Table 1.
Summary of prospective studies, including RCTs and open-label studies
| Study | Design | Inclusion criteria | Intervention groups | Antidepressant effects | Response rate | Relapse rate | Safety and tolerability | Limitations | Prolonged | TRD |
|---|---|---|---|---|---|---|---|---|---|---|
| aan het Rot et al. [22] | Single arm, open-label, 12 days |
Aged over 18 years Previously responded to a single IV ketamine dose (≥ 50% reduction in MADRS) MDD, lack of response to ≥ 2 antidepressants trials in current MDE |
Ketamine 0.5 mg/kg IV 6 times over 12 days (n = 10 starting, n = 9 completing) No control group |
For participants who completed the study (9/10; 1 withdrew for nonresponse) by dose 6 all had significant improvement in depressive symptoms (mean reduction in MADRS of 85%); no significant changes in peak BPRS+ scores (χ2(5) = 3.41, P = 0.6) were seen across the 6 doses |
Response criteria: ≥ 50% reduction in MADRS score from the pre-ketamine baseline Response rate 90% (9/10) |
88.9% (8/9) relapsed on average 19 days after sixth infusion (range 6–45 days) |
Mild, transient AEs with significant dissociative effects in n = 3 Most common AEs: abnormal sensations, headache, and weakness or fatigue |
Lack of formal cognitive testing Compared efficacy of single IV ketamine dose to other pre-selected samples with favorable responsivity No control group |
Y | Y |
| Abdallah et al. [33] | RCT, 2 week |
Aged 21–65 years MDD with ongoing MDE (MADRS ≥ 18) Lack of response to ≥ 1 antidepressant trial in current trial |
Rapamycin 6 mg or placebo 2 h prior to ketamine 0.5 mg/kg IV (n = 23) | Significant prolongation of antidepressant effects observed after week 2 by time interaction (F(8,245) = 2.02, P = 0.04). A higher response rate (41%) and remission rates (29%) following rapamycin + ketamine versus placebo + ketamine (13%, P = 0.04, and 7%, P = 0.003) |
Response criteria: 50% reduction in MADRS score Response rate 41% (n = 7/17) |
Not reported in study |
Mild, transient AEs with significant dissociative effects Most common AEs: fatigue, headaches, nausea, and pain |
Lacked treatment by time interaction which may result in limited statistical power Unclear method for monitoring AEs (suicide ideation) |
Y | Y |
| Chen et al. [23] | RCT, 6 week |
Aged 21–65 years MDD or BP disorder or MDE (HAM-D ≥ 16) Response (≥ 50% reduction of HAM-D) after single ketamine dose Lack of response to ≥ 2 antidepressant trials |
Ketamine 0.5 mg/kg IV twice, then increasing DCS daily (250–1000 mg) (n = 16) vs ketamine 0.5 mg/kg IV twice with placebo (n = 16) | Significant antidepressant effect observed on day 4 after two doses of ketamine (P = 0.003); no significant HAM-D reduction in follow-up between DCS or placebo (P = 0.30) |
Response criteria: ≥ 50% reduction of HAMD Response rate 65.6% (21/32) |
Not reported in study |
Mild, transient non-significant AEs in DCS group include dizziness, sedation, hand tremor, and itching No significant difference in AEs between groups |
Lacked independent study of DCS treatment, other antidepressant treatments were not discontinued Unclear method for monitoring AEs (suicide ideation) All participants had responded to ketamine; unclear if extrapolation to those with severe suicidal symptoms is possible |
Y | Y |
| Costi et al. [24] | RCT, 2 week |
Aged 21–65 years MDD with ongoing MDE (QIDS-SR ≥ 14; CGI-S ≥ 4) Lack of response to ≥ 2 antidepressant trials (≤ 50% improvement) |
Ketamine 0.5 mg/kg IV once, then increasing lithium daily (600–1200 mg) (n = 18) vs ketamine 0.5 mg/kg IV twice with placebo (n = 16) | No significant difference in depression severity between treatment groups at week 2 (P = 0.91); also, no difference between treatment groups in continuing the antidepressant effect of ketamine | Not reported in study | Relapse rate at end of 2-week study was 25% (2/8) |
Mild, transient AEs with significant dissociative effects No significant difference in AEs between groups |
Low lithium treatment dosages Too short a study duration to see full potential effects TRD sample limits generalizability to broader MDD population |
Y | Y |
| Cusin et al. [25] | Single arm, open-label, 3 week |
Aged 18–65 years MDD with ongoing MDE (HAM-D ≥ 20) Lack of response to ≥ 3 antidepressant trials in current trial Suicide ideation for > 3 months |
Ketamine 0.5–0.75 mg/kg IV 6 times (n = 14 starting, n = 12 completing) No control group |
