Lumateperone for Late-Life Depression (IRL Grey-C)

The purpose of this research study is to examine how well a medication called lumateperone (Caplyta) works to relieve depression in older adults with treatment-resistant depression. Lumateperone (Caplyta) is approved by the U.S. Food and Drug Administration to treat Major Depressive Disorder in adults who are also taking another antidepressant medication. This study will compare lumateperone (Caplyta) to placebo (a sugar pill without medication).

Study Overview

• Status: Not yet recruiting
• Conditions: Late Life Depression (LLD); Depression / Major Depressive Disorder; Treatment Resistant Depression (TRD)
• Intervention / Treatment: Drug: Lumateperone; Drug: Placebo

Detailed Description

This study is a 10-week, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of adjunctive lumateperone in older adults with treatment-resistant depression (TRD). Approximately 100 participants aged ≥60 years with unipolar, non-psychotic major depressive disorder will be enrolled across two study sites. Participants will continue their existing antidepressant medication at a stable dose throughout the study and will be randomized to receive either lumateperone or matching placebo administered adjunctively during the treatment phase.

• Screening: Participants who sign consent will go through a screening process. This will involve answering questions about medical history, medications, demographics, mood and emotions as well as completing a brief cognitive test.
• Baseline: If the participant is eligible from the screening visit, they will complete a baseline visit in our research clinic. This will involve answering questions and completing questionnaires about mood and emotions, completing tasks on an iPad to assess thinking, attention, and memory as well as a physical exam. The physical exam will include gathering height and weight, an evaluation for potential medication side effects, a fasting blood draw to measure blood lipids and glucose, and an electrocardiogram (ECG).
• Study Medication: Participants will be randomized (like flipping a coin) to take either lumateperone or placebo (sugar pill). The research team and participant will be blinded to each participant's study medication. Participants will not get to choose whether they take lumateperone or placebo.
• Monitoring visits: We will ask participants to complete visits in the research clinic after one week, two weeks, four weeks, six weeks, and eight weeks following the baseline visit. These visits will be to assess depression symptoms, medication changes, and side effects. We may ask participants to complete additional visits in person or over the phone if they are needed to manage side effects or worsening in depressive symptoms.
• Endpoint visit: After 10-weeks we will ask participants to complete an endpoint visit in the research clinic to measure the effects of lumateperone or placebo. This visit includes answering questions and completing questionnaires about mood and emotions, medication changes, and side effects. Participants will complete tasks on an iPad to assess your thinking, attention, and memory. There will also be a fasting blood draw to measure blood lipids and glucose as well as another ECG.
• Extra visit (if needed): We may ask participants to complete one additional endpoint visit for a final assessment of symptoms.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anna Kinghorn, MS; Phone Number: 314-362-8761; Email: akinghorn@wustl.edu
• Study Contact Backup: Name: Julie Schweiger; Phone Number: 314-362-3153; Email: schweigj@wustl.edu

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85713
      • University of Arizona
      • Principal Investigator: Jordan Karp, MD
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
      • Principal Investigator: Eric J Lenze, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >=60
• Current unipolar non-psychotic major depression determined by SCID-5
• MADRS score >=20 at screening and >=18 at baseline
• Treatment-resistance defined as documented history of non-response to at least two oral medications of adequate dose and duration in this episode or previous episode, OR clinician determination that treatment augmentation is appropriate
• Currently taking oral antidepressant prescribed at least minimum therapeutic dose and for at least six weeks duration
• MMSE score of >/=24

Exclusion Criteria:

• Dementia
• High risk for suicide, defined as a 4 or 5 on C-SSRS (indicating active suicidal ideation with current or recent intent or plan), and unable to be managed safely in the clinical trial. Urgent psychiatric referral will be made in these cases.
• High risk alcohol use: defined as a score of 6 or more on the AUDIT-C
• Medically inappropriate for participation as determined by PIs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lumateperone; The starting dose of lumateperone or placebo will typically be 21 mg/day for the first week. Those participants who are taking moderate or strong CYP3A4 inhibitors will start at 10.5 mg/ day. The dose will be increased for most participants to 42 mg/ day at Week 2 and maintained until Week 10. Participants with moderate or severe hepatic impairment (Child-Pugh class B or C) will be maintained at 21 mg/day. Participants who are taking strong CYP3A4 inhibitors will be maintained at 10.5 mg/ day. Participants who are taking moderate CYP3A4 inhibitors will increase as tolerated to 21 mg/ day.	Drug: Lumateperone; Participants will be randomized to take either lumateperone or placebo along with their existing antidepressant for 10 weeks. Dose will range from 10.5mg-42mg over the course of the study.; Other Names: Caplyta
Placebo Comparator: Placebo; The starting dose of lumateperone or placebo will typically be 21 mg/day for the first week. Those participants who are taking moderate or strong CYP3A4 inhibitors will start at 10.5 mg/ day. The dose will be increased for most participants to 42 mg/ day at Week 2 and maintained until Week 10. Participants with moderate or severe hepatic impairment (Child-Pugh class B or C) will be maintained at 21 mg/day. Participants who are taking strong CYP3A4 inhibitors will be maintained at 10.5 mg/ day. Participants who are taking moderate CYP3A4 inhibitors will increase as tolerated to 21 mg/ day.	Drug: Placebo; Participants will be randomized to take either lumateperone or placebo along with their existing antidepressant for 10 weeks. Dose will range from 10.5mg-42mg over the course of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Montgomery-Asberg Depression Rating Scale (MADRS) total score	To evaluate whether adjunctive lumateperone reduces depressive symptoms compared with placebo.	From baseline to the end of treatment at week 10.

Collaborators and Investigators

• Sponsor: Eric Lenze
• Collaborators: Intra-Cellular Therapies, Inc.
• Investigators: Principal Investigator: Eric J Lenze, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: May 28, 2026
• First Submitted That Met QC Criteria: May 28, 2026
• First Posted (Actual): June 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: major depression; Late life depression treatment; Treatment resistant depression in older adults; lumateperone
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; lumateperone
• Other Study ID Numbers: 202604086

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Contact PI

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes