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.

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.

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.

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.

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.

Access to study data will be available via the NDCT.