Significant antidepressant effect observed after week 3 (response rate 41.7%; remission rate 16.7%) Improvements in HAM-D scores approached statistical significance at week 3 (Cohen d = 0.48; P = 0.052); however, significant differences in HAM-D scores were observed after week 6 (Cohen d = 1.01; P = 0.002). 80% (4/5) of responders had prolonged antidepressant effects for 2 weeks, and 1/5 for 6 weeks |
Response criteria: ≥ 50% reduction of HDRS Response rate 35.7% (5/14) |
Relapse rate at 2-week FU 80% (4/5) |
Mild, transient AEs with no significant dissociative effects Most common: headache and nausea |
No control group Unclear method for monitoring AEs Unclear if symptom improvement between doses 1–6 were related to increased dosage or cumulative effect |
Y | Y |
| Ibrahim et al. [26] | RCT, 4 week |
Aged 18–65 MDD with ongoing MDE (MADRS ≥ 22) Lack of response to ≥ 2 antidepressant trials (≤ 25% MADRS) |
Ketamine single dose 0.5 mg/kg IV then riluzole 100–200 mg daily vs ketamine single dose 0.5 mg/kg IV (n = 21) then placebo once daily (n = 21) |
Significant antidepressant effect was observed immediately after ketamine dose prior to randomization (response rate 62%); no significant improvements in MADRS were observed between treatment groups after week 4 Relapse times were not significant with the ketamine–riluzole group taking 17.2 days and the ketamine–placebo group 9.8 days |
Response criteria: ≥ 50% reduction of MADRS Response rate 61.9% (26/42) |
Relapse rate at 2-week FU 73.1% (19/26) |
Mild, transient AEs with no significant dissociative effects (during ketamine IV) No differences in AEs or overall discontinuation between groups |
Unclear method of monitoring AEs Medically unwell population; unclear if extrapolation to general population is possible |
Y | Y |
| Ionescu et al. [32] | RCT, 3 week |
Aged 18–65 years MDD with ongoing MDE (HDRS ≥ 20, HDRS suicide item score ≥ 2) SI for ≥ 3 months Lack of response to ≥ 3 antidepressant trials in current episode |
Patients were randomized to receive ketamine 0.5 mg/kg IV (n = 13) or saline placebo (n = 13) twice weekly for 2 weeks (n = 26 starting, n = 19 completing) |
In the entire cohort, HDRS scores improved across infusions with no statistical differences between treatment groups; no differences in depression severity or suicide ideation between groups were observed (P = 0.47, P = 0.32, respectively) At 2 weeks 25% (3/12) in the ketamine group and 33% (4/12) in the placebo group responded; similarly, 17% (2/12) in the ketamine group and 8% (1/12) in the placebo group remitted; there was no significant difference between groups in remittance (P ≥ 0.05) |
Response criteria: ≥ 50% improvement on the HDRS Response rate (ketamine) 3/12 (25%) Response rate (placebo) 4/12 (33%) |
Relapse rate (ketamine) (at 3-month FU) 83.3% (10/12) Relapse rate (placebo) (at 3-month FU) 83.3% (10/12) |
Not mentioned |
No active control Limited statistical power due to small sample size Unclear method for monitoring AEs Restriction to outpatients |
Y | Y |
| Lenze et al. [35] | RCT, 8 week |
Aged 18–65 years MDD with ongoing MDE (MADRS ≥ 22) Lack of response to ≥ 2 antidepressant trials in current episode |
96-h ketamine IV 0.6 mg/kg and clonidine 0.6 mg orally daily (n = 10) vs 40 min ketamine 0.5 mg/kg IV and clonidine 0.6 mg orally daily (n = 10) | No significance difference in MADRS changes at treatment completion (P = 0.35) nor during 8 weeks of FU (P ≤ 0.05), both groups had sustained reduction in depressive symptoms compared to baseline. No significant difference in sustained reduction of depression (sustained reduction rate 40% vs 20%) |
Response criteria: ≥ 50% reduction in MADRS Total response rate 40% (4/10) in 96-h group at 2 weeks to 20% (2/10) at 8 weeks 20% (2/10) in 96-h group at 2 weeks to 10% (1/10) at 8 weeks |
Not reported in study |
Mild, transient AEs with no significant dissociative effects, no AEs attributable to clonidine No differences in AEs or overall discontinuation between groups |
Clonidine dose was higher in 96-h arm Limited statistical power due to small sample size Unclear method for monitoring dissociative AEs |
Y | Y |
| Loo et al. [27] | Placebo-controlled, open-label, 5 week |
Aged ≥ 18 years MDD with ongoing MDE (MADRS ≥ 20) Lack of response to ≥ 1 antidepressant trials in current episode |
Sequential cohorts (total n = 15) received either IV ketamine (n = 4), IM (n = 5) or SC (n = 6) at five weekly ascending doses (0.1–0.5 mg/kg) with midazolam 0.01 mg/kg randomly inserted |
