Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole

Abstract

Glutamatergic abnormalities may underlie bipolar disorder (BD). The glutamate-modulating drug riluzole may be efficacious in bipolar depression, but few in vivo studies have examined its effect on glutamatergic neurotransmission. We conducted an exploratory study of the effect of riluzole on brain glutamine/glutamate (Gln/Glu) ratios and levels of N-acetylaspartate (NAA). We administered open-label riluzole 100-200 mg daily for 6 weeks to 14 patients with bipolar depression and obtained imaging data from 8-cm(3) voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) at baseline, day 2, and week 6 of treatment, using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 T. Imaging data were analyzed using the spectral-fitting package, LCModel; statistical analysis used random effects mixed models. Riluzole significantly reduced Hamilton Depression Rating Scale (HAM-D) scores (d=3.4; p<0.001). Gln/Glu ratios increased significantly by day 2 of riluzole treatment (Cohen's d=1.2; p=0.023). NAA levels increased significantly from baseline to week 6 (d=1.2; p=0.035). Reduction in HAM-D scores was positively associated with increases in NAA from baseline to week 6 in the ACC (d=1.4; p=0.053), but was negatively associated in the POC (d=9.6; p<0.001). Riluzole seems to rapidly increase Gln/Glu ratios-suggesting increased glutamate-glutamine cycling, which may subsequently enhance neuronal plasticity and reduce depressive symptoms. Further investigation of the Gln/Glu ratio as a possible early biomarker of response to glutamate-modulating therapies is warranted.

Figure 1

Parasagittal (top) and axial (bottom) views of the brain from T1-weighted images illustrate the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) voxel placement in one subject.

Figure 2

(a) Contour plots of real 2D spectra from the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) in one subject. In each case, the X axis is frequency (f2 in p.p.m.) and the Y axis is J (f1 in Hz). The spectral region from approximately −40 to +40 Hz is shown. The main metabolite resonances recognizable in the plots are labeled. Although myo-inositol (mI) and glutamine (Gln) resonances are not well resolved in these plots, the additional information available from 2D MRS allows improved fitting of these metabolites. Cho, choline; Cr, creatine; Glu, glutamate, GSH, glutathione; H₂O, water; MMs, macromolecules; NAA, N-acetylaspartate. (b) Sample 1D spectra extracted from the same 2D data sets at J=0.0 Hz. Raw data are visible as a black line and the LCModel spectral fit is in red, with the residual shown in the top panel. Metabolite resonances identifiable in this spectral extraction are labeled; it must be noted that glutamine (Gln) resonances are not apparent at J=0.0 Hz. Cho, choline; Cr, creatine; Glu, glutamate; mI, myo-inositol; NAA, N-acetylaspartate. The color reproduction of this figure is available on the html full text version of the manuscript.

Figure 3

The mean scores on the Hamilton Depression Rating Scale (HAM-D) over 6 weeks of riluzole treatment. Error bars represent 95% confidence interval.

Figure 4

The glutamine/glutamate (Gln/Glu) ratio in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) as measured by J-resolved proton magnetic resonance spectroscopy (¹H-MRS) at baseline, day 2 of riluzole treatment, and week 6 of riluzole treatment. Dashed line shows the mean Gln/Glu ratio in combined ACC and POC as measured by ¹H-MRS at baseline, day 2 of riluzole treatment, and week 6 of riluzole treatment. Error bars represent 95% confidence interval.

Figure 5

The N-acetylaspartate (NAA) level in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) as measured by J-resolved proton magnetic resonance spectroscopy (¹H-MRS) at baseline, day 2 of riluzole treatment, and week 6 of riluzole treatment. Dashed line shows mean NAA level in combined ACC and POC as measured by ¹H-MRS at baseline, day 2 of riluzole treatment, and week 6 of riluzole treatment. NAA levels are represented in arbitrary units (AU). Error bars represent 95% confidence interval.

Figure 6

Scatter plot for change in N-acetylaspartate (NAA) in the anterior cingulate cortex (ACC) vs change in Hamilton Depression Rating Scale (HAM-D) from baseline to week 6 of riluzole treatment. Change in NAA is represented in arbitrary units (AU). It must be noted that this figure has one less data point than does Figure 7 because of technically unevaluable data in the ACC for one subject.

Figure 7

Scatter plot for change in N-acetylaspartate (NAA) in the parieto-occipital cortex (POC) vs change in Hamilton Depression Rating Scale (HAM-D) from baseline to week 6 of riluzole treatment. Change in NAA is represented in arbitrary units (AU).