An interventional study of Accelerated Intermittent Theta Burst Stimulation (iTBS) and Ketogenic Diet in Major Depressive Disorder (MDD) and Treatment Resistant Depression (TRD), sponsored by Sunnybrook Health Sciences Centre. Recruiting at 1 site in Canada. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-10-28.
Sponsored by Sunnybrook Health Sciences Centre · Not applicable, Interventional, and Treatment
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:
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:
3,041 studies on the registry are indexed under Depressive Disorder, Major; 588 are open to participants now.
This study's planned enrollment of 60 is below the median of 79 across 2,530 interventional studies indexed under Depressive Disorder, Major.
Browse Depressive Disorder, Major studies →Sunnybrook Health Sciences Centre is the lead sponsor of 584 studies on the registry; 135 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 2 (33%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
DSM diagnostic criteria
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
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)
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.
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.
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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline through week 12
Changes in ¹H-MRS Neurochemical Metabolites
Proton magnetic resonance spectroscopy will quantify changes in metabolites associated with neuroplasticity and metabolic function. Metabolite concentrations will be compared from baseline to post-treatment to determine whether nutritional ketosis enhances neurochemical responses to iTBS.
Time frame: Baseline to Week 8 (post-iTBS)
Changes in Resting-State Functional Connectivity
Resting-state fMRI will be used to assess changes in intrinsic functional connectivity within fronto-cingulate and fronto-striatal networks.
Time frame: Baseline to Week 8 (post-iTBS)
Changes in Task-Evoked Brain Activation
Task-based fMRI will be used to measure changes in activation within predefined mood-regulation circuits. Contrast maps from an emotional processing task will be compared from baseline to post-treatment to assess neural circuit engagement associated with iTBS combined with dietary intervention.
Time frame: Baseline to Week 8 (post-iTBS)
Change in Secondary Depression Scores
Baseline grid-version of the 17-item Hamilton Depression Rating Scale (HDRS) score. The HDRS is a 17-item clinician-administered rating scale designed to assess severity of depressive symptoms. The score range is 0 to 52, with higher score indicating more severe depression.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Change in Self-Reported Depressive Symptoms
Self-reported depressive symptom severity will be assessed using the PHQ-9 with changes measured from baseline to each assessment point through the end of treatment. Higher scores on the PHQ-9 represent greater depressive severity.
Time frame: 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)
Functional Disability
Functional disability will be measured using the WHODAS 2.0, with changes evaluated from baseline to the end of treatment. Higher WHODAS scores indicate greater impairment.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)
Well-being
Well-being will be evaluated using the WHO-5 Well-Being Index, measured from baseline to the end of treatment. Higher WHO-5 scores represent better well-being.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)
Change in Anxiety Measure
Anxiety symptom severity will be assessed using the Generalized Anxiety Disorder-7 (GAD-7), with improvement examined from baseline to the end of treatment. Higher GAD-7 scores reflect more severe anxiety
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)
BMI (Anthropometric Outcomes)
Anthropometric outcomes, including BMI, will be recorded to evaluate changes in adiposity and fat distribution from baseline to the end of treatment.
Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)
Waist-to-Hip Ratio (Anthropometric Outcomes)
Anthropometric outcomes, including waist circumference and waist-to-hip ratio, will be recorded to evaluate changes in adiposity and fat distribution from baseline to the end of treatment. Higher waist-to-hip ratios indicate greater central adiposity.
Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)
NIH Toolbox Dimensional Change Card Sort Test (Executive Functioning)
Executive functioning will be assessed using the NIH Toolbox Dimensional Change Card Sort Test, with changes evaluated from baseline to the end of treatment. Higher scores reflect better cognitive performance.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
NIH Flanker Inhibitory Control and Attention Test (Executive Functioning)
Executive functioning will be assessed using the NIH Flanker Inhibitory Control and Attention Test, with changes evaluated from baseline to the end of treatment. Higher scores reflect better cognitive performance.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Working Memory
Working memory will be measured using the NIH Toolbox List Sorting Working Memory Test, with changes compared from baseline to post-treatment. Higher scores indicate stronger working memory ability.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Episodic Memory
Episodic memory will be assessed using the NIH Toolbox Auditory Verbal Learning Test and the Picture Sequence Memory Test, with changes evaluated from baseline to the end of treatment. Higher scores indicate better episodic memory performance.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
NIH Toolbox Oral Symbol Digit Test (Processing Speed)
Processing speed will be evaluated using the NIH Toolbox Oral Symbol Digit Test, with changes assessed from baseline to post-treatment. Higher scores reflect faster processing speed.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
NIH Toolbox Pattern Comparison Processing Speed Test (Processing Speed)
Processing speed will be evaluated using the NIH Toolbox Pattern Comparison Processing Speed Test, with changes assessed from baseline to post-treatment. Higher scores reflect faster processing speed.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Treatment Expectancy
Treatment expectancy will be assessed using the Stanford Expectations of Treatment Scale (SETS), administered at baseline to evaluate participants' expectations prior to the intervention. Higher scores on the SETS indicate stronger positive treatment expectancy.
Time frame: Baseline
Perceived Physical Capacity
The modified Rating of Perceived Exertion (RPE) scale will be used to assess participants' perceived physical effort and tolerance during routine physical activities and daily tasks. This subjective measure captures how hard the body feels it is working based on internal sensations such as breathing, cardiovascular strain, muscle fatigue, and overall exertion, providing an index of perceived functional capacity for physical activity.
Time frame: Baseline, Days 1-5 of iTBS treatment, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Objective Physical Capacity
Objective indices of physical capacity and fatigue will be obtained using handgrip dynamometry. Maximal voluntary force (MVF) will be measured as the average of three maximal-effort trials, reflecting peak isometric grip strength and overall neuromuscular capacity of the hand and forearm muscles.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Fatigue
Time to exhaustion (TTE) during a sustained submaximal grip task will be used to quantify fatigue resistance and endurance, defined as the duration for which participants can maintain a prescribed grip force before they are unable to sustain the target level.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Change in HbA1c Levels
Changes in fasting HbA1c (measured in mmol/mol) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Fasting Glucose Levels
Changes in fasting glucose (measured in mmol/L) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Lipid Profile
Changes in lipid profile (total cholesterol, LDL, HDL, triglycerides; measured in mmol/mol) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Liver Function Panel
Changes in liver function (ALT, AST, ALP; measured in U/L) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Total Protein and Albumin
Changes in total protein and albumin (measured in g/L) across the study period.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Change in Total Bilirubin
Changes in total bilirubin (measured in mg/dL) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Electrolytes
Changes in electrolytes (measured in mmol/L) across the study period
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Urea and Calcium
Changes in urea and calcium (measured in mg/dL) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in BDNF
Changes in BDNF (measured in ng/mL) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in IL-6 and TNF-alpha Levels
Changes in inflammatory markers (measured in pg/mL) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in CRP Levels
Changes in CRP (measured in mg/L) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Changes in DTI-derived Structural Connectivity
DTI will be used to assess changes in structural connectivity within fronto-cingulate and fronto-striatal networks.
Time frame: Baseline to Week 8 (post-iTBS)
Change in Insulin Levels
Change in insulin level (measured in µU/mL) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in GDF15 Levels
Changes in GDF15 levels (measured in pg/mL) across the study period.
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Sleep Quality
Changes in sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) across the study period. Scores range from 0-21, with a higher score indicating worse sleep quality.
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)
Plan to share: Yes — De-identified individual participant data (IPD) and relevant supporting documentation (including the study protocol, statistical analysis plan, and data dictionary) will be shared to enable secondary research. Data will be shared with qualified researchers for scientifically sound analyses, subject to approval and execution of a data use agreement in accordance with Sunnybrook Research Institute policies. Requests for access will be reviewed to ensure scientific merit, feasibility, and protection of participant confidentiality.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report
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.
No publications or documents are linked to this record.
Started Oct 2026 (actual). Primary completion is estimated for Jan 2028, 15 months after the start.
Of 647 non-industry interventional studies with no phase under Depressive Disorder, Major, half reached primary completion within 35 months of starting (the median), counting those still running; a quarter within 19 and three quarters within 55. This study's planned 15 months is below that.
Counting every sponsor, half of 687 studies reached it within 33 months; a quarter within 17 and three quarters within 55.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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