Different theories were put forward to explain the etiopathogenesis of depression. This has been a major challenge for the development of treatment options, since only 30% of patients with MDD who receive an adequate treatment experience full remission (1). Some of the neurobiological factors theoretically associated with depression are the activation of the inflammatory system, hypothalamic-pituitary-adrenal axis disturbances, dysfunctional neuroanatomic circuits (particularly the default mode network), abnormal neural activity, neurotransmitter dysfunction, polymorphisms in the 5-HTT promoter region (5HTTLPR) and interactions between brain derived neurotrophic factor (BDNF); and neurotrophic tyrosine kinase receptor 2 (NTRK2) polymorphisms (2).

Theories of neurotransmitter dysfunction in depression are well established. The monoamine theory proposes that depression is caused by a decrease of the extracellular availability of noradrenaline and serotonin. Hence, the therapeutic effect of antidepressants aimed to increase their availability. Despite the multiple studies about various multimodal pharmacological and psychological treatments of depression, the evidence for the efficacy and tolerability of these treatment options remains insufficient (3).

The delayed, and in many cases poor, response to the current antidepressants may suggest that there are more neurotransmitters involved in the pathophysiology of depression than those accounted for by the monoamine theory. Prominent among them is the glutamatergic system which may contribute to the dysfunction and perceived treatment poor response (2). Given the complexity of mood disorders and the setbacks of previous monoaminergic targets, there has been growing evidence about non-invasive neuromodulating techniques that target networks such as the limbic-cortical system framework, producing both local and regional effects (4). Growing evidence from animal and human studies shows that structural pathology, network, and connectivity dysfunction related to deficits in excitatory glutamate neurons and inhibitory GABA interneurons in the cortical and limbic areas of the brain are implicated in the genesis of depressive symptoms. As current pharmacotherapeutic treatment for depression which focused on the monoamine hypothesis has significant limitations, glutamatergic related mechanisms promise to produce superior therapeutic interventions (5). This article reviews the proposed glutamatergic mechanisms of neuromodulation in the treatment of depression.

Glutamate is the principal excitatory neurotransmitter in the brain, and glutamatergic mechanisms play significant roles in nearly all key functions affected in depressed states (6). Postmortem studies have put forward evidence linking glial cell abnormalities, whose role is synaptic glutamate removal, and the pathophysiology of mood disorders (7). Lower glutamine/glutamate levels have also been found in the cortex of patients with depression (8). The “much faster than usual” antidepressant effect of ketamine, discussed later, further solidifies the role of glutamate in treatment-resistant major depression. Ionotropic (N-methyl-D-aspartate [NMDA], α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors [AMPA], and kainate receptors [not discussed herein] and metabotropic (mGluR) glutamate receptors have been shown to be responsible for modulation of mood and associated functions that are impaired in depression (9). These observations have brought about the hypothesis that NMDA and/or AMPA receptors might be novel therapeutic targets for treating depression. Figure 1 summarizes the interplay among NMDA-R inhibition, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and ketamine metabolites hydroxynorketamines (HNK), taking ketamine—a glutamatergic agent that has been intensively investigated over the past 20 years—as an example.

The assessment of glutamate and glutamate receptors is of high interest across many neuropsychiatric disorders. However, compared to other neurotransmitter systems, its in-vivo assessments pose several challenges (44). The most common assessment approach is the so-called “molecular imaging” with positron emission tomography (PET) and single photon emission computed tomography (SPECT). These techniques have the advantage of being an in vivo technique and having an excellent safety profile (45). Specific tracers are available for PET/SPECT molecular imaging of subtypes of the ionotropic (NMDA, AMPA, and kainate receptors) and metabotropic glutamate receptors (mGluRs).

Due to conformational issues and the difficulty of utilizing brain-penetrating ligands for amino acid receptors, there has been little advance in developing radiotracers for ionotropic glutamate receptors, with the exception of the NMDA receptor (GluN2B subunit ligand). On the other hand, mGluR imaging, particularly for subtypes 5 and 1, has been found effective (44), and has been used in studying the pathophysiology, endophenotypes, and drug development for depression (46–48).

Moreover, ¹H magnetic resonance spectroscopy (MRS) is also a non-invasive method for the assessment of levels of neurometabolites including glutamatergic ones in the brain (49). MRS takes advantage of differential protons' magnetic fields depending on their chemical environment. Using this property, it helps distinguish between different chemical compounds, and quantify their concentrations, including glutamate-related metabolites (50). The metabolites are measured in a specified volume, the voxel. MRS was widely used in depression studies showing that patients with depression had lower glutamate and glutathione (GSH) levels; however, due to overlapping signals and low concentrations, this method is prone to signal-to-noise ratio challenges. New methodological improvements are needed to boost this ratio and increase the likelihood of generating robust and reliable results in the study of depression (51, 52).

Furthermore, one can indirectly assess the glutamatergic synapsis in the cortex using transcranial magnetic stimulation (TMS) with paired pulse protocol. The intracortical facilitation (ICF) metric has been associated with glutamate tonus in the motor cortex (53, 54). In particular, pharmacological studies with paired-pulse TMS have demonstrated that both GABA-A agonist (55, 56) and NMDA antagonist reduced ICF (57, 58). Thus, ICF is assumed to be mainly associated with glutamate receptor-mediated excitatory functions in the motor cortex. Only few studies have assessed the role of ICF in depression with heterogenous results (59–61). New evidence on glutamatergic tonus from non-motor cortex (such as DLPFC) areas with combined TMS-EEG protocols is needed.

Although, none of the above methods is the perfect and reliable technique to assess glutamatergic pathways in patients with depression. The combination of clinical and multimodal neuroimaging assessments is the best approach for robust and reproducible protocols.

The International Neuromodulation Society defines therapeutic neuromodulation as “the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body (62).

In the last decades, several non-invasive brain stimulation techniques have been used to treat depression in humans, including rTMS or tDCS. Reduced connectivity in the prefrontal cortex and anterior cingulate gyrus and reduced neuroplasticity are found in depressive disorders and play important roles in the pathophysiology of depression (63–66).

Brain stimulation's effect on depression might be through neuroplasticity modulation. Electroconvulsive therapy (ECT) is among the oldest brain stimulation techniques that have been used to treat refractory depression. ECT impacts plasticity-associated transcripts and their proteins in the hippocampus (67). Also, several clinical studies have shown an increase in connectivity and cerebellar volume in patients with MDD (68–72) and white matter modulation in the pathways between the frontal and limbic areas after receiving ECT therapy (73). Animal models showed that ECT influences the glutamatergic system; rat models with decreased glutamate, exhibited NR2B upregulation after ECT.

TMS is a non-invasive technique of brain stimulation that uses the principles of electromagnetic induction to produce an electrical current in the brain surface. A magnetic field induces a secondary electrical current. There are different types of TMS including rTMS which generates repetitive magnetic pulses from seconds to minutes. rTMS is a Food and Drug Administration (FDA) approved treatment for patients with MDD who are resistant to antidepressant treatment. rTMS might stimulate neurogenesis like ECT, and also modulate brain activity and neurotransmitters including dopamine and serotonin. Cortical excitability modulation might be impaired in patients with depression, and TMS might improve cortical modulation (74), and modulate functional connectivity between the central executive work and default mode network (75).

Non-invasive brain stimulation offers a potential alternative, non-pharmacologic approach to treat unipolar depression and treatment resistant depression (TRD), even though there is some evidence about the efficacy and safety of non-invasive neuromodulation techniques to treat unipolar depression, especially in the case of ECT and rTMS (92).

The rationale for neuromodulation for depression is based on a neural network theory that posits a specific set of structurally and functionally connected brain regions that work together to maintain normal mood regulation (93, 94), however, little is known about the specific mechanisms.

