Ketogenic Diet and Neuromodulation in Treatment Resistant Depression

NCT07376018 | Not Yet Recruiting

• 1 other identifier: 6944
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to test whether combining a ketogenic diet (KD) with personalized, accelerated intermittent theta burst stimulation (iTBS) produces greater reductions in depressive symptoms than iTBS combined with a standard healthy diet in adults with treatment-resistant depression. The trial also aims to determine whether participants can feasibly follow a ketogenic diet during an accelerated iTBS treatment course and whether the diet produces measurable changes in ketone levels. Specifically, the study aims to determine whether the combined intervention:

1. 1.Reduces depressive symptoms
2. 2.Increases circulating ketone levels
3. 3.Is feasible and tolerable during accelerated iTBS treatment

Conditions

Treatment Resistant Depression (TRD); Major Depressive Disorder (MDD)

Keywords

Major Depressive Disorder; MDD; TRD; TMS; Glucose Control; Ketogenic Diet; Metabolic Health; Transcranial Magnetic Stimulation; iTBS; Dietary Intervention; Metabolic Psychiatry; MRS; fMRI; Intermittent Theta-Burst Stimulation

Outcome Measures

Primary Outcomes (3)

• Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS)

  Change in depression symptomatology as assessed by the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) (range 0-60). Higher scores indicate worse outcomes (greater severity of depressive symptoms)

  Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS)

• Changes in Ketone Levels

  Change in fasting morning β-hydroxybutyrate concentrations over the treatment period relative to baseline. Fasting β-hydroxybutyrate will be measured daily via finger-stick ketone testing, and longitudinal change will be analyzed across the treatment period.

  Baseline through week 12

• Safety and Tolerability

  Frequency, severity, and relatedness of adverse events and clinically significant laboratory abnormalities, and discontinuations due to adverse effects, with specific attention to KD-related effects (e.g., hypoglycemia, dehydration, electrolyte disturbances, gastrointestinal symptoms, dyslipidemia) and mood destabilization/suicidality.

  Baseline through week 12

Secondary Outcomes (19)

• Changes in ¹H-MRS Neurochemical Metabolites

  Baseline to Week 4 (post-iTBS)

• Changes in Resting-State Functional Connectivity

  Baseline to Week 4 (post-iTBS)

• Changes in Task-Evoked Brain Activation

  Baseline to Week 4 (post-iTBS)

• Changes in Metabolic Biomarkers

  Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS)

• Change in Secondary Depression Scores

  Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS)

Study Arms (2)

Ketogenic Diet

EXPERIMENTAL

Participants in this arm will begin a well-formulated ketogenic diet (low carbohydrate, moderate protein, high fat) for a 3-week dietary lead-in period prior to neuromodulation, and will continue the diet for a total of 12 weeks. The diet is designed to achieve and maintain nutritional ketosis (blood ketone levels of 0.5 to 3 mmol/L). Dietitian support will be provided through scheduled counseling and ongoing monitoring using daily finger-stick ketone and glucose testing.

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS)

Canadian Food Guide-Aligned Diet

ACTIVE COMPARATOR

Participants in this arm will begin a Canadian Food Guide-aligned diet for a 3-week dietary lead-in period prior to neuromodulation and will continue the diet for a total of 12 weeks. The diet will emphasize balanced intake of vegetables, fruits, whole grains, and protein foods, without specific macronutrient restrictions. Dietitian counseling will be matched in frequency and duration to the ketogenic diet arm. Nutritional monitoring will include dietary logs and metabolic assessments without targeted induction of ketosis. Participants will perform daily finger-stick glucose testing.

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS)

Interventions

Accelerated Intermittent Theta Burst Stimulation (iTBS) DEVICE

Intermittent theta burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation (rTMS), is a non-invasive brain stimulation technique approved by the FDA and Health Canada for the treatment of TRD. In this study, participants will receive an accelerated course of image-guided, neuronavigated left dorsolateral prefrontal cortex (DLPFC) iTBS targeted based on functional connectivity with the subgenual anterior cingulate cortex (sgACC). Stimulation will consist of 600 pulses per session, delivered at 110% of resting motor threshold, with 50-minute inter-session intervals, for 8 sessions per day over 5 consecutive days.

Also known as: repetitive transcranial magnetic stimulation (rTMS)

Canadian Food Guide-Aligned Diet; Ketogenic Diet

Eligibility Criteria

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

You may qualify if:

• Age 18-65 of any sex, gender identity, ethnicity and socioeconomic status
• Currently experiencing a major depressive episode as defined by DSM-5-TR criteria and confirmed by a study physician
• Presenting with at least moderate symptom severity (MADRS ≥ 20)
• Meeting criteria for treatment-resistant depression (TRD), defined as non-response to at least two adequate antidepressant trials
• Neuromodulation-naïve (no past rTMS or electroconvulsive therapy)
• Able to provide informed consent
• Available for the 15-week intervention and willing to follow either a ketogenic or Canadian Food Guide-aligned diet

You may not qualify if:

• Medical/psychiatric co-morbidities that prevent participation in the study or where depression is not the primary psychiatric symptom of concern
• History of epilepsy, stroke, or major neurological conditions, psychosis, or substance dependence within the last 6 months
• Physical or cognitive disability interfering with participation
• Females who are pregnant (self-report or via blood work), nursing, or planning a pregnancy during the timespan of the study BMI \< 20 kg/m²
• Suicide attempts in the past 12 months
• Active suicidal intent as confirmed by study psychiatrist
• Active eating disorder in the past 12 months
• Currently following a KD
• Habitual low-carb diet in the past 6 months
• GI disorders or food allergies incompatible with dietary protocols
• Alcohol use \>3 drinks/day or \>14/week
• Use of anticonvulsants (benzodiazepines with a dose of \<2 lorazepam equivalents will be permitted), GABA agonists, or medications reducing TMS efficacy
• Serious medical illness
• Contraindications to MRI
• Unwillingness to perform daily finger-stick testing

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre: lead
• Baszucki Group: collaborator

Study Sites (1)

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Central Study Contacts

Sean M Nestor, M.D., PhD

CONTACT

416-347-0257; sean.nestor@utoronto.ca; sean.nestor@sunnybrook.ca

Jo Donguk, PhD

CONTACT

donguk.jo@sri.utoronto.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Psychiatrist

Model Details: This study uses a randomized, parallel-group interventional design in which adults with treatment-resistant depression are assigned to one of two dietary conditions (ketogenic diet or Canadian Food Guide-aligned diet) while receiving the same accelerated, connectivity-guided iTBS protocol. This design allows investigators to examine the effects of metabolic state on response to neuromodulation while holding stimulation parameters constant across groups. Both groups receive equivalent contact time with clinicians and dietitians to control for nonspecific therapeutic effects. The study incorporates multimodal assessments, including clinical, metabolic, and neuroimaging measures, to evaluate how changes in metabolism relate to brain network engagement and clinical response during iTBS. This structure supports both mechanistic investigation and comparison of clinical outcomes between diet conditions.

Study Record Dates

• First Submitted: January 21, 2026
• First Posted: January 29, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: February 5, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: The study protocol and informed consent form will be published prior to study initiation. Trial results will be disseminated as soon as feasible after study completion. De-identified IPD will be available beginning 12 months after publication of the primary results (or 12 months after study completion if no publication occurs).
• Access Criteria: Shared data will include de-identified IPD and supporting documents (study protocol, statistical analysis plan, and data dictionary). Access will be limited to researchers with appropriate institutional affiliation and documented ethics approval, who submit a methodologically sound proposal. Requests will be reviewed by the study Principal Investigator (or designated data access committee). Approved users will obtain access through secure, institutionally approved data-sharing systems. All users must sign a data use agreement that prohibits re-identification, onward sharing, and any use outside the approved proposal.

Locations

CA (1)