Frequently Asked Questions

Most treatment-emergent adverse events with initial and repeat 14-day zuranolone courses were mild or moderate, and the study reported no new or unexpected safety findings with repeat treatment courses over up to 1 year. In the safety set, at least 1 treatment-emergent adverse event occurred in 68.0% (493/725) of the 30-mg Cohort and 68.8% (137/199) of the 50-mg Cohort; among patients with treatment-emergent adverse events, 90.9% in the 30-mg Cohort and 85.4% in the 50-mg Cohort were mild or moderate.

Serious adverse events occurred in 2.8% (20/725) of the 30-mg Cohort and 4.5% (9/199) of the 50-mg Cohort. The authors state that treatment-emergent adverse events occurred primarily while on treatment in cycles 1 and 2, and that the safety profile with repeat courses was generally consistent with the initial course.

The most commonly reported side effects were somnolence, dizziness, headache, and sedation. Across the full study, adverse events reported by at least 10% of patients were headache (14.2%) and somnolence (11.9%) in the 30-mg Cohort, and somnolence (16.1%), dizziness (15.1%), headache (12.6%), and sedation (10.1%) in the 50-mg Cohort.

During the initial 28-day treatment cycle, the most common adverse events were somnolence (9.7%), headache (8.8%), and dizziness (5.9%) in the 30-mg Cohort, and dizziness (15.1%), somnolence (13.6%), sedation (8.5%), headache (8.0%), and nausea (5.0%) in the 50-mg Cohort.

Adverse effects led to dose reduction more often at 50 mg than at 30 mg. Treatment-emergent adverse events led to dose reduction in 6.1% (44/725) of the 30-mg Cohort and 18.6% (37/199) of the 50-mg Cohort, and they led to study withdrawal in 4.4% (32/725) and 8.0% (16/199), respectively.

In the 30-mg Cohort, adverse events leading to withdrawal that occurred in at least 2 patients included anxiety, depression, suicidal ideation, dizziness, confusional state, insomnia, nausea, and pulmonary embolism. The paper also notes that most withdrawals due to adverse events occurred in treatment cycle 1.

Depressive symptoms improved by Day 15 after the initial 14-day course in both cohorts. Mean change from baseline in HAMD-17 total score at Day 15 was -15.2 (SD 7.1) in the 30-mg Cohort and -16.0 (SD 6.0) in the 50-mg Cohort.

Among patients with nonmissing HAMD-17 scores, 73.5% (505/687) in the 30-mg Cohort and 80.5% (149/185) in the 50-mg Cohort achieved a Day 15 HAMD-17 response, defined as at least a 50% reduction from baseline. The study also states that most patients achieved a CGI-I response by Day 8 that was sustained through Day 70 in study period 1 among those remaining in follow-up.

Many initial responders did not require frequent retreatment over 1 year. Among responders who continued in follow-up beyond Day 28, 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort received only the initial 14-day treatment course during their time in the study.

Most patients received only 1 or 2 total treatment courses: 68.5% (335/489) in the 30-mg Cohort and 79.5% (116/146) in the 50-mg Cohort. The mean number of repeat treatment courses was 1.2 (SD 1.3) and 0.8 (SD 1.1), respectively.

The median time to first repeat treatment course was 135 days in the 30-mg Cohort and 249 days in the 50-mg Cohort based on Kaplan-Meier estimation. In the initial study period, the estimated median time to relapse was 109 days for the 30-mg Cohort and 224 days for the 50-mg Cohort.

The study required at least 56 days between treatment courses, so Day 70 was the earliest possible date for retreatment eligibility after a 14-day course.

Yes, many initial responders regained response after repeat treatment. After a second treatment course, Day 15 HAMD-17 response was achieved by 64.3% (171/266) of patients in the 30-mg Cohort and 64.6% (42/65) in the 50-mg Cohort.

In the 30-mg Cohort, response rates after later repeat courses were 63.6% (96/151) in treatment cycle 3, 66.7% (62/93) in cycle 4, and 71.8% (28/39) in cycle 5. In the 50-mg Cohort, response rates after repeat courses beyond the second were 50.0% (14/28), 40.0% (6/15), and 0/5 for cycles 3, 4, and 5, but the authors note that 30 or fewer patients received more than 2 total 50-mg courses, limiting interpretation.

Repeat treatment was based on structured symptom monitoring followed by clinician confirmation. Patients completed the PHQ-9 remotely every 2 weeks and had in-clinic HAMD-17 assessments every 8 weeks; if the PHQ-9 score was at least 10, the patient returned within 1 week for a clinician-administered HAMD-17.

A patient qualified for a repeat treatment course only if the follow-up HAMD-17 total score was at least 20 and at least 56 days had passed since the last zuranolone dose. Patients who relapsed before Day 70 could instead have an existing antidepressant adjusted or start a new antidepressant at the investigator's discretion.

Patients could remain on standard-of-care antidepressants if they had been on a stable dose for at least 60 days before their first zuranolone dose and planned to continue that antidepressant through Day 28. At baseline, 41.9% (304/725) of the 30-mg Cohort and 41.2% (82/199) of the 50-mg Cohort were receiving an antidepressant.

The study reports that the incidence and timing of treatment-emergent adverse events were not notably different between patients who received zuranolone alone and those who received zuranolone plus a stable baseline antidepressant.

The main limitation is that SHORELINE was an open-label, nonrandomized study, so it was not designed for comparative safety or efficacy assessments. The authors specifically state that the lack of randomization limits interpretation of the efficacy findings.

They also note that the 50-mg Cohort was smaller than the 30-mg Cohort, especially in treatment cycles 3 through 5, which limits interpretation of later repeat-course results in that cohort. For example, after the second treatment course, 30 or fewer patients in the 50-mg Cohort received additional courses.