The purpose of this clinical research study is to understand how effective and safe an investigational study drug called lumateperone is and whether it works to reduce the severity of depressive symptoms in adults with Major Depressive Disorder (MDD) and early life trauma. The main questions it aims to answer are:

Aim 1: To assess the efficacy of lumateperone 42 mg administered once daily compared with placebo in the treatment of patients with Major Depressive Disorder and early life abuse.

Aim 2: To assess neurocircuitry encoding of threat and reward learning as predictors of lumateperone response and as mechanisms of treatment action, and assess the change from pre-dose to post-dose of task-evoked brain activation.

Inclusion Criteria:

1. Provide written informed consent before the initiation of any study-specific procedures.

   NOTE: Patients who are unable to independently provide informed consent will be ineligible to participate in this study.

2. Male or female, between the ages of 21 and 70 years, inclusive;

3. Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria for Major Depressive Disorder (MDD) without psychotic symptoms, as confirmed by a trained rater using the modified Structured Clinical Interview (DIAMOND) for DSM-5,

4. MADRS total score ≥ 22 at Screening (Visit 1) and Baseline (Visit 2)

5. Endorse >=1 physical or sexual assault prior to age 16 on the interview-based trauma assessment.

   Many studies refer to early life trauma as prior to age 18. Here we define early life assault as less than 16, rather than 18, in order to ensure a clearer separation between early life and adulthood. While another option might be to restrict even further (e.g., age of trauma < 10), for feasibility (e.g., facilitating recruitment) and generalizability (e.g., results extend to MDD and early life trauma more broadly than just early childhood trauma), we decided on physical or sexual assault prior to age 16.

   Regarding the focus on physical or sexual assault, there are two main reasons. First, the definition of physical and sexual assault can more easily be operationalized through a behavioral description of an event (e.g., has anyone hit you with a fist, has anyone hit you with an object, etc), enabling more precise assessment and detection. Second, there is a robustly elevated risk for mood disorders following assaultive traumas relative to non-assaultive traumas. As such, there is greater clinical need to establish adjunctive treatments among those experiencing assaultive traumas.

6. Participants must have been treated with the same dose of antidepressant therapy for at least 6 weeks, with less than 50% improvement, and be committed to stay on the same stable dosing regimen for the Screening period and for the entire study, at or above the minimally adequate dose in the ATRQ. Documentation of stable and ongoing ADT must be verified by documentation from the subject's psychiatrist, pharmacist, primary care physician, or other qualified healthcare professional.

7. Females of childbearing potential agree to use at least an acceptable method of birth control (including but not limited to hormonal contraception, intrauterine device, vasectomized partner, bilateral tubal occlusion, condom with or without spermicide, cap with spermicide, diaphragm with spermicide, sponge with spermicide, or double barrier methods) from the time informed consent is provided through the end of the SFU period. NOTE: Females of non-childbearing potential (defined as either permanently sterilized, or post-menopausal females [defined as at least one year with no menses without an alternative medical explanation]) are exempt from the birth control requirement.

8. Ability to follow study instructions and likely to complete all required visits.

Exclusion Criteria:

1. Has a current primary DSM-5-TR psychiatric diagnosis other than Major depressive disorder. These include: PTSD, OCD, Bipolar Disorder, Schizophrenia, schizoaffective disorder, or other psychotic disorder. Intellectual disability, Dementia or other cognitive disorders. Moderate or severe substance use disorder (excluding for nicotine)
2. In the opinion of the Investigator, the patient has a significant risk for suicidal behavior during the course of his/her participation in the study or

2a. At Screening (Visit 1), the patient scores "yes" on Items 4 or 5 in the Suicidal Ideation section of the C-SSRS within 6 months prior to Screening; or

2b. At Screening (Visit 1), the patient has history of suicidal attempt(s) within 1 year prior to Screening (Visit 1); or

2c. At Baseline/randomization (Visit 2), the patient scores "yes" on Items 4 or 5 in the Suicidal Ideation section of the C-SSRS since the Screening Visit; or

2d. At Screening (Visit 1) or Baseline (Visit 2), scores ≥ 4 on Item 10 (suicidal thoughts) on the rater administered MADRS; or

2e.Considered to be an imminent danger to himself/herself or others.

