The metabolic overdrive hypothesis proposes that mania in bipolar disorder is linked to heightened cerebral energy metabolism through hyperglycolysis and glutaminolysis. Evidence from chronobiology, metabolomics, and magnetic resonance spectroscopy suggests that energy dysregulation is central to bipolar disorder pathophysiology. During mania, impaired oxidative glucose metabolism leads neurons to use glutamate as an alternative energy source via oxidative phosphorylation. Astrocytes produce glutamate through glycolysis, which is then used by neurons to replenish the tricarboxylic acid (TCA) cycle intermediates. This process results in increased brain metabolism and excitatory activity, which underlie the subjective experience of mania. While this mechanism is adaptive under normal conditions, chronic activation may become pathological. The paper discusses the role of insulin signaling, mitochondrial dysfunction, and metabolic pathways in bipolar disorder. It also explores the link between hyperglycolysis, glutamate metabolism, and mania, citing evidence from other conditions like epilepsy and traumatic brain injury. The study highlights the potential of ketone bodies, such as beta-hydroxybutyrate, as alternative energy substrates that may help restore oxidative phosphorylation and reduce the need for glutamate as an energy source. The paper concludes that understanding these metabolic processes could provide new insights into the biological basis of mania and inform potential treatments.The metabolic overdrive hypothesis proposes that mania in bipolar disorder is linked to heightened cerebral energy metabolism through hyperglycolysis and glutaminolysis. Evidence from chronobiology, metabolomics, and magnetic resonance spectroscopy suggests that energy dysregulation is central to bipolar disorder pathophysiology. During mania, impaired oxidative glucose metabolism leads neurons to use glutamate as an alternative energy source via oxidative phosphorylation. Astrocytes produce glutamate through glycolysis, which is then used by neurons to replenish the tricarboxylic acid (TCA) cycle intermediates. This process results in increased brain metabolism and excitatory activity, which underlie the subjective experience of mania. While this mechanism is adaptive under normal conditions, chronic activation may become pathological. The paper discusses the role of insulin signaling, mitochondrial dysfunction, and metabolic pathways in bipolar disorder. It also explores the link between hyperglycolysis, glutamate metabolism, and mania, citing evidence from other conditions like epilepsy and traumatic brain injury. The study highlights the potential of ketone bodies, such as beta-hydroxybutyrate, as alternative energy substrates that may help restore oxidative phosphorylation and reduce the need for glutamate as an energy source. The paper concludes that understanding these metabolic processes could provide new insights into the biological basis of mania and inform potential treatments.