Abstract
Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR “magnetic resonance spectroscopy”). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = −0.38; 95% CI, −0.69 to −0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.
Highlights
These authors contributed : Sho Moriguchi, Akihiro TakamiyaElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, JapanResearch Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, CanadaDepartment of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, JapanTemerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, CanadaThe heterogeneity of the illness features that characterize depression makes it difficult to elucidate the underlying pathology of the illness and its treatment
Several proton magnetic resonance spectroscopy (1H-MRS) studies have examined regional levels of glutamatergic metabolites in patients with depression compared with controls
There were significantly lower levels of Glx within the medial frontal cortex in patients with depression compared with controls (SMD = −0.38; 95% confidence intervals (CIs), −0.69 to −0.07; I2 = 81%; p = 0.2) (Table 2, Fig. 2)
Summary
These authors contributed : Sho Moriguchi, Akihiro Takamiya. Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada. Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Canada. The glutamate hypothesis of depression was proposed in the 1990s, when antagonists of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor, were found to possess antidepressant-like mechanisms of action in mice [1]. Infusion of low-dose ketamine, which is an NMDA receptor antagonist, is associated with robust decreases in depressive symptoms in depressed patients [2]. Recent data suggest that glutamatergic dysfunction is involved in the biological mechanisms underlying depression [3]. Positron emission tomography (PET) studies have reported reduced metabotropic glutamate receptor subtype 5 density in patients with depression, which was further substantiated by a post-mortem study [4]
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