Medically stable based on physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening and where applicable at DB period baseline
Medically stable based on clinical laboratory tests performed at screening and where applicable at DB period baseline
Meets the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) diagnostic criteria for recurrent or single episode MDD, without psychotic features, based upon clinical assessment and confirmed by Structured Clinical Interview for DSM-5 Axis I Disorders - Clinical Trials Version (SCID-CT)
Has moderate-to-severe depression as measured by a rater-administered MADRS total greater than or equal to (\>=) 26 score and corresponding to a CGI-S score of \>=4 at screening and DB baseline
Has a Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score of \>=15 at screening and DB baseline
You may not be if
The participant experiences a \>=25 percent (%) decrease in the MADRS total score between screening and DB baseline
The participant experiences a \>=25% decrease in the QIDS-SR-16 total score between screening and DB baseline
Has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 3 months prior to the start of the screening period, per the investigator's clinical judgment or based on the Columbia-Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior within the past 6 months prior to the start of the screening period
Has a history of moderate-to-severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening
Has a history or evidence of clinically meaningful noncompliance with antidepressant therapy (ADT)s
Clareo Health | A Study of Lumateperone Versus Placebo in Participants With Major Depressive Disorder
