Clinical Summary
Clinical Summary: Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study
Patients with major depressive disorder often need faster symptom relief than standard antidepressants provide, but clinicians also need to know whether benefit can be safely recaptured if symptoms return. These interim SHORELINE data address a practical question in longitudinal care: how often patients needed repeat 14-day zuranolone courses over 1 year, and what happened to tolerability and symptom response when they did.
Design
SHORELINE (NCT03864614) was an open-label, phase 3, observational study.
N
924 patients (30-mg Cohort [n = 725]; 50-mg Cohort [n = 199]) received ≥ 1 dose of zuranolone
Population
Eligible patients were 18–75 years old with a diagnosis of MDD per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for ≥ 4 weeks, HAMD-17 total score ≥ 20, and Montgomery-Asberg Depression Rating Scale total score ≥ 28 at screening and before dosing at Day 1.
Duration
over ≤ 1 year
Key Findings
- Most treatment-emergent adverse events were mild or moderate, but tolerability was less favorable at 50 mg: ≥1 TEAE occurred in 68.0% (493/725) of the 30-mg Cohort and 68.8% (137/199) of the 50-mg Cohort, TEAEs leading to dose reduction occurred in 6.1% (44/725) and 18.6% (37/199), and TEAEs leading to study withdrawal occurred in 4.4% (32/725) and 8.0% (16/199), respectively.
- Depressive symptoms improved rapidly after the initial 14-day course: mean (SD) HAMD-17 change from baseline at Day 15 was −15.2 (7.1) in the 30-mg Cohort and −16.0 (6.0) in the 50-mg Cohort, with HAMD-17 response at Day 15 in 73.5% (505/687) and 80.5% (149/185) of patients who had nonmissing HAMD-17 scores.
- Among responders who continued follow-up, many did not need frequent retreatment over 1 year: 42.9% (210/489) of the 30-mg Cohort and 54.8% (80/146) of the 50-mg Cohort received only the initial 14-day treatment course, while 68.5% (335/489) and 79.5% (116/146) received 1 or 2 total treatment courses.
- Time to needing another course was prolonged, especially in the 50-mg Cohort: the median time to first repeat treatment course based on KM estimation was 135 days for the 30-mg Cohort and 249 days for the 50-mg Cohort; the estimated median time to relapse in the initial study period was 109 and 224 days, respectively.
- Repeat treatment often recaptured response in initial responders: after a second treatment course, HAMD-17 response at Day 15 was 64.3% (171/266) in the 30-mg Cohort and 64.6% (42/65) in the 50-mg Cohort; in the 30-mg Cohort, response after later courses was 63.6% (96/151), 66.7% (62/93), and 71.8% (28/39) for treatment cycles 3, 4, and 5.
Clinical Bottom Line
A 14-day course of zuranolone produced rapid symptom improvement in many adults with major depressive disorder, and repeat courses could recapture response for patients who relapsed over follow-up. In practice, the 50-mg Cohort had longer time to repeat treatment but higher rates of dose reduction and study withdrawal due to adverse events.
Practice Implications
- Discuss repeat-course treatment planning up front: in this study, a minimum of 56 days was required between courses, and the median time to first repeat treatment course was 135 days with 30 mg and 249 days with 50 mg.
- Monitor sedation-related adverse events closely during treatment cycles, especially early and at higher dose, because common TEAEs included somnolence, dizziness, headache, and sedation, and TEAEs leading to dose reduction occurred in 18.6% (37/199) of the 50-mg Cohort versus 6.1% (44/725) of the 30-mg Cohort.
- Use structured symptom monitoring to identify relapse and retreatment need, consistent with the study approach in which PHQ-9 was assessed every 2 weeks and a PHQ-9 score ≥ 10 triggered in-clinic HAMD-17 confirmation; repeat treatment required HAMD-17 total score ≥ 20.
- Set expectations that not all initial responders will need multiple retreatments: among responders who stayed beyond Day 28, 68.5% (335/489) in the 30-mg Cohort and 79.5% (116/146) in the 50-mg Cohort received only 1 or 2 total treatment courses during up to 1 year in the study.