3. MRI contraindications: History of shrapnel or other metal or electronic implants in the body(such as pacemakers, aneurysm clips, ferrous surgical devices, metallic tattoos on the head, etc.). The patient has received electroconvulsive therapy (ECT), vagal nerve stimulation, or repetitive trans-cranial magnetic stimulation within the past 1 year;

4. The patient has known hypersensitivity or intolerance to lumateperone, or to any of the excipients

5. Treatment with a depot/long-acting injectable antipsychotic within 1 cycle before Screening (Visit 1)

6. The following agents are excluded and must be discontinued at Screening (Visit 1):

6a. Any moderate or strong cytochrome P450 3A4 inhibitor (CYP3A4), or any CYP3A4 inducer 6b. Central opioid agonists/antagonists, including tramadol 6c. Central opioid agonists/antagonists, including tramadol 6d. Dietary supplements and medical foods unless approved by the Sponsor or designee. Daily multivitamin use is permitted

7. Monoamine oxidase inhibitors within 14 days prior to Baseline/Randomization (Visit 2)

8.Other drugs with known psychotropic properties or any non-psychotropic drugs with known or potentially significant central nervous system.

9. The patient plans to initiate psychotherapy or make changes to existing psychotherapy during the study (patients who are participating in stable psychotherapy or psychotherapy as a part of their treatment are allowed to enroll);

10. The patient has participated in a previous clinical trial with lumateperone, or has had exposure to any investigational product within 6 months of the baseline visit or participated in > 2 clinical studies of an investigational product with a central nervous system indication.

11. The patient is pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum pregnancy test at Screening (Visit 1). On Day 1 (Baseline/Visit 2), female patients of childbearing potential must have a negative urine pregnancy test prior to study drug administration;

12. The patient has a positive test for alcohol or drugs of abuse (eg, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, or opioids/opiates) at Screening (Visit 1).

13. The patient has abnormal laboratory values or clinical findings at Screening (Visit 1) including, but not limited to:

13a. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 × the upper limit of normal (ULN) 13b. Total bilirubin > 1.0 × ULN 13c. Hemoglobin < 8 g/dL (80 g/L) for females and < 9 g/dL (90 g/L) for males 13d. Absolute neutrophil count (ANC) < 1200 cells/μL (1.2 × 109 cells/L); 13e. Thyroid-stimulating hormone (TSH) outside of normal reference range AND free T3 or free T4 outside of the reference range. Free T3 and Free T4 will only be evaluated if TSH is outside of reference range; 13f. Poorly controlled diabetes as defined by a glycosylated hemoglobin (HbA1c) >7.5%, despite standard care [> 58 mmol/mol]; 13g. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody immunoglobulin M at screening; positive hepatitis C antibody at Screening (Visit 1), with the exception of a patient for whom the reflex HCV RNA test is negative; 13h. Any other clinically significant abnormal laboratory result obtained at screening (Visit 1)

14. ECG abnormalities where the patient has corrected QT interval using the Fridericia formula (QTcF) > 450 msec for males or > 470 msec for females and/or heart rate < 50 bpm, or evidence of clinically significant bundle-branch blocks at Screening (Visit 1)

15. The patient has any of the following conditions:

Cardiac: uncontrolled angina, or history of a myocardial infarction within 3 months prior to screening, or history of a clinically significant cardiac arrhythmia including antipsychotic drug-induced corrected QT interval prolongation, or any other cardiac disorder;

Malignancy: Any diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in remission for at least 5 years;

Gastrointestinal: history of gastric bypass or any other condition that results in malabsorption;

Endocrine: hypo- or hyperthyroidism unless treated and stable with no medication changes for at least three months prior to screening, diabetes, unless considered stable with no changes in treatment for at least three months prior to screening;

Hepatic: Hepatitis B or Hepatitis C; moderate or severe hepatic impairment (Child-Pugh B or C);

Pulmonary: history of diagnosed and untreated obstructive sleep apnea;

Neurological: history of epilepsy, seizure or convulsion, or electroencephalogram with clinically significant abnormalities, delirium, dementia, amnestic, or central sleep apnea, or significant brain trauma, or other cognitive disorder; History of movement disorders.

Infectious: History of human immunodeficiency virus (HIV) infection.

Note: Any other medical condition, or medical conditions that are stable with treatment (eg, hypertension, hypercholesterolemia, or thyroid abnormalities) are allowed as long as the condition has been stable for at least 3 months prior to Screening (Visit 1); treatments for these conditions are documented, kept stable, and are expected to be unchanged during the study; and the condition is not thought to affect safe participation in the study or relevant study outcomes in the opinion of the Investigator.

16. The patient is judged by the Investigator to be inappropriate for the study;

17. Patient is homeless;

18. Patient does not speak english;