Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study

Abstract

Objectives: This study used proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder, and to identify baseline neurochemical predictors of clinical remission.

Method: Adolescents with bipolar disorder who were experiencing a manic or mixed episode (N = 25) were treated with open-label, extended-release divalproex (serum levels 85-125 μg/mL) and underwent (1)H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent (1)H MRS scanning at the same time points. Glutamate (Glu) and glutamate+glutamine (Glx) concentrations were measured in three voxels: anterior cingulate cortex (ACC), left ventrolateral prefrontal cortex (LVLPFC), and right ventrolateral prefrontal cortex (RVLPFC), and were compared between bipolar and healthy subjects. Within the bipolar subjects, Glu and Glx concentrations at baseline and each time point were also compared between remitters and nonremitters after divalproex treatment.

Results: At baseline, no differences in Glu or Glx concentrations between bipolar and healthy subjects were observed. Group (HC vs. BP) by time effects revealed an interaction for Glu in the ACC, and change over time effects for Glx were noted in the ACC in patients with bipolar disorder (increase from day 0 to day 7 and then a decrease from day 7 to day 28) but not in HC. Remitters had significantly lower baseline Glx concentrations in LVLPFC, and in remitters the change in LVLPFC Glu correlated with the change in YMRS score.

Conclusions: Successful treatment of mania with divalproex may be predicted by lower baseline concentrations of Glx in the LVLPFC. In addition, in remitters, the degree of symptomatic improvement is related to the change in Glu concentrations in this region, suggesting that divalproex may work via modulation of the prefrontal glutamatergic system in youth with bipolar disorder.

Figure 1

Placement of proton magnetic resonance spectroscopy (¹H MRS) voxel for anterior cingulate (A) and left (B) and right (C) ventrolateral prefrontal cortex. Note: In addition, a representative spectrum (anterior cingulate cortex [ACC] in a healthy subject) and its Linear Combination (LC) Model fitting output are shown (D).

Figure 2

Mean Young Mania Rating Scale (YMRS) scores significantly improved from baseline (F(2,42.1)=12.6, p<0.001) over the course of 28 days of treatment with extended release divalproex in bipolar adolescents experiencing an acute manic or mixed episode. Note: However, in these patients, Children's Depression Rating Scale - Revised (CDRS-R) did not significantly change over the course of treatment (F(2,40.7)=2.1, p=0.1). Error bars represent standard deviations.

Figure 3

Left ventrolateral prefrontal cortex (LVLPFC) concentrations of glutamate/glutamine (Glx) were significantly lower in patients who experienced remission (p<0.005) and no patient with a LVLPFC Glx concentration >6.7 mM was classified as a remitter. Note: Horizontal bars represent the means for both groups.