No significance difference in MADRS between 0.1 mg/kg vs 0.0 mg/kg at week 1 (P = 0.066); however, there was a significant improvement in MADRS at week 2 vs 0.0 mg/kg (P = 0.001). All routes of ketamine administration resulted in comparable MADRS scores; 50% of patients (5/10) achieved remission status The midazolam condition resulted in no significant changes in BPRS+ or CADSS. The mean time to relapse was 23.2 days |
Response criteria: ≥ 50% improvement in MADRS Response rate 80% (12/15) |
Relapse rate 80% (8/10) at end of 5-week study |
Mild, transient AEs with dose-related dissociative effects (ketamine), fewest AEs were noted with SC administration (ketamine) Most common AEs (ketamine) fatigue, lightheadedness, dizziness, blurred vision, and emotional lability |
Treatment assignment was sequential rather than randomized Treatment effect used ascending doses rather than randomized dose design Limited statistical power due to small sample size |
Y | Y |
| Mathew et al. [34] | RCT, 32 days |
Aged 21–70 years MDD with ongoing MDE (IDS-C30 ≥ 32) Lack of response to ≥ 2 antidepressant trials in current episode |
Patients were randomized to lamotrigine (300 mg) or placebo (n = 26), then each group was given ketamine 0.5 mg/kg IV; responders (n = 14) were then randomized into riluzole continuation (100–200 mg/day) |
Significant MADRS response (≥ 50% reduction from baseline) was seen in 65% and 54% of patients at the 24-h and 72-h time points Riluzole showed no significance difference in time-to-relapse compared to placebo group (24.4 days vs 22.0 days, P = 0.68), with a relapse rate of 80% vs 50% of riluzole and placebo trial completers, respectively; the RCT was terminated early. Lamotrigine did not significantly improve MADRS scores post-ketamine (P = 0.36) |
Response criteria: ≥ 50% reduction in MADRS score at 24 h relative to the previous day's baseline Response rate (72 h post-ketamine) 53.8% (14/26) |
Relapse rate (riluzole) 80% (4/5) at end of 32 days study Relapse rate (placebo) 50% (4/8) at end of 32-day study |
Mild to moderate, transient AEs with dissociative effects No significant difference in AEs between groups |
Failed to collect blood levels of lamotrigine Limited statistical power due to small sample size |
Y | Y |
| Murrough et al. [28] | Single arm, open-label, 12 days |
MDD with ongoing MDE (IDS-C30 ≥ 32) Lack of response to ≥ 2 antidepressant trials in current episode No antidepressants in past 2 weeks |
Ketamine 0.5 mg/kg IV up to six times over a 12-day period (n = 24 starting, n = 21 completing) No control group |
Significant mean improvement in MADRS observed at 2 h after first ketamine dose (P ≤ 0.001), these effects were largely sustained for rest of treatment period; study end response was strongly predicted by response at 4 h (94% sensitive, 71% specific); overall response rate was 70.8% The median time for responders to relapse after last ketamine dose was 18 days |
Response criteria: ≥ 50% improvement in MADRS Response rate 70.8% (17/24) |
Relapse rate (at end of FU) 83.3% (20/24) | Mild, transient AEs with significant dissociative effects |
No control group Limited statistical power due to small sample size Unclear method for monitoring AEs |
Y | Y |
| Phillips et al. [29] | RCT, 6 weeks |
Aged 18–65 years MDD with ongoing MDE (MADRS ≥ 25) Lack of response to ≥ 2 antidepressant trials in current episode |
Patients were randomized to receive midazolam 30 µg/kg IV or ketamine 0.5 mg/kg IV (n = 41); after relapse of depressive symptoms patients received ketamine 0.5 mg/kg IV 6 times over 2 weeks (n = 41 starting, n = 39 completing), responders then received 4 doses of ketamine 0.5 mg/kg IV once weekly (n = 23) | Compared to midazolam, ketamine had a significant improvement in MADRS 24 h post-infusion (P = 0.03); MADRS scores were maintained with no significant changes with once-weekly maintenance infusions (P = 0.49). Response rate at end of repeated infusions was 59% |
Response criteria (ketamine): ≥ 50% decrease in MADRS total score from baseline Response rate (ketamine) 58.9% (23/39) |
Not reported in study | Mild, transient AEs with significant dissociative effects |
Lack of dissociative side effects with active placebo (midazolam) No active control in repeated or maintenance phases |
Y | Y |
| Rasmussen et al. [13] | Single arm, open-label, 2 week |
