Major depressive disorder (MDD) is a debilitating illness that places a great burden on global health. A ketogenic diet, which has traditionally been used for treating refractory epileptic disorders, is being increasingly explored for its potential of alleviating other neuropsychiatric conditions. Providing an up-to-date summary on the ketogenic diet’s potential to alleviate MDD, its neurobiological basis, and preliminary clinical evidence. A structured literature survey was performed, and a narrative review was written. Basic science provides cues for the biological mechanisms underlying the antidepressant effects of ketosis. Ketosis may circumvent frontal cortical glucose hypometabolism, reduce oxidative stress and neuroinflammation, and restore neurotransmitter homeostasis by increasing gamma-aminobutyric acid (GABA) levels and decreasing excitatory neurotransmitter levels. Another interesting domain affected by ketosis and potentially linked to mood and mental health is the gut microbiome. Emerging clinical evidence supports the efficacy of ketosis induction in treating patients with mood disorders. Evidence supports the antidepressant potential of the ketogenic diet. However, further substantial research into the underlying mechanisms of action and clinical effects is required.

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