Ketogenic Diet and Neuromodulation in Treatment Resistant Depression

Official title

Adjunctive Low-carb Ketogenic Diet to Enhance Imaging-guided Neuromodulation in Treatment Resistant Depression

Overview

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

Interventions

• Device Accelerated Intermittent Theta Burst Stimulation (iTBS)
  Intermittent theta burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation (rTMS), is a non-invasive brain stimulation technique approved by the FDA and Health Canada for the treatment of TRD. In this study, participants will receive an accelerated course of imaging-guided, neuronavigated left dorsolateral prefrontal cortex (DLPFC) iTBS targeted based on functional connectivity with the subgenual anterior cingulate cortex (sgACC). Stimulation protocol consists of 1800 pu
• Behavioral Ketogenic Diet
  A well-formulated ketogenic diet consisting of low carbohydrate, moderate protein, and high fat intake, designed to achieve and maintain nutritional ketosis (blood ketone levels of 0.5 to 3 mmol/L). Delivered with dietitian-led counseling and monitored via finger-stick ketone and glucose testing.
• Behavioral Canadian Food Guide-Aligned Diet
  A Canadian Food Guide-aligned diet emphasizing balanced intake of vegetables, fruits, whole grains, and protein foods, without specific macronutrient restrictions. Delivered with dietitian counseling matched in frequency and duration to the ketogenic diet arm, and monitored via dietary logs, metabolic assessments, and finger-stick glucose testing.

Primary outcome measures

• Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS) [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)]
• Changes in Ketone Levels [Time frame: Baseline through week 12]
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [Time frame: Baseline through week 12]

Secondary outcome measures (12)

• Changes in ¹H-MRS Neurochemical Metabolites [Time frame: Baseline to Week 8 (post-iTBS)]
• Changes in Resting-State Functional Connectivity [Time frame: Baseline to Week 8 (post-iTBS)]
• Changes in Task-Evoked Brain Activation [Time frame: Baseline to Week 8 (post-iTBS)]
• Change in Secondary Depression Scores [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)]
• Change in Self-Reported Depressive Symptoms [Time frame: Baseline, Week 3 (pre-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS), Week 10 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)]
• Functional Disability [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)]
• Well-being [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)]
• Change in Anxiety Measure [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS)]
• BMI (Anthropometric Outcomes) [Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)]
• Waist-to-Hip Ratio (Anthropometric Outcomes) [Time frame: Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS)]
• NIH Toolbox Dimensional Change Card Sort Test (Executive Functioning) [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)]
• NIH Flanker Inhibitory Control and Attention Test (Executive Functioning) [Time frame: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Canada · 1 center

• Sunnybrook Health Sciences Centre — Toronto

Identifiers

NCT: NCT07376018 · 6944

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