Ketogenic Diet and Neuromodulation in Treatment Resistant Depression

Trial details

Who runs it

Sunnybrook Health Sciences Centre

Trial code

NCT07376018

Record updated

28 October 2026

Original description

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:Read full original descriptionShow less

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

Inclusion: 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: Concomitant major unstable medical illness as determined by a study physician; Use of anticonvulsants (benzodiazepines with a dose of <2 lorazepam equivalents will be permitted), GABA agonists, or medications reducing TMS efficacy; Lifetime diagnosis of bipolar I or bipolar II disorder, or a primary psychotic disorder, as confirmed by a structured psychiatric interview; 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; Active eating disorder in the past 12 months; GI disorders or food allergies incompatible with dietary protocols; Current psychotic symptoms; 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; Currently following a Ketogenic diet; Habitual low-carb diet in the past 6 months; Alcohol use >3 drinks/day or >14/week; 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.

ClinicalTrials.gov NCT07376018