The study was terminated early due to Sponsor decision, closure of this combination therapy program is unrelated to any safety issues, no signals of concern.

This will be a multicenter, randomized, double-blind study designed to assess the efficacy, safety and tolerability of an oral Aripiprazole/Escitalopram combination therapy in participants with MDD who have demonstrated an incomplete response to a prospective trial of Escitalopram, and report a treatment history for the current MDD episode of an inadequate response to at least one and no more than three adequate trials of an approved antidepressant other than Escitalopram. An inadequate response is defined as less than a 50% reduction in depressive symptom severity as assessed by the participant's self-report on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ) and evaluated by the investigator as part of the participant's medical and psychiatric history. An adequate trial is defined as an antidepressant treatment for at least 6 weeks duration (or at least 3 weeks for combination treatments) at an approved dose as specified in the ATRQ.

The study will be organized as follows:

• Screening Phase
• Single-blind Prospective Treatment Phase
• Single-blind Continuation Phase (Responder) or Double-blind Randomization Phase (non-Responder)
• 30 day Post Treatment Follow-up

Assigned Interventions:

• Escitalopram monotherapy
• Aripiprazole/Escitalopram combination therapy
• Aripiprazole monotherapy

Inclusion Criteria:

• Participants with a current diagnosis of a major depressive episode. The current depressive episode must be ≥ 8 weeks in duration
• Participants willing to discontinue all prohibited psychotropic medication starting from the time of signing the informed consent and during the study period
• Participants with a 17-item Hamilton Depression Rating Scale (HAM-D17) total score ≥ 18 at the Baseline Visit for the Prospective Treatment Phase.

Exclusion Criteria:

• Lack of prior treatment with an antidepressant during the current depressive episode
• Participants who report treatment with adjunctive or monotherapy antipsychotic treatment during the current depressive episode.
• Participants experiencing hallucinations, delusions or any psychotic symptomatology in the current depressive episode
• Participants with epilepsy or significant history of seizure disorders
• Participants with a clinically significant current diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder
• Participants who have received electroconvulsive therapy (ECT) in the last 10 years.

Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.

Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.

Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.