ReviewRegion and state specific glutamate downregulation in major depressive disorder: A meta-analysis of 1H-MRS findings
Highlights
► We conducted a meta-analysis on 1H-MRS-findings in major depressive disorder (MDD). ► Glutamate and Glx concentrations are lower in the anterior cingulate cortex in MDD. ► Glx is decreased in all brain regions together in current episode patients. ► Whether glutamate changes in MDD are indeed state-dependent needs confirmation.
Introduction
Major depressive disorder (MDD) is a usually recurring psychiatric illness characterized by depressed mood and/or loss of interest, along with a variety of other emotional–motivational, cognitive and motor symptoms. MDD was the fourth contributor to global burden of disease in 2000 and will rank second by 2020, according to WHO estimates (Organization, 2008).
In the past decades progress has been made in the identification of the neurotransmitters and brain areas involved in MDD. Glutamate is one such neurotransmitter for which evidence of impaired functioning in diverging MDD-models has been accumulating (reviewed in Mitchell and Baker, 2010). This rising interest in the glutamatergic system as an underlying pathophysiological mechanism in MDD may be explained by several factors, among which are its known interaction with the monoamines that antidepressants act upon (reviewed in Hashimoto, 2009), post-mortem findings of increased prefrontal glutamate concentrations in MDD patients (Hashimoto et al., 2007), and the efficacy of glutamate N-methyl-d-aspartate receptor (NMDAR)-antagonists (reviewed in Skolnick et al., 2009).
Glutamate plays a key role in brain function and development (Meldrum, 1994). It takes part in the glutamate–glutamine cycle, in which glutamine is both the non-neuroactive precursor and a metabolite, enabling the right amount of physiological glutamate neuron firing and preventing neurotoxicity (Gras et al., 2006) (Fig. 1).
Studies on glutamate and glutamine concentrations in the brain may be divided into in vivo and post-mortem measurements. In vivo analyses include fluid spectrometry of blood, plasma and cerebrospinal fluid and non-invasive procedures, e.g. proton magnetic resonance spectroscopy (1H-MRS). The latter is superior to other techniques in assessing in vivo glutamate concentrations by brain region of interest. A number of 1H-MRS-studies on glutamate, glutamine and Glx – a composite measure of mainly glutamate and glutamine and some GABA (gamma-aminobutyric acid) – in the brains of MDD patients have been performed, the first dating back to over a decade ago, while most studies were published in the past five years.
There are four reasons why a systematic review of this topic has now become warranted and viable. First, in recent years – in particular 2009 – many 1H-MRS-studies in MDD have been published, increasing the feasibility of a meta-analysis. Second, both depressed and recovered MDD patients have been included in 1H-MRS-studies, potentially allowing quantification of in vivo state-specific glutamate concentrations. Third, in multiple 1H-MRS-studies specific brain areas have been investigated, creating the possibility of analyzing glutamate and glutamine per region. And fourth, while several studies point to decreased glutamate concentrations in MDD, other authors have found evidence that glutamate is upregulated in certain brain regions. In such cases of apparent discrepancies, a systematic review may disentangle their nature and degree, although it is beyond the scope of this work to unravel the possible contribution of each spectroscopy parameter to the results. We thus performed a meta-analysis of the findings on in vivo glutamate and glutamine concentrations in MDD detected by 1H-MRS. By doing so, we aimed to address the following questions:
- (1)
Do currently available studies point to lower, higher or equal concentrations of glutamate, glutamine and Glx in MDD compared to controls?
- (2)
Do such concentration differences vary by brain region of interest, patient characteristics and field strength?
Section snippets
Criteria for considering studies for this review
Based on their titles and abstracts, papers reporting on the following were selected: (1) in vivo proton 1H-MRS studies; (2) patients diagnosed with MDD based on DSM-III-R, DSM-IV or ICD-10 diagnostic criteria and a comparison group consisting of healthy controls; and (3) measurements and reporting of either glutamate, glutamine, a glutamate/creatine ratio, or glutamate combined with glutamine (Glx). No time or language restrictions were applied. Full-text revision of the selected studies was
Characteristics of included studies
Broad searches yielded 733 hits, 689 of which did not meet the inclusion criteria, based on inspection of titles and/or abstracts. At full-text review, 28 studies were excluded, mostly because no data on Glx, glutamate or glutamine were provided. Two of these studies were excluded as they reported on identical study populations and measurements as previous, already included papers (Bhagwagar et al., 2008, Rosenberg et al., 2004). Thus, 16 articles were used for meta-analysis (Auer et al., 2000,
Discussion
In this meta-analysis we compared levels of glutamate, glutamine, and their composite measure (Glx) assessed by magnetic resonance imaging (1H-MRS) in 281 MDD patients with 301 controls. We detected a consistent decrease in Glx and glutamate concentrations in the ACC of MDD patients. In addition, Glx was decreased in all brain regions together only during depressive episodes, i.e. when excluding remitted patients.
Our findings of involvement of the ACC in MDD are consistent with previous
Disclosure/conflict of interest
All authors declare they have no conflict of interest. No funding was provided for this project.
Acknowledgements
We thank Michael Borenstein, Heleen Boos, and Sander Haijma for their valuable advice on the statistics and software used for this meta-analysis.
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