Mechanisms Of Orbitofrontal Stimulation in Depression (MOOD)

May 11, 2026 updated by: Subha Subramanian

Mechanisms Of Orbitofrontal Stimulation in Depression (MOOD)

The orbitofrontal cortex (OFC), a region involved in emotional regulation, decision making, and reward processing, is a key area linked to antidepressant response. This study tests whether noninvasive stimulation of the OFC using transcranial magnetic stimulation (TMS) can improve depressive symptoms. TMS uses magnetic fields generated by a coil placed next to the scalp to alter brain activity.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The main purpose of this study is to test a new treatment target for major depressive disorder (MDD) and to understand the brain mechanisms that may lead to antidepressant response. The treatment target of this study is the right orbitofrontal cortex (OFC), a brain region towards the front of the brain involved in emotion regulation, reward-processing, and decision-making. Other studies have shown that stimulating the OFC can improve depression symptoms. However, no study has yet directly compared the effects of real (active) versus placebo (sham) OFC stimulation on both mood and brain function. Comparison of active versus sham treatment is key in medical research. This study aims to fill that gap by comparing active versus sham stimulation of the right OFC in people with MDD who are currently experiencing moderate to severe symptoms. Participants will take part in a two phases: a triple-blind, randomized, sham-controlled phase, followed by an open-label phase where all participants receive active OFC stimulation.

Aim 1:

To determine whether active TMS targeting the right OFC, compared to sham stimulation at the same site, reduces depressive symptom severity in individuals with MDD.

Aim 2:

To test whether active TMS to the right OFC, compared to sham stimulation at the same site, reduces ruminative symptoms in individuals with MDD.

Study Type

Interventional

Enrollment (Estimated)

80

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 18-65 years
  • Must be able to read, speak and understand English
  • DSM-5 diagnosis of major depressive disorder, experiencing a moderate to severe depressive episode (Hamilton Depression Rating Scale score greater than or equal to 17 points)
  • Must be judged by study staff to be capable of completing the study procedures
  • Participants will be in stable outpatient treatment with no recent (within the past 30 days) hospitalizations or changes in their medication regimens

Exclusion Criteria:

  • DSM-5 moderate to severe substance use disorder within the past three months, based on Structured Clinical Interview for DSM-5

  • Conditions that might result in increased risks of side effects or complications from rTMS or MRI, including:

    • History of fainting spells of unknown or undetermined etiology that might constitute seizures
    • Diagnosis of epilepsy with the exception of a single seizure of benign etiology (e.g., febrile seizures) in the judgment of a board-certified neurologist
    • Current or past history of a neurological disorder, such as stroke, a progressive neurologic disease, or intracranial brain lesion(s); and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment
    • Any unstable medical condition
    • Any metal in the brain or skull (excluding dental fillings) unless cleared by the responsible covering MD
    • Any devices which could be affected by TMS or MRI such as a pacemaker, medication pump, nerve stimulator, cochlear implant, TENS unit, ventriculo-peritoneal shunt unless cleared by the responsible covering MD
    • Pregnancy; All female participants will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study. The pregnancy test will be administered by study staff trained to administer point of care pregnancy testing that complies with institutional laboratory policies

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Active OFC stimulation
Continuous intermittent theta burst stimulation (cTBS, a type of inhibitory TMS) to the right OFC.
Device: Active TMS
TMS uses magnetic fields generated by a coil placed next to the scalp to alter brain activity at a specific region (i.e., OFC) protocol. Here, active TMS protocol is continuous intermittent theta burst stimulation (cTBS, a type of inhibitory TMS) to the right OFC. Investigators will use the MagVenture MagPro system's active/sham coil (e.g., Cool-B65 A/P) to deliver either active or sham TMS. All participants will be randomized to receive active or sham TMS to the OFC in the first phase. In the second phase, all participants will receive active TMS to the OFC. The active protocol to the right OFC is: continuous intermittent theta burst stimulation (cTBS, a type of inhibitory TMS).
Sham Comparator: Sham OFC stimulation
Sham TMS treatment to the right OFC
Device: Sham TMS
The MagVenture MagPro system's active/sham coil (e.g., Cool-B65 A/P) will be used to deliver either active or sham TMS. The sham mode reproduces the same clicking sound and scalp sensation as active stimulation but does not induce cortical activation. The built-in MagPro double-blind feature ensures operator, participant, and investigator blinding. All participants will be randomized to receive active or sham TMS to the OFC in the first phase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Beck Depression Inventory II (BDI-II)
Time Frame: The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.
The BDI-II is a 21-item self-report questionnaire assessing the severity of depressive symptoms over the past two weeks. Each item is rated from 0 to 3, reflecting increasing symptom severity. The total score range is 0 to 63 points, where higher scores indicate worse depressive symptoms. The investigators will examine the change in BDI-II scores in each experimental phase (randomized and open-label).
The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.
Hamilton Depression Rating Scale (HDRS) - 24 item version
Time Frame: The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.
The HDRS is a clinician-rated scale assessing the severity of depressive symptoms across mood, somatic, and cognitive domains. Items are scored on either 3- or 5-point scales depending on the symptom. The score ranges from 0 to 76, with higher scores reflecting greater severity.
The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.
Rumination Response Scale (RRS)
Time Frame: The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.
The RRS is a 22-item self-report questionnaire measuring the tendency to engage in repetitive, negative thinking about one's distress or mood. Each item is rated from 1 ("almost never") to 4 ("almost always"). Scores range from 22 to 88 points, with higher scores indicating greater rumination.
The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Subha Subramanian

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 15, 2026

Primary Completion (Estimated)

December 1, 2030

Study Completion (Estimated)

December 1, 2030

Study Registration Dates

First Submitted

November 6, 2025

First Submitted That Met QC Criteria

November 13, 2025

First Posted (Actual)

November 17, 2025

Study Record Updates

Last Update Posted (Actual)

May 14, 2026

Last Update Submitted That Met QC Criteria

May 11, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2025P000673

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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