Table 1.

Glutamatergic drugs tested for use in mood disorders

Broad glutamatergic modulators	Mechanism of action	Evidence for depression	Route of administration	Dose	Acute side effects
Ketamine	NMDA antagonism and AMPA receptor activation	(1)	intravenous (also intramuscular, intranasal, oral, sublingual)	0.5mg/kg	Acute: transient psychotomimetic and dissociative effects, increased blood pressure and tachycardia. Chronic: possibly abuse, neurotoxicity, cystitis, and dissociative side effects
Esketamine	NMDA antagonism. Three- to four-fold higher affinity for NMDA receptors than ketamine	(2)	intravenous	0.20 mg/kg or 0.40 mg/kg	Most common side effects were nausea, headache, and transient dissociation
		(2)	intranasal	28mg, 56mg, and 84mg twice weekly for two weeks	Transient elevations in blood pressure and heart rate, but dissociative symptoms diminished with repeated dosing
Dextromethorphan	Non-selective, non-competitive NMDA receptor antagonist; also acts on opioid receptors and, at higher doses, as a sigma-1 receptor agonist and inhibitor of the serotonin and norepinephrine transporters	Not effective*	oral	60mg/day	NA
Nuedexta (combination of dextromethorphan and quinidine)	Same as above; also inhibits cytochrome 2D6, increasing dextromethorphan levels	(3)	oral	45 dextromethorphan/ 10mg quinidine twice daily	Gastrointestinal complaints, dizziness, and sedation; one patient reported severe insomnia
AVP-786 (combination of (d6)-dextromethorphan and quinidine)	Same as above; also inhibits cytochrome 2D6, increasing dextromethorphan levels	NA**	oral	NA	NA
Nitrous oxide (N2O)	Non-competitive NMDA receptor inhibitor; acts on other targets	(2)	inhalation	50% N2O/50% O2	Anxiety, headache, and nausea/vomiting
AZD6765 (lanicemine)	Low-trapping, non-selective NMDA receptor channel blocker	One large study was positive and a larger study was negative	intravenous	50 mg, 100mg, 150mg	No psychotic or dissociative side effects
Subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists
CP-101,606/traxoprodil☨	NR2B subunit NMDA selective antagonist	(2)	intravenous	0.75 mg/kg per hour for 1.5 hours followed by 0.15 mg/kg per hour for 6.5 hours	Potentially cardiotoxic (QTc prolongation)
MK-0657 (CERC-301)	NR2B subunit NMDA selective antagonist	Not effective	oral	20mg	No serious or dissociative side effects
Glycine-site partial agonists
D-cycloserine	Glycine partial agonist	(2)	oral	1,000mg/day	Frequent gastrointestinal symptoms, dizziness, sleep disturbances, peripheral neuropathy, depression, tinnitus, and visual disturbances; seizures and psychosis occur in <5% of patients.
GLYX-13	Glycine partial agonist	(2)	intravenous	5 or 10 mg/kg	Dizziness (10%), but no psychotomimetic properties or serious adverse events
Sarcosine	Glycine transporter-I inhibitor and potentiator for NMDA function	(2)	oral	1,000–1,500mg/day	Mild sleep-related complaints
AV-101	Highly selective glycine receptor antagonist	NA***	oral	1,080 or 1,440 mg/day	NA
Metabotropic glutamate receptor modulators
AZD2066	mGluR5 antagonist	Not effective	oral	12–18 mg/day	One serious adverse event; mild gastrointestinal symptoms, headache, and sleep-related complaints
RO4917523/basimglurant	mGluR5 negative allosteric modulator	Not effective	oral	0.5mg or 1.5mg/day	Dizziness (23%) and two cases of mania
JNJ40411813/ADX71149	mGluR2 positive allosteric modulator	Not effective	oral	50–150 mg	Vertigo was the most reported side effect
R04995819	mGluR2/mGluR3 antagonist and a negative allosteric modulator	Not effective	oral	5, 15, or 30mg/day	Not reported

Levels of evidence: (1) ≥2 double-blind, randomized-controlled trials (DB-RCT); (2) at least one double-blind, randomized-controlled trial; (3) Prospective uncontrolled trial with ≥10 subjects; Not effective - ineffective in at least one DB-RCT. AMPA - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA - N-methyl-D-aspartate.

^☨drug development stopped due to cardiotoxicity;

^*In bipolar depression;

^**completed;

^***ongoing study.