This is a randomized, double-blind, active-controlled, multi-center study to evaluate the efficacy of AXS-05, compared to bupropion, in preventing the relapse of depressive symptoms in subjects with major depressive disorder (MDD) who have responded to treatment with AXS-05.

Eligible subjects will receive open-label AXS-05 during the 10-week open-label treatment period, during which they will be monitored for response and remission. Subjects meeting the response and remission criteria during the open-label period will be randomized (1:1) to the double-blind period to continue treatment with AXS-05 or switch to treatment with bupropion (105 mg) tablets. Randomized subjects will receive double-blind treatment for 26 weeks or until they experience a relapse.

Inclusion Criteria:

• Currently meets DSM-5 criteria for diagnosis of MDD without psychotic features
• Current major depressive episode of at least 4 weeks in duration

Exclusion Criteria:

• Previously participated in another clinical study of AXS-05; received any investigational drug or device treatment within 30 days of (Screening) Visit 1, or has been prescribed Auvelity.
• Unable to comply with study procedures
• Medically inappropriate for study participation in the opinion of the investigator