How to Decide on Repeat Zuranolone for Major Depressive Disorder
How should clinicians determine whether an adult with major depressive disorder who initially responded to zuranolone should receive a repeat treatment course?
Adults with major depressive disorder may improve after a 14-day zuranolone course but later experience return of depressive symptoms. The SHORELINE study provides a structured retreatment workflow based on serial patient-reported PHQ-9 monitoring, clinician-confirmed HAMD-17 severity, and a minimum interval between courses.
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Confirm that the patient was an initial Day 15 responder
In SHORELINE, only patients who achieved HAMD-17 response at Day 15 after the initial treatment course were eligible to continue in the retreatment pathway. Response was defined as a 50% or greater reduction in HAMD-17 total score from baseline.
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Begin scheduled relapse surveillance after Day 28
After the initial treatment cycle, monitor symptoms with remote PHQ-9 assessment every 2 weeks and in-clinic HAMD-17 every 8 weeks. This was the study's operational strategy for identifying return of clinically significant depressive symptoms during follow-up.
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Use PHQ-9 score 10 or higher as the trigger for urgent reassessment
If the PHQ-9 score is 10 or higher, have the patient return to clinic within 1 week for a clinician-administered HAMD-17. In SHORELINE, this PHQ-9 threshold was the trigger for evaluating whether relapse had progressed enough to justify another treatment course.
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Confirm retreatment eligibility with HAMD-17 and timing criteria
A repeat treatment course required a follow-up HAMD-17 total score of 20 or higher and at least 56 days since the last zuranolone dose. Because the original course lasted 14 days, Day 70 was the earliest date a repeat course could be given.
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Manage earlier relapse with standard antidepressant adjustment instead of early retreatment
Patients who relapsed before Day 70 were not eligible for another zuranolone course in the study. In that situation, investigators could adjust an existing antidepressant or start a new antidepressant at their discretion.
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Set expectations about likely retreatment timing and frequency
Among initial responders who continued in follow-up, the median time to first repeat treatment course was 135 days in the 30-mg Cohort and 249 days in the 50-mg Cohort. Most patients received 1 or 2 total treatment courses over up to 1 year, rather than frequent repeated courses.
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Discuss the chance of recapturing benefit with retreatment
Among patients who received a second course, Day 15 HAMD-17 response was regained in 64.3% of the 30-mg Cohort and 64.6% of the 50-mg Cohort. In the 30-mg Cohort, response rates after later courses remained in a similar range, while interpretation of later 50-mg repeat-course results was limited by small sample sizes.
Clinical Considerations
- This retreatment pathway was studied only in patients who achieved HAMD-17 response by Day 15 after the initial course and remained in follow-up beyond Day 28.
- SHORELINE was an open-label, nonrandomized study, so the observed retreatment outcomes do not establish comparative efficacy.
- Later repeat-course results in the 50-mg Cohort are difficult to interpret because 30 or fewer patients received more than 2 total 50-mg courses.
- The study excluded patients with treatment-resistant depression, significant current suicide risk, bipolar disorder, schizophrenia, active psychosis, and regular recent use of benzodiazepines, barbiturates, or other GABA-A receptor modulators.
Bottom Line
In SHORELINE, repeat zuranolone was not given simply for symptom worsening; it required PHQ-9 score 10 or higher, HAMD-17 score 20 or higher, and at least 56 days since the last dose.
