Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder

Key inclusion criteria:

• Have a primary Diagnostic and Statistical Manual of Mental Disorders Fifth EditionText Revised (DSM-5-TR) diagnosis of MDD without psychotic features confirmed byStructured Clinical Interview for DSM 5 Disorders, Clinical Trials Version (SCID 5CT) at screening (this may be a first or recurrent episode).

• Participant's current major depressive episode must be confirmed by independentassessment.

• The symptoms of the current MDD episode have been present for more than 4 weeksprior to the Screening Visit, but no longer than 12 months prior to the ScreeningVisit.

• Have a MADRS total score of 25 or higher at Screening and Baseline.

• A change in MADRS total score between Screening and Baseline of ≤20%.

Key exclusion criteria:

• Have failed 2 or more courses of antidepressant treatment at sufficient doses for atleast 6 to 8 weeks for the current MDD episode.

• Currently or in the past year have been diagnosed with a personality disorder perthe DSM-5-TR or in the past 3 years have been diagnosed with any of the followingDSM-5-TR disorders: anorexia nervosa, bulimia nervosa, or binge eating disorder.Participants with comorbid generalized anxiety disorder, social anxiety disorder,simple phobias, or panic disorder for whom MDD is considered the primary diagnosisare not excluded.

• Have a lifetime diagnosis of bipolar 1 or 2, schizophrenia, schizoaffective,schizophreniform, obsessive compulsive disorder, or posttraumatic stress disorder (PTSD).

• Have moderate to severe substance or alcohol use disorder, per DSM-5-TR criteria,within the 12 months prior to screening (excluding nicotine).

• Are actively suicidal (e.g., any suicide attempts within the past 12 months) or areat serious suicidal risk as indicated by any current suicidal intent, including aplan, as assessed by the Columbia Suicide Severity Rating Scale (C SSRS) (score of "YES" on suicidal ideation Item 4 or 5 within 3 months prior to Visit 1 [screening])and/or based on clinical evaluation by the Investigator; or are homicidal, in theopinion of the Investigator. Participants who are currently hospitalized for MDDsymptoms or suicidality are not allowed into the study. If there is a recent history (within 3 months of screening) of hospitalization due to MDD symptoms, theparticipant should be discussed with the Medical Monitor for eligibility.