Table 1.
Trials of ketamine efficacy for depression meeting inclusion criteria.
| Author | Design | Diagnosis | Sample |
Treatment |
||
|---|---|---|---|---|---|---|
| Experimental group | Control group | Experimental group | Control group | |||
| Berman et al. (2000) | Single dose Crossover—washout ≥1 week |
DSM-IV | 9 | – | IV racemic 0.5 mg/kg | Saline placebo |
| Zarate et al. (2006) | Single dose Crossover—washout ≥1 week |
DSM-IV HAMD-21 ≥ 18 failed ≥2 antidepressants | 18 | – | IV racemic 0.5 mg/kg | Saline placebo |
| Diazgranados et al. (2010) | Single dose Crossover—washout ≥2 weeks |
DSM-IV MADRS ≥20 failed ≥1 antidepressant & ≥ 1 mood stabiliser | 18 | – | IV racemic 0.5 mg/kg | Saline placebo |
| Zarate et al. (2012) | Single dose Crossover—washout ≥2 weeks |
DSM-IV MADRS ≥20 failed ≥1 antidepressant & ≥ 1 mood stabiliser | 15 | – | IV racemic 0.5 mg/kg | Saline placebo |
| Murrough et al. (2013) | Single dose Parallel |
DSM-IV IDS-C ≥ 32 | 47 | 25 | IV racemic 0.5 mg/kg | Midazolam 0.045 mg/kg |
| Sos et al. (2013) | Single dose Crossover—washout ≥1 week |
DSM- IV MADRS ≥20 failed ≥3 antidepressants | 30 | – | IV racemic 0.27 mg/kg loading 0.27 mg/kg maintenance | Saline placebo |
| Lai et al. (2014) | Up to 5 treatmentsa Crossover—washout ≥1 week |
DSM-IV MADRS ≥20 failed ≥5 antidepressants | 4 | – | IV racemic ketamine 0.1, 0.2, 0.3 & 0.4 mg/kg | Saline placebo |
| Lapidus et al. (2014) | Single dose Crossover—washout ≥1 week |
DSM-IV IDS-C ≥30 failed ≥1 antidepressant | 20 | – | IN racemic ketamine 50 mg | Saline placebo |
| Downey et al. (2016) | Single dose Parallel |
DSM-IV | 21 ketamine 20 lanicemineb | 19 | IV racemic ketamine 0.5 mg/kg, lanicemine 100 mg | Saline placebo |
| Hu et al. (2016) | Single dose Parallel |
DSM-IV HDRS-17 ≥24 | 13 | 14 | IV racemic ketamine 0.5 mg/kg | Saline placebo |
| Li et al. (2016) | Single dose Parallel |
DSM-IV failed ≥3 medications | 32 | 16 | IV racemic ketamine 0.2 & 0.4 mg/kg | Saline placebo |
| Loo et al. (2016) | Up to 5 treatmentsc Crossover—washout ≥1 week |
DSM IV MADRS ≥20 failed ≥1 antidepressant | 15 | – | IV, IM & SC racemic ketamine 0.5 mg/kg | Midazolam 0.01 mg/kg |
| Singh et al. (2016a) | 2 treatmentsd Parallel |
DSM-IV IDS-CR ≥ 34 failed ≥2 antidepressants | 20 | 10 | IV esketamine 0.2 & 0.4 mg/kg | Saline placebo |
| Singh et al. (2016b) | 4 treatments twice weekly & 6 treatments thrice weekly Parallel |
DSM-IV IDS-CR ≥34 failed ≥2 antidepressants | 18 × 2 weekly, 17 × 3 weekly |
17 × 2 weekly, 16 × 3 weekly | IV racemic ketamine 0.5 mg/kg | Saline placebo |
| George et al. (2017) | Up to 5 treatmentse Crossover—washout ≥1 week |
DSM IV MADRS ≥20 failed ≥1 antidepressant | 16 | – | SC racemic ketamine 0.1, 0.2, 0.3, 0.4 & 0.5 mg/kg | Midazolam 0.01 mg/kg |
| Grunebaum et al. (2017) | Single dose Parallel |
DSM-IV HDRS-17 ≥16 | 7 | 9 | IV racemic ketamine 0.5 mg/kg | Midazolam 0.02 mg/kg |
| Su et al. (2017) | Single dose Parallel |
DSM-IV failed ≥2 antidepressantsss | 23, 24 | 24 | IV racemic ketamine 0.2 & 0.5 mg/kg | Saline placebo |