Aged ≥ 18 years MDD or BP with ongoing MDE (MADRS ≥ 25) Lack of response to ≥ 2 antidepressant trials in current episode |
Ketamine 0.5 mg/kg IV up to four times twice weekly (n = 10) No control group |
For participants who completed the study (n = 10), by end of treatment had significant improvement in depressive symptoms (mean reduction in MADRS of 71% (P = 0.0009); no significant improvements in BPRS or YMRS. Of the remitting patients (n = 5), 2/5 sustained improvement during 4 weeks FU |
Response criteria: ≥ 50% decrease in MADRS total score from baseline Response rate 80% (8/10) |
Relapse rate 60% (3/5) | Mild, transient AEs with significant dissociative effects |
No control group Limited statistical power due to small sample size |
Y | Y |
| Shiroma et al. [30] | Single arm, open-label, 12 days |
Aged 18–70 years MDD with ongoing MDE (HDRS ≥ 14) Lack of response to ≥ 2 antidepressant trials in current episode |
Ketamine 0.5 mg/kg IV up to six times over a 12-day period (n = 14 starting, n = 12 completing) No control group |
For participants who completed six infusions (12/14), significant antidepressant was observed after 12 days (response rate 91.7%; remission rate 66.6%); the mean time in patients who relapsed (6/10) was 16 days (range 7–28 days) |
Response criteria: ≥ 50% improvement MADRS Response rate 91.7% (11/12) |
Relapse rate (at 4 weeks FU) 54.5% (6/11) | Mild, transient AEs with significant dissociative effects |
No control group Limited statistical power due to small sample size Unclear method for monitoring AEs |
Y | Y |
| Singh et al. [37] | RCT, 4 weeks |
Aged 18–64 years MDD with ongoing MDE (IDS-C30 ≥ 34) Lack of response to ≥ 1 antidepressant trial in current episode |
Patients were randomized into four arms to receive either: ketamine 0.5 mg/kg IV twice weekly (n = 18 starting, 12 completing), ketamine 0.5 mg/kg IV thrice weekly (n = 17 starting, 11 completing), saline placebo twice weekly (n = 17 starting, 1 completing) or saline placebo thrice weekly (n = 16 starting, 1 completing) | Significant improvement in MADRS score from baseline at 15 days was observed in both ketamine frequency groups compared to the placebo (P ≤ 0.001, P ≤ 0.001 respectively). Similarly, the mean MADRS change continued to improve from baseline to 29 days in both ketamine frequency groups. No statistical difference was seen between the ketamine groups throughout the study to 18 days FU |
Response criteria: ≥ 50% from baseline in MADRS score Response rate (ketamine 2 times/week) 92.3% (12/13) *excluded discontinued patients for reasons other than lack of efficacy Response rate (ketamine 3 times/week) 84.6% (11/13) *excluded discontinued patients for reasons other than lack of efficacy |
Not reported in study |
Mild, transient AEs with significant dissociative effects No significant difference in AEs between similar treatment groups |
No active control Limited statistical power due to small sample size Unclear method for monitoring AEs |
Y | Y |
| Vande Voort et al. [12] | Single arm, open-label, 2 weeks |
Aged 18–64 years MDD or BP with ongoing MDE Lack of response to ≥ 2 antidepressant trials in current episode |
Ketamine 0.5 mg/kg IV up to 6 times thrice weekly (n = 12 starting, n = 7 completing) No control group |
The entire cohort (n = 12) including non-remitters (7/12), by end of treatment had improvement in depressive symptoms (mean reduction in MADRS of 41.5%; this improvement in MADRS was more significant in remitters MADRS of 79.1% (P ≤ 0.001) No significant improvements in YMRS. All remitting patients, (5/5) sustained improvement during 4-week FU; overall response rate of 58.3% |
Response criteria: ≥ 50% reduction from baseline in MADRS total score Response rate 58.3% (7/12) |
Relapse rate (at 4 weeks FU) 80% (4/5) | Mild, transient AEs with significant dissociative effects |
No control group Limited statistical power due to small sample size Unclear method for monitoring AEs |
Y | Y |
| Wilkinson et al. [31] | Open-label, 10 week |
Aged 18–65 years MDD with ongoing MDE (IDS-C30 ≥ 34) Lack of response to ≥ 2 antidepressant trials in current episode |
Ketamine 0.5 mg/kg IV up to 4 times over 2 weeks concurrent with 12 sessions of CBT over 10 weeks (n = 16) No control group |
Significant antidepressant effect was observed after 2 weeks (response rate 50%; remission rate 43.8%); the median time for responders who relapsed (5/8) was 12 weeks following ketamine exposure Nonresponders showed significