Mindfulness Engaged Neurostimulation for Depression (MEND II) (MEND II)

Mindfulness Engaged Neurostimulation for Depression

Repetitive Transcranial Magnetic stimulation (rTMS) is an FDA-approved therapy for treatment resistant depression (TRD) that involves brief magnetic stimulation pulses on the dorsolateral prefrontal cortex (DLPFC) brain region. But studies of rTMS alone show remission rates of ~30%. Additionally, rTMS has not been shown to improve cognitive functioning that may be an independent factor predicting treatment success. This study will develop a novel multimodal treatment, which combines intermittent theta burst stimulation (iTBS) - a type of rTMS with digital mindfulness training to engage brain plasticity, enhance cognition and alleviate depression symptoms in individuals with TRD.

Study Overview

• Status: Recruiting
• Conditions: Depressive Disorder; Depression; Depressive Symptoms; Major Depressive Disorder; Treatment Resistant Depression
• Intervention / Treatment: Combination product: Medi-TBS

Detailed Description

This study aims to develop a novel multimodal treatment for treatment resistant depression (TRD), which combines intermittent theta burst stimulation (iTBS), a type of FDA-approved rTMS protocol, with digital mindfulness training. We propose that this multimodal treatment will suppress posterior Default Mode Network (pDMN) brain activity as measured with electroencephalography (primary outcome and neural target), as well as enhance cognition and alleviate depression symptoms in patients with TRD (secondary outcomes). The study will conduct a two-arm randomized controlled trial to demonstrate neural target engagement by the multimodal iTBS + digital mindfulness training relative to an active control training combined with iTBS.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jyoti Mishra, PhD; Phone Number: 858-232-2855; Email: braine@ucsd.edu

Study Locations

• United States
  • California
    • San Diego, California, United States, 92037
      • Recruiting
      • UC San Diego Health Psychiatry
      • Contact: Jyoti Mishra, PhD; Phone Number: 8582322855; Email: braine@ucsd.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosis of major depressive episode (MDE, in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), in the context of unipolar major depressive disorder.
• At least one failed antidepressant medication trial at level 3 in the Antidepressant -Treatment History Form: Short Form (ATHF-SF) classification.
• Montgomery-Åsberg Depression Rating Scale (MADRS) Score >19 (moderate - severe depression).
• No increase or initiation of new antidepressant therapy in the four weeks prior to screening.
• Demonstrated capacity to give informed consent.

Exclusion Criteria:

• Inability to provide informed consent.
• Medically unstable patients.
• Concomitant neurological disorder or a history of a seizure disorder.
• Exhibiting current suicidal behavior rating on the Columbia Suicide Severity Rating Scale (C-SSRS)
• Patients who are pregnant or breastfeeding.
• Any psychotic disorder or current active psychotic symptoms.
• Patients who have intracranial implants, other medical device or condition deemed unsafe for TMS.
• Contraindication to MRI scanning.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Medi1-TBS; This arm will receive a multimodal treatment with a digital mindfulness training focused on attention to breathing for up to 10 min session dose for up to 20 sessions combined with neuro-navigated iTBS type of rTMS (for 20 treatments over 4 weeks) targeting the left dorsolateral prefrontal cortex (DLPFC) brain region.	Combination product: Medi-TBS; The multimodal intervention involves combining FDA-approved repetitive transcranial magnetic stimulation (rTMS) with digital mindfulness exercises.
Active Comparator: Medi3-TBS; This arm will receive a multimodal treatment with a digital mindfulness training focused on intermittent deep breathing for up to 10 min session dose for up to 20 sessions combined with neuro-navigated iTBS type of rTMS (for 20 treatments over 4 weeks) targeting the left dorsolateral prefrontal cortex (DLPFC) brain region.	Combination product: Medi-TBS; The multimodal intervention involves combining FDA-approved repetitive transcranial magnetic stimulation (rTMS) with digital mindfulness exercises.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in EEG source localized pDMN alpha activity	EEG alpha band (8-12 Hz) activity source-localized to the posterior Default Mode Network (pDMN) brain region extracted on distracted trials of the Breath Attention Assessment of Mindfulness task serves as the primary neural target.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Selective Attention	Processing speed of response to target stimuli on a standard continuous performance task that measures the ability to selectively attend and promptly respond to a goal-relevant target stimulus serves as the secondary cognitive target.	4 weeks
Change in Flanker Inhibition	Efficiency of inhibiting visuo-spatially flanking distractors to target stimuli in the Flanker task serves as the secondary cognitive target.	4 weeks
Change in Montgomery Åsberg Depression Rating Scale Scores (MADRS)	The MADRS will be used to evaluate % depressive symptom response defined as 50% change in the MADRS score from baseline as well as remission defined as MADRS score <7 at post-intervention. Scale range: 0-54, higher score is worse depression.	8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Working Memory	Span-weighted efficiency will be measured on a standard Delayed Match to Sample Task	4 weeks
Change in Mindful Attention Awareness Scale (MAAS)	The MAAS will be used to evaluate change in subjective state mindfulness. Scale range: 6-84, higher score is greater mindfulness	4 weeks
Change in Rumination Reflection Questionnaire (RRQ)	The RRQ will be used to evaluate change in subjective rumination. Scale range: 22-88, higher score is greater rumination	4 weeks
Change in Patient Health Questionnaire 9 item scale (PHQ9)	The PHQ9 scale will be used as an additional measure to evaluate change in depressive symptom response. Score range: 0-27, higher score is greater depression	8 weeks
Change in Generalized Anxiety Disorder 7 item scale (GAD7)	The GAD7 scale will be used as a measure to evaluate change in anxiety symptom response. Score range: 0-21, higher score is greater anxiety.	8 weeks

Collaborators and Investigators

• Sponsor: University of California, San Diego

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: March 30, 2026
• First Submitted That Met QC Criteria: March 30, 2026
• First Posted (Actual): April 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Behavior; Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: MEND II

Plan for Individual participant data (IPD)

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

IPD Plan Description

In compliance with National Institute of Mental Health requirements for data sharing, collected data will be shared via the National Database for Clinical Trials related to Mental Illness (NDCT).

Data submissions will include raw and processed data including basic demographic data, cognitive, behavioral, clinical data, and electroencephalography (EEG) data. All data will be structured as per a Data Dictionary that will be used for data harmonization purposes; data structure definitions will be taken from the existing NIMH Data Archive (NDA) Data Dictionary as recommended, however, if any data are not defined in the existing NDA Data Dictionary, then a new definition will be requested.

• IPD Sharing Time Frame: We will submit raw/descriptive data semi-annually (every January and July) and submit all other data at the time of publication of the initial report from the project.
• IPD Sharing Access Criteria: Access to study data will be available via the NDCT.

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