥65 years received 40 Hz amplitude-modulated auditory stimulation daily via a smartphone for 28 days through earphones/headphones. Safety was assessed through adverse event (AE) monitoring and changes in clinical scores for depression, cognitive function, and hearing thresholds. Acceptability was evaluated by adherence rates, listening time, dropout reasons, volume levels, intent for future use, and subjective impressions of the sound source on a 7-point Likert scale. Results: Among 28 participants (mean age 69.1 years, 53.6% female), six reported 12 AEs, with six considered device-related (e.g., ear discomfort, jaw pain, musculoskeletal stiffness). The AEs observed were mild or moderate. Scores for cognitive function, depression, and hearing thresholds did not worsen during the study period. Adherence was observed in 96.4%, with 85.7% expressing interest in continuing. Most participants rated the sounds’ unnaturalness between 2 and 3 and discomfort between 1 and 3 on the 7-point Likert scale. Conclusions: The intervention was well tolerated and acceptable in study participants, with no major safety concerns identified. Auditory stimulation did not cause severe discomfort or reduce acceptability. Further studies should explore the long-term effects and broader clinical applications.

Aim: This phase 3, multicenter, open‐label study aimed to evaluate the efficacy and safety of SDT‐001, a dual‐task digital device, compared to standard treatment (environmental and/or psychosocial treatment: treatment as usual; TAU) in the comparison part and to evaluate the safety, tolerability, and long‐term efficacy of SDT‐001 in the repetition part in Japanese children and adolescents with attention‐deficit/hyperactivity disorder (ADHD).Methods: In the comparison part, participants on standard treatment were randomized (2:1) to SDT‐001 (n = 109; 25 min/day for 6 weeks, with a 4‐week follow‐up) or TAU (n = 55) groups. Participants (n = 126) from the comparison part transitioned to a single‐arm repetition part with SDT‐001 (6 weeks and followed for 12 weeks). Primary endpoint in the comparison part was changed from baseline to 6 weeks in ADHD rating scale IV (ADHD‐RS‐IV) inattention scores.Results: In the comparison part, SDT‐001 demonstrated superiority to TAU, with significantly greater improvements from baseline to week 6 in ADHD‐RS‐IV inattention (adjusted mean difference [95% confidence interval], −2.97 [−4.38, −1.56]; P < 0.0001), total (−4.56 [−6.75, −2.38]; P < 0.0001), and hyperactivity‐impulsivity (−1.55 [−2.64, −0.46]; P = 0.0056) scores. Additionally, other secondary endpoints showed improvements in symptoms in the SDT‐001 group. In the repetition part, SDT‐001 showed sustained reductions in ADHD‐RS‐IV scores till 12 weeks after completion of the 6‐week treatment. No new severe adverse events or safety concerns were reported.Conclusion: SDT‐001 demonstrated superior efficacy at week 6 in ADHD‐RS‐IV compared to TAU, and reductions in scores were maintained up to the following 12 weeks, indicating its potential as a novel digital therapeutic option for ADHD management.

Aim: The study aimed to assess the efficacy and safety of SDT‐001, a digital therapeutic, in Japanese children and adolescents with attention‐deficit/hyperactivity disorder (ADHD).Methods: This phase 2, multicenter, randomized, double‐blind, sham‐controlled study (jRCT1080225158) was conducted for a duration of up to 14 weeks. After screening, eligible participants were randomized to receive SDT‐001 or single‐task intervention for 25 min/day for 6 weeks and followed for 4 weeks after the intervention. A post hoc analysis was also performed to compare the effects of SDT‐001 or a single‐task to a nonrandomized, open‐labeled, observational group (as the reference follow‐up group; without single‐ or dual‐task training; and continuing psychosocial treatment, including environmental adjustment).Results: Overall, 262 participants were enrolled in the study between July 2020 and July 2021. Of these, 261 participants were included in the analysis (SDT‐001, n = 108; single‐task, n = 107; observation, n = 46). ADHD Rating Scale‐IV (ADHD‐RS‐IV) scores (physician's assessment) decreased gradually, with greater reduction in SDT‐001 versus the single‐task group at week 6 (ADHD‐RS‐IV‐Total score, least‐squares mean change from baseline [95% confidence interval] −7.5 [9.0, −6.1] vs. −6.5 [−7.9, −5.0], P = 0.2112). Reductions in inattention and hyperactivity/impulsivity scores were maintained during 4‐week follow‐up after treatment completion. At week 6, the scores of both groups improved compared to the nonrandomized observation group in post hoc analysis.Conclusion: These findings suggest SDT‐001 as a promising treatment option, addressing the challenges of psychosocial treatment and pharmacotherapy in Japanese children and adolescents with ADHD.