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

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.