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NCT Number: NCT07376018

Ketogenic Diet and 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

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Key information

Conditions

Major Depressive Disorder (MDD) Depressive Disorder Depressive Disorder, Major Depressive Disorder, Treatment-Resistant Mental Disorders Mood Disorders Treatment Resistant Depression (TRD)

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location contact

Sean M Nestor, M.D., PhD

CONTACT

[email protected]

416-347-0257

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Other names: repetitive transcranial magnetic stimulation (rTMS)

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.

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.

Primary outcomes

  1. 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)

  2. 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.

  3. 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.

Secondary outcomes

  1. Changes in ¹H-MRS Neurochemical Metabolites

    Time frame: Baseline to Week 8 (post-iTBS)

    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.

  2. Changes in Resting-State Functional Connectivity

    Time frame: Baseline to Week 8 (post-iTBS)

    Resting-state fMRI will be used to assess changes in intrinsic functional connectivity within fronto-cingulate and fronto-striatal networks.

  3. Changes in Task-Evoked Brain Activation

    Time frame: Baseline to Week 8 (post-iTBS)

    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.

  4. Change in Secondary Depression Scores

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  5. 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)

    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.

  6. 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)

    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.

  7. 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)

    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.

  8. 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)

    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

  9. BMI (Anthropometric Outcomes)

    Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)

    Anthropometric outcomes, including BMI, will be recorded to evaluate changes in adiposity and fat distribution from baseline to the end of treatment.

  10. Waist-to-Hip Ratio (Anthropometric Outcomes)

    Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)

    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.

  11. NIH Toolbox Dimensional Change Card Sort Test (Executive Functioning)

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  12. NIH Flanker Inhibitory Control and Attention Test (Executive Functioning)

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  13. Working Memory

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  14. Episodic Memory

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  15. Waist-to-Hip Ratio (Anthropometric outcome)

    Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)

    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.

  16. NIH Toolbox Oral Symbol Digit Test (Processing Speed)

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  17. NIH Toolbox Pattern Comparison Processing Speed Test (Processing Speed)

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  18. Treatment Expectancy

    Time frame: Baseline

    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.

  19. Perceived Physical Capacity

    Time frame: Baseline, Days 1-5 of iTBS treatment, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  20. Objective Physical Capacity

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  21. Fatigue

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    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.

  22. Change in HbA1c Levels

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in fasting HbA1c (measured in mmol/mol) across the study period.

  23. Change in Fasting Glucose Levels

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in fasting glucose (measured in mmol/L) across the study period.

  24. Change in Lipid Profile

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in lipid profile (total cholesterol, LDL, HDL, triglycerides; measured in mmol/mol) across the study period.

  25. Change in Liver Function Panel

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in liver function (ALT, AST, ALP; measured in U/L) across the study period.

  26. Change in Total Protein and Albumin

    Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)

    Changes in total protein and albumin (measured in g/L) across the study period.

  27. Change in Total Bilirubin

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in total bilirubin (measured in mg/dL) across the study period.

  28. Change in Electrolytes

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in electrolytes (measured in mmol/L) across the study period

  29. Change in Urea and Calcium

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in urea and calcium (measured in mg/dL) across the study period.

  30. Change in BDNF

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in BDNF (measured in ng/mL) across the study period.

  31. Change in IL-6 and TNF-alpha Levels

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in inflammatory markers (measured in pg/mL) across the study period.

  32. Change in CRP Levels

    Time frame: Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS)

    Changes in CRP (measured in mg/L) across the study period.

Study contacts

Contact information is provided by the study sponsor or research team.

Nidhi Shah

CONTACT

[email protected]

Sean M Nestor, M.D., PhD

CONTACT

[email protected]; [email protected]

416-347-0257

Sponsors and collaborators

Lead sponsor

Sunnybrook Health Sciences Centre

Other

Collaborators

  • Baszucki Group

Registry information

Official study title

Adjunctive Low-carb Ketogenic Diet to Enhance Imaging-guided Neuromodulation in Treatment Resistant Depression

Acronym: ALIGN

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Jan 29, 2026
Registry last updated
Aug 7, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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