Elsevier

Journal of Affective Disorders

Volume 241, 1 December 2018, Pages 192-199
Journal of Affective Disorders

Research paper
Lithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A 1H-MRS study

https://doi.org/10.1016/j.jad.2018.08.039Get rights and content

Highlights

  • Euthymic BD patients exhibited higher NAA and Cho compared to controls;

  • Lithium monotherapy was associated with increased ACC NAA levels compared to controls;

  • Lithium use was associated with decreased ACC myo-inositol levels compared to non-users.

Abstract

Objective

In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (1H-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC.

Methods

129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (1H-MRS) using a PRESS ACC single voxel (8cm3) sequence.

Results

BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy).

Conclusion

The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics.

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 #2012/237962. In addition, this study was partially financed by Conselho

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      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).

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