| Arabzadeh et al. (2018) | 84 treatments twice weekly Parallel |
DSM-V HDRS-17 ≥20 | 41 | 40 | O racemic ketamine 50 mg/day | Saline placebo |
| Canuso et al. (2018) | 8 treatments Parallel |
DSM-IV-TR MADRS ≥22 | 35 | 31 | IN esketamine 84 mg | Saline placebo |
| Cao et al. (2018) | Single dose Parallel |
DSM-IV-TR HDRS-17 ≥ 18 failed ≥2 antidepressants | 55 | 18 | IV racemic ketamine 0.2 & 0.5 mg/kgf | Saline placebo |
| Chen et al. (2018) | Single dose Parallel |
DSM-IV-TR failed ≥3 antidepressants | 8, 8 | 8 | IV racemic ketamine 0.2 & 0.5 mg/kg | Saline placebo |
| Daly et al. (2018) | Single dose Parallel |
DSM-IV-TR IDS-CR ≥ 34 failed ≥2 antidepressants | 11, 11, 12 | 33 | IN esketamine 28, 56 & 84 mg | Saline placebo |
| Fava et al. (2018) | Single dose Parallel |
DSM-IV-TR MADRS ≥20 failed ≥2 antidepressants | 18, 20, 22, 20 | 19 | IV racemic ketamine 0.1, 0.2, 0.5 & 1.0 mg/kg | Midazolam 0.045 mg/kg |
| Gálvez et al. (2018) | 8 treatments Parallel |
DSM-V-TR MADRS ≥22 failed ≥2 antidepressants | 3 | 2 | IN racemic ketamine 100 mg | Midazolam 4.5 mg |
| Grunebaum et al. (2018) | Single dose Parallel |
DSM-IV-TR HDRS-17 ≥ 16 | 40 | 40 | IV racemic ketamine 0.5 mg/kg | Midazolam 0.02 mg/kg |
| Nugent et al. (2018) | Single dose Crossover—washout ≥2 weeks |
DSM-IV MADRS ≥20 failed ≥1 antidepressant | 35 | – | IV racemic ketamine 0.5 mg/kg | Saline placebo |
| Sinyor et al. (2018) | 6 treatments Parallel |
MINI SSI >20 | 5 | 4 | IV racemic ketamine 0.5 mg/kg | Midazolam 0.045 mg/kg |
| Domany et al. (2019) | 9 treatments Parallel |
MINI MADRS ≥19 failed ≥2 antidepressants | 22 | 19 | O racemic ketamine 1.0 mg/kg | Saline placebo |
| Fedgchin et al. (2019) | 8 treatments Parallel |
DSM-IV MADRS ≥28 failed ≥2 antidepressants | 117, 116 | 113 | IN esketamine 56 & 84 mg | Saline placebo with bittering agent |
| Ionescu et al. (2019) | 6 treatments Parallel |
DSM-IV HDRS-28 ≥20 failed ≥3 antidepressants | 13 | 13 | IV racemic ketamine 0.5 mg/kg | Saline placebo |
| Phillips et al. (2019) | Single dose Crossover—washout ≥1 week |
DSM-IV-TR MADRS ≥25 failed ≥2 antidepressants | 43 | – | IV racemic ketamine 0.5 mg/kg | Midazolam 30 μg/kg |
| Popova et al. (2019) | 8 treatments Parallel |
DSM-V IDS-CR ≥34 failed ≥2 antidepressants | 114 | 109 | IN esketamine 56 & 84 mg | Saline placebo with bittering agent |
| Domany et al. (2020) | Single dose Parallel |
DSM-IV-TR C-SSRS ≥3 | 9 | 9 | IV racemic ketamine 0.2 mg/kg | Saline placebo |
| Fu et al. (2020) | 8 treatments Parallel |
DSM-V MADRS >28 | 111 | 112 | IN esketamine 84 mg | Saline placebo with bittering agent |
| Milak et al. (2020) | Single dose Parallel |
DSM-IV MADRS ≥22 | 5, 6, 8, 5, 9 | 5 | IV racemic ketamine 0.1, 0.2, 0.3, 0.4 & 0.5 mg/kg | Saline placebo |
| Ochs-Ross et al. (2020) | 8 treatments Parallel |
DSM-V IDS-CR ≥31 failed ≥2 antidepressants | 72 | 66 | IN esketamine 84 mg | Saline placebo with bittering agent |
| Shiroma et al. (2020) | 6 treatments Fg Parallel |
