Proton MR spectroscopy of the hippocampus at 3 T in patients with unipolar major depressive disorder: correlates and predictors of treatment response

Abstract

Various lines of research suggest that neurotrophic processes in the hippocampus are key mechanisms in major depressive disorder and are of relevance for response to antidepressive treatment. We performed proton magnetic resonance spectroscopy (1H-MRS) of the hippocampus at 3 T in 18 unmedicated subjects with unipolar major depressive episodes and in 10 age- and gender-matched healthy volunteers. Thirteen patients underwent a second examination after 8 wk treatment with either citalopram (n=7) or nortriptyline (n=6). Of these patients, 11 MRS datasets could be used for the assessment of treatment correlates. In the cross-sectional comparison, we observed a significant reduction of the metabolic ratios Glx/Cr (Glx=glutamine, glutamate and gamma-aminobutyric acid) and glutamine (Gln)/Cr in the patient group. The Gln/Glx ratio also showed a trend towards significant reduction. The individual effect of treatment correlated with an increase in the absolute concentrations of N-acetylaspartate (NAA) and of choline compounds (Cho). Low baseline NAA and Cho levels predicted positive treatment effects. There was no difference in any clinical or metabolic measure, either at baseline or at follow-up between the two treatment groups (citalopram, nortriptyline). Our data provide first evidence for a reduction of Gln in the hippocampus of subjects with major depression. Furthermore, we provide first evidence in patients with major depression for neurorestorative effects in the hippocampus by pharmacological treatment expressed by a correlation of NAA and Cho increases with treatment response. This accounts in particular for those patients with low NAA and Cho baseline levels.

Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden

“…11 In last decade, a large and compelling body of literature on biochemical changes in MDD has appeared, but only a few works have focused on the hippocampus, sometimes leading to inconsistent conclusions. Two studies reported diminished levels of Glx within the head of the left hippocampus in severely ill patients with treatment-resistant depression 12 and untreated patients with first-episode depression, 13 although a subsequent study by Milne and colleagues 14 was unable to confirm such a finding. With regard to Cho concentrations, patients with treatment-resistant depression 15 or with previous recurrences 14 have been shown to have a greater spectroscopic signal in the hippocampus, although other authors have reported low or normal Cho levels in patients with a current depressive episode, with subsequent increases after successful response to electroconvulsive therapy 16 or pharmacological treatment.…”

“…With regard to Cho concentrations, patients with treatment-resistant depression 15 or with previous recurrences 14 have been shown to have a greater spectroscopic signal in the hippocampus, although other authors have reported low or normal Cho levels in patients with a current depressive episode, with subsequent increases after successful response to electroconvulsive therapy 16 or pharmacological treatment. 13 Previous studies of hippocampal levels of NAA have failed to observe deficiencies in depressed patients 8 despite alterations in neuroplasticity and/or neurogen esis having been repeatedly suggested to underlie MDD. 3,17 Nevertheless, some works have revealed increases in NAA levels associated with treatment response.…”

Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: An autoradiographic study

“…A 3T MRS study showed reduced Glx/creatinine ratios (Glx = glutamate, glutamine and GABA) and glutamine/Cr in the hippocampus of patients with MDD [7]. Also AMPA (GluR1, GluR3), kainate (GluR5), and NMDA (NR2B) were decreased in the perirhinal cortex of the patients with major depression [5], and decreased glutamate and glutamine levels in the frontal cortex of patients with depression were reported [3].…”

“…The chronic, recurring character of depression is illustrated by the fact that 17-20% of the worldwide population suffers from it [33] with 15% of those suffering from major depression committing suicide [7]. The lag period of the therapeutic effect usually takes several weeks (3-6 weeks) and its not achieved in 1/3 of patients [10] which indicates that the therapeutic effect is dependent on the effects beyond the elevation of monoamines [20].…”

Physiologic and Characteristic Distributions of Glutamate/Glutamine in Patients with Major Depressive Disorder

“…In recent years, quantification studies of brain Glx in patients with MDD using 1 H-MRS have been carried out that showed significant reductions in Glx in several brain regions 3)4) . Such regions include the anterior cingulate cortex (ACC) 5) 6) , dorsolateral prefrontal cortex (DLPFC) 7) , dorsomedial prefrontal cortex 8) , amygdala 7) , and hippocampus 9) , areas also thought to be associated with mood regulation and the pathophysio- According to our review of prior studies, the region showing the greatest reduction in Glx has not been investigated in individual patients. We therefore aimed to investigate the physiologic and characteristic distribution of Glx in each region within individuals, and to compare differences between healthy controls and patients with MDD.…”