Major Depressive Disorder (MDD)ALIGNNCT07376018
Ketogenic Diet and Neuromodulation in Treatment Resistant Depression
A study testing Accelerated Intermittent Theta Burst Stimulation (iTBS), Ketogenic Diet and Canadian Food Guide-Aligned Diet in people with Major Depressive Disorder (MDD) and Treatment Resistant Depression (TRD), run by Sunnybrook Health Sciences Centre at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Disorder (MDD), Treatment Resistant Depression (TRD)
- What is being tested?
- Accelerated Intermittent Theta Burst Stimulation (iTBS), Ketogenic Diet and Canadian Food Guide-Aligned Diet
- Type of treatment
- Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteCanada
- Study dates
- Oct 2026to Jan 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 21Show fewer
- 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
- 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
- Contraindications to MRI
- Unwillingness to perform daily finger-stick testing
- Inability to access or prepare KD-compliant foods if assigned
- Unable to provide informed consent on their own
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Nidhi Shah contact
Canada1 site
Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N 3M5
Sean M Nestor, M.D., PhD, 416-347-0257, sean.nestor@utoronto.ca
About this study
Official title: Adjunctive Low-carb Ketogenic Diet to Enhance Imaging-guided Neuromodulation in Treatment Resistant Depression
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?
Read more
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
- Being tested
- Accelerated Intermittent Theta Burst Stimulation (iTBS), Ketogenic Diet, Canadian Food Guide-Aligned Diet
- 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
- Medical subject headings
- Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Accelerated Intermittent Theta Burst Stimulation (iTBS)Device
Also called repetitive transcranial magnetic stimulation (rTMS)
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.
Ketogenic DietBehavioural
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.
Canadian Food Guide-Aligned DietBehavioural
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Device: Accelerated Intermittent Theta Burst Stimulation (iTBS); Behavioral: Canadian Food Guide-Aligned Diet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Baseline through week 12
Secondary outcomes (35)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline to Week 8 (post-iTBS)
Change in Insulin Levels
Change in insulin level (measured in µU/mL) across the study period.
Measured: 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.
Measured: 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.
Measured: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2026
- Study startOct 2026 (estimated)
- Primary completionJan 2028 (estimated)
- Study completionJan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive Disorder (MDD)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sunnybrook Health Sciences Centre
- Sponsor type
- University, hospital or other
- Collaborators
- Baszucki Group
- Responsible party
- Principal investigator, Dr. Sean Michael Nestor, Sunnybrook Health Sciences Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07376018
- Sponsor's protocol ID
- 6944
- Acronym
- ALIGN
- Status last verified
- Aug 2026
- First submitted
- 21 Jan 2026
- Last updated
- 25 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- 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.
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Adjunctive Low-carb Ketogenic Diet to Enhance Imaging-guided Neuromodulation in Treatment Resistant Depression
- ClinicalTrials.gov ID
- NCT07376018
- Acronym / sponsor ID
- ALIGN / 6944
- Keywords
- Major Depressive Disorder, MDD, TRD, TMS, Glucose Control, Ketogenic Diet, Metabolic Health, Transcranial Magnetic Stimulation
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Sunnybrook Health Sciences CentreUniversity, hospital or other
- Collaborators
- Baszucki Group
- Study start
- Oct 2026 (estimated)
- Primary completion
- Jan 2028 (estimated)
- Study completion
- Jan 2028 (estimated)
- First posted
- 29 Jan 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Ketogenic Diet | Experimental | Device: Accelerated Intermittent Theta Burst Stimulation (iTBS), Behavioral: Ketogenic DietParticipants 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. |
| Canadian Food Guide-Aligned Diet | Active comparator | Device: Accelerated Intermittent Theta Burst Stimulation (iTBS), Behavioral: Canadian Food Guide-Aligned DietParticipants 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (21 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Accelerated Intermittent Theta Burst Stimulation (iTBS)Also: repetitive transcranial magnetic stimulation (rTMS)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. | Device | Canadian Food Guide-Aligned Diet, Ketogenic Diet |
| Ketogenic DietA 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. | Behavioural | Ketogenic Diet |
| Canadian Food Guide-Aligned DietA 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. | Behavioural | Canadian Food Guide-Aligned Diet |
Primary outcome
Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS)
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
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.
Changes in Ketone Levels
Time frame: Baseline through week 12
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.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time frame: Baseline through week 12
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.
35 secondary outcomes
Changes in ¹H-MRS Neurochemical Metabolites
Time frame: Baseline to Week 8 (post-iTBS)
Changes in Resting-State Functional Connectivity
Time frame: Baseline to Week 8 (post-iTBS)
Changes in Task-Evoked Brain Activation
Time frame: Baseline to Week 8 (post-iTBS)
Change in Secondary Depression Scores
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Change in Self-Reported Depressive Symptoms
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
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
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
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)
Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)
Waist-to-Hip Ratio (Anthropometric Outcomes)
Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)
NIH Toolbox Dimensional Change Card Sort Test (Executive Functioning)
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
NIH Flanker Inhibitory Control and Attention Test (Executive Functioning)
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Working Memory
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Episodic Memory
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
NIH Toolbox Oral Symbol Digit Test (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)
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Treatment Expectancy
Time frame: Baseline
Perceived Physical Capacity
Time frame: Baseline, Days 1-5 of iTBS treatment, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Objective Physical Capacity
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Fatigue
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Change in HbA1c Levels
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Fasting Glucose Levels
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Lipid Profile
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Liver Function Panel
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Total Protein and Albumin
Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Change in Total Bilirubin
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Electrolytes
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in Urea and Calcium
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in BDNF
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in IL-6 and TNF-alpha Levels
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in CRP Levels
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Changes in DTI-derived Structural Connectivity
Time frame: Baseline to Week 8 (post-iTBS)
Change in Insulin Levels
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in GDF15 Levels
Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)
Change in 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)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2026.
- Individual participant dataSharing planned: 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Nidhi Shah contact
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Accelerated Intermittent Theta Burst Stimulation (iTBS), Ketogenic Diet and Canadian Food Guide-Aligned Diet in people with Major Depressive Disorder (MDD) and Treatment Resistant Depression (TRD), run by Sunnybrook Health Sciences Centre at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 25 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sean M Nestor, M.D., PhD (416-347-0257, sean.nestor@utoronto.ca; sean.nestor@sunnybrook.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS) (time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2026.