DSM-IV-TR IDS-CR ≥ 32 failed ≥2 antidepressants | 25 | 29 | IV racemic ketamine 0.5 mg/kg | Midazolam 0.045 mg/kg |
| Sumner et al. (2020) | Single dose Crossover—washout ≥3 weeks |
DSM-IV MADRS ≥20 failed ≥2 treatments—drug or psychological | 30 | – | IV racemic ketamine 0.5 mg/kg | Remifentanil 1.7 ng/ml |
| Tiger et al. (2020) | Single dose Parallel |
MINI MADRS ≥20 failed ≥1 selective serotonin reuptake inhibitor | 20 | 10 | IV racemic ketamine 0.5 mg/kg | Saline placebo |
| Dwyer et al. (2021) | Single dose Crossover—washout ≥2 weeks |
DSM-V CDRS-R >40 failed ≥1 antidepressant | 17 | – | IV racemic ketamine 0.5 mg/kg | Midazolam 0.045 mg/kg |
| Ionescu et al. (2021) | 8 treatments Parallel |
DSM-V MADRS >28 | 114 | 113 | IN esketamine 84 mg | Saline placebo with bittering agent |
| Lijffijt et al. (2021) | Single dose Parallel |
DSM-V MADRS ≥27 | 20 | 13 | IV racemic ketamine 0.1, 0.25 & 0.5 mg/kg | Midazolam 0.03 mg/kg |
| Takahashi et al. (2021) | 8 treatments Parallel |
DSM-V MADRS ≥20 failed ≥1 & <5 antidepressants | 122 | 80 | IN esketamine 28, 56 & 84 mg | Saline placebo |
| Gallagher et al. (2022) | 4 treatments Parallel |
DSM-V HDRS-24 ≥27 | 13 | 12 | IV racemic ketamine 0.5 mg/kg | Midazolam 0.045 mg/kg |
| Ahmed et al. (2023) | 2 treatments Parallel |
“current diagnosis of treatment-resistant MDD” failed ≥2 antidepressants | 18 | 18 | IV racemic ketamine 0.5 mg/kg | Saline placebo |
| Loo et al. (under review) | 8 treatments Parallel |
DSM-V MADRS ≥20 failed ≥2 antidepressants | 86 | 88 | SC racemic ketamine 0.5 & 0.5–0.9 mg/kg | Midazolam 0.025 & 0.025–0.045 mg/kg |
| NCT02106325 | Single dose Parallel |
MINI MADRS ≥24 | 11 | 10 | IV racemic ketamine 0.25 mg/kg | Diphenhydramine 25 mg |
| NCT03434041 | 8 treatments Parallel |
DSM-V MADRS ≥28 failed ≥1 & ≤5 antidepressants | 124 | 126 | IN esketamine 56–84 mg | Intranasal spray |
| NCT03539887 | Single dose Parallel |
DSM-IV-TR MADRS ≥12 | 17 | 11 | IN racemic ketamine 50 mg | Saline placebo |
CDRS-R: Children's Depression Rating Scale–Revised, C-SSRS: Columbia Suicide Severity Rating Scale, DSM: Diagnostic and Statistical Manual of Mental Disorders, HDRS: Hamilton Depression Rating Scale, IDS-CR: Inventory of Depressive Symptomatology—Clinician Rating, MADRS: Montgomery-Asberg Depression Rating Scale, MDD: Major Depressive Disorder, MINI: Mini International Neuropsychiatric Interview, SSI: Scale of Suicidal Ideation, IV: Intravenous, IN: Intranasal, SC: subcutaneous, O: oral, IM: intramuscular.
a
Data from first dose analysed only.
b
Lanicemine group not included in analyses.
c
Data from first dose analysed only.
d
Data from before the second dose was analysed as responders/non-responders received dose-escalation.
e
Data from first dose analysed only.
f
Results were presented for both active conditions combined (0.2 and 0.5 mg/kg) so the weighted combined average was calculated for analysis.
g
Data was extracted from the first five treatments only as the final sixth dose was active in both ketamine and midazolam experiment arms.