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

Abstract

While an excess of glucocorticoids is associated with hippocampal pathology in mood disorders, lithium exerts robust neuroprotective and neurotrophic effects. Here, 21 stably remitted bipolar I patients who had been on chronic lithium maintenance therapy, on average, for more than a decade, and 19 carefully matched healthy controls were studied using 3 T 1 Hmagnetic resonance spectroscopy of left and right hippocampus. Salivary cortisol samples were obtained to assess activity of the hypothalamus-pituitary-adrenal system. Absolute concentrations of N-acetylaspartate (NAA), choline-containing compounds and total creatine were similar in euthymic bipolar patients and healthy controls. Hippocampal glutamate concentrations were significantly increased as an effect of patient status (patients > controls) and laterality (left hippocampus > right hippocampus). Hippocampal glutamate content (Glu) was strongly correlated with NAA. Across groups and within the patient group, diurnal saliva cortisol levels showed a significant inverse relationship with both Glu and NAA. Taken together, these results add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.

Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study

“…These findings are in keeping with those of previous crosssectional studies, which reported greater brain NAA levels in Li-treated patients with bipolar disorder versus those without current Li treatment 13,14 or comparable brain NAA levels between Li-treated patients and controls. [15][16][17] Contrary to our findings, a single study in patients with shorter duration of illness showed no differences in brain NAA levels between Li-treated and untreated patients. 15 Two additional studies reported greater brain NAA levels among Li-treated patients than controls.…”

“…[8][9][10][11] A single prospective study reported a small NAA increase after 4 weeks of Li treatment, 3 whereas another investigation found an NAA decrease after 6 weeks of Li exposure. 12 Cross-sectional studies have also been inconsistent, with reports of greater 13,14 as well as comparable [15][16][17] brain NAA levels in Li-treated versus control participants.…”

MR Spectroscopic Studies of the Brain in Psychiatric Disorders

“…Four other studies reported results for glutamate, but not for the combined Glx signal. Two of these reported elevated glutamate in bipolar patients (Colla et al 2009;Lan et al 2009). One additional study examined Glx in older adolescents and young adults (mean age = 22) and found elevated Glx in the bipolar patients (Cecil et al 2002).…”

Neurobiological trait abnormalities in bipolar disorder

“…153 There has been little consistency in the results of studies to date examining other neurochemicals with proton MRS. Interestingly, in a recent study of 21 stable remitted patients with BD taking lithium, patients were found to have increased hippocampal glutamate, which correlated strongly with NAA concentrations. 134 There was also a negative correlation between hippocampal glutamate and diurnal cortisol, and the authors suggest that the high glutamate levels may be related to chronic lithium maintenance, which acts to protect the hippocampus from adverse effects of stress and glucocorticoids. 134 Phosphorus MRS Increased levels of phosphomonoesters (PMEs) imply an increased rate of membrane phospholipid turnover, whereas decreased PME levels indicate a stalling of membrane synthesis.…”

“…134 There was also a negative correlation between hippocampal glutamate and diurnal cortisol, and the authors suggest that the high glutamate levels may be related to chronic lithium maintenance, which acts to protect the hippocampus from adverse effects of stress and glucocorticoids. 134 Phosphorus MRS Increased levels of phosphomonoesters (PMEs) imply an increased rate of membrane phospholipid turnover, whereas decreased PME levels indicate a stalling of membrane synthesis. Interestingly, PME appears to be increased in both the depressed and manic phases of BD, 135 but reduced in frontal and temporal regions during the euthymic phase compared with healthy controls.…”