Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder: A 3-T 1H-MRS Study

Abstract

Objective: Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using proton magnetic resonance spectroscopy (H-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy.

Methods: Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 ± 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome.

Results: Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels.

Conclusions: This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions.

Figure 1

Figure 1A. Axial and sagital view of the two-dimensional matrix acquired by the MRSI sequence. The green line indicates the region selected for magnetic field homogenization purposes. Signal from outside this region was suppressed to avoid contamination. The individual spectra of the voxels in yellow (axial view) were all summed up to study a single ROI placed on the cingulate cortex (yellow ROI on sagital view). Figure 1B. Original spectrum in yellow and fitted line of the Lactate, NAA, Cr and Cho signals in blue.

Figure 1

Figure 1A. Axial and sagital view of the two-dimensional matrix acquired by the MRSI sequence. The green line indicates the region selected for magnetic field homogenization purposes. Signal from outside this region was suppressed to avoid contamination. The individual spectra of the voxels in yellow (axial view) were all summed up to study a single ROI placed on the cingulate cortex (yellow ROI on sagital view). Figure 1B. Original spectrum in yellow and fitted line of the Lactate, NAA, Cr and Cho signals in blue.

Figure 2

Individual changes in brain lactate from baseline (depressive episode) to endpoint (after 6 weeks of lithium (Li) monotherapy in drug-naïve BD). Brain Lactate presented in mmol/L.