Ketogenic Diet with Accelerated Brain Stimulation for Treatment‑Resistant Depression

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

Adults with treatment‑resistant major depressive disorder are assigned to receive either a ketogenic diet or a standard healthy diet, each combined with personalized accelerated iTBS for 12 weeks (plus a 3‑week lead‑in). The trial compares changes in depression severity using clinician‑rated and self‑report scales, and monitors safety and feasibility of maintaining a ketogenic diet during treatment. Researchers will also track how ketone levels change over time. The study is designed to determine if the ketogenic diet provides additional benefit beyond iTBS with a standard diet and whether the approach is safe and tolerable.

Why it matters

Who can join: the full rules

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

Where it's running

• Sunnybrook Health Sciences Centre
  Toronto, Ontario, Canada Recruiting

Study contacts

• Study coordinator: Nidhi Shah
• Email: align@sunnybrook.ca
• Phone: 416-728-1018

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.