Copyright ©The Author(s) 2021.
World J Psychiatr. Jul 19, 2021; 11(7): 297-315
Published online Jul 19, 2021. doi: 10.5498/wjp.v11.i7.297
Table 1 Dietary glutamate and depression
HumanIn non-obese participants, diets high in levels of glutamic acid were associated with greater depression symptomatologyKumar et al[43]
Adult miceWhile 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 decrementsBaek et al[44]
Neonatal ratsSubcutaneous 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 axisQuines et al[35]
MiceAnxiolytic and memory-enhancing effects at low doses of MSG; however, at higher doses, anxiety and memory retardation were observedOnaolapo et al[45]
MiceHigher doses of dietary glutamate resulted in an increase in plasma glutamate and glutamine but no difference in total brain glutamate or glutamine levelsOnaolapo et al[21,45,46]
MiceAnxiolytic 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]
MiceAnxiogenic effect was observed following subchronic oral administration of MSG Onaolapo et al[49]
Table 2 Endogenous glutamate and depression
HumanUsing a proton magnetic resonance spectroscopy techniqueCompared to control subjects, glutamine levels in the cerebrospinal fluid of the depressed patients were elevatedLevine et al[54]
HumanHigh performance liquid chromatography with fluorometric detectionPlasma levels of glutamate as well as alanine and L-serine were reflective of the severity of depressionMitani et al[55]
HumanSingle voxel (1)H-Magnetic resonance spectroscopy in 19 patients with major depressive episodesA significant decrease was observed in the levels of glutamate and glutamine in the anterior cingulateAuer et al[56]
HumanMagnetic resonance spectroscopyDepressed patients had reduced glutamine and glutamate levels in the dorsomedial/dorsal anterolateral prefrontal cortexHasler et al[57]
HumanMagnetic resonance spectroscopyCompared with controls, depressed patients showed an increase in glutamine levelsGodlewska et al[59]
HumanMeta-analysisDecreased levels of glutamatergic metabolites were observed in the medial frontal cortex of depressed subjectsMoriguchi et al[60]
HumanMeta-analysisGlutamate and glutamine concentrations were found to be lower in the anterior cingulate cortex in patients compared to controlsLuykx et al[58]
HumanFunctional magnetic resonance imaging and magnetic resonance spectroscopyPatients with anhedonic major depression showed decreased glutamine but normal glutamate and gamma-aminobutyric acid concentrationsWalter et al[61]
HumanResting state functional magnetic resonance imagingDecreased amplitude of low frequency fluctuation level in right putamen and right middle temporal cortex correlated positively with glutamate concentration in female patients with depressionZhang et al[66]
MicePreclinical studyBlockade of glutamate transporter-1 in the central amygdala and prefrontal cortex induced both anhedonia and anxietyJohn et al[62,63]
Table 3 Gut brain axis and depression
Germ-free miceGerm-free (GF) mice showed impaired social interactions, anxiety and derangement of brain-derived neurotrophic factor levelsCrumeyrolle-Arias et al[83], Huo et al[85], and Kamimura et al[86]
GF and SPF miceExposure 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 stressArentsen et al[84]
C57BL/6J male miceChronic administration of prebiotic (fructo-oligosaccharides and galacto-oligosaccharides) have been associated with antidepressant and anxiolytic effectsKamimura et al[86]
Glutamate and non-glutamate supplemented mediaGamma amino-butyric acid (GABA)-producing Lactococcus lactis strain increased GABA production in the glutamate supplemented mediumBurokas et al[87]
Table 4 Glutamate-based therapies in depression
Receptor type
Randomized, double-blind studyNMDAR antagonistA 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 studyNMDAR antagonistA single ketamine infusion (0.5 mg/kg over 40 min) had a rapid, robust and mildly sustained antidepressant effect (1 wk) in treatment resistant MDDZarate et al[104]
Open label studyNMDAR antagonistRapid anti-depressant effects of a single ketamine infusion in persons with treatment-resistant bipolar depressionDiazGranados et al[105]
PreclinicalNMDAR antagonistMemantine 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 administrationKitanaka et al[112]
Double-blind placebo controlledNMDAR antagonistMemantine administered at doses of between 5-20 mg/d, showed no significant effects on depression phenotypesParsons et al[110], Kos and Popik[111], and Muhonen et al[114]
PreclinicalNMDAR antagonistThe antidepressant effects of amantadine have been observed in situations where it is administered in combination with standard antidepressants such as fluoxetine and imipramineCzarnecka et al[115] and Maj and Rogóz[116]
PreclinicalNMDA (NR2B) receptor blockersRo 25-6981 exhibited behavioural antidepressant-like effects in the forced swim testMathews et al[118] and Refsgaard et al[119]
PreclinicalNR2B-selective NMDA antagonistCP-101,606 that was well-tolerated and devoid of psychotropic side effects was also used in a clinical trial involving subjects with traumatic brain injuryRefsgaard et al[119]
Randomized, placebo-controlled, double-blind studyNR2B-selective NMDA antagonistCP-101,606 demonstrated efficacy in treatment-refractory MDD subjectsMerchant et al[120]
Cross-over pilot studyNR2B-selective NMDA antagonistOral 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 measurePreskorn et al[121]
PreclinicalAMPA-antagonistLY392098 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 modelsLi et al[122] and Lauterborn et al[123]
PreclinicalmGLuLY341495, MSG0039, and MPEP exhibited significant antidepressant effects in rodent models of behavioural despairJaso et al[7] and Chaki et al[130]