The paper proposes that mania in bipolar disorder is characterized by heightened cerebral energy metabolism, facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism is impaired, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Astrocytes produce denovo glutamate, which can be converted to alpha-ketoglutarate and then to glutamine, providing a mitochondrial fuel source for neurons. This upregulation of glycolysis and glutaminolysis leads to a state of heightened metabolism and excitatory activity, underlying the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, in bipolar disorder, it may become a pathological process due to chronic impairment of oxidative metabolism. The paper discusses evidence from various areas of research, including chronobiology, metabolomics, and magnetic resonance spectroscopy, supporting these metabolic features of bipolar disorder. It also explores the potential of ketone bodies as an alternative energy substrate to glucose, which may restore oxidative phosphorylation and mitigate the need for glutamate as an alternative energy source, thereby preventing manic episodes. The hypothesis suggests that future research should investigate markers of hyperglycolysis and glutaminolysis during states of mania and euthymia in bipolar disorder using magnetic resonance spectroscopy (MRS).The paper proposes that mania in bipolar disorder is characterized by heightened cerebral energy metabolism, facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism is impaired, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Astrocytes produce denovo glutamate, which can be converted to alpha-ketoglutarate and then to glutamine, providing a mitochondrial fuel source for neurons. This upregulation of glycolysis and glutaminolysis leads to a state of heightened metabolism and excitatory activity, underlying the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, in bipolar disorder, it may become a pathological process due to chronic impairment of oxidative metabolism. The paper discusses evidence from various areas of research, including chronobiology, metabolomics, and magnetic resonance spectroscopy, supporting these metabolic features of bipolar disorder. It also explores the potential of ketone bodies as an alternative energy substrate to glucose, which may restore oxidative phosphorylation and mitigate the need for glutamate as an alternative energy source, thereby preventing manic episodes. The hypothesis suggests that future research should investigate markers of hyperglycolysis and glutaminolysis during states of mania and euthymia in bipolar disorder using magnetic resonance spectroscopy (MRS).