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Licensed Unlicensed Requires Authentication Published by De Gruyter May 15, 2020

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

  • Alessandro Ricci

    Mr. Alessandro Ricci is a second year student in the Faculty of Medicine of Queen's University. He is especially interested in projects involving cognition, mood and new interventions in Psychiatry.

    , Maia A. Idzikowski

    Ms. Maia A. Idzikowski is a second year medical student at Queen's University, and completed undergraduate studies in the Queen's University Accelerated Route to Medicine (QuARMS) Program. Throughout the past year, she has been involved in several projects in the fields of psychiatry and anesthesiology.

    , Claudio N. Soares

    Dr. Claudio N. Soares is professor and head full professor and head of the Department of Psychiatry at Queen's University.

    and Elisa Brietzke

    Elisa Brietzke, MD, PhD, is psychiatrist and professor at the Department of Psychiatry at Queen's University.

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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.

Corresponding author: Elisa Brietzke, Department of Psychiatry, Queen's University School of Medicine, 752 King Street West, K7L7X3, Kingston, ON, Canada; Kingston General Hospital, Kingston, ON, Canada; and Centre for Neuroscience Studies (CNS), Queen's University, Kingston, ON, Canada, 75 Stuart St., Kingston, ON, K7L 2V7, Canada, E-mail:

Funding source: Queen's University- School of Medicine

About the authors

Alessandro Ricci

Mr. Alessandro Ricci is a second year student in the Faculty of Medicine of Queen's University. He is especially interested in projects involving cognition, mood and new interventions in Psychiatry.

Maia A. Idzikowski

Ms. Maia A. Idzikowski is a second year medical student at Queen's University, and completed undergraduate studies in the Queen's University Accelerated Route to Medicine (QuARMS) Program. Throughout the past year, she has been involved in several projects in the fields of psychiatry and anesthesiology.

Claudio N. Soares

Dr. Claudio N. Soares is professor and head full professor and head of the Department of Psychiatry at Queen's University.

Elisa Brietzke

Elisa Brietzke, MD, PhD, is psychiatrist and professor at the Department of Psychiatry at Queen's University.


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Received: 2019-08-08
Accepted: 2019-10-11
Published Online: 2020-05-15
Published in Print: 2020-08-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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