Glutamate is an α-amino acid that is useful in the biosynthesis of proteins and important in intermediary metabolism, through its ability to link carbohydrate and amino acid metabolism via the tricarboxylic acid cycle[39,40]. Glutamate (in addition to being synthesized in the body in humans) is also derived from dietary sources such as cheese, meat, and several food-seasonings including monosodium glutamate[21,41].

While endogenous brain glutamate has been linked to the pathophysiology of psychiatric conditions such as schizophrenia and mood disorders, the possible role of dietary glutamate (Table 1) in the development of neuropsychiatric conditions is still being evaluated[42]. There have been suggestions that the consumption of diets containing high concentrations of monosodium glutamate could increase body levels of glutamic acid, resulting in hyperglutamatergic neurotransmission, which could possibly contribute to the development of depression[43]. Also, a few studies have reported that factors such as chronic stress that reduce brain levels of glutamate and glutamine causing hypoactive glutamatergic signaling in the mouse prefrontal cortex are also associated with the development of depression[44], suggesting that regarding brain glutamatergic transmission a delicate balance always needs to be maintained.

In the last few years, reports from preclinical studies have associated the use of monosodium glutamate with the development of behavioural phenotypes such as anxiety and depression; and the ability to influence brain endogenous glutamate and glutamatergic neurotransmission[35,42,44-46]. There have also been reports from studies that monosodium glutamate could directly influence the concentrations of brain neurotransmitters such as serotonin and glutamate[21,35,45,47], although there have also been reports to the contrary[48].

The relationship between dietary monosodium glutamate and depression has been examined by a few studies[35,43,47]. The results of a clinical analysis that examined the relationship between the consumption of a diet high in glutamic acid and the development of depressive symptoms in a group of persons with schizophrenia revealed that in non-obese patients the consumption of high dietary glutamic acid was associated with an increase in depressive symptoms, although this was linked to the susceptibility of persons with one psychiatric condition to develop other co-morbidities[42]. A preclinical study by Quines et al[35] that examined the effects of monosodium glutamate administered parenterally in the neonatal period with exposure to behavioural paradigms on postnatal days 60-64 reported the presence of anxiety and behavioural despair. However, studies from our laboratory revealed that while orally administered monosodium glutamate was associated with the development of anxiety behaviour, especially in male mice[21,45,49], an antidepressant effect was observed in the behavioural-despair paradigms irrespective of sex[47]. The results of these studies from our laboratory suggest that the antidepressant response observed when monosodium glutamate was administered by gavage (compared to the response following parenteral administration) could have been influenced by the gut microbiota or the gut-brain axis, or by the ability of monosodium glutamate (at these doses) to minimally increase brain levels of glutamate which could have antidepressant benefits as previously reported[44].

Glutamate plays an important role in the modulation of synaptic plasticity and transmission. It is also the precursor of the inhibitory neurotransmitter gamma amino-butyric acid (GABA). Studies have shown that dysregulation of glutamatergic transmission or alterations in brain concentrations of glutamate is associated with derangement of brain function, development of excitotoxic brain injury, and cell death[24,47]. There have also been reports showing that alterations in glutamatergic neurotransmission contribute significantly to the development of peripheral and central nervous system disorders[50]. In the last few years, the possible relationships that exist between glutamate/glutamatergic system and the development of neuropsychiatric disorders such as depression have continued to be examined[22,24,51].

Several studies have linked dysregulation of glutamate neurotransmission with the development and progression of neurodevelopmental, neurodegenerative and psychiatric disorders such as autism, epilepsy and schizophrenia[52,53]. There is also emerging evidence (Table 2) linking the pathogenesis of depression to alterations in glutamate and glutamate signalling[12,52]. Levine et al[54], using a proton magnetic resonance spectroscopy (MRS) technique examined the relationship between cerebrospinal fluid (CSF) metabolites, such as glutamate and glutamine on depressive symptoms in hospitalized persons with severe unmedicated depression, and reported that compared to control subjects, glutamine level in the CSF of depressed patients was elevated. Also, using high performance liquid chromatography with fluorometric detection, Mitani et al[55] examined the relationship between plasma levels of glutamate on severity of depression and concluded that plasma levels of glutamate as well as alanine and L-serine were reflective of the severity of depression. The impact of brain glutamate levels on depression and depression phenotypes have been studied extensively[56-60]. Auer et al[56] and Hasler et al[57] using MRS reported region-specific changes in the levels of brain glutamate in patients with depression. The result of a recent meta-analysis of MRS studies also supported the hypothesis that glutamatergic neurotransmission was involved in the pathophysiology of depression[60]. In another meta-analysis, Luykx et al[58] also reported region and state specific alterations in glutamate and glutamine concentrations in depression. The importance of glutamatergic neurotransmission in depression has been further supported by studies that showed altered glutamine concentrations despite normal glutamate levels[59,61].

