Clinical Trial of Lumateperone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder

Inclusion Criteria:

1. Male or female patients between the ages of 18 and 65 years, inclusive;

2. Meet DSM-5 diagnostic criteria for MDD (a diagnosis of MDD with psychotic featureswill be acceptable) as confirmed by the Investigator or Sponsor-approved rater usingthe Mini-International Neuropsychiatric Interview (MINI), and meet all the followingcriteria:

3. The start of the current major depressive episode (MDE) is at least 8 weeks butnot more than 18 months prior to Screening;

4. Has at least moderate severity of illness based on rater-administered MADRStotal score ≥ 24 at Screening and at Baseline;

5. Has at least moderate severity of illness based on CGI-S score ≥ 4 at Screeningand at Baseline;

6. Has a Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14 at Screening and at Baseline;

7. Has sufficient history and medical record confirmation verifying the ADT andthe current MDE is causing clinically significant distress or impairment insocial, occupational, or other important areas of functioning.

8. Currently having an inadequate response to ADT (less than 50% improvement) asconfirmed by the Investigator and taking at least the minimum effective dose (perpackage insert) of one of the following antidepressants as monotherapy treatment forat least 6 weeks duration:

9. citalopram/escitalopram

10. fluoxetine

11. paroxetine

12. sertraline

13. duloxetine

14. levomilnacipran/milnacipran (if locally approved for MDD)

15. venlafaxine/desvenlafaxine

16. buproprion

17. vilazodone

18. vortioxetine

Exclusion Criteria:

1. Within the patient's lifetime, has a confirmed DSM-5 psychiatric diagnosis otherthan MDD, including:

2. Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder or otherpsychotic disorder;

3. Bipolar Disorder;

4. Within 6 months of Screening, has a confirmed DSM-5 psychiatric diagnosis other thanMDD including:

5. Anxiety disorders such as Panic Disorder or Generalized Anxiety Disorder;Obsessive-compulsive Disorder; Posttraumatic Stress Disorder as primarydiagnoses.

6. Eating disorder;

7. Substance use disorders (excluding nicotine);

8. Personality disorder of sufficient severity to have a major impact on thepatient's psychiatric status;

9. Within 12 months of Screening, has had any other psychiatric condition (otherthan MDD) that has been the main focus of treatment;

10. The patient experiences a ≥ 25% decrease in the MADRS total score between Screeningand Baseline;

11. The patient experiences a ≥ 25% decrease in the QIDS-SR-16 total score betweenScreening and Baseline;

12. In the opinion of the Investigator, the patient has a significant risk for suicidalbehavior during participation in the study or:

13. At Screening, the patient scores "yes" on Suicidal Ideation Items 4 or 5 of theColumbia-Suicide Severity Rating Scale (C-SSRS) within 6 months prior toScreening, or at Baseline, the patient scores "yes" on Suicidal Ideation Items 4 or 5 since the Screening Visit;

14. At Screening, the patient has had 1 or more suicide attempts within 2 yearsprior to Screening;

15. At Screening or Baseline, the patient scores ≥ 5 on MADRS Item 10 (SuicidalThoughts), or

16. The patient is considered to be in imminent danger to him/herself or others.

17. The patient has a first MDE at age 60 years or older.