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 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.
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 (MADRS ≥ 20)
Meeting criteria for treatment-resistant depression (TRD), defined as non-response to at least two adequate antidepressant trials
Disqualifiers
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
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 image-guided, neuronavigated left dorsolateral prefrontal cortex (DLPFC) iTBS targeted based on functional connectivity with the subgenual anterior cingulate cortex (sgACC). Stimulation will consist of 600 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.
Treatment groups
60 Participants
are divided into 2 treatment groupsGroup A: Ketogenic DietExperimental treatment 1 intervention
Group B: Canadian Food Guide-Aligned DietActive comparator 1 intervention
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) (range 0-60). Higher scores indicate worse outcomes (greater severity of depressive symptoms)
Time frame
Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS)2
Changes in Ketone Levels
Change in fasting morning β-hydroxybutyrate concentrations over the treatment period relative to baseline. Fasting β-hydroxybutyrate will be measured daily via finger-stick ketone testing, and longitudinal change will be analyzed across the treatment period.
Time frame
Baseline through week 123
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.
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 4 (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. Connectivity between the individualized DLPFC stimulation target and the subgenual anterior cingulate cortex will be quantified. Baseline-to-post-treatment changes will be used to evaluate diet-related enhancement of iTBS-induced network modulation.
Time frame
Baseline to Week 4 (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 4 (post-iTBS)4
Changes in Metabolic Biomarkers
Changes in fasting metabolic and inflammatory biomarkers across the study period. Biomarkers include HbA1C, fasting glucose, lipid profile, total protein, albumin, total bilirubin, ALT, AST, ALP, electrolytes, urea, calcium, BDNF, IL-6, TNF-α, and C-reactive protein (CRP), with pregnancy testing (hCG) in females where applicable.
Time frame
Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (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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