There is ample evidence that glucose metabolism as assessed by 18F FDG PET in the pregenual anterior cingulate cortex (PACC) is increased in major depressive disorder (MDD) (1). Elevated cerebrospinal fluid (CSF) lactate concentrations in MDD patients might indicate that increased glycolytical metabolization of glucose to lactate either alone or in conjunction with mitochondrial dysfunction results in an accumulation of lactate and contribute to pathophysiological mechanisms of MDD. However, until now, no study investigated PACC glucose and lactate levels in MDD in vivo. In this work, J-resolved proton magnetic resonance spectroscopy (1H-MRS) was therefore used to test whether patients with MDD have increased PACC glucose and lactate levels.In 20 patients with major depression (MD) and 20 age and sex matched healthy controls spectra were acquired from the PACC using a maximum echo JPRESS protocol (2) at 3T (Achieva, Philips Healthcare, Best, The Netherlands) (Figure 1) with a minimum echo time of TE=28 ms and a repetition time of TR=1600 ms. The echo increment to encode the indirect dimension was set to 2 ms. 100 steps were acquired obtaining 8 averages per TE. After zero and first order phase correction and visual artifact inspection (ghosting, bad water suppression, line shape distortions) data were quantified using Profit 2.0 (3). Based on the high-resolution 3D T1 weighted images the fraction of cerebral spinal fluid (CSF), grey matter (GM) and white matter (WM) were calculated using SPM8 and a custom written MATLAB script. The metabolite concentrations normalized to internal creatine were corrected for differences in volume tissue composition as previously reported (4, 5). All metabolite concentrations regardless of the Cramer-Rao Lower Bound (CRLB) value were included in the statistic (no CRLB threshold was used) with the exception of infinitely high CRLB values (in case a metabolite could not be fitted in a data set) to avoid bias towards higher concentrations (6).Data from one patient with comorbid diabetes was excluded from the analysis because chronic hyperglycemia might result in elevated brain glucose levels (7). In addition, two patient spectra had to be excluded because of insufficient data quality. The resulting groups consisted of 17 subjects with depression (mean age, 31.7 years; 10 females) and 20 control subjects (mean age, 28.1 years; 11 females). Data from 5 depressive and 7 healthy subjects were excluded from the glucose analysis and data from 3 depressive subjects were excluded from the lactate analysis because of infinitely high CRLB values. Results show significant increases of glucose and lactate in patients (Figure 2), which are also associated with depression severity (Figure 3). There was a significant positive correlation of symptom severity with glucose (r= .41, p = .038) and a trend for a correlation with lactate (r= .33, p = .051) concentrations (Figure 4).Our findings indicate impaired brain energy metabolism in MDD with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate. The here reported increases in glucose concentration in PACC are consistent with the increased glucose metabolism as measured by FDG PET in this area in depressive patients (1,8). The increased glucose concentration we report here in the PACC may therefore reflect heightened glucose supply to this region due to increased cerebral blood flow (CBF) (8). Targeting these metabolic disturbances may affect the balance of metabolic pathways regulating neuronal energetics and may result in an attenuation of the elevated basal activity of brain regions within the neural circuitry of depression.