Bipolar disorder (BPD) is a relatively common psychiatric disorder for which lithium is the gold standard of treatment. Lithium is an inhibitor of the enzyme inositol monophosphatase (IMPase), leading to marked decreases in brain myo-inositol (myo-Ins) levels. Although lithium remains the most effective treatment for bipolar disorder (BPD), tolerance and safety issues complicate its clinical use. The antioxidant drug, ebselen, has been proposed as a possible lithium-mimetic based on its ability in animals to inhibit IMPase and lower brain inositol, actions which it shares with lithium. It has been shown in animals that ebselen administration lowered brain myo-inositol (myo-Ins) levels, consistent with functional inhibition of IMPase (1), and subsequently in a healthy volunteer study it has been shown that three 600mg doses of ebeslen over 24 hours lowered levels of myo-Ins in anterior cingulate cortex but not in occipital cortex, as measured by magnetic resonance spectroscopy (MRS) at 3T (2). The aim of the present study was to replicate this finding using a higher dose of ebselen and at ultra high field strength (7T). MRS at 7T was chosen because of the increase in signal-to-noise ratio (SNR) and spectral resolution, allowing for more precise metabolite quantification as well as a clearer identification of separate glutamate and glutamine resonances as compared to 3T (3).

20 healthy volunteers (18-40 years) were studied in a double-blind, cross-over design with ebselen and placebo in identical capsules. Spectra were measured from two 8ml voxels (Figure 1, one in the frontal and the other in the occipital cortices) at 7T using a whole body MR system (Siemens, Erlangen) with a Nova Medical 32-channel receive array head-coil. Spectra were acquired using a Stimulated Echo Acquisition Mode (STEAM) pulse sequence (TE = 11ms, TR = 5s, number of transients = 64) with variable power radiofrequency pulses with optimized relaxation delays (VAPOR) water suppression and outer volume saturation (4). First- and second-order shims were first adjusted by gradient-echo shimming (5). The second step involved only fine adjustment of first order shims using FASTMAP (6). Unsuppressed water spectra acquired from the same voxel were used to remove residual eddy current effects and to reconstruct the phased array spectra. Metabolites were quantified with LCModel (7) using the unsuppressed water signal as a reference. Concentrations were corrected for the individual cerebrospinal fluid (CSF) fraction within the 1H MRS voxel using tissue-segmented MPRAGE images. Differences in metabolite concentrations between placebo and ebselen administration were determined using separate multivariate analysis of variance (MANOVA) for anterior cingulate cortex and occipital cortex. Significant effects on the MANOVA were followed up with a post-hoc paired-sample t-test.Figure 1 shows representative spectra obtained from two VOIs in both the ebselen and placebo conditions. Artifact free spectra with good SNR, spectral resolution and excellent water suppression were obtained in both brain regions. Also, the linewidth and SNR values estimated by LCModel were similar between the placebo and ebselen conditions in both VOIs (p>0.05, Tables 1 and 2). This excellent repeatability and spectral quality allowed detection of an effect of ebselen on myo-Ins, Glx (Glutamate+Glutamine) and glutathione (GSH) in the frontal cortex VOI. Compared to the placebo subjects, ebselen-administered subjects exhibited significantly decreased myo-Ins (p=0.028), Glx (p=0.001) and GSH (p=0.033) in frontal cortex, but not in occipital cortex (p>0.05) (Tables 1 and 2). In agreement with the previous animal and in vivo human studies, we have confirmed that ebselen decreases myo-Ins concentration in the human brain, indicating functional blockade of IMPase at the doses employed. Consistent with its reported inhibitory action on glutaminase, ebselen also lowers indications of glutamate activity. These positive results may not only lead to subsequent clinical trials in patients with BPD but also demonstrate how MRS continues to play an ever-increasing role in drug discovery studies.