Brain Metabolic Alterations in Medication-Free Patients With Bipolar Disorder

Background Bipolar disorder (BD) has substantial morbidity and incompletely understood neurobiological underpinnings. Objective To investigate brain chemistry in medication-free individuals with BD. Design Two-dimensional proton echo-planar spectroscopic imaging (PEPSI) (32 × 32, 1-cm 3 voxel matrix) acquired axially through the cingulate gyrus was used to quantify regional brain chemistry. Setting The Center for Anxiety and Depression at the University of Washington in Seattle and the Bipolar Research Programs at McLean Hospital and the Massachusetts General Hospital in Boston. Participants Thirty-two medication-free outpatients with a diagnosis of BD type I (BDI) or BD type II (BDII), predominantly in a depressed or mixed-mood state, were compared with 26 age- and sex-matched healthy controls. Main Outcome Measures Tissue type (white and gray) and regional analyses were performed to evaluate distribution of lactate; glutamate, glutamine, and γ-aminobutyric acid (Glx); creatine and phosphocreatine (Cre); choline-containing compounds (Cho); N -acetyl aspartate; and myo -inositol. Chemical relationships for diagnosis and mood state were evaluated. Results Patients with BD exhibited elevated gray matter lactate ( P = .005) and Glx ( P = .007) levels; other gray and white matter chemical measures were not significantly different between diagnostic groups. Isolated regional chemical alterations were found. An inverse correlation between 17-item Hamilton Depression Rating Scale scores and white matter Cre levels was observed for BD patients. Conclusions Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions.