Changes in brain Glx in depressed bipolar patients treated with lamotrigine: a proton MRS study

Background Lamotrigine is a useful treatment in bipolar depression but requires several weeks of dose titration before its clinical effects can be assessed. Animal experimental studies suggest that lamotrigine lowers glutamate release. The aim of the current study was to assess the effect of lamotrigine on brain glutamate in depressed bipolar patients and to determine whether baseline glutamate could be used to predict clinical response. Methods We studied 21 bipolar patients who received lamotrigine treatment for a current episode of depression. Before starting lamotrigine and after 10–12 weeks treatment, patients underwent proton magnetic resonance spectroscopy (MRS) scanning at 3 Tesla where levels of glutamate (measured as Glx) were determined in anterior cingulate cortex (ACC). Results Overall, lamotrigine treatment had no significant effect on Glx levels in ACC. However, in patients who responded clinically to lamotrigine treatment Glx concentrations were significantly increased. Baseline levels of Glx did not predict response to lamotrigine. Limitations The main limitation of the study was the modest sample size. Most patients were medicated which may have modified the effect of lamotrigine on glutamate activity. MRS at 3T cannot give a reliable estimate of glutamate separate from its main metabolite, glutamine, and thus changes in Glx may not give a precise estimate of effects of lamotrigine on glutamate itself. Conclusion Lamotrigine does not appear to have a direct effect on glutamate levels in ACC in bipolar patients. However, therapeutic improvement during lamotrigine was associated with increased Glx, suggesting that alterations in glutamatergic activity might be related to recovery from bipolar depression

Brain glutamate in medication-free depressed patients: A proton MRS study at 7 Tesla

Background: The possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths (1.5- 3 Tesla), it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 Tesla (7T) allows clear spectral resolution of glutamate and glutamine. Method: We studied 55 unmedicated depressed patients and 50 healthy controls who underwent MRS scanning at 7T with voxels placed in anterior cingulate cortex, occipital cortex and putamen. Neurometabolites were calculated using the unsuppressed water signal as a reference. Results: Compared to controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 14% in the putamen (p< 0.001). Conclusions: The increase in glutamine in putamen is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the putamen. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted

Brain glutamate in medication-free depressed patients: A proton MRS study at 7 Tesla

Background: The possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths (1.5- 3 Tesla), it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 Tesla (7T) allows clear spectral resolution of glutamate and glutamine. Method: We studied 55 unmedicated depressed patients and 50 healthy controls who underwent MRS scanning at 7T with voxels placed in anterior cingulate cortex, occipital cortex and putamen. Neurometabolites were calculated using the unsuppressed water signal as a reference. Results: Compared to controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 14% in the putamen (p&lt; 0.001). Conclusions: The increase in glutamine in putamen is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the putamen. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted.</p

Changes in brain Glx in depressed bipolar patients treated with lamotrigine: a proton MRS study

Background Lamotrigine is a useful treatment in bipolar depression but requires several weeks of dose titration before its clinical effects can be assessed. Animal experimental studies suggest that lamotrigine lowers glutamate release. The aim of the current study was to assess the effect of lamotrigine on brain glutamate in depressed bipolar patients and to determine whether baseline glutamate could be used to predict clinical response. Methods We studied 21 bipolar patients who received lamotrigine treatment for a current episode of depression. Before starting lamotrigine and after 10–12 weeks treatment, patients underwent proton magnetic resonance spectroscopy (MRS) scanning at 3 Tesla where levels of glutamate (measured as Glx) were determined in anterior cingulate cortex (ACC). Results Overall, lamotrigine treatment had no significant effect on Glx levels in ACC. However, in patients who responded clinically to lamotrigine treatment Glx concentrations were significantly increased. Baseline levels of Glx did not predict response to lamotrigine. Limitations The main limitation of the study was the modest sample size. Most patients were medicated which may have modified the effect of lamotrigine on glutamate activity. MRS at 3T cannot give a reliable estimate of glutamate separate from its main metabolite, glutamine, and thus changes in Glx may not give a precise estimate of effects of lamotrigine on glutamate itself. Conclusion Lamotrigine does not appear to have a direct effect on glutamate levels in ACC in bipolar patients. However, therapeutic improvement during lamotrigine was associated with increased Glx, suggesting that alterations in glutamatergic activity might be related to recovery from bipolar depression

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla

Introduction: Lithium remains the most effective treatment for bipolar disorder but 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 inositol monophosphatase (IMPase) and lower brain inositol, actions which it shares with lithium. Objectives: The primary aim of the study was to determine whether treatment with ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen treatment on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate+glutamine (Glx). Methods: We studied 20 healthy volunteers who were tested on two occasions receiving either ebselen (3600mg over 24 hours) or identical placebo in a double-blind, random-order, cross-over design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy (1H MRS) at 7 tesla (7T) with voxels placed in anterior cingulate and occipital cortex (Figure 1). Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel. Results: Ebselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol as well as those of glutathione, glutamine, glutamate and Glx (Table 1). Conclusions: The study suggests that at the dosage used, ebselen produces a functional inhibition of IMPase in the human brain. The ability of ebselen to lower indices of glutamate activity are consistent with its action, reported in animal experimental work, to inhibit the enzyme, glutaminase. Ebselen appears to have potential as a repurposed treatment for bipolar disorder and it would be of interest to see if similar biochemical alterations are produced by ebselen treatment in this patient group