Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Abstract

Proton magnetic resonance spectroscopy ( 1 HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline 1 HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR ¼ 30/3000 ms, 3 Â 3 Â 3 cm 3 and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate + glutamine ([Glx]), glutamate ([Glu]), and creatine + phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

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

“…50,51 Our results are also in general agreement with a recent report of increased levels of glutamate in post-mortem frontal cortex samples from patients with bipolar disorder 27 and an 1 H-MRS investigation at 1.5 T that previously reported increased anterior cingulate cortical glutamate in bipolar depression. 52 However, information on antidepressant intake in the latter study is lacking while a subset of patients are reported to have received lithium.…”

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

“…Fifth, we report metabolite levels in AU. We avoided internal referencing to creatine because of recent reports suggesting creatine abnormalities in BD (Frye et al, 2007;Ö ngür et al, 2009a) and internal referencing to water was not possible, lacking usable water unsuppressed spectra in this study. Our approach does not correct for inter-subject sources of variance, but the longitudinal within-subject design of our study and statistical analysis mitigates the problems of variability inherent to many cross-sectional MRS studies.…”

“…Increased Glx levels have been shown in the depressed (Bhagwagar et al, 2007;Frye et al, 2007), manic (Cecil et al, 2002;Michael et al, 2003), and euthymic (Dager et al, 2004) phases of BD, as well as in rapid-cycling BD (Michael et al, 2009). However, the physiological significance of Glx is unclearFunderscoring the need for separate glutamate and glutamine measures.…”

Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden

“…We used absolute metabolite levels instead of ratios with creatine to avoid a bias through systematic drifts in the magnitude of the creatine resonance, as suggested by previous studies. 18,[21][22][23][24] VOI tissue segmentation and total hippocampal volume To control for the effect of potential structural differences in the region studied, we assessed tissue composition within the VOIs and total hippocampal volume as follows. The amount of each tissue -grey matter, white matter and CSF -was quantified for each VOI, so the scans were first separated in the 3 different tissues using SPM8 software (Wellcome Trust Centre for Neuroimaging, www.fil.ion.ucl.ac.uk/spm) running under MATLAB 7.8.0 (MathWorks).…”