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Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe and treatment-resistant depression, but its biological mechanisms remain poorly understood. Given the pivotal role of mitochondria in cellular energy metabolism and their proposed involvement in the pathology of depression, we aimed to investigate whether ECT alters mitochondrial metabolism.

Methods: We included 102 patients with major depressive disorder referred for ECT at 7 Swedish hospitals. Fasting serum samples were collected at 3 time points: immediately before the first ECT session (T0), 30 minutes after the first session (T1), and before the sixth session (T2). Proton nuclear magnetic resonance spectroscopy was used to quantify metabolites related to the tricarboxylic acid cycle and amino acid metabolism.

Results: Acutely (T0→T1), serum levels of citrate, glucose, glutamine, and pyruvate increased significantly, while formate and phenylalanine decreased. Across the treatment course (T0→T2), alanine and pyruvate levels increased, whereas the ketone bodies acetoacetate, acetone, and 3-hydroxybutyrate decreased significantly. An exploratory analysis indicated that the reduction in ketone bodies (T0→T2) was confined to patients showing clinical improvement, as defined by the Clinical Global Impressions-Improvement scale.

Conclusions: ECT induces both acute and sustained alterations in mitochondrial energy metabolism. These findings suggest that ECT modulates systemic mitochondrial function, warranting further investigation into how these metabolic changes relate to clinical improvement.