The putative cellular mechanisms of action to this group of therapies involve the action over the glutamatergic neuronal firing, depending on the technique and polarity used, TMS and ECT will depolarize the cell membrane and generate an action potential while tDCS have an impact on the action potential depending on the polarity, cathodal stimulation will decrease, and anodal stimulation will increase the action potential. The after-effects are mediated by “long-term potentiation (LTP)-like” mechanisms where the upregulation of neurotransmitter release facilitates the opening of AMPARs and indirectly that of NMDARs (95). The mechanism of action of tDCS in psychiatric disorders has been attributed to the effects of anodal stimulation (96). Studies often report the anode placement over the frontal cortex while the cathodal electrode placement reports are more inconsistent, however, there are reports of inflammation reduction and neuroprotective effects by cathodal stimulation (97).

In this review, we looked for the possible clinical impact of different neuromodulation techniques over glutamate pathways and we found three rTMS studies (Table 1): 2 with TRD patients (98, 99) and another with MDD patients (100) that were not taking any pharmacological treatment. MRI spectroscopy was performed before and after the intervention to assess the glutamate/GABA ratio (Table 1). The studies found modifications on the glutamatergic and GABAergic neurotransmission after high-frequency rTMS treatment on DLPFC. Specifically, an increase of the glutamine/creatine ratio (100) and GABA concentrations (98, 99) on the left DLPFC after ~20–25 daily sessions. Indeed, this justify further research on glutamate biomarkers for the optimization of rTMS protocols in depression.

Given that deficits in glutamate in cortical and limbic regions are implicated in MDD and causally related to depressive-like behaviors; treatment that reverses or normalizes glutamate can improve depressive symptoms. Glutamate receptors, specifically the metabotropic subgroup II receptors of mGluRs are targets of interest in developing novel antidepressants (103). Preclinical studies have demonstrated that the antagonism and negative allosteric modulation of mGlu2/3 receptor has antidepressant properties (104, 105). Indeed, the expression mGluR2/3 receptors reduction is observed in the anterior cingulate cortex among patients with MDD (106, 107). Furthermore, significant increase in CSF levels of glutamate and glutamine among MDD patients compared to healthy control (108) has been observed and linked to hyperactivation of NMDA receptors (109), inflammatory process (110, 111) and serotonergic signaling (111). Similarly, a systematic review and meta-analysis evidence shows that even peripheral blood glutamate levels were significantly increased in MDD patients compared to the controls (112).

While pharmacological techniques have targeted the glutamatergic receptors as a therapeutic target for treating depressive disorders, neuromodulation techniques offer alternative or augmentative treatment for the same. Non-invasive brain stimulation techniques including the non-convulsive TMS and tDCS and convulsive ECT and MST provide safe options targeting specific areas in dorsolateral prefrontal cortex (DLPFC) which is a key site for the frontoparietal network (FPN). In hypoactive state, (FPN) is associated with hyperactivity of the default mode network (DMN) that may promote depressive behavior and cognitions such as self-referential processing, depressive rumination and negative bias observed in MDD (113–115).

Provided at high frequency (HF-TMS), low frequency (LF-TMS), theta-bursts (TBS) and deep (dTMS) (116, 117); clinical trials have demonstrated the efficacy and safety of TMS treatment. HF-TMS over the left DLPFC is shown to have a superior effectiveness compared to sham treatment in individuals with depression even when used without concomitant antidepressant (118, 119), and has the benefit of accelerating clinical response (120) and also effective as a monotherapy for both unipolar or bipolar depression (121). In case of poor response to HF-rTMS, LF-TMS can be especially advantageous and safe when there is high risk of seizures and poor tolerability to pain (117, 122).

Similar to TMS techniques, tDCS targets left DLPFC primarily aiming to counterbalance the hyperactivity of the DMN secondary to hypoactivity of the frontoparietal network of the left DLPFC (123). tDCS combined with antidepressant produce faster and greater response compared to the antidepressant alone or tDCS alone (119). In a non-inferiority trial, tDCS failed to show its non-inferiority to escitalopram, but was still superior to placebo (124).

