Neurocircuitry Mechanisms and Efficacy of Lumateperone as Adjunctive Therapy for Major Depressive Disorder and History of Early Life Abuse

NCT07369115 | Not Yet Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: Study00008399
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Early Life Trauma; Major Depressive Diorder

Outcome Measures

Primary Outcomes (1)

• The primary efficacy endpoint is the absolute change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores from Baseline to end of Treatment visit at Week 6 in subjects on ADT plus Lumateperone or matching placebo.

  The MADRS is a 10-item questionnaire with each item scored between 0 and 6, resulting in a total score between 0 and 60, with scores above 34 indicating severe depression. Higher MADRS scores indicate more severe depression. The questionnaire is most frequently used in clinical studies to measure outcomes in antidepressant efficacy studies. This scale exhibits construct validity (internal homogeneity) and the concepts of endogenous and non-endogenous depression. The questionnaire includes questions on the following symptoms: (1) apparent sadness; (2) reported sadness; (3) inner tension; (4) reduced sleep; (5) reduced appetite; (6) concentration difficulties; (7) lassitude; (8) inability to feel; (9) pessimistic thoughts; (10) suicidal thoughts. The MADRS must be administered using the Structured Interview Guide for the MADRS (SIGMA). The MADRS total score at screening is a major inclusion criterion of the study, as well as the primary outcome measure for the study.

  Change from Baseline MADRS score at enrollment to end of study (week 7)

Secondary Outcomes (1)

• The key secondary efficacy endpoint is the change from baseline to end of Week 7 in the Clinical Global Impression of Severity (CGI-S) score.

  From enrollment to end of study at 7 weeks

Study Arms (2)

Active Drug Arm - Lumateperone

ACTIVE COMPARATOR

Lumateperone, 42 mg, for 6 weeks to be taken orally once daily for 25 participants

Drug: Lumateperone 42 mg

Inactive Drug Arm - Placebo

PLACEBO COMPARATOR

25 Participants will receive a matching placebo capsule for 6 weeks to be taken orally once daily.

Other: Placebo

Interventions

Placebo OTHER

A matching placebo will be taken orally by participants once daily for 6 weeks.

Inactive Drug Arm - Placebo

Lumateperone 42 mg DRUG

Lumateperone, 42 mg, will be orally taken by participants once daily for 6 weeks.

Active Drug Arm - Lumateperone

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Male or female, between the ages of 21 and 70 years, inclusive;
• 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,
• MADRS total score ≥ 22 at Screening (Visit 1) and Baseline (Visit 2)
• 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.
• 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.
• 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.
• Ability to follow study instructions and likely to complete all required visits.

You may not qualify if:

• 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)
• 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
• a. 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
• b. At Screening (Visit 1), the patient has history of suicidal attempt(s) within 1 year prior to Screening (Visit 1); or
• c. 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
• d. At Screening (Visit 1) or Baseline (Visit 2), scores ≥ 4 on Item 10 (suicidal thoughts) on the rater administered MADRS; or
• e.Considered to be an imminent danger to himself/herself or others.
• \. 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;
• \. The patient has known hypersensitivity or intolerance to lumateperone, or to any of the excipients
• \. Treatment with a depot/long-acting injectable antipsychotic within 1 cycle before Screening (Visit 1)
• \. The following agents are excluded and must be discontinued at Screening (Visit 1):
• a. 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
• \. Monoamine oxidase inhibitors within 14 days prior to Baseline/Randomization (Visit 2)
• Other drugs with known psychotropic properties or any non-psychotropic drugs with known or potentially significant central nervous system.
• \. 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);

Sponsors & Collaborators

• University of Texas at Austin: lead

Study Sites (1)

Health Discovery Building

Austin, Texas, 78701, United States

Location

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MeSH Terms

Interventions

lumateperone

Central Study Contacts

Julie Farrington, MD

CONTACT

512-495-5566; julie.farrington@austin.utexas.edu

Josh Cisler, PhD

CONTACT

josh.cisler@austin.utexas.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Trials Director

Model Details: One group will receive the drug Lumateperone, and the other will receive a placebo.

Study Record Dates

• First Submitted: January 23, 2026
• First Posted: January 27, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030
• Last Updated: January 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)