Brain lactate and pH in schizophrenia and bipolar disorder: a systematic review of findings from magnetic resonance studies

Abstract

Converging evidence from molecular to neuroimaging studies suggests brain energy metabolism abnormalities in both schizophrenia and bipolar disorder. One emerging hypothesis is: decreased oxidative phosphorylation leading to accumulation of lactic acid from glycolysis and subsequent acidification of tissue. In this regard, integrating lactate and pH data from magnetic resonance spectroscopy (MRS) studies in both diseases may help us understand underlying neurobiological mechanisms. In order to achieve this goal, we performed a systematic search of case-control studies examining brain lactate or pH among schizophrenia and/or bipolar patients by using MRS. Medline/Pubmed and EBSCO databases were searched separately for both diseases and outcomes. Our search yielded 33 studies in total composed of 7 lactate and 26 pH studies. In bipolar disorder, 5 out of 6 studies have found elevated lactate levels especially in the cingulate cortex and 4 out of 13 studies reported reduced pH in the frontal lobe. In contrast, in schizophrenia a single study has examined lactate and reported elevation, while only 2 out of 13 studies examining pH have reported reduction in this measure. There were no consistent patterns for the relationship between lactate or pH levels and medication use, disease type, mood state, and other clinical variables. We highlight the need for future studies combining ¹H-MRS and ³¹P-MRS approaches, using longitudinal designs to examine lactate and pH in disease progression across both schizophrenia and bipolar disorders.

Fig. 1

Schematic view of astrocyte and neuron glucose metabolism and consequences of reduced oxidative phosphorylation. a Schematic representation of astrocyte and neuron glucose metabolism. Neurons and astrocytes can take up glucose from the circulation. This glucose enters glycolysis pathway and produces pyruvate, which is subsequently converted to either lactate or water and CO2 together with 38 ATP by oxidative phosphorylation within the mitochondria. The lactate produced within astrocytes can also shuttle to neurons through transporters and can be used as an energy substrate following its conversion to pyruvate within the cytoplasm of neurons. This pyruvate is a substrate for oxidative phosphorylation taking part within mitochondria. b The relationship between reduced oxidative phosphorylation and lactate production, pH decrease. Reduced oxidative phosphorylation leads to a shift into glycolysis. Glycolysis results in increased production of lactate, which causes acidification of tissue and decrease in intracellular pH

Fig. 2

PRISMA flow chart showing study selection process. This flow chart shows study selection process including identification, screening, eligibility, and inclusion steps