A Study to Evaluate the Efficacy of Sage-217 in the Treatment of Adult Participants With Major Depressive Disorder (MDD)

Inclusion Criteria:

1. Participant with diagnosis of MDD as diagnosed by Structured Clinical Interview forDiagnostic and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial Version [SCID-5-CT], with symptoms that have been present forat least a 4-week period.
2. Participant has a Hamilton Rating Scale for Depression (HAM-D) total score ≥24 atscreening and Day 1 (prior to dosing).
3. Participants taking antidepressants must have been taking these medications at thesame dose for at least 60 days prior to Day 1. Participants who have stopped takingantidepressants within 60 days must have stopped for longer than 5 half-lives of theantidepressant prior to Day 1. Participants receiving psychotherapy must have beenreceiving therapy on a regular schedule for at least 60 days prior to Day 1.
4. Participant is willing to delay start of other antidepressant or antianxietymedications and any new pharmacotherapy regimens, including as-needed benzodiazepineanxiolytics and sleep aids, until after completion of the Day 42 visit.

Exclusion Criteria:

1. Participant is currently at significant risk of suicide, as judged by theInvestigator, or has attempted suicide associated with the current episode of MDD.
2. Participant has onset of the current depressive episode during pregnancy or 4 weekspostpartum, or the participant has presented for screening during the 6-monthpostpartum period.
3. Participant has a body mass index (BMI) ≤18 or ≥45 kg/m^2 at Screening, which issubject to a broader evaluation of medical comorbidities.
4. Participant has treatment-resistant depression, defined as persistent depressivesymptoms despite treatment with adequate doses of antidepressants within the currentmajor depressive episode (excluding antipsychotics) from two different classes for atleast 4 weeks of treatment.
5. Participant has a medical history of seizures, bipolar disorder, schizophrenia, and/orschizoaffective disorder.
6. Participant has a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior toscreening.
7. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids,regularly or as-needed, at Day -28.