Ketogenic diet for mood disorders from animal models to clinical application

Abstract

Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative therapeutic approaches including diets are, therefore, under investigation. Ketogenic diet (KD) is effective for treatment-resistant epilepsy and metabolic diseases, however, only a few clinical studies suggest its beneficial effect also for mental disorders. Animal models are a useful tool to uncover the underlying mechanisms of therapeutic effects. Women have a twice-higher prevalence of mood disorders but very little is known about sex differences in nutritional psychiatry. In this review, we aim to summarize current knowledge of the sex-specific effects of KD in mood disorders. Ketone bodies improve mitochondrial functions and suppress oxidative stress, inducing neuroprotective and anti-inflammatory effects which are both beneficial for mental health. Limited data also suggest KD-induced improvement of monoaminergic circuits and hypothalamus–pituitary–adrenal axis—the key pathophysiological pathways of mood disorders. Gut microbiome is an important mediator of the beneficial and detrimental effects of diet on brain functioning and mental health. Gut microbiota composition is affected in mood disorders but its role in the therapeutic effects of different diets, including KD, remains poorly understood. Still little is known about sex differences in the effects of KD on mental health as well as on metabolism and body weight. Some animal studies used both sexes but did not find differences in behavior, body weight loss or gut microbiota composition. More studies, both on a preclinical and clinical level, are needed to better understand sex-specific effects of KD on mental health.

The Potential Effects of the Ketogenic Diet in the Prevention and Co-Treatment of Stress, Anxiety, Depression, Schizophrenia, and Bipolar Disorder: From the Basic Research to the Clinical Practice

“…A comprehensive overview of preclinical and clinical evidence supporting the use of a KD in the management of mood and anxiety disorders and discussed its relationship with inflammatory processes and potential mechanisms of action for its therapeutic effects [ 76 ]. Another review intended to summarize the current knowledge of the sex-specific effects of KDs on mood disorders, from animal models to clinical applications [ 77 ].…”

Metabolic Insights into Neuropsychiatric Illnesses and Ketogenic Therapies: A Transcriptomic View

“…Bioenergetic pathways such as glycolysis, TCA cycle, and oxidative phosphorylation facilitate glucose-based energy production [11]. Various genetics [12,13], postmortem [14][15][16][17][18], and preclinical [19,20] studies provide support for abnormalities of these pathways in neuropsychiatric illnesses. Alternatively, fatty acids provide another form of fuel.…”

“…Several case reports have also noted the utility of the ketogenic diet in reducing the Positive and Negative Syndrome Scale (PANSS) scores in schizophrenia patients [8,[34][35][36]. Furthermore, exogenous ketone supplementation, through the administration of ketone esters or ketone salts, has surfaced as a promising therapeutic strategy for inducing ketosis, modulating metabolic pathways, and improving behavioral deficits in various animal models of neuropsychiatric diseases [20,29,37].…”

Complete remission of depression and anxiety using a ketogenic diet: case series

“…It is also utilized as a substrate for sirtuins and PARP enzymes associated with DNA repair and longevity. A sustained increase in NAD+ may underlie the pleiomorphic benefits of KMT across multiple neuropsychiatric conditions ( 28 ). In terms of the frequent abnormal alarms set off in the amygdala during anxiety, nutritional ketosis may provide an acute and long-term intervention to reduce generalized anxiety, panic attacks, obsessive doubt, and symptoms of post-traumatic stress disorder (PTSD).…”