Ketogenic Diet and Neuromodulation in Treatment Resistant Depression

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 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