Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients☆
Introduction
There is some evidence drawn from neurochemical studies that severe depression is accompanied by perturbation of the metabolism of excitatory amino acids, especially of glutamate (Glu) (Altamura et al., 1993). Normal glutamate metabolism depends on intact neuronal and glial cell function (Gallo and Ghiani, 2000, Magistretti et al., 1999). Both cell types showed distinct histomorphological alterations in the anterior cingulum of depressives (Ongur et al., 1998, Rajkowska, 2000). Recently, a significant reduction of glutamate/glutamine (Glx) in the bilateral anterior cingulum in severely depressed patients was demonstrated by means of proton magnetic resonance spectroscopy (1H-MRS) (Auer et al., 2000). MRS provides a unique opportunity to assess brain metabolite levels in vivo (Maier, 1995). If reduced Glx metabolism were pivotal for depression, effective electroconvulsive therapy (ECT), well known for its strong antidepressive effect, should be able to reverse the Glx deficit. We, therefore, investigated 17 severely depressed patients referred for ECT due to treatment resistance. MRS was used to assess metabolic changes in the left anterior cingulum before and after ECT. The left cingulum was chosen, since it was demonstrated by Drevets et al. (1997) that abnormalities in metabolism are left lateralized and we, therefore, expected effects of ECT on glutamate metabolism to be pronounced in this region.
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Patients
Seventeen patients fulfilling the diagnostic criteria for severe recurrent unipolar major depressive disorder (American Psychiatric Association, 1994) were enrolled in this study. Diagnosis was made independently by two experienced psychiatrists, only one of them (N.M.) directly involved in this study, employing a checklist for DSM-IV diagnosis (Hiller et al., 2000). All but one of the patients were off medication 5.1±2.7 days prior to MRS. Only lorazepam, which was shown not to influence brain
Results
Prior to ECT, Glx (glutamate/glutamine) was significantly reduced to a fraction of approximately 67% in the left anterior cingula of all patients compared to healthy controls (ANCOVA; F=24.6, P<0.0001; Fig. 3). Even after correction for CSF, age and GM, this group effect (depressives vs. controls) remained significant (F=7.2, d.f.=4, P<0.0001). Eleven of the 17 patients enrolled in this study had very low Glx resonances (Fig. 2a). Segmentation revealed a significantly higher CSF fraction
Discussion
Our results corroborate the report of reduced glutamate/glutamine (Glx) in the anterior cingulum (Auer et al., 2000). In contrast to Auer et al., we examined the left hemispheric anterior cingulum of strictly unipolar, severely depressed and treatment-resistant off-medication patients.
The increased CSF fraction in the patients’ voxels may indicate cingulate volume reduction, probably due to histopathological changes such as reduced glia cell density and neuronal cell size (Ongur et al., 1998).
Acknowledgements
This work was supported by an ‘innovative medical research’ grant (IMF) from the University of Münster, FRG (ER 219918).
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2022, Handbook of Clinical NeurologyCitation Excerpt :Similarly, reduced GABA levels have been demonstrated in the occipital cortex of patients with major depression (Sanacora et al., 1999) and in the PFC of patients with treatment-resistant depression (Price et al., 2009). Established antidepressant treatments including selective serotonin reuptake inhibitors and electroconvulsive therapy can revert the pattern of aberrant metabolite concentration along with clinical remission, which underlines MRS's role in identifying putative stimulation network targets (Pfleiderer et al., 2003; Bhagwagar et al., 2004; Zhang et al., 2013). Several studies have investigated stimulation-induced changes of metabolite concentration in healthy subjects as well as in neurologic and psychiatric patients (see Cuypers and Marsman, 2021).
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Bettina Pfleiderer and Nikolaus Michael contributed equally to this article.