Table 2.

Completed double-blind, placebo-controlled trials assessing ketamine and other putative rapid-acting antidepressants

Drug	Study design	Drug administration regimen	Placebo	N	Patient condition	Primary outcome	Results	Ref
Ketamine	Double-blind, crossover	Single 0.5 mg/kg, 40-min intravenous infusion	Saline	9	Major and bipolar depressed patients	HDRS	Decrease in depression scores; Initial effect at 240 min; Sustained for at least 72 h	[20]
	Double-blind, crossover	Single 0.5 mg/kg, 40-min intravenous infusion	Saline	18	Treatment-resistant depressed patients	HDRS	Decrease in depression scores; Initial effect at 110 min; Sustained 7 days on average Maximum effect at 24 h post-infusion (drug effect: 71%; placebo: 0% response)	[21]
	Double-blind, crossover (augmentation to mood stabilizer)	Maintained lithium or valproate therapy + Single 0.5 mg/kg, 40-min intravenous ketamine infusion	Saline	18	Treatment-resistant bipolar depressed patients	MADRS	Decrease in depression scores; Initial effect at 40 min; Sustained 3 days on average Maximum effect at 48 h post-infusion (drug effect: 71%; placebo: 6% response)	[37]
	Double-blind, crossover (augmentation to mood stabilizer)	Maintained lithium or valproate therapy + Single 0.5 mg/kg, 40-min intravenous ketamine infusion	Saline	15	Treatment-resistant bipolar depressed patients	MADRS	Decrease in depression scores; Initial effect at 40 min; Sustained 3 days on average Maximum effect at 40 min post-infusion (drug effect: 71%; placebo effect: 0%)	[38]
	Double-blind, parallel arm	Single 0.5 mg/kg, 40-min intravenous infusion	Midazolam	73	Treatment-resistant depressed patients	MADRS	Decrease in depression scores; Initial effect at 24 h; Sustained 7 days on average Maximum effect at 24 h post-infusion (drug effect: 64%; placebo: 28% response)	[36]
	Double-blind, crossover	Single 0.54 mg/kg, 30-min intravenous infusion	Saline	27	Major depressed patients	MADRS	Decrease in depression scores; Initial effect at 24 h; Sustained 7 days on average Maximum effect at 24 h	[358]
	Double-blind, crossover	Single 50 mg intranasal administration	Saline	20	Major depressed patients	MADRS	Decrease in depression scores; Initial effect at 24 h; Sustained 7 days on average Maximum effect at 24 h	[24]
	Double-blind, parallel arm (augmentation to SSRIs)	Newly 4-week escitalopram treatment + Single 0.5 mg/kg, 40-min intravenous ketamine infusion	Saline	30	Major depressed patients	MADRS	By 4 weeks ketamine decreased depression score by 92.3 % versus 57.1 % for placebo Initial effect at 2 h	[359]
	Double-blind	0.5 mg/kg, 40-min intravenous infusion 2–3 times a week over a 15-day period	Saline	67	Treatment-resistant depressed patients	MADRS	Maintained antidepressant action for at least 15 days	[360]
(S)-ketamine	Double-blind, parallel arm	Single 0.2 or 0.4 mg/kg, 40-min intravenous infusion	Saline	29	Treatment-resistant depressed patients	MADRS	Decrease in depression scores (not dose-dependent); Initial effect at 2 h; Persisted 35 days (for 0.4 mg/kg dose) Maximum effect at 24 h (drug response: 64–67%; placebo response: 0%)	[35]
Memantine	Double-blind, parallel arm	Starting dose of 5 mg/day (capsules) up to a maximum of 20 mg/day for a total period of 8 weeks	Saline	26	Major depressed patients	MADRS	No statistical separation from the placebo control treatment	[110]
	Double-blind	One capsule daily; dosing titration: week 1, 5 mg/day; week 2, 10 mg/day; weeks 3–8, 20 mg/day	Saline	117	Major depressed patients	PANSS	No statistical separation from the placebo control treatment	[361]
	Double-blind, (augmentation to traditional antidepressant)	Flexible dose 5–20 mg/day (capsules); target dose of 20 mg/day; total augmentation period: 8 weeks	Saline	31	Major depressed patients (partial or non-responsive to their antidepressant)	MADRS	No statistical separation from the placebo control treatment	[362]
AZD6765 (lanicemine)	Double-blind	Single 100 mg, 60-min intravenous infusion	Saline	34	Treatment-resistant depressed patients	MADRS	No separation from placebo at 24 h post-infusion	[114]
	Double-blind	3-week period of 100–150 mg, 60-min intravenous infusions (3 non-consecutive infusions per week) – patients were allowed to be on their prior antidepressant medications	Saline	152	Treatment-resistant depressed patients	MADRS	Decrease in depression scores at 2 weeks following the last infusion	[114]
	Double-blind, parallel arm	15 intravenous infusions of 50 or 100 mg lanicemine over a 12-week period	Saline	240	Treatment-resistant depressed patients	MADRS	No significant separation between lanicemine and placebo treatment	[115]
CP-101,606 (taxoprodil)	Double-blind, parallel arm	40 mg paroxetine + 0.75 mg/kg CP-101,606 intravenous infusion for 1.5 h followed by 0.15 mg/kg/h for 6.5 h	Saline	30	Major depressed patients (paroxetine treatment non-responders)	MADRS	Decrease in depression scores 5 and 8 days post-treatment (8.4 and 6.2 point difference from placebo respectively) No antidepressant response 48 h post-treatment	[116]
MK-0657 (CERC-301)	Double-blind, crossover	Oral capsules of 4 mg/day and increased 2 mg/day until reaching 8 mg/day; total administration period - 12 days	Saline	5	Treatment-resistant depressed patients	MADRS	No significant improvement in patients receiving MK-0657 compared with placebo-treated controls Moderate decrease in HDRS scores on days 5–6, 9–10 and 12	[122]
GLYX-13 (Rapastinel)	Double-blind, parallel arm	Single 1, 5 or 10 mg/kg, 40-min intravenous infusion	Saline	116	Major depressed patients	HDRS	Decrease in depression scores; Initial effect at 24 h for all doses; Sustained 14 days on average (for 1 and 5 mg/kg) Maximum effect at 24 h; Sustained for at least 7 days	[127]
Scopolamine	Double-blind, crossover	15-min intravenous infusion of 4 μg/kg scopolamine for 7 sessions (3–4 days no-drug intervals between sessions)	Saline	20	Major and bipolar depressed patients	MADRS	Decrease in depression scores as soon as three days after the first treatment	[76]
	Double-blind, crossover	15-min intravenous infusion of 4 μg/kg scopolamine for 3 sessions (3–5 days no-drug intervals between sessions)	Saline	22	Major depressed patients	MADRS	Decrease in depression scores as soon as three days after the first treatment Initial session: drug response: 32%, placebo response: 6.5 % Second session: drug response: 53%; scopolamine’s effect persisted from the initial session	[77]
	Double-blind, crossover	15-min intravenous infusion of 4 μg/kg scopolamine for 3 sessions (3–5 days no-drug intervals between sessions)	Saline	5	Major depressed patients	MADRS	Decrease in depression scores following a single administration Sex-dependent antidepressant responses of the drug: 71% response for women; 38% response for men	[78]
RG1578 (decoglurant)	Double-blind, parallel arm	6-week treatment with 5, 15 or 30 mg RG1578	Saline	310	Treatment-resistant depressed patients (on SSRI or SNRI during the study)	MADRS	No significant improvement in patients receiving RG1578 compared with placebo-treated controls	[199]

Abbreviations: HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, serotonin-selective reuptake inhibitor