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. Author manuscript; available in PMC: 2018 Jun 18.
Published in final edited form as: CNS Drugs. 2018 Mar;32(3):197–227. doi: 10.1007/s40263-018-0492-x

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