Adjunctive Low-carb Ketogenic Diet to Enhance Imaging-guided Neuromodulation in Treatment Resistant Depression
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Changes in Ketone Levels
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Ketogenic Diet
Participants in this arm will follow 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 of finger-stick ketone and glucose testing.
干预措施: Accelerated Intermittent Theta Burst Stimulation (iTBS) (Device)
Canadian Food Guide-Aligned Diet
Participants in this arm will follow 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 approximately 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 finger-stick glucose testing.
干预措施: Accelerated Intermittent Theta Burst Stimulation (iTBS) (Device)
Ketogenic Diet
Participants in this arm will follow 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 of finger-stick ketone and glucose testing.
干预措施: Ketogenic Diet (Behavioral)
Canadian Food Guide-Aligned Diet
Participants in this arm will follow 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 approximately 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 finger-stick glucose testing.
干预措施: Canadian Food Guide-Aligned Diet (Behavioral)
结局指标
主要结局
Changes in Ketone Levels
时间窗: Baseline through week 12
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.
Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS)
时间窗: Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS)
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)
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
时间窗: Baseline through week 12
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.
Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS)
时间窗: Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS)
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)
Safety and Tolerability
时间窗: Baseline through week 12
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.
次要结局
- Change in Fasting Glucose Levels(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Changes in ¹H-MRS Neurochemical Metabolites(Baseline to Week 8 (post-iTBS))
- Changes in Resting-State Functional Connectivity(Baseline to Week 8 (post-iTBS))
- Changes in Task-Evoked Brain Activation(Baseline to Week 8 (post-iTBS))
- Change in Secondary Depression Scores(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Change in Self-Reported Depressive Symptoms(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(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS))
- Well-being(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(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS), Week 26 (post-iTBS), Week 52 (post-iTBS))
- BMI (Anthropometric Outcomes)(Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS))
- Waist-to-Hip Ratio (Anthropometric Outcomes)(Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS))
- NIH Toolbox Dimensional Change Card Sort Test (Executive Functioning)(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- NIH Flanker Inhibitory Control and Attention Test (Executive Functioning)(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Working Memory(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Episodic Memory(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Waist-to-Hip Ratio (Anthropometric outcome)(Baseline, Day 5 (post-iTBS), Week 5 (post-iTBS), Week 8 (post-iTBS))
- NIH Toolbox Oral Symbol Digit Test (Processing Speed)(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- NIH Toolbox Pattern Comparison Processing Speed Test (Processing Speed)(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Perceived Physical Capacity(Baseline, Days 1-5 of iTBS treatment, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Objective Physical Capacity(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Fatigue(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Change in HbA1c Levels(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in Lipid Profile(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in Liver Function Panel(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in Total Protein and Albumin(Baseline, Week 5 (post-iTBS), Week 8 (post-iTBS), Week 12 (post-iTBS))
- Change in Total Bilirubin(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in Electrolytes(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in Urea and Calcium(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in BDNF(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in IL-6 and TNF-alpha Levels(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Change in CRP Levels(Baseline, Day 1 of iTBS, Week 5 (post-iTBS), Week 8 (post-iTBS))
- Changes in ¹H-MRS Neurochemical Metabolites(Baseline to Week 4 (post-iTBS))
- Changes in Resting-State Functional Connectivity(Baseline to Week 4 (post-iTBS))
- Changes in Task-Evoked Brain Activation(Baseline to Week 4 (post-iTBS))
- Changes in Metabolic Biomarkers(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Change in Secondary Depression Scores(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Change in Self-Reported Depressive Symptoms(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Functional Disability(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Well-being(Baseline, Day (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Change in Anxiety Measure(Baseline, Day (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Anthropometric Outcomes(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Physiological Measures(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Executive Functioning(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Working Memory(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Episodic Memory(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Processing Speed(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Treatment Expectancy(Baseline)
- Perceived Physical Capacity(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Objective Physical Capacity(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
- Fatigue(Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS))
研究者
Dr. Sean Michael Nestor
Psychiatrist
Sunnybrook Health Sciences Centre