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 Edition Text Revised (DSM-5-TR) diagnosis of MDD without psychotic features confirmed by Structured Clinical Interview for DSM 5 Disorders, Clinical Trials Version (SCID 5 CT) at screening (this may be a first or recurrent episode). Participant's current major depressive episode must be confirmed by independent assessment. The symptoms of the current MDD episode have been present for more than 4 weeks prior to the Screening Visit, but no longer than 12 months prior to the Screening Visit. 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 for the current MDD episode. Have currently or in the past year any of the following DSM-5-TR disorders: personality disorder, 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 diagnosis are not excluded. Have a lifetime diagnosis of bipolar 1 or 2, schizophrenia, 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 (e.g., any suicide attempts within the past 12 months) or are at serious 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 the opinion of the Investigator.