There is a large and compelling literature on glutamatergic abnormalities in mood disorders, consisting of peripheral glutamate and related metabolite measures, postmortem markers related to glutamatergic neurotransmission, and insights into mechanisms of action of psychotropic agents. Proton MRS studies are crucial in this field because they provide noninvasive, in vivo assessments of glutamatergic function. The sophistication and utility of proton MRS studies has been improving over recent years and this approach can now be used to examine the relationship between glutamatergic function and diagnosis, clinical state (mania, euthymia, depression), treatment response, or specific emotional/cognitive interventions. On the other hand, we consider our current observations provisional due to the methodological and study design variability of studies as discussed further below; additional work is needed before we can draw firm conclusions from the data.
The Meaning of Glutamate-related Measures
As our ability to quantify glutamate and glutamine improved, the debate over the exact meaning of these measures has intensified. Glutamate and glutamine are found intracellularly (in neurons and glial cells) and extracellularly, and they serve diverse functions. The ratio of glutamate in the metabolic vs. neurotransmitter pools is critically important to our analysis, but there is a paucity of information on this topic. Even the notion of separate compartments of glutamate in these pools is controversial [83
] and further studies are needed to settle this debate. Therefore, MRS measures of these metabolites cannot be attributed directly to one specific function. However, MRS-visible glutamate and glutamine are in fact likely to be related to glutamatergic neurotransmission for several reasons: First, glutamate does not readily pass blood-brain barrier and most brain glutamate is synthesized from glucose within the CNS [84
] although some may be synthesized from other amino acids or 3-hydroxybutyrate. Second, although glutamate and glutamine are amino acids and building blocks of proteins glutamate and glutamine bound in macromolecular assemblies do not contribute to the spectroscopic measures [85
]. Third, 13
C NMR studies of the glutamatergic system indicate a close coupling of overall neuronal activity and glutamate-glutamine fluxes. In the cerebral cortex synaptic glutamate release and glutamate-glutamine cycling consumes approximately 60–80% of the energy produced by oxidative metabolism of glucose. With raises in glutamate-glutamine cycling beyond the resting state, glucose oxidation increases to meet the rise in energy demand with a 1:1 stochiometry. In contrast with earlier conceptualizations, this evidence suggests that synaptic glutamate-glutamine cycling cannot be differentiated from overall glutamate metabolism [83
]. Broadly speaking, Glx reflects the total glutamatergic pool available for synaptic/metabolic activity in the form of glutamate or glutamine. This pool can expand via replenishment from the TCA or contract via incomplete reuptake/cycling or degradation. On the other hand, glutamate and glutamine levels reflect neuronal and glial distribution of glutamatergic metabolites, respectively. This framework is certainly over-simplistic and will need to be revised, but it is a good starting point for interpreting the existing literature.
Synthesis of Findings
In our review of the current 1
H MRS literature, we found clear patterns in Glx levels in major depressive disorder and bipolar disorder. Glx consists mostly of glutamate and glutamine although there are minor contributions from GABA, aspartate, and other metabolites. The preponderance of evidence indicates that Glx levels are reduced in major depressive disorder () and elevated in bipolar disorder (), although these statements only apply to the relatively limited neuroanatomical regions studied thus far. In addition, there are exceptions to each of these statements in the literature: most studies of acutely ill patients report reductions in Glx in major depressive disorder but studies of remitted patients find no change [71
] or elevation [72
]. In bipolar disorder, almost all studies report elevated Glx independent of disease state, with one negative study and one study finding Glx reduction in one of several brain regions studied - the lentiform nucleus where spectral quality is often poor [81
]. Given the multiple sources of variance among studies (in patient selection, clinical and demographic characteristics, and technical differences), the consistency of the literature across most studies is compelling.
Relatively few studies have quantified glutamate and glutamine separately in mood disorders. In major depressive disorder, three out of four studies have reported results consistent with a reduction in glutamine, and the fourth reported normal glutamine but elevated glutamate. Data on bipolar depression are thin, but one study [76
] found elevated glutamate and normal glutamine levels, and glutamine levels increased with lamotrigine administration. The common theme across major depressive disorder and bipolar depression appears to be a reduction of glutamine relative to
glutamate (either reduced glutamine or elevated glutamate). In this context, the finding of elevated glutamine with normal glutamate in mania [73
] is interesting and complementary, suggesting that the relative level of cortical glutamine may be a marker differentiating depression from mania. Euthymic subjects with either major depressive disorder or bipolar disorder did not show a clear pattern of glutamate or glutamine changes.
Implications and Interpretations
Glutamatergic neurotransmission is abnormal in both major depressive disorder and bipolar disorder but the two disorders are differentiated by the magnitude of the glutamatergic pool (Glx). The finding of increased Glx in all mood states in bipolar disorder may reflect an underlying predisposition to bipolar disorder. Given the relationship between Glx and glycemic control such a predisposition may be related to abnormalities in systemic metabolism and/or brain bioenergetics. On a pragmatic note, depressive episodes due to bipolar disorder or major depressive disorder may be differentiated from one another using proton MRS, which if confirmed could have implications for diagnostic imaging.
