Exploring the mechanisms of action of the antidepressant effect of the ketogenic diet

Rev Neurosci. 2020 Aug 27;31(6):637-648. doi: 10.1515/revneuro-2019-0073.


The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms - for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.

Keywords: epilepsy; inflammation; ketogenic diet; major depressive disorder.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain / metabolism*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism*
  • Diet, Ketogenic*
  • Epilepsy / drug therapy
  • Epilepsy / metabolism*
  • Gastrointestinal Microbiome / immunology
  • Gastrointestinal Microbiome / physiology
  • Humans
  • Microbiota / immunology
  • Microbiota / physiology