Ketogenic Diet and Neuromodulation in Treatment Resistant Depression
Trial statusNot yet recruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18-65
SponsorSunnybrook Health Sciences Centre
About this trial
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
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
Disqualifiers
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
Trial design
Design model
Parallel
Treatments tested in this trial
Accelerated Intermittent Theta Burst Stimulation (iTBS)
DeviceIntermittent 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 pulses per session, delivered at 110% of resting motor threshold, with 50-minute inter-session intervals, for 8 sessions per day over 5 consecutive days.
Ketogenic Diet
BehavioralA 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.
Canadian Food Guide-Aligned Diet
BehavioralA 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.
Treatment groups
60 Participants
are divided into 2 treatment groupsGroup A: Ketogenic DietExperimental treatment 2 interventions
Group B: Canadian Food Guide-Aligned DietActive comparator 2 interventions
Trial outcomes
Primary outcomes
1
Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS)
Change in depression symptomatology as assessed by the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS). Higher scores indicate worse outcomes (greater severity of depressive symptoms). Week 8 will be used as the primary endpoint.
Time frame
Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)2
Changes in Ketone Levels
Change in β-hydroxybutyrate concentrations over the treatment period relative to baseline. β-hydroxybutyrate will be measured daily via finger-stick ketone testing during the lead-in and iTBS phases, and a minimum of three times per week during the post-iTBS dietary continuation phase. Longitudinal change will be analyzed across the treatment period.
Time frame
Baseline through week 123
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Frequency, severity, and relatedness of adverse events and clinically significant laboratory abnormalities, and discontinuations due to adverse effects, with specific attention to KD-related effects (e.g., hypoglycemia, dehydration, electrolyte disturbances, gastrointestinal symptoms, dyslipidemia) and mood destabilization/suicidality, alongside treatment retention and dietary adherence.
Time frame
Baseline through week 12Secondary outcomes
1
Changes in ¹H-MRS Neurochemical Metabolites
Proton magnetic resonance spectroscopy will quantify changes in metabolites associated with neuroplasticity and metabolic function. Metabolite concentrations will be compared from baseline to post-treatment to determine whether nutritional ketosis enhances neurochemical responses to iTBS.
Time frame
Baseline to Week 8 (post-iTBS)2
Changes in Resting-State Functional Connectivity
Resting-state fMRI will be used to assess changes in intrinsic functional connectivity within fronto-cingulate and fronto-striatal networks.
Time frame
Baseline to Week 8 (post-iTBS)3
Changes in Task-Evoked Brain Activation
Task-based fMRI will be used to measure changes in activation within predefined mood-regulation circuits. Contrast maps from an emotional processing task will be compared from baseline to post-treatment to assess neural circuit engagement associated with iTBS combined with dietary intervention.
Time frame
Baseline to Week 8 (post-iTBS)4
Change in Secondary Depression Scores
Baseline grid-version of the 17-item Hamilton Depression Rating Scale (HDRS) score. The HDRS is a 17-item clinician-administered rating scale designed to assess severity of depressive symptoms. The score range is 0 to 52, with higher score indicating more severe depression.
Time frame
Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Sunnybrook Health Sciences Centre
Lead sponsor
Baszucki Group
Collaborator
Source ClinicalTrials.gov
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