In addition to diagnosis-driven abnormalities in the glutamate system, we also found episode-driven ones. In depressive episodes, both unipolar and bipolar, one sees a relative reduction in glutamine compared with glutamate. This pattern appears to be reversed in mania with an increased glutamine/glutamate ratio [73
]. Elevated glutamine/glutamate ratio in mania is in line with findings in other conditions with putatively elevated glutamatergic neurotransmission: first episode schizophrenia [87
], administration of the psychotomimetic compound phencyclidine in animals [88
], and experimental ischemia [89
]. Indeed, synaptic glutamate taken up by glial cells is the major substrate for glutamine synthesis [90
] and glutamine levels may be an indicator of glutamatergic neurotransmitter activity in humans [87
] and in animals [93
], and even relevant to glutamatergic excitotoxicity [94
]. Based on this, glutamatergic neurotransmitter flux may be decreased during depression (both in major depressive disorder and bipolar disorder) and increased during mania. This speculation is consistent with differential regulation of glucose metabolism - closely coupled to glutamatergic neurotransmission- demonstrated in PET studies in mood disorders [95
Finally, the divergence in Glx findings across bipolar disorder and major depressive disorder and in glutamate/glutamine findings across mania and depression are intriguing because glial cell deficits have been reported in both conditions [47
]. Given the central role of glial cells in glutamate and glutamine maintenance/recycling, the reported glial abnormalities seem closely relevant to the MRS findings in mood disorders. This dynamic pattern may arise as a result of changes in circuit activity, cerebral metabolism and other factors acting on the background of fixed abnormalities in glial cells. Animal models of impaired glial cell function will be particularly helpful in dissecting which factors may lead to the abnormalities seen in mood disorders. Moreover, a vast body of evidence implicates cellular and structural brain changes in addition to glutamatergic neurotransmission in mood disorders [97
]. It is likely that these two sets of changes are interrelated. E.g. abnormalities in glial cell number and function directly impact Glu handling in the brain. Likewise, abnormalities in neuronal packing density, dendritic arborization, and synapse density may underlie impoverishment of glutamatergic neurotransmission. Additional studies focusing on these relationships (e.g. between grey matter density and glutamate-related metabolite levels) would be valuable in addressing this issue.
To summarize, we have reviewed the 1H MRS literature focusing on glutamate-related metabolites in major depressive disorder and bipolar disorder. We conclude that there are robust Glx differences between the two conditions and that there is a weaker but suggestive literature on the relative levels of Gln and Glu coupled to mood states across the two conditions. While this pattern of findings focuses attention on glutamatergic mechanisms with potential pathophysiological significance, more work is needed to fully understand the nature of these abnormalities and to develop effective treatment strategies to address them.
The current MRS literature on mood disorders should be evaluated in the context of differences in sample characteristics and MRS methodologies that may affect the level of glutamate-related metabolites. No power analysis was reported in any study but small sample sizes were noted to be a limitation in several reports. Short washout periods and/or inclusion of medicated subjects were other common limitations, as the glutamate-related metabolite levels are known to be affected by medications used in mood disorders.
Although our review on the relation of methodological factors with the direction of findings did not reveal any specific patterns, this review likely does not have adequate power to detect patterns if they exist due to the number of studies and the quality of data available. Thus, these confounders cannot be excluded at the level of individual studies. Furthermore, the current literature does not highlight any systematic differences between brain regions examined, but this does not rule out such differences and additional studies may uncover region-specific alterations for glutamate-related measures in mood disorders. One region where the pattern of findings may diverge is the OCC; as reviewed above some studies report Glx elevations in OCC even in MDD. Finally, our conclusions are preliminary and given the many potential confounds (in MRS methods, brain regions studied, the challenge of measuring Gln, the potential disconnect between in vivo MRS and postmortem studies) additional definitive studies are needed to substantiate these conclusions and confirm their significance.
MRS holds substantial promise to advance our insight into glutamatergic pathology in mood disorders. Additional studies quantifying glutamate and glutamine separately and comparing with healthy controls are needed to confirm the patterns of these metabolites both in major depressive disorder and bipolar disorder. Furthermore, comparison of glutamate-related measures in depressed and manic episodes and in euthymia -ideally in the same patient group- is needed. In addition, quantification of glutamate-related metabolites in non-affected relatives is of interest to assess abnormalities associated with susceptibility to the disorder. The possible clinical utility of MRS for the differentiation of bipolar and unipolar depression needs to be explored further in adequately powered MRS studies where head-to-head comparisons can be carried out. Finally, 13C-MRS, a technique based on measuring the flow of 13C-labeled molecules through MRS-visible metabolites has the unique potential to provide detailed information about the reaction rates of glutamatergic metabolism steps and thus reveal the specific processes which are disturbed.