A Study of Lumateperone Versus Placebo in Participants With Major Depressive Disorder

The purpose of the study is to assess how well each dose of lumateperone (Dose 1 and 2) works when given alone as compared to placebo in participants with major depressive disorder (MDD; a medical condition characterized by a persistent feeling of deep sadness, hopelessness, and a loss of interest in activities for a prolonged period of time and interfere with ability to function).

Inclusion criteria: * 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 Exclusion criteria: * 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