title: Bimodal effect of lithium plasma levels on hippocampal glutamate concentrations in bipolar II depression: a pilot study.
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.
authors.affiliation: 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.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Zanetti
authors.affiliation: 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).
authors.forename: Maria C
authors.initials: MC
authors.lastname: Otaduy
authors.affiliation: 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).
authors.forename: Rafael T
authors.initials: RT
authors.lastname: de Sousa
authors.affiliation: 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).
authors.forename: Wagner F
authors.initials: WF
authors.lastname: Gattaz
authors.affiliation: 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).
authors.forename: Geraldo F
authors.initials: GF
authors.lastname: Busatto
authors.affiliation: 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).
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Leite
authors.affiliation: 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).
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
mesh_terms: D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects; D018692:Antimanic Agents / Q000097:blood / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D001938:Brazil; D016903:Drug Monitoring; D005260:Female; D018698:Glutamic Acid / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018020:Lithium Compounds / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D010865:Pilot Projects; D066244:Proton Magnetic Resonance Spectroscopy; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; D018698:Glutamic Acid
keywords: bipolar disorder; depression; glutamate; hippocampus; lithium; magnetic resonance spectroscopy