Major depressive disorder (MDD) is the second leading contributor to the global burden of chronic diseases, as measured by years lived with disability. Additionally, MDD is associated with an increased risk of developing various conditions such as diabetes mellitus, heart disease, cancer, and stroke, which further adds to the disease burden. Notably, MDD significantly increases the risk of suicide, with up to 50% of the 800,000 worldwide suicides occurring during a depressive episode. The prevalence of mental disorders has been on the rise in Western societies, coinciding with the nutritional decline in typical Western diets. Traditional, nutrient-rich foods have been progressively replaced by ultra-processed foods, which are linked to heightened health risks, including type-2 diabetes, cardiovascular diseases, cancer, and depression. The ketogenic diet is a unique dietary approach that drastically limits carbohydrate intake, inducing a state of ketosis characterized by elevated levels of circulating ketone bodies. Ketone bodies, namely acetoacetate, β-hydroxybutyric acid, and acetone, are primarily produced through ketogenesis in the liver's mitochondrial matrix. Ketosis can be achieved through fasting or by consuming a low-carbohydrate diet, typically containing fewer than 20 grams of net carbs per day. Ketosis has historical roots and was a common physiological state during human evolution, particularly in the Paleolithic era when social structures were based on small groups of hunter-gatherers. In modern medicine, the ketogenic diet has been employed for nearly a century to treat refractory epilepsy. Although there is compelling evidence of the positive effects of the ketogenic diet on the brain and mental well-being, research on its effectiveness in psychiatric illnesses is still emerging. Ketosis may address various pathologies associated with depression, including frontal glucose hypometabolism, imbalances in GABA/glutamate neurotransmitter signaling, oxidative stress, mitochondrial dysfunction, inflammation (both cerebral microglial dysfunction and low-grade systemic inflammation), and perturbations in the gut microbiome. The primary hypothesis of our study is that adherence to a high-fat (≥60%) ketogenic diet, in addition to standard psychiatric care, will lead to a reduction in depressive symptoms at 4 and 8 weeks following the intervention, compared to standard psychiatric care involving a balanced mixed diet consisting of around 60% carbohydrates, with moderate amounts of fats and protein.

This study is a prospective, assessor-blinded, controlled trial with a randomized, parallel-arm design, categorized as a phase 2 trial. The focus of the study centers on a nutritional intervention as the independent variable, and it will be conducted at the University Psychiatric Clinics (UPK) in Basel, Switzerland. Participants will undergo supervised dietary training and counseling over the course of 8 weeks. The 8-week observation period is crucial for determining the effectiveness of prescribed depression treatments. Individuals eligible for the study are those who meet the diagnostic criteria for (unipolar) major depressive disorder or are currently experiencing a depressive episode within the context of bipolar affective disorder, according to ICD-10 criteria. Participants will be randomly assigned to receive either a low-carbohydrate (\<20g/day) ketogenic diet or a standard balanced mixed diet. Any discussion regarding diets between assessors and patients (or trial partners) will be strictly prohibited during the trial. Dietary support will be provided, primarily in the initial days, to ensure diet adherence, address issues, and monitor potential adverse effects. Dietitians will offer guidance on setting up and maintaining the diet, utilizing recipe cards, meal planning, dietary resources, and assisting with common challenges. The MAD ketogenic diet approach will be utilized in this study, as it has shown improved adherence compared to the classic ketogenic diet, with similar anti-seizure efficacy.

The ketogenic diet presents several benefits due to its non-pharmacological nature, demonstrating safety and over a century of efficacy in epilepsy management. Emerging evidence suggests its potential advantages in addressing metabolic and neuropsychiatric conditions, potentially exceeding the effectiveness of traditional antidepressant treatments, without the associated risks of third-line interventions such as ketamine application and electroconvulsive therapy. Moreover, the ketogenic diet is cost-effective and can be self-administered by patients, enhancing their sense of self-efficacy.