Study to Assess 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 perDSM-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 post traumatic 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 (eg, any suicide attempts within the past 12 months) or are atserious suicidal risk as indicated by any current suicidal intent, including a plan,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.