This study is being done to learn whether NBI-1065845 may help adults with depression maintain improvement in their symptoms over time. Researchers want to compare the investigational medication to a placebo to better understand how well it works.

You may be eligible for this study if you meet the following criteria.

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.

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.

Participation lasts at least 5 months and may last longer depending on how long you remain eligible and choose to stay in the study. Some participants may take part for more than 2 years.

Study Visits

You will attend regular study visits with the research team. Most participants will have monthly visits, along with a few visits that occur more often at certain times during the study.

During study visits, you may:

• Meet with the study doctor and research staff
• Answer questions about your mood, symptoms, and overall health
• Complete questionnaires about how you are feeling
• Review your medications and any changes in your health
• Receive the study medication and study-related care

Some study visits may be completed virtually from home.

What Will I Do During the Study?

If you qualify and decide to participate:

1. You will continue taking your current antidepressant medication.
2. You will receive the investigational medication NBI-1065845 during the first part of the study.
3. After this period, you will be randomly assigned to either continue receiving NBI-1065845 or receive a placebo.
4. You will take the assigned study treatment every day as instructed.
5. You will attend study visits so the research team can monitor your health and symptoms.

At-Home Activities

At home, you will:

• Take your assigned study treatment each day as instructed
• Continue taking your current antidepressant medication
• Report any changes in your health or symptoms to the study team
• Attend virtual visits when scheduled

Participants may receive reimbursement for study-related travel and other approved study expenses. The total amount varies because participation length differs from person to person.

All study medication and study-related procedures are provided at no cost.

There is no cost for you to participate in our research study.