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Sponsor: Sunnybrook Health Sciences Centre
Conditions: Major Depressive Disorder (MDD), Treatment Resistant Depression (TRD)
Interventions: Accelerated Intermittent Theta Burst Stimulation (iTBS), Ketogenic Diet, Canadian Food Guide-Aligned Diet
Countries: Canada
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
Sex: ALL
Age: 18 Years to 65 Years
Healthy volunteers: No
Study type: INTERVENTIONAL
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
- Toronto, Ontario, Canada