Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder

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 (1H-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 1H-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3T 1H-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. The association between brain lactate with mitochondrial activity and antidepressant efficacy were also assessed. Methods Twenty medication-free outpatients with short length of illness BD (80% drug-naive) in a current major depressive episode were matched with healthy controls. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood levels 0.48±0.19mmL). CC lactate was measured before (week 0) and after lithium therapy (week 6) using 1H-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 healthy controls. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared to baseline (p=0.002). No association between reduction in CC lactate levels over time and remission at week 6 was observed. 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. Clinical trial number NCT01919892

Lactate in bipolar disorder: A systematic review and meta‐analysis

“…proposed that the correlation between glutathione and lactate in BD patients indicated a greater level of compensatory response to mitochondrial dysfunction . In contrast to the study by Machado‐Vieira et al ., the BD patients in the Soeiro‐de‐Souza et al . study were on stable medication regimens .…”

“…A recent MRS study by Machado‐Vieira et al . assessed lactate levels in the cingulate cortex of BD depressed patients (80% drug‐naïve [ n = 16], and 20% drug‐free [ n = 4] for 6 months) and 16 non‐psychiatric HC and found significantly higher lactate levels ( P = 0.04) in BD patients ( n = 20) compared to HC . In the same study, Machado‐Vieira et al .…”

“…In the same study, Machado‐Vieira et al . also compared the cingulate cortex lactate levels pre‐ and post‐lithium treatment (6 weeks) . Cingulate cortex lactate was significantly lower ( P = 0.002) post‐lithium treatment, and there was no difference compared to the cingulate cortex lactate in HC .…”

“…Of the six studies included in our meta‐analysis on brain lactate levels, five reported increased lactate levels in BD, while one study reported similar and decreased lactate levels for manic and euthymic BD patients, respectively. Interestingly, studies by Machado‐Vieira et al . and Friedman et al .…”

“…A shift from aerobic to anaerobic energy metabolism causes metabolite levels to shift, including lactate . This abnormality is worth noting as lactate is a direct marker for mitochondrial dysfunction and a biomarker used to evaluate a patient's response to treatment . Interestingly, previous literature has shown that lactate is altered in the brain and cerebrospinal fluid (CSF) in patients with BD .…”