Supplementary Material for: KETO-MOOD: Ketogenic Diet for Microbiome Optimization and Overcoming Depression: A Protocol for a Randomized Controlled Trial

Major Depressive Disorder (MDD) significantly impacts millions worldwide, with limited success in achieving remission for many patients, leading to high disease burden and increased suicide risk. Psychotherapy and antidepressants, although effective, do not provide relief for all, prompting the search for alternative treatments. Ketogenic diets have demonstrated positive effects on brain health. Our study aims to investigate the efficacy of the ketogenic diet in alleviating MDD symptoms, filling a critical gap in psychiatric treatment options and offering a novel dietary approach with potential to mitigate disease burden and enhance mental well-being. This phase randomized controlled trial will evaluate the efficacy of a ten-week program of dietitian counseling and ketogenic meal provision versus an intervention with similar dietetic contact promoting a healthy, insulin-lowering, non-ketogenic diet. The primary outcome is the change in the Patient Health Questionnaire nine-item depression score. Secondary outcomes include cognitive and affective mindfulness, self-efficacy, sleep, cognitive function, work and social adjustment, and various immunological, metabolic, and microbiome markers at weeks 6 and 10. This study addresses a critical gap in depression treatment by exploring the ketogenic diet's potential as a novel intervention. Given the global impact of depression and limitations of current therapies, this research is valuable for its potential neuroprotective and metabolic benefits. It aims to advance psychiatric treatment strategies by clarifying the diet's effects on depression and its underlying mechanisms.

重度抑郁症（Major Depressive Disorder, MDD）在全球范围内影响数百万人群，多数患者难以实现症状完全缓解，由此带来沉重的疾病负担并升高自杀风险。心理治疗与抗抑郁药物虽具有一定疗效，但无法为所有患者提供症状缓解，这推动了替代治疗方案的探索。生酮饮食（Ketogenic Diet）已被证实对大脑健康具有积极作用。本研究旨在探究生酮饮食缓解重度抑郁症症状的有效性，填补精神治疗方案中的关键空白，并提供一种有望减轻疾病负担、提升心理健康水平的新型饮食干预手段。本项随机对照试验（randomized controlled trial）将评估为期十周的干预方案疗效：一组接受营养师咨询与生酮膳食供应，另一组则接受频次相近的饮食相关指导，倡导健康、降低胰岛素水平的非生酮饮食。主要结局指标为患者健康问卷9项抑郁量表评分的变化。次要结局指标包括第6周和第10周时的认知与情感正念水平、自我效能感、睡眠质量、认知功能、工作与社会适应能力，以及各类免疫学、代谢学与微生物组（microbiome）标志物水平。本研究通过探索生酮饮食作为新型干预手段的潜力，填补了抑郁症治疗领域的关键空白。鉴于抑郁症的全球影响与当前治疗手段的局限性，本研究凭借其潜在的神经保护与代谢获益具备重要研究价值。本研究旨在通过阐明饮食干预对抑郁症的作用及其潜在机制，推动精神治疗策略的发展。