Therapeutic Potential of Exogenous Ketone Supplement Induced Ketosis in the Treatment of Psychiatric Disorders: Review of Current Literature

Abstract

Globally, psychiatric disorders, such as anxiety disorder, bipolar disorder, schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD) are becoming more prevalent. Although the exact pathological alterations are not yet clear, recent studies have demonstrated that widespread changes of very complex metabolic pathways may partially underlie the pathophysiology of many psychiatric diseases. Thus, more attention should be directed to metabolic-based therapeutic interventions in the treatment of psychiatric disorders. Emerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts or ketone esters, generates rapid and sustained nutritional ketosis and metabolic changes, which may evoke potential therapeutic effects in cases of central nervous system (CNS) disorders, including psychiatric diseases. Therefore, the aim of this review is to summarize the current information on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone supplementation elevates blood levels of the ketone bodies: D-β-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone. These compounds, either directly or indirectly, beneficially affect the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor 3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial uncoupling protein (UCP) expression. The result of downstream cellular and molecular changes is a reduction in the pathophysiology associated with various psychiatric disorders. We conclude that supplement-induced nutritional ketosis leads to metabolic changes and improvements, for example, in mitochondrial function and inflammatory processes, and suggest that development of specific adjunctive ketogenic protocols for psychiatric diseases should be actively pursued.

Keywords: exogenous ketone supplements; inflammation; ketosis; mitochondrial dysfunction; psychiatric diseases.

Figure 1

Mitochondrial ketone body metabolism: ketogenesis in liver cells (hepatocytes) and ketolysis in brain cells (neuron) (A). Main βHB-evoked metabolic effects and their consequences, which may evoke alleviating effects on different psychiatric diseases (B) (see text for more detailed putative mechanisms by which βHB may evoke alleviating effects on psychiatric diseases). Abbreviations: A, acetone; A₁R and A_2AR, different types of adenosine receptors; AcAc, acetoacetate; ATP, adenosine triphosphate; BBB, blood–brain barrier; βHB, D-beta-hydroxybutyrate (R-3-hydroxybutyrate); β-OHBD, βHB dehydrogenase; COX-2, cyclooxygenase-2; ETC, electron transport chain; GABA, gamma-aminobutyric acid; HMGL, hydroxymethylglutaryl-CoA-lyase; HMGS, hydroxymethylglutaryl-CoA-synthase; IL-1β, interleukin-1β; NADH/FADH₂, nicotinamide adenine dinucleotide/flavin adenine dinucleotide; NLRP3, NOD-like receptor pyrin domain 3; NMDAR, N-methyl-D-aspartate receptor; SCOT, succinyl-CoA:3-ketoacid CoA transferase; thiolase, acetoacetyl-CoA-thiolase; UCP, uncoupling proteins.