Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder

Abstract

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

“…However, a high field strength (7T) MRS study found no difference in anterior cortical glutamate levels between cases of MDD and healthy controls, although increased glutamatergic activity was detected in the pathways to the basal ganglia [ 55 ]. A recent MRS study of depression found that increased total glutamate/glutamine (Glx) corresponded to more severe or untreated MDD and was correlated with reductions in GABA levels [ 56 ]. This suggests that impaired GABA functioning plays a role in glutamate excitotoxicity-induced depression.…”

The molecular pathophysiology of depression and the new therapeutics

“…Imbalance of inhibitory and excitatory neurotransmission in the PFC and hippocampus has been involved in depression and convergent evidence from clinical and preclinical studies indicates that dysfunction of glutamatergic and GABAergic systems may contribute the pathophysiology of MDD 44,56 . MDD is generally accompanied by low GABA levels or GABAergic interneuron numbers, possibly disinhibiting glutamate release 320 . Ketamine was reported to inhibit presynaptic NMDARs of GABAergic interneurons present in excitatory neurons within the hippocampus and/or mPFC regions, resulting in the release of tonic inhibition that subsequently leads to increased firing of pyramidal neurons, augmenting synaptic transmission, thus orchestrating quick‐acting antidepressant functions 44,313,314 .…”

“…44,56 MDD is generally accompanied by low GABA levels or GABAergic interneuron numbers, possibly disinhibiting glutamate release. 320 Ketamine was reported to inhibit presynaptic NMDARs of GABAergic interneurons present in excitatory neurons within the hippocampus and/or mPFC regions, resulting in the release of tonic inhibition that subsequently leads to increased firing of pyramidal neurons, augmenting synaptic transmission, thus orchestrating quick-acting antidepressant functions. 44,313,314 Importantly, the burst of glutamate is thought to occur via blockade of NMDARs on GABA interneurons, which are more sensitive to the openchannel blocking actions of ketamine.…”

Improving the reproducibility of proton magnetic resonance spectroscopy brain thermometry: Theoretical and empirical approaches

“…We combined the data from coil elements using unsuppressed water signal as a reference. 19,20 We removed the residual water signal using a singular value decomposition-based method [21][22][23] and performed spectral alignment among the 30 water-suppressed FIDs by aligning the second to the 30th FIDs to the first one, using a fitting procedure like that of Near et al, using the Lorentzian lineshape function. 24…”