The study will evaluate the efficacy of NBI-1065845 compared with placebo as an adjunctive treatment in participants with MDD on improving symptoms of depression.

Key Inclusion Criteria:

• Participant has a primary diagnosis of recurrent MDD (moderate or severe) or persistent depressive disorder.
• Participant has had an inadequate response to oral antidepressant treatments in the current episode of depression.
• Participant must have been taking oral antidepressants for at least 8 weeks and is willing to continue the same oral antidepressants at the same dose and frequency of administration throughout participation in the study.
• Total Hamilton Depression Rating Scale-17 Item (HAM-D17) score ≥22 at screening and at study baseline (Day 1).
• Willing and able to comply with all study procedures and restrictions in the opinion of the investigator.

Key Exclusion Criteria:

• A current or prior psychiatric disorder diagnosis in the last 1 year that was the primary focus of treatment other than MDD.
• Are considered by the investigator to be at imminent risk of suicide or injury to self or others.
• Participants depressive symptoms have previously demonstrated nonresponse to electroconvulsive therapy (ECT) in the current major depressive episode.