As for convulsive modalities, ECT has been used for decades as second line treatment for MDD and in some cases such as acute suicidal or psychotic features, it can be used as a first line. ECT is now considered safe, effective and tolerable with increased efficacy with increased in association with medications, when combined with nortriptyline and lithium and venlafaxine and lithium (125, 126). MST is a TMS variant with a more focused superficial field and minimal stimulation of inner brain structures such as hippocampus (127), thus having lower incidences of cognitive deficits unlike ECT (128) but with antidepressant effect similar to RUL ECT (129, 130). Animal models reveal a better understanding of the antidepressant mechanism of neuromodulatory techniques such as deep brain stimulation (DBS), which is observed to work through activating brain derived neurotrophic factor (BDNF) related pathways. DBS targeting the ventral medial prefrontal cortex is thought to exert its antidepressant-like and cognitive enhancement effect by increasing expression of BDNF, Akt, and mammalian target of rapamycin (mTOR), and observed to restore stress-induced synaptic loss in the hippocampus (131).

While abnormal projection of excitatory glutamate neurons in the brain regions could contribute to structural alteration, emotional stress and depression alter GABAergic function that impairs the fine-tune and control glutamate related excitatory function leading to dysfunction in these neural circuits (132, 133). Brain imaging studies have shown structural and functional alterations in depression, particularly the decreased volume of the hippocampus and the subgenual and anterior cingulate cortex of the prefrontal cortex (134, 135). Functional brain imaging shows dysfunction in three major networks related to depression, including default mode network (DMN) responsible for resting taste introspection and ruminations, the salience network (SAL) processing salient information from external sources and the central network (CEN) responsible for working memory and attention (136). Unlike the monoamine system with the main role of providing extrinsic inputs to the cerebral cortex, Glutamate provides both excitatory and inhibitory control of information flow in the brain (132, 137, 138).

The alteration of glutamate in CSF, blood and brain tissue related to synthesis, metabolism and reuptake into neuronal or glial cells is linked to decreased glutamate in the subgenual of anterior cingulate cortex associated with reduced connectivity with insula and decreased BOLD response to emotional stimuli in MDD patients (139). Alteration of the glutamatergic pathway could be linked to acute and chronic stress affecting specific circuits relevant to increased or decreased connectivity observed in individuals with MDD. Indeed, chronic stress is thought to cause atrophy of glutamate neurons contributing in volume reduction in cortical and limbic structures implicated in depression (63, 140). The alteration of glutamatergic neurons secondary to stress could also be attributed to neuroendocrine mechanism related to HPA and elevation of adrenal glucocorticoids which are implicated in the etiopathogenesis of depression. While administration of glucocorticoids may lead to dendritic atrophy and reduction in number of synapsis in the hippocampus and PFC, survival of neurons may be enhanced by downstream regulation of glucocorticoids by major neurotrophic factors such as (BDNF) which plays a role in regulation and function of neurons (141–145).

Non-invasive brain stimulation offers a potential alternative, non-pharmacological approach to treat unipolar depression and TRD. While pharmacological techniques have targeted the glutamatergic receptors as a therapeutic target for treating depressive disorders, neuromodulation techniques offer alternative or augmentative treatment for the same. Non-invasive brain stimulation techniques including the non-convulsive TMS and tDCS and convulsive ECT and MST provide safe options targeting specific areas in DLPFC which is a key site for the frontoparietal network (FPN). The rationale for neuromodulation for depression is based on a neural network theory that posits a specific set of structurally and functionally connected brain regions that work together to maintain normal mood regulation. However, little is known about the specific mechanisms and further research is needed to investigate the considerable potential of ionotropic and metabotropic receptors in relation to multi-target treatment of depressive disorders.

ME-G and KP-B conceptualized the idea. MK coordinated research activity planning and execution. GC-K acquired funding and worked on references. MK and SO reviewed and edited the manuscript. All authors approved the final version of the manuscript. All authors participated in writing the first draft of the manuscript.

The publication of this article was funded by Children's Hospital of Mexico Federico Gomez.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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