Ketogenic Diet and Neuromodulation in Treatment Resistant Depression (ALIGN)

Sunnybrook Health Sciences Centre

Status: Begins enrollment in 1 month

Conditions: Treatment Resistant Depression (TRD); Major Depressive Disorder (MDD)

Treatments: Device: Accelerated Intermittent Theta Burst Stimulation (iTBS)

Study type: Interventional

Funder types: Other

Identifiers

NCT07376018

6944

Details and patient eligibility

About

The goal of this clinical trial is to test whether combining a ketogenic diet (KD) with personalized, accelerated intermittent theta burst stimulation (iTBS) produces greater reductions in depressive symptoms than iTBS combined with a standard healthy diet in adults with treatment-resistant depression. The trial also aims to determine whether participants can feasibly follow a ketogenic diet during an accelerated iTBS treatment course and whether the diet produces measurable changes in ketone levels.

Specifically, the study aims to determine whether the combined intervention:

1. Reduces depressive symptoms
2. Increases circulating ketone levels
3. Is feasible and tolerable during accelerated iTBS treatment

Participants will begin either a KD or a Canadian Food Guide-aligned diet (CFGD) with a 3-week dietary lead-in period, after which they will undergo a course of personalized, accelerated iTBS while continuing their assigned diet. Before and after the iTBS treatment course, participants will complete clinical assessments, provide blood samples for metabolic testing, and undergo MRI scans to assess brain connectivity. Ketone levels will be measured daily throughout the 12-week dietary intervention. Within-group and between-group differences will be compared to characterize changes in clinical outcomes, metabolism, and brain functioning.

Enrollment: 60 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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 (MADRS ≥ 20)
• Meeting criteria for treatment-resistant depression (TRD), defined as non-response to at least two adequate antidepressant trials
• Neuromodulation-naïve (no past rTMS or electroconvulsive therapy)
• Able to provide informed consent
• Available for the 15-week intervention and willing to follow either a ketogenic or Canadian Food Guide-aligned diet

Exclusion criteria

• Medical/psychiatric co-morbidities that prevent participation in the study or where depression is not the primary psychiatric symptom of concern
• History of epilepsy, stroke, or major neurological conditions, psychosis, or substance dependence within the last 6 months
• Physical or cognitive disability interfering with participation
• Females who are pregnant (self-report or via blood work), nursing, or planning a pregnancy during the timespan of the 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 KD
• 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
• Serious medical illness
• Contraindications to MRI
• Unwillingness to perform daily finger-stick testing

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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60 participants in 2 patient groups

Ketogenic Diet

Experimental group

Description:

Participants in this arm will begin a well-formulated ketogenic diet (low carbohydrate, moderate protein, high fat) for a 3-week dietary lead-in period prior to neuromodulation, and will continue the diet for a total of 12 weeks. The diet is designed to achieve and maintain nutritional ketosis (blood ketone levels of 0.5 to 3 mmol/L). Dietitian support will be provided through scheduled counseling and ongoing monitoring using daily finger-stick ketone and glucose testing.

Treatment:

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS)

Canadian Food Guide-Aligned Diet

Active Comparator group

Description:

Participants in this arm will begin a Canadian Food Guide-aligned diet for a 3-week dietary lead-in period prior to neuromodulation and will continue the diet for a total of 12 weeks. The diet will emphasize balanced intake of vegetables, fruits, whole grains, and protein foods, without specific macronutrient restrictions. Dietitian counseling will be matched in frequency and duration to the ketogenic diet arm. Nutritional monitoring will include dietary logs and metabolic assessments without targeted induction of ketosis. Participants will perform daily finger-stick glucose testing.

Treatment:

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS)