Ketogenic Diet and Neuromodulation in Treatment Resistant Depression

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)

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.

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.

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.

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.

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.

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.

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.

Self-reported depressive symptom severity will be assessed using the PHQ-9 with changes measured from baseline to each assessment point through the end of treatment. Higher scores on the PHQ-9 (0-27) represent greater depressive severity.

Functional disability will be measured using the WHODAS 2.0, with changes evaluated from baseline to the end of treatment. Higher WHODAS scores indicate greater impairment.

Well-being will be evaluated using the WHO-5 Well-Being Index, measured from baseline to the end of treatment. Higher WHO-5 scores represent better well-being.

Anxiety symptom severity will be assessed using the Generalized Anxiety Disorder-7 (GAD-7), with improvement examined from baseline to the end of treatment. Higher GAD-7 scores reflect more severe anxiety

Anthropometric outcomes, including BMI, waist circumference, and waist-to-hip ratio, will be recorded to evaluate changes in adiposity and fat distribution from baseline to the end of treatment. Higher waist-to-hip ratios indicate greater central adiposity.

Resting systolic/diastolic blood pressure and heart rate will be measured to assess physiological changes. Higher blood pressure values reflect worse cardiovascular status.

Executive functioning will be assessed using the NIH Toolbox Dimensional Change Card Sort Test and the Flanker Inhibitory Control and Attention Test, with changes evaluated from baseline to the end of treatment. Higher scores reflect better cognitive performance.

Working memory will be measured using the NIH Toolbox List Sorting Working Memory Test, with changes compared from baseline to post-treatment. Higher scores indicate stronger working memory ability.

Episodic memory will be assessed using the NIH Toolbox Auditory Verbal Learning Test and the Picture Sequence Memory Test, with changes evaluated from baseline to the end of treatment. Higher scores indicate better episodic memory performance.

Processing speed will be evaluated using the NIH Toolbox Oral Symbol Digit Test and the Pattern Comparison Processing Speed Test, with changes assessed from baseline to post-treatment. Higher scores reflect faster processing speed.

Treatment expectancy will be assessed using the Stanford Expectations of Treatment Scale (SETS), administered at baseline to evaluate participants' expectations prior to the intervention. Higher scores on the SETS indicate stronger positive treatment expectancy.

The modified Rating of Perceived Exertion (RPE) scale will be used to assess participants' perceived physical effort and tolerance during routine physical activities and daily tasks. This subjective measure captures how hard the body feels it is working based on internal sensations such as breathing, cardiovascular strain, muscle fatigue, and overall exertion, providing an index of perceived functional capacity for physical activity.

Objective indices of physical capacity and fatigue will be obtained using handgrip dynamometry. Maximal voluntary force (MVF) will be measured as the average of three maximal-effort trials, reflecting peak isometric grip strength and overall neuromuscular capacity of the hand and forearm muscles.

Time to exhaustion (TTE) during a sustained submaximal grip task will be used to quantify fatigue resistance and endurance, defined as the duration for which participants can maintain a prescribed grip force before they are unable to sustain the target level.