Abnormalities of the glutamatergic system such as those associated with glutamate clearance at the synaptic cleft and glutamate-related alterations in astrocytic energy modulation have also been observed in depression[61,62]. The results of preclinical studies have also demonstrated that blockade of astrocytic glutamate uptake in the prefrontal cortex and central nucleus of the amygdala was associated with the development of anhedonia and anxiety[62,63]. Furthermore, results from post-mortem and magnetic resonance imaging studies have also revealed the presence of altered expression of glutamate-related genes, elevated levels of glutamate, reduced glutamine/glutamate ratio, and/or reduced levels of glutathione (a reservoir of neuronal glutamate) in brain regions such as the medial prefrontal cortex (which have been linked to depression symptomatology) in persons with depression[64-67].

Finally, the rapid antidepressant effects of drugs such as tianeptine and NMDA receptor antagonist ketamine further validate the importance of glutamate and the glutamatergic transmission in depression[22,68,69]. While reports provide some evidence for the involvement of endogenous glutamate in the pathogenesis and treatment of depression[22,50,69,70], the complexity of the disorder would suggest that the dysregulation of glutamate needs to occur in multiple sites (Figure 1) such as the gastrointestinal tract and brain, as can be seen if there is a communication link involving exogenous glutamate, the gut, endogenous glutamate, and then the brain in a multidirectional pathway which we would call the “GLUTAMATE-GUT-GLUTAMATE-BRAIN AXIS”.

The impact of the gut (microbiota and gut peptides) in times past was not considered significant in brain development and functioning. Previously, it was believed that the commensal bacteria and their genes which constitute the gut microbiome enjoy a symbiotic relationship with man. In this relationship, they reside in a nutritionally enriched and protected habitat of the human gastrointestinal tract, while they in turn protect humans against colonization of the gut by pathogenic bacteria and provide the body with a rich source of indigestible nutrients. In the light of new evidence, it is now clear that they also play a key role in the brain, either in health or disease.

The gut-brain axis or microbiome-gut-brain axis describes the bidirectional, at times multidimensional system of communication that links the gastrointestinal tract with the central nervous system. It ensures that not only does the central nervous system modulate gastrointestinal function; the gut can also regulate or modulate brain signalling and impact brain structure and function[19]. There is now ample evidence supporting the view that the microbiome-gut-brain axis can influence the development or progression of central nervous system disorders. Some of these include observations of psychiatric co-morbidities occurring in several enteric neuropathies such as chronic inflammatory intestinal disorders[38,71,72]. The presence of altered gut microbial flora and concentration in neurodevelopmental disorders such as autism[73,74] as well as the results of microbial challenge using pathogenic bacteria or pharmacological manipulations with pre or probiotics, are also pointers to the possible roles played by the gut microbiota in the development of brain disorders[72,75]. Further reports have also shown that the gut microbiota influences brain function via its ability to modulate endocrine, immunologic and neurocrine signalling pathways; and brain neurotransmitters[38,76].

Also, several possible mechanisms through which microbiome-gut-brain communication could impact the genesis or progression of central nervous system disorders have been proposed. There have been suggestions that communications occur through the activation of neurotransmitters such as serotonin, dopamine, GABA and noradrenaline in the enteric nervous system; these neurotransmitters are secreted by gut microbiota and are akin to the neurotransmitters in the central nervous system[76]. The possible role of gut peptides and metabolites as mediators of the gut-brain crosstalk have also been suggested[77].

Studies have continued to demonstrate the deleterious effects that alterations in gut microbiome composition and microbiome-related metabolites could exert on the development of obesity, autoimmune disorders, inflammatory bowel disease, irritable bowel syndrome, and neuropsychiatric disorders[77-80]. Also, scientific information showing how gut microbes and gut stimuli (such as intragastric infusion of glucose or fatty acid) can directly influence emotional and cognitive functions[81,82] are pointers to the possible involvement of the gut-brain axis in psychiatric disorders. Several preclinical studies have also shown that the gut microbiota modulates brain behaviours such as behavioural despair, anhedonia and anxiety-like behaviours that have construct validity with clinical depression and anxiety[83-86]. Arentsen et al[84] and Kamimura et al[86] showed that compared to specific pathogen-free (SPF) mice, germ-free (GF) mice showed impaired social interactions choosing to spend more time with an object than conventionally raised mice. Huo et al[85] also observed that the exposure of GF mice and SPF mice to chronic restraint stress paradigm was associated with an increase in open field exploration time in GF compared to the SPF mice; with SPF mice exhibiting more anxiety-like behaviours compared to GF mice. Chronic prebiotic administration has also been shown to exhibit anxiolytic and antidepressant behaviours in mice. The ability of the prebiotic to modulate behaviour correlated positively with its effects on hippocampal and hypothalamic gene expression and its ability to ensure a balance in the concentrations of short-chain fatty acids[87].

Although the mechanisms by which the gut microbiota influences mood and mood-related behaviours are still being studied; there have been suggestions that because the gut and brain share peptide and receptor similarities the gut microbiome is able to modulate brain function through the activity of gut peptides[77]. Also, studies evaluating the impact of gut microbiome modulation (using prebiotics and probiotics) on brain function have demonstrated that chronic treatment with prebiotic had both antidepressant and anxiolytic effects, which could be linked to reduction in stress-induced corticosterone and proinflammatory cytokine release, and modification of the expression of specific genes in the hippocampus[86,87]. Also, probiotics such as GABA-producing Lactococcus lactis strain have been shown to possess the capacity to modulate behaviours. In one study, in which Lactococcus lactis was grown in both glutamate and non-glutamate supplemented media, a significant increase in GABA production was observed in the glutamate supplemented medium[87], reinforcing the importance of glutamate in the modulation of mood and mood disorders.

There is now ample evidence suggesting that microbes play the role of signalling components in the gut-brain axis. This emerging concept of a microbiota-gut-brain axis suggests that our ability to modulate the gut microbiota may be a potential tool towards the development of novel therapies for complex brain disorders such as psychiatric disorders[19,71,72] (Table 3).

Glutamate is a multifunctional amino acid that is involved in intermediary metabolism in the gastrointestinal tract and is also crucial for the normal functioning and development of the brain. In the gut, it is derived from exogenous sources including dietary proteins and from free glutamate present in food additives; also, a fraction of the free glutamate in the lumen is from bacterial synthesis[88]. In the central and enteric nervous systems, respectively, glutamate is the major excitatory neurotransmitter[50,89].

Glutamate and the glutamatergic pathways are also crucial to microbiota-gut-brain communication. There is increasing evidence that glutamate is both a neurotransmitter and neuromodulator of several functions[77,89]. Glutamate receptors and their transduction molecules have been demonstrated on the epithelial cells of the gut, splanchnic, vagal, and/or pelvic afferents[89-91]. The stimulation of gut glutamate receptors by dietary or luminal glutamate has been associated with the activation of vagal afferents which directly or indirectly influence brain areas such as the cerebral cortex, limbic system, hypothalamus and basal ganglia[90,92]. Also, the activation of glutamate receptors present on splanchnic, vagal, and/or pelvic afferents, allows the communication of sensory inputs to regions of the brain involved in the gut-brain axis, while, also influencing efferent pathways that convey excitatory or inhibitory inputs to the gastrointestinal tract[89,91].

While in health, the enteric ganglia and the brain are impermeable to dietary or luminal glutamate; there have been reports suggesting that glutamate permeability in these systems increases in diseased states such as enteric neuropathies, or conditions that alter the integrity of the blood-brain-barrier. The gut microbiome also influences brain glutamate, with the results of metabolomic studies revealing that alterations in the composition of the gut saprophytic microflora also affected brain concentrations of glutamate[93,94]. Although there is enough scientific evidence in support of the impact of central glutamate and the glutamatergic system in depression, there is however a dearth of information regarding the possible ways luminal glutamate (either from dietary sources or microbial activities) may influence depression pathophysiology.

However, from the foregoing, it is evident that while exogenous glutamate (from dietary sources or secreted by gut microbiota) can influence brain function through activation of the gut glutamatergic pathways, endogenous glutamate can be influenced by gut microbial composition or metabolites to impact brain function. This shows that glutamate may be more important in the bidirectional communication system of the microbiome-gut-brain axis than previously considered.

Ketamine: In humans, ketamine’s ability to alleviate depressive symptoms (Table 4) was first highlighted by a small, randomized, double-blind study demonstrating that a single subanaesthetic (0.5 mg/kg) dose of ketamine administered intravenously improved depressive symptoms within 72 h in seven persons with treatment resistant MDD[68]. A larger, double-blind, placebo-controlled, crossover study also found that a single ketamine infusion (0.5 mg/kg over 40 min) had a rapid, robust and mildly sustained antidepressant effect (1 wk) in treatment-resistant MDD[104]. Adverse effects that included confusion, euphoria, dizziness, perceptual disturbances, blood pressure elevation and increased libido were self-limiting[104].

Since the first clinical study that demonstrated the antidepressant effects of ketamine, several other studies have continued to examine its efficacy across other depression phenotypes[104,105]. Diazgranados et al[105] demonstrated the rapid anti-depressant effects of a single ketamine infusion in persons with treatment-resistant bipolar depression, which was replicated in a double-blind, randomized, crossover, placebo-controlled study[104]. The impact of ketamine on reducing suicides has also been examined. Ketamine was reported to have a rapid and significant anti-suicidal effect in persons with MDD[101]. While the discovery of ketamine’s antidepressant effect was met with enthusiasm, its associated sedative and psychotomimetic effects remain limitations to its use. Therefore, efforts continue to be directed towards blunting these effects. Studies have tried to research the effects of augmenting ketamine with other drugs that are probably better-tolerated; these drugs such as riluzole and lamotrigine have been examined for their ability to either improve ketamine antidepressant effects and/or reduce its psychotomimetic effects[106-108]. However, a number of these studies reported that these add-ons showed no significant ability to improve the course of the antidepressant response (compared to ketamine alone) or reduce the side effects of ketamine[107,108]. Anand et al[106] on the other hand reported lamotrigine’s ability to decrease the perceptual abnormalities induced by ketamine.

Memantine and amantadine: The dampening of the enthusiasm that arose from the rapid and robust antidepressant effects of ketamine due its psychotomimetic side-effects prompted research into the possible antidepressant activities of other non-competitive NMDA receptor antagonists such as memantine, which has been reported to be devoid of these effects, at least at therapeutic doses[109-111]. The anti-depressant effects of memantine, a low-affinity, non-competitive, open-channel NMDA receptor antagonist which is approved for use in the management of Alzheimer’s disease has been extensively studied [104,112]. The results of a preclinical study by Kos and Popik[111] revealed a dose-dependent antidepressant-like response in the tail-suspension test, with the response observed at a dose of 15 mg/kg persisting with sub-chronic administration. However, the results of clinical studies have shown mixed results[110,111]. In one double-blind, placebo-controlled trial in which memantine was administered at doses of between 5-20 mg/d, no significant effects were observed[113]. This result was also supported by another double-blind placebo-controlled study that examined the effect of memantine administered at 10 mg/kg on late-onset depression[113]. However, the result of a large double-blind randomized Finnish study reported a significant antidepressant effect with memantine in persons with co-morbid alcohol dependence[114].

Amantadine is another NMDA receptor antagonist with possible influence on the serotonergic, dopaminergic and monamine-oxidase systems. The antidepressant effects of amantadine have been observed in situations where it is administered in combination with standard antidepressants such as fluoxetine and imipramine[115,116]. However, clinical trials are limited, mostly using amantadine as an augmentation agent (up to 300 mg/daily) in treatment resistant MDD, where it had shown some modest effects[117].

Subtype-selective NMDA (NR2B) receptor blockers: Investigations into subtype-selective blockers of the NMDA receptor (Table 4) have also been undertaken to by-pass the psychotomimetic effects of ketamine. Along this line, agents such as Ro 25-6981 that can block NR2B receptors have been studied. In preclinical experiments, the NR2B antagonist Ro 25-6981 exhibited behavioural antidepressant-like effects in the forced swim test[118]. The NR2B-selective NMDA antagonist (CP-101,606) that was well-tolerated and devoid of psychotropic side effects was also used in a clinical trial involving subjects with traumatic brain injury[119].

Other selective NMDA NR2B antagonists such as MK-0657 have also been examined. Again, in a randomized, placebo-controlled, double-blind study, the anti-depressant efficacy of CP-101,606 was demonstrated in treatment-refractory MDD subjects[120], while the result of a crossover pilot study that evaluated the potential antidepressant efficacy and tolerability of an oral formulation of MK-0657 in persons with treatment-resistant MDD observed a significant antidepressant effect compared with placebo using recognized secondary efficacy scales; with no improvement noted when symptoms were assessed using the primary efficacy measure[121].

The AMPA glutamate receptors are main contributors in excitatory neurotransmission, as they mediate the fast, rapidly desensitizing excitation of many synapses. The potential beneficial role of AMPA receptor modulators (Table 4) in the treatment of mood disorders has been highlighted by studies that have shown that AMPA receptor potentiators such as LY392098 and LY451616 possess antidepressant effects in a number of animal models of depression; including the inescapable stressors, learned-helplessness models, and exposure to chronic mild stress models[122]. Also, they do not seem to affect the extracellular concentration of monoamines[122]; yet they enhance the neurotrophic actions of BDNF mRNA and protein in primary neuronal cultures[122,123]. However, of the AMPA receptor positive allosteric modulators being investigated for MDD treatment, ORG-26576 was amongst the most-promising until it failed Phase II trial. Currently, while the potential roles of AMPA receptor modulators in experimental models of depression are still being researched, the world is still waiting for drugs whose actions are primarily linked to this. Stimulation of the AMPA receptor has also been associated with mediating the antidepressant-like effects of ketamine and group II mGlu receptor antagonist MGS0039[124], with suggestions that increased transmission via glutamatergic AMPA receptors possibly provide a common mechanism of antidepressant response[51].

Kainate receptors are now recognized as important mediators of the pre- and postsynaptic actions of glutamate and GABA, through mechanisms that are still being evaluated[125]. The results of some studies have associated genetic variations in certain kainate receptor subtypes with the therapeutic outcome of antidepressant medications like citalopram and venaflaxine[125-127]. While it is generally accepted that kainate receptors have modulatory effects on synaptic transmission, the paucity of selective kainate receptor subtype agonists or antagonists has hampered research into the possible mechanisms through which kainite receptors modulate brain function and/or impact the pathogenesis and treatment of depressive disorders[125].

mGlu receptors have been shown to regulate glutamate’s neuronal transmission through the ability to alter neurotransmitter release or modulate the post-synaptic responses to glutamate release. There is enough evidence from studies to support the notion that regulation of glutamatergic neurotransmission through mGlu receptors is associated with the development of mood, leading to suggestions that they could serve as novel targets in depression management[128,129]. Modulation of the mGlu receptor has also been reported to increase neurogenesis and neurotransmitter release that has now been associated with therapeutic response in humans[128]. Several mGlu2, mGlu3 and mGlu5 receptors’ (Table 4) negative allosteric modulators (LY341495, MSG0039, MPEP) have been reported to have significant antidepressant effects in rodent models of behavioural despair[7,130]. Also type III mGluRs (4-8) are mostly expressed presynaptically, modulating glutamate release and response; but while a number of preclinical studies have identified possible type III mGluR novel drug targets such as the mGluR7[131,132], there is a dearth of clinical studies evaluating the possible therapeutic benefits of these type III mGluRs in depression. There have however been reports that a positive allosteric modulator of mGluR7 (AMN082) has antidepressant-like properties in rodent models of behavioural despair[7], that can be linked to its ability to modulate glutamate transmission in the hippocampus[133].