Bimodal effect of lithium plasma levels on hippocampal glutamate concentrations in bipolar II depression: a pilot study

Marcus V Zanetti; Maria C Otaduy; Rafael T de Sousa; Wagner F Gattaz; Geraldo F Busatto; Claudia C Leite; Rodrigo Machado-Vieira

doi:10.1093/ijnp/pyu058

Bimodal effect of lithium plasma levels on hippocampal glutamate concentrations in bipolar II depression: a pilot study

Int J Neuropsychopharmacol. 2014 Oct 31;18(6):pyu058. doi: 10.1093/ijnp/pyu058.

Authors

Marcus V Zanetti¹, Maria C Otaduy², Rafael T de Sousa², Wagner F Gattaz², Geraldo F Busatto², Claudia C Leite², Rodrigo Machado-Vieira²

Affiliations

¹ Mood Disorders Program, Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Brazil (Drs Zanetti, de Sousa, Gattaz, and Machado-Vieira); Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil (Drs Zanetti, Gattaz, Busatto, and Machado-Vieira); Laboratory of Psychiatric Neuroimaging, LIM-21, Department and Institute of Psychiatry, University of Sao Paulo, Brazil (Drs Zanetti and Busatto); Department of Radiology, University of Sao Paulo, Brazil (Drs Otaduy and Leite); Experimental Therapeutics and Pathophysiology Branch (ETPB), National Institute of Mental Health, NIH, Bethesda, MD (Dr Machado-Vieira). zanetti.mv@gmail.com.
² Mood Disorders Program, Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Brazil (Drs Zanetti, de Sousa, Gattaz, and Machado-Vieira); Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil (Drs Zanetti, Gattaz, Busatto, and Machado-Vieira); Laboratory of Psychiatric Neuroimaging, LIM-21, Department and Institute of Psychiatry, University of Sao Paulo, Brazil (Drs Zanetti and Busatto); Department of Radiology, University of Sao Paulo, Brazil (Drs Otaduy and Leite); Experimental Therapeutics and Pathophysiology Branch (ETPB), National Institute of Mental Health, NIH, Bethesda, MD (Dr Machado-Vieira).

Abstract

Background: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium.

Methods: Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction.

Results: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (≥ 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time.

Conclusions: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.

Trial registration: ClinicalTrials.gov NCT01919892.

Keywords: bipolar disorder; depression; glutamate; hippocampus; lithium; magnetic resonance spectroscopy.

Publication types

Controlled Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Affect / drug effects
Antimanic Agents / blood
Antimanic Agents / therapeutic use*
Bipolar Disorder / blood
Bipolar Disorder / diagnosis
Bipolar Disorder / drug therapy*
Bipolar Disorder / psychology
Brazil
Drug Monitoring
Female
Glutamic Acid / drug effects*
Hippocampus / drug effects*
Hippocampus / metabolism
Humans
Lithium Compounds / blood
Lithium Compounds / therapeutic use*
Male
Pilot Projects
Proton Magnetic Resonance Spectroscopy
Time Factors
Treatment Outcome
Young Adult

Substances

Antimanic Agents
Lithium Compounds
Glutamic Acid

Associated data

ClinicalTrials.gov/NCT01919892