Lactate: A Theranostic Biomarker for Metabolic Psychiatry?

Abstract

Alterations in neurometabolism and mitochondria are implicated in the pathophysiology of psychiatric conditions such as mood disorders and schizophrenia. Thus, developing objective biomarkers related to brain mitochondrial function is crucial for the development of interventions, such as central nervous system penetrating agents that target brain health. Lactate, a major circulatory fuel source that can be produced and utilized by the brain and body, is presented as a theranostic biomarker for neurometabolic dysfunction in psychiatric conditions. This concept is based on three key properties of lactate that make it an intriguing metabolic intermediate with implications for this field: Firstly, the lactate response to various stimuli, including physiological or psychological stress, represents a quantifiable and dynamic marker that reflects metabolic and mitochondrial health. Second, lactate concentration in the brain is tightly regulated according to the sleep-wake cycle, the dysregulation of which is implicated in both metabolic and mood disorders. Third, lactate universally integrates arousal behaviours, pH, cellular metabolism, redox states, oxidative stress, and inflammation, and can signal and encode this information via intra- and extracellular pathways in the brain. In this review, we expand on the above properties of lactate and discuss the methodological developments and rationale for the use of functional magnetic resonance spectroscopy for in vivo monitoring of brain lactate. We conclude that accurate and dynamic assessment of brain lactate responses might contribute to the development of novel and personalized therapies that improve mitochondrial health in psychiatric disorders and other conditions associated with neurometabolic dysfunction.

Keywords: brain; imaging; lactate; metabolic psychiatry; mitochondria; neurometabolism; redox.

Figure 1

The implication of altered metabolic health on the molecular, intracellular, tissue level, and neurobehavioural effects of lactate in the brain. Metabolic syndrome (MS) is associated with mitochondrial dysfunction and impaired lactate oxidation. (A) In response to incremental exercise testing, participants with MS generate more circulating lactate at lower power outputs compared to individuals who do not have MS. Trained athletes who are metabolically fit can produce relatively less lactate at higher outputs. (B) In response to visual stimulus, participants with panic disorder produce more lactate in the visual cortex compared to a healthy control group. (C) In response to a personalized exercise prescription applied over 12 months, pre-type 2 diabetes was reversed, and the lactate response to incremental physical exercise was improved to reflect an improvement in mitochondrial function. Elevated concentrations of circulating or brain lactate can have effects on the brain, signalling at the molecular, cellular, tissue, and brain nuclei level to influence behaviour which map onto Research Domain Criteria (RDoC) domains. Figure inspired by [65], with graphical data adapted from [3,35,88].

Figure 2

Therapeutic interventions that could influence lactate metabolism in the brain. Lactate concentration can be manipulated using metabolic therapies and subsequent changes measured with functional magnetic resonance spectroscopy (fMRS) in the brain or serum lactate in peripheral circulation (see dotted arrows). The concentration of lactate in the brain is primarily dependent on the rate of production influenced by the rates of glycolysis and glycogenolysis in the brain and body. On the other hand, the rate of lactate consumption relies on brain mitochondria. Mitochondria could be therapeutically manipulated in various ways (see solid arrows), and the outcome of interventions could be measured by observing changes in lactate dynamics.