Metabolic shifts, a consequence of hyperosmolarity, are a hallmark of mental disorders

Abstract

Mental and neurodevelopmental disorders are heterogeneous, complex, and overlapping entities. Despite progress, their neurobiological underpinnings are not well understood, and current treatments have limited efficacy. However, a growing number of studies have shown impaired brain and systemic energy metabolism evidenced by low-grade inflammation, metabolic syndrome, mitochondrial dysfunction, and abnormal glucose utilization, although their underlying mechanisms remain poorly understood. This paper reviews metabolic shifts in mental disorders, examines the underlying mechanisms driving these metabolic abnormalities in patient subgroups, and explores targeted therapeutic strategies. We argue here that this inflammation results in hyperosmolarity because of increased protein concentration in the extracellular fluid, resulting from vascular leakages. Hyperosmolarity exerts pressure on the capillaries resulting in altered blood flow (hypoperfusion and/or hyper perfusion). Another consequence of hyperosmolarity is metabolic shifts such as aerobic glycolysis. Hyperosmolarity is also responsible for releasing neurotransmitters such as serotonin, dopamine, glutamate, or gamma-aminobutyric acid (GABA). Drugs known to interfere with metabolism such as methylene blue and lipoic acid have been found to have antidepressant, anxiolytic, and neuroprotective effects (both in animals and in humans) in a large array of mental disorders. We suggest that metabolic shifts are a hallmark of mental disorders and that treatments aiming to alleviate these metabolic shifts may improve patients' prognoses. Mechanisms-based treatments should be tested in future clinical trials, where subgroups of patients characterized as having the most profoundly impaired metabolism should be included, following the rules of precision psychiatry.