Ketogenic Diet for Schizophrenia: Clinical Implication

Zoltán Sarnyai; Ann-Katrin Kraeuter; Christopher M. Palmer

Disclosures

Curr Opin Psychiatry. 2019;32(5):394-401. 

In This Article

Impaired Cerebral Glucose and Energy Metabolism in Schizophrenia

One of the most consistent dysfunctions underlying the pathophysiology of schizophrenia is in the energy metabolism pathways, along with mitochondrial dysfunction and oxidative stress.[14,15] Systemic glucose metabolism abnormalities are manifested as hyperglycaemia, impaired glucose tolerance, and/or insulin resistance in first-onset, antipsychotic-naive schizophrenic patients.[16,17,18] Numerous transcriptomic, proteomic and metabolomic studies have identified the glycolysis–gluconeogenesis pathway as being consistently disrupted both in brain and cerebrospinal fluid.[9,19,20] A recent study by Sullivan et al.[21] examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia and controls subjects and found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. Specifically, in pyramidal neurons, monocarboxylate transporter 1 mRNA expression was increased, and HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression were decreased, collectively suggesting abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.[22] The involvement of glucose metabolism abnormalities is further emphasized by the analysis of seven glycolytic enzymes (triosephosphate isomerase, phosphoglycerate mutase 1, glyceraldehyde-3-phosphate dehydrogenase, hexokinase 1, aldolase C, enolase 2 and phosphoglycerate kinase 1) showing that a multivariate signal of all seven enzymes was capable of distinguishing N-methyl-D-aspartate (NMDA) antagonist-treated, schizophrenia-like, rats from controls.[23] In-vivo evidence for brain bioenergetic abnormalities in patients with schizophrenia and their unaffected siblings have been recently provided by using[31] P magnetization transfer spectroscopy by showing a reduction in intracellular pH, suggesting a relative increase in the contribution of glycolysis to ATP synthesis, with resultant build-up of lactic acid.[24] Interestingly, elevated lactate levels were found in the postmortem DLPFC of patients with schizophrenia.[22] Pyruvate, the final product of glycolysis, and NADPH are lower in the thalamus in people with schizophrenia compared with controls[25] and are also lower in a NMDA receptor hypofunction animal model.[26] In a similar model, up-regulation of transketolase, which links glycolysis with the pentose-phosphate pathway and is responsible for mitigating oxidative stress, was found in the hippocampus.[27]

Mitochondria are the power stations of cells. They produce chemical energy in the form of ATP through the electron transport chain in the process of oxidative phosphorylation by using reduced electron carriers generated by the tricarboxylic acid (TCA) cycle consuming the glycolytic end-product pyruvate (Figure 1). There has been considerable evidence gathered to support the role of mitochondrial dysfunctions in schizophrenia.[19,28–33,34,35] The Complex I of the electron transport chain has received particular attention, which is supported by a recent study showing reduced protein level and functioning for the core Cytochrome c oxidase subunit 1, NADH dehydrogenase ubiquinone flavoprotein 2, one of the most severely affected subunits in schizophrenia.[36] Furthermore, a direct link between mitochondrial function and schizophrenia-related deficits has been established by showing that isolated active normal mitochondria transfer into schizophrenia-derived lymphoblasts induces long-lasting improvement in various mitochondrial functions including cellular oxygen consumption and mitochondrial membrane potential (Δ ψ m), improved differentiation of schizophrenia-derived inducible pluripotent stem cells into neurons, and by an activation of the glutamate–glutamine cycle. Moreover, in a translationally valid animal model, the maternal immune activation model, it was shown that intra-prefrontal cortex injection of isolated active normal mitochondria transfer in adolescent rats exposed prenatally to a viral mimic prevents mitochondrial Δ ψ m and attentional deficit at adulthood.[37]

Figure 1.

Schematic representation of glucose metabolism and energy production in the cell. Glucose is taken up by glucose transporters and fuelled into glycolysis by the rate-limiting enzyme hexokinase to produce two molecules of ATP (adenosine-triphosphate), which is used as energy substrate, and the glycolysis end-products lactate and pyruvate. The pentose-phosphate pathway (PPP) provides ribose for the backbone of RNA and DNA molecules and NADH (nicotinamide adenine dinucleotide) to regulate free radicals produced during mitochondrial ATP synthesis. Lactate can be used for energy production during intense synaptic excitation. Pyruvate enters into the mitochondria and metabolized into acetyl-CoA, which is used in the tricarboxylic acid cycle (TCA) to provide precursors of certain amino acids, such as the excitatory neurotransmitter glutamate, which then can be converted into the inhibitory transmitter GABA (gamma-amino-butyric acid), as well as the reducing agent NADH, which is fed into the oxidative phosphorylation (OXPHOS, electron transport) pathway resulting in the synthesis of ATP (30–36 molecules) by the enzyme ATP synthase.

Taken together, these data provide strong evidence implicating impaired glucose/energy metabolism and mitochondrial function in schizophrenia. Therefore, a therapeutic method that restores appropriate or circumvents impaired energy metabolism may offer a novel approach for the treatment of schizophrenia.

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