Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule

Table 1 Dietary glutamate and depression

Subject	Outcome	Ref.
Human	In non-obese participants, diets high in levels of glutamic acid were associated with greater depression symptomatology	Kumar et al[43]
Adult mice	While chronic immobilization stress decreased sodium-coupled neutral amino acid transporter (SNAT)-1 and 2 in neurons and glutamate transporter (GLT)1, SNAT3, and SNAT5 in astrocytes in the medial prefrontal cortex, glutamine—supplemented diet ameliorated these decrements	Baek et al[44]
Neonatal rats	Subcutaneous injection of monosodium glutamate (MSG) increased the immobility time in the forced swim test and the freezing reaction in the contextual fear conditioning. MSG also increased serotonin uptake in the cerebral cortices and caused deregulation of the hypothalamic-pituitary-adrenal axis	Quines et al[35]
Mice	Anxiolytic and memory-enhancing effects at low doses of MSG; however, at higher doses, anxiety and memory retardation were observed	Onaolapo et al[45]
Mice	Higher doses of dietary glutamate resulted in an increase in plasma glutamate and glutamine but no difference in total brain glutamate or glutamine levels	Onaolapo et al[21,45,46]
Mice	Anxiolytic response in females, and anxiogenic response in males following dietary MSG. A decrease in behavioural despair was observed in both sexes (females more than males)	Onaolapo et al[46,47]
Mice	Anxiogenic effect was observed following subchronic oral administration of MSG	Onaolapo et al[49]

Table 2 Endogenous glutamate and depression

Subject	Method	Outcome	Ref.
Human	Using a proton magnetic resonance spectroscopy technique	Compared to control subjects, glutamine levels in the cerebrospinal fluid of the depressed patients were elevated	Levine et al[54]
Human	High performance liquid chromatography with fluorometric detection	Plasma levels of glutamate as well as alanine and L-serine were reflective of the severity of depression	Mitani et al[55]
Human	Single voxel (1)H-Magnetic resonance spectroscopy in 19 patients with major depressive episodes	A significant decrease was observed in the levels of glutamate and glutamine in the anterior cingulate	Auer et al[56]
Human	Magnetic resonance spectroscopy	Depressed patients had reduced glutamine and glutamate levels in the dorsomedial/dorsal anterolateral prefrontal cortex	Hasler et al[57]
Human	Magnetic resonance spectroscopy	Compared with controls, depressed patients showed an increase in glutamine levels	Godlewska et al[59]
Human	Meta-analysis	Decreased levels of glutamatergic metabolites were observed in the medial frontal cortex of depressed subjects	Moriguchi et al[60]
Human	Meta-analysis	Glutamate and glutamine concentrations were found to be lower in the anterior cingulate cortex in patients compared to controls	Luykx et al[58]
Human	Functional magnetic resonance imaging and magnetic resonance spectroscopy	Patients with anhedonic major depression showed decreased glutamine but normal glutamate and gamma-aminobutyric acid concentrations	Walter et al[61]
Human	Resting state functional magnetic resonance imaging	Decreased amplitude of low frequency fluctuation level in right putamen and right middle temporal cortex correlated positively with glutamate concentration in female patients with depression	Zhang et al[66]
Mice	Preclinical study	Blockade of glutamate transporter-1 in the central amygdala and prefrontal cortex induced both anhedonia and anxiety	John et al[62,63]

Table 3 Gut brain axis and depression

Subject	Outcome	Ref.
Germ-free mice	Germ-free (GF) mice showed impaired social interactions, anxiety and derangement of brain-derived neurotrophic factor levels	Crumeyrolle-Arias et al[83], Huo et al[85], and Kamimura et al[86]
GF and SPF mice	Exposure of GF mice and specific pathogen-free (SPF) mice to chronic restraint stress paradigm revealed an increase in open field exploration time in GF compared to SPF mice. Also, SPF mice exhibited more anxiety-like behavior than GF mice under the same external stress	Arentsen et al[84]
C57BL/6J male mice	Chronic administration of prebiotic (fructo-oligosaccharides and galacto-oligosaccharides) have been associated with antidepressant and anxiolytic effects	Kamimura et al[86]
Glutamate and non-glutamate supplemented media	Gamma amino-butyric acid (GABA)-producing Lactococcus lactis strain increased GABA production in the glutamate supplemented medium	Burokas et al[87]

Table 4 Glutamate-based therapies in depression

Study	Receptor type	Outcome	Ref.
Randomized, double-blind study	NMDAR antagonist	A single subanaesthetic (0.5 mg/kg) dose of ketamine administered intravenously improved depressive symptoms within 72 h in seven persons with treatment resistant major depressive disorder (MDD)	Berman et al[68]
Double-blind, placebo-controlled, crossover study	NMDAR antagonist	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	Zarate et al[104]
Open label study	NMDAR antagonist	Rapid anti-depressant effects of a single ketamine infusion in persons with treatment-resistant bipolar depression	DiazGranados et al[105]
Preclinical	NMDAR antagonist	Memantine exhibited 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	Kitanaka et al[112]
Double-blind placebo controlled	NMDAR antagonist	Memantine administered at doses of between 5-20 mg/d, showed no significant effects on depression phenotypes	Parsons et al[110], Kos and Popik[111], and Muhonen et al[114]
Preclinical	NMDAR antagonist	The antidepressant effects of amantadine have been observed in situations where it is administered in combination with standard antidepressants such as fluoxetine and imipramine	Czarnecka et al[115] and Maj and Rogóz[116]
Preclinical	NMDA (NR2B) receptor blockers	Ro 25-6981 exhibited behavioural antidepressant-like effects in the forced swim test	Mathews et al[118] and Refsgaard et al[119]
Preclinical	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	Refsgaard et al[119]
Randomized, placebo-controlled, double-blind study	NR2B-selective NMDA antagonist	CP-101,606 demonstrated efficacy in treatment-refractory MDD subjects	Merchant et al[120]
Cross-over pilot study	NR2B-selective NMDA antagonist	Oral formulation of MK-0657 in persons with treatment-resistant MDD showed a significant antidepressant effect compared with placebo while no improvement in symptoms was noted using the primary efficacy measure	Preskorn et al[121]
Preclinical	AMPA-antagonist	LY392098 and LY451616 exhibited antidepressant effects in a number of animal models of depression; including the inescapable stressors, learned-helplessness models, and exposure to chronic mild stress models	Li et al[122] and Lauterborn et al[123]
Preclinical	mGLu	LY341495, MSG0039, and MPEP exhibited significant antidepressant effects in rodent models of behavioural despair	Jaso et al[7] and Chaki et al[130]

NMDA: N-methyl-D-aspartate; NMDAR: N-methyl-D-aspartate receptor; AMPA: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; mGLu: Metabotropic glutamate.