Ketogenic Diet and Neuromodulation in Treatment Resistant Depression (ALIGN)

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?

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 Overview

• Status: Not yet recruiting
• Conditions: Major Depressive Disorder (MDD); Treatment Resistant Depression (TRD)
• Intervention / Treatment: Device: Accelerated Intermittent Theta Burst Stimulation (iTBS); Behavioral: Ketogenic Diet; Behavioral: Canadian Food Guide-Aligned Diet

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sean M Nestor, M.D., PhD; Phone Number: 416-347-0257; Email: sean.nestor@utoronto.ca; sean.nestor@sunnybrook.ca
• Study Contact Backup: Name: Nidhi Shah; Email: nidhi.shah@sunnybrook.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
      • Contact: Sean M Nestor, M.D., PhD; Phone Number: 416-347-0257; Email: sean.nestor@utoronto.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketogenic Diet; 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); 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.; Other Names: repetitive transcranial magnetic stimulation (rTMS); Behavioral: Ketogenic Diet; 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.
Active Comparator: Canadian Food Guide-Aligned 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); 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.; Other Names: repetitive transcranial magnetic stimulation (rTMS); Behavioral: Canadian Food Guide-Aligned Diet; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	Baseline through week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline
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.	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.	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.	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.	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.	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.	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.	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	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.	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.	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.	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.	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.	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.	Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
Waist-to-Hip Ratio (Anthropometric outcome)	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.	Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (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.	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.	Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
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.	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.	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.	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.	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.	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.	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.	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.	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.	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	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.	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.	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.	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.	Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Collaborators: Baszucki Group

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: January 21, 2026
• First Submitted That Met QC Criteria: January 21, 2026
• First Posted (Actual): January 29, 2026

Study Record Updates

• Last Update Posted (Actual): August 7, 2026
• Last Update Submitted That Met QC Criteria: August 4, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: MDD; fMRI; Transcranial Magnetic Stimulation; Major Depressive Disorder; Ketogenic Diet; MRS; TMS; Dietary Intervention; TRD; iTBS; Glucose Control; Metabolic Health; Intermittent Theta-Burst Stimulation; Metabolic Psychiatry
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; Magnetic Field Therapy; Diet, Carbohydrate-Restricted; Transcranial Magnetic Stimulation; Diet, Ketogenic
• Other Study ID Numbers: 6944

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing 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).

IPD Sharing 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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No