Study in Major Depressive Disorder With NMRA-335140 (BTRX-335140) vs Placebo

Inclusion Criteria

Participants are eligible to be included in the study only if they meet all the following criteria:

• Are adult men or women between 18 to 65 years of age (inclusive) at informed consent
• Have a primary DSM-5 diagnosis of MDD, with prominent symptoms of anhedonia confirmed by Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version (SCID-5-CT)
• The current episode must have started at least 3 weeks prior to screening visit but no more than 12 months before the screening visit.
• Have not failed 2 or more courses of antidepressant treatment in the current episode
• Have no more than a 3-point change in HAMD 17 between screening and baseline
• Have sufficient history or an independent report to confirm that symptoms are causing functional impairment or clinically significant distress
• Meet the blinded rule list based on clinical scale criteria
• Have body mass index (BMI) between 18-40 kg/m2 (inclusive)
• Are medically stable (in the opinion of the investigator and Sponsor/Sponsors delegate) based on medical history, vital signs, clinical laboratory tests, and 12-lead electrocardiogram (ECG) performed at screening and baseline
• Agree to the following birth control:
• Nonvasectomized men must agree to use a condom with spermicide, if sexually active during the study, until 90 days after the last dose of study drug administration. No restrictions are required for a vasectomized man, provided his vasectomy was performed 4 months or more prior to the first dose of study drug. A man who has been vasectomized less than 4 months prior to the first dose of study drug must follow the same restrictions as a nonvasectomized man. Additionally, men must refrain from sperm donation during study treatment and for at least 90 days following the last dose of study drug.
• Women of child-bearing potential (women not surgically sterilized and between menarche and 2 years postmenopausal) must have a negative serum pregnancy test at screening and a negative urine pregnancy test at enrollment and agree to use reliable birth control (eg, oral contraceptives or Norplant®; a reliable double barrier method of birth control (diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam); intrauterine devices; partner with vasectomy; or abstinence) during the study and for 10 days following the last dose of the study drug (BTRX-335140 or placebo). Women will be considered surgically sterile, if they have had tubal ligation, bilateral salpingo oophorectomy, or a hysterectomy.

Note: Abstinence will be allowed if, in the investigator's judgement, it is determined that the participant is reliable, that abstinence is the preferred and usual lifestyle of the participant, and that abstinence will be continued for the duration of the study including the 10 days (women) or 90-day period (men) following last dose of study drug as noted above.

• Or engaged exclusively in a non-heterosexual relationship
• Willing and able to give written informed consent to participate
• Able to understand and comply with instructions in English
• Are judged by the investigator to be reliable and agree to keep all appointments for clinic visits, tests, and procedures, including venipuncture, and examinations required by the protocol

Exclusion Criteria

Participants will be excluded from the study if they meet any of the following criteria:

• Have a history of any of the following DSM-5 disorders within the specified timeframe:
• Currently or in the past year: diagnosis of personality disorder, attention deficit disorder/attention deficit hyperactivity disorder, anorexia nervosa, or bulimia nervosa. Participants with comorbid generalized anxiety disorder, social anxiety disorder, or panic disorder for whom MDD is considered the primary diagnosis are not excluded.
• Lifetime: diagnosis of bipolar 1 or 2, schizophrenia, obsessive compulsive disorder, or post-traumatic stre