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

Machado-Vieira, Rodrigo MD, PhD; Zanetti, Marcus V. MD, PhD; Otaduy, Maria C. PhD; De Sousa, Rafael T. MD, PhD; Soeiro-de-Souza, Marcio G. MD, PhD; Costa, Alana C.; Carvalho, Andre F. MD, PhD; Leite, Claudia C. PhD; Busatto, Geraldo F. MD, PhD; Zarate, Carlos A. Jr MD; Gattaz, Wagner F. MD, PhD

Journal of Clinical Psychopharmacology: February 2017 - Volume 37 - Issue 1 - p 40–45
doi: 10.1097/JCP.0000000000000616
Original Contributions

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 3-T 1H-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 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 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.

From the *Laboratory of Neuroscience (LIM-27), Institute and Department of Psychiatry, University of São Paulo; †Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil; ‡Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD; and §Laboratory of Magnetic Resonance in Neuroradiology (LIM-44), Institute and Department of Radiology, University of São Paulo, São Paulo; ‖Department of Clinical Medicine and Translational Psychiatry Research Group Faculty of Medicine, Federal University of Ceara, Fortaleza; and ¶Laboratory of Psychiatric Neuroimaging (LIM-21), Institute and Department of Psychiatry, University of São Paulo, São Paulo, Brazil.

Received February 29, 2016; accepted after revision October 11, 2016.

Reprints: Rodrigo Machado-Vieira, MD, PhD, National Institute of Mental Health, National Institute of Health, 10 Center Dr, Clinical Center, Unit 7SE, Rm. 7-5341, Bethesda, MD (e-mail:;

This study was sponsored by São Paulo Research Foundation (FAPESP, Brazil, 2009/14891-9, RM-V). The Laboratory of Neuroscience (LIM-27) is also supported by the Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS) and JNK Empreendimentos e Incorporações.

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