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 learn if combining a ketogenic diet with a personalized, accelerated brain stimulation treatment (iTBS) works better than iTBS with a standard healthy diet to reduce depression symptoms in adults with treatment-resistant depression. The main questions it aims to answer are:

• Does iTBS combined with a ketogenic diet improve depression symptoms more than iTBS combined with a standard healthy diet?
• Does the ketogenic diet change ketone levels over time?
• Is it safe, tolerable, and feasible to follow a ketogenic diet during accelerated iTBS treatment? We will compare a ketogenic diet to a Canadian Food Guide-aligned diet, both combined with iTBS, measuring depression severity using standard clinician-rated and self-report scales. Participants will:
• Follow either a ketogenic diet or a standard healthy diet for 12 weeks, starting with a 3-week lead-in period before iTBS begins
• Undergo a course of personalized, imaging-guided accelerated iTBS while continuing their assigned diet
• Complete clinical and cognitive assessments, blood tests, and brain MRI scans before and after treatment
• Have their ketone levels checked regularly throughout the 12-week period

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). Higher scores indicate worse outcomes (greater severity of depressive symptoms). Week 8 will be used as the primary endpoint.

  Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

• Changes in Ketone Levels

  Change in β-hydroxybutyrate concentrations over the treatment period relative to baseline. β-hydroxybutyrate will be measured daily via finger-stick ketone testing during the lead-in and iTBS phases, and a minimum of three times per week during the post-iTBS dietary continuation phase. Longitudinal change will be analyzed across the treatment period.

  Baseline through week 12

• Incidence of Treatment-Emergent Adverse Events [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, alongside treatment retention and dietary adherence.

  Baseline through week 12

Secondary Outcomes (35)

• Changes in ¹H-MRS Neurochemical Metabolites

  Baseline to Week 8 (post-iTBS)

• Changes in Resting-State Functional Connectivity

  Baseline to Week 8 (post-iTBS)

• Changes in Task-Evoked Brain Activation

  Baseline to Week 8 (post-iTBS)

• Change in Secondary Depression Scores

  Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

• Change in Self-Reported Depressive Symptoms

  Baseline, Week 3 (pre-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS), Week 10 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)

Study Arms (2)

Ketogenic Diet

EXPERIMENTAL

Participants in this arm will follow 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 of finger-stick ketone and glucose testing.

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS); Behavioral: Ketogenic Diet

Canadian Food Guide-Aligned Diet

ACTIVE COMPARATOR

Participants in this arm will follow 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 approximately 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 finger-stick glucose testing.

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS); Behavioral: Canadian Food Guide-Aligned Diet

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 imaging-guided, neuronavigated left dorsolateral prefrontal cortex (DLPFC) iTBS targeted based on functional connectivity with the subgenual anterior cingulate cortex (sgACC). Stimulation protocol consists of 1800 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

Ketogenic Diet BEHAVIORAL

A well-formulated ketogenic diet consisting of low carbohydrate, moderate protein, and high fat intake, designed to achieve and maintain nutritional ketosis (blood ketone levels of 0.5 to 3 mmol/L). Delivered with dietitian-led counseling and monitored via finger-stick ketone and glucose testing.

Ketogenic Diet

Canadian Food Guide-Aligned Diet BEHAVIORAL

A Canadian Food Guide-aligned diet emphasizing balanced intake of vegetables, fruits, whole grains, and protein foods, without specific macronutrient restrictions. Delivered with dietitian counseling matched in frequency and duration to the ketogenic diet arm, and monitored via dietary logs, metabolic assessments, and finger-stick glucose testing.

Canadian Food Guide-Aligned 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 (PHQ ≥ 10)
• Meeting criteria for treatment-resistant depression (TRD), defined as either: (1) failure to achieve a clinical response to ≥2 adequate antidepressant treatment trials for unipolar depression, OR (2) inability to tolerate ≥2 separate antidepressant treatment trials for unipolar depression, as assessed using the Antidepressant Treatment History Form (ATHF), with a score of ≥3 in the current episode
• No rTMS treatment received in the current depressive episode (prior rTMS in a previous episode is permitted); no failure to respond to a course of electroconvulsive therapy (ECT) in the current depressive episode
• Able to provide informed consent
• Available for the 12-week intervention and willing to follow either a ketogenic or Canadian Food Guide-aligned diet
• No increase or initiation of any antidepressant or antipsychotic medication in the 4 weeks prior to screening

You may not qualify if:

• Concomitant major unstable medical illness as determined by a study physician
• Lifetime diagnosis of bipolar I or bipolar II disorder, or a primary psychotic disorder, as confirmed by a structured psychiatric interview
• Current psychotic symptoms
• Diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalised anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD
• Diagnosis of any personality disorder assessed by a study investigator to be primary and/or causing greater impairment than MDD
• History of epilepsy, stroke, or major neurological conditions, or a history of a primary seizure disorder or a seizure associated with an intracranial lesion
• Physical or cognitive disability interfering with participation
• Pregnancy, nursing, or intent to become pregnant during 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 Ketogenic diet
• Habitual low-carb diet in the past 6 months
• GI disorders or food allergies incompatible with dietary protocols

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; Diet, Ketogenic

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics; Diet, Carbohydrate-Restricted; Diet Therapy; Nutrition Therapy; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Central Study Contacts

Sean M Nestor, M.D., PhD

CONTACT

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

Nidhi Shah

CONTACT

nidhi.shah@sunnybrook.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: 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, imaging-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 approximately equivalent contact time with clinicians and dietitians to control for nonspecific therapeutic effects. The study incorporates multimodal assessments, including clinical, cognitive, 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: October 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028
• Last Updated: September 25, 2026

Record last verified: 2026-08

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)