Research paperLithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A 1H-MRS study
Section snippets
Background
The neurobiology of bipolar disorder (BD) has not been fully elucidated, although some part of the knowledge about its neurobiology has emerged from studies on lithium's mechanism of action as a first-line mood stabilizer (Yatham et al., 2013). Modern neuroimaging techniques, such as proton magnetic resonance spectroscopy (1H-MRS), allow in vivo measurement of three non-glutamatergic brain metabolites implicated in both the neurobiology of BD and lithium´s mechanisms of action:
Study aims
The aims of this study were to investigate the association of lithium use in BD type I (specifically during euthymia state) and levels of NAA, mI and Cho in the ACC, thereby exploring the mechanisms that can modulate mood. To better investigate the influence of medications and the impact of BD on metabolite levels, 79 healthy subjects (HC) who were medication free and had no family history of psychiatric disorders were also included in this study.
Material and methods
One hundred and twenty-nine euthymic BD I subjects were included in the study. The inclusion criteria for patients in this study were: age range between 18–45 years old, diagnosis of BD type I, no medication change and being in euthymia for the past 2 months, Young Mania Rating Scale (YMRS) (Young et al., 1978) and Hamilton Depression Rating Scale (HDRS-21) (Hamilton, 1967) < 8 points and fulfilling DSM-IV (DSM-IV, 2000) criteria of remission at the time of the scan. Subjects or patients with
Results
The sample comprised one hundred and twenty-nine (85 females, 65.8%) euthymic BD type I patients and seventy-nine (41 females, 51.8%) HC. The BD group had higher (p = 0.006) mean age (32 years, SD 9.5) compared to the HC group (28.4 years, SD 8.1). Regarding medication use: 31.7% were using anticonvulsants, 72% were using lithium and 36.4% were using second-generation antipsychotics (detailed information given in Table 1)
The segmentation analysis for the ACC voxel of interest revealed that the
Discussion
To the best of our knowledge, this is the largest 1H-MRS study conducted to date investigating the impact of mood stabilizers on ACC brain metabolites in BD type I during euthymia. Elevated ACC NAA and Cho levels were found in the BD group compared to the HC group. Also, the results revealed that lithium use among BD subjects was associated with higher NAA levels and decreased mI levels.
NAA, a metabolite with putative roles in amino acid metabolism and protein and fatty acid synthesis, was
Author statement
Contributors: Marcio Gerhardt Soeiro-de-Souza, Maria Concepcion Garcia Otaduy, Rodrigo Machado-Vieira, Ricardo Alberto Moreno, Fabiano G. Nery, Claudia Leite, Beny Lafer
We would like to thank the healthy volunteers that participated in this study and the team of professionals that work at the Institute of Psychiatry (IPq) Hospital das Clínicas, São Paulo. Furthermore we declare that The Research Ethics Board of the Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo
Conflict of interests
This study was funded by São Paulo Research Foundation (FAPESP) grants #2005–56,464–9 and #2012/23,796–2. In addition, this study was partially financed by Conselho Nacional de Pesquisa (CNPq) grant #478,466/2009. The authors have no other financial disclosure to report.
Acknowledgments
We would like to thank the healthy volunteers that participated in this study and the team of professionals that work at the Institute of Psychiatry (IPq) Hospital das Clínicas, São Paulo. The English language in this manuscript was revised by Andrew Clifford Davis ([email protected]).
Funding and Financial Disclosure
This study was funded by São Paulo Research Foundation (FAPESP) grants #2005-56464-9 and #2012/23796–2. In addition, this study was partially financed by Conselho
References (90)
- et al.
Increased brain myo-inositol 1-phosphate in lithium-treated rats
Biochem. Biophys. Res. Commun.
(1976) - et al.
Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors
Neurosci. Biobehav. Rev.
(2011) - et al.
Brain proton magnetic resonance spectroscopy: introduction and overview
Neuroimaging Clin. N. Am.
(2013) - et al.
1H magnetic resonance spectroscopy investigation of the dorsolateral prefrontal cortex in bipolar disorder patients
J. Affect. Disord.
(2005) - et al.
Decreased N-acetylaspartate in children with familial bipolar disorder
Biol. Psychiatry
(2003) - et al.
In vivo quantification of brain metabolites by 1H-MRS using water as an internal standard
Magn. Reson. Imaging
(1993) - et al.
Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder
Neuropsychopharmacol.
(2001) - et al.
NMR chemistry analysis of red blood cell constituents in normal subjects and lithium-treated psychiatric patients
Biol. Psychiatry
(1985) - et al.
Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder
Psychiatry Res.
(2015) - et al.
Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder
Biol. Psychiatry
(2004)
FSL
Neuroimage
Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia
Psychiatry Res.
Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder
Psychiatry Res.
Measurement of brain phosphoinositide metabolism in bipolar patients using in vivo 31P-MRS
J Affect Disord.
Alterations in brain phosphorous metabolism in bipolar disorder detected by in vivo 31P and 7Li magnetic resonance spectroscopy
J. Affect. Disord.
Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy
J. Affect Disord.
Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy
J. Affect Disord.
Neurometabolites in schizophrenia and bipolar disorder - a systematic review and meta-analysis
Psychiatry Res.
A Longitudinal (6-week) 3T (1)H-MRS Study on the Effects of Lithium Treatment on Anterior Cingulate Cortex Metabolites in Bipolar Depression
Eur. Neuropsychopharmacol.
A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness
Prog. Neuropsychopharmacol. Biol. Psychiatry
N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology
Prog. Neurobiol.
Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2′s neurotrophic effects?
Biol. Psychiatry
Inositol-1-phosphatase in red blood cells of manic-depressive patients before and during treatment with lithium
Biol. Psychiatry
Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania
Biol. Psychiatry
Increased gray matter volume in lithium-treated bipolar disorder patients
Neurosci. Lett.
Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla
Neuroimage
Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients
Schizophr. Res.
Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder
Eur. Neuropsychopharmacol.
Erythrocyte choline concentrations in psychiatric disorders
Biol. Psychiatry
Proton magnetic resonance spectroscopy changes after lithium treatment. Systematic review
Psychiatry Res. Neuroimaging
Lithium prophylaxis inhibits choline transport in post-mortem brain
Lancet
Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder
Biol. Psychiatry
31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis
Psychiatry Res.
Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders
Biol. Psychiatry
Similarities of biochemical abnormalities between major depressive disorder and bipolar depression: a proton magnetic resonance spectroscopy study
J. Affect Disord.
A 1HMRS study of the anterior cingulate gyrus in euthymic bipolar patients
Hum Psychopharmacol.
Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder
Arch. Gen. Psychiatry
The Albert Lasker Medical Awards. Inositol trisphosphate, calcium, lithium, and cell signaling
JAMA
Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands
Biochem. J.
Lithium-induced increases in red blood cell choline and memory performance in Alzheimer-type dementia
Biol. Psychiatry
Elevated Choline-Containing Compound Levels in Rapid Cycling Bipolar Disorder
Neuropsychopharmacol.
Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy
Bipolar Disord.
T2 measurement and quantification of glutamate in human brain in vivo
Magn. Reson. Med.
Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol
Mol. Psychiatry
Brain metabolic alterations in medication-free patients with bipolar disorder
Arch. Gen. Psychiatry
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2022, Psychiatry Research - NeuroimagingCitation Excerpt :An effect of age was reported with lower mI levels in BD older than 40 years old compared to controls in the left frontal and right parietal WM whereas in gray matter mI was lower in patients younger than 40 years of age compared to controls in the medial parietal region (Bustillo et al., 2019). Reduced concentrations have been reported both in patients taking lithium (Soeiro-de-Souza et al., 2018) and irrespective of lithium treatment (Atagun et al., 2018). Higher levels of mI have, instead, been reported in children with BD compared to controls (Davanzo et al., 2003) and in adolescents who did not respond to lithium treatment compared to responders (Patel et al., 2006).
Anterior cingulate cortex neuro-metabolic changes underlying lithium-induced euthymia in bipolar depression: A longitudinal <sup>1</sup>H-MRS study
2021, European NeuropsychopharmacologyCitation Excerpt :Therefore, we might speculate that in individuals with current BDep, increased Cho/Cr and mI/Cr could be an indication of neuronal damage, possibly due to increased oxidative stress, inflammation and cellular energy dysfunction (Berk et al., 2011; Maes et al., 2011). Moreover, increased Cho/Cr has also been reported in unipolar depression and during euthymia in BD type I subjects (Soeiro de Souza et al., 2018), indicating this might be a common finding of unipolar and BD (Ende et al., 2006). After lithium treatment, some ACC neurometabolites changes were found to be associated with better clinical response.
Altered brain creatine cycle metabolites in bipolar I disorder with childhood abuse: A <sup>1</sup>H magnetic resonance spectroscopy study
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Participants were recruited over the past 15 years by two research sites (PROMAN and PROGRUDA) specialized in BD from the Institute of Psychiatry of the University of São Paulo. This sample is part of two larger studies published by our group (Soeiro de Souza et al., 2018a; Soeiro de Souza et al., 2018b). None of the participants received any financial incentives.
Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of <sup>1</sup>H-MRS studies
2021, European NeuropsychopharmacologyCitation Excerpt :Similalry, no between-group was recorded in the medicated sub-group regarding NAA (Supplementary Material, Fig. S 4C). However, some studies provided evidence of increased levels of NAA in euthymic subjects on lithium (Soeiro-de-Souza et al., 2018b) and after anticonvulsant treatment (Croarkin et al., 2015). Sixteen studies evaluated Cho in the ACC (Table 1), comprising 982 subjects (538 BD and 444 HC).
Effects of infliximab on brain neurochemistry of adults with bipolar depression
2021, Journal of Affective DisordersCitation Excerpt :Previous studies have investigated the effects of different modalities of pharmacological treatments on NAA levels in BD. Lithium was the first agent to be associated with increases in NAA due to its potential neurotrophic and neuroprotective effects (Moore et al., 2000), and this has since been supported by replicated evidence (Brambilla et al., 2005; Silverstone et al., 2003; Soeiro-de-Souza et al., 2018), including findings from lithium clinics, which controlled for duration, dosage and compliance with lithium treatment (Hajek et al., 2012). Two studies with olanzapine and quetiapine failed to detect an effect (Chang et al., 2012; DelBello et al., 2006), whereas two smaller, pilot trials with galantamine, a cholinesterase inhibitor, and lovastatin, a statin, documented increases in NAA concentrations in the hippocampus and cingulate gyrus, respectively (Iosifescu et al., 2009; Lotfi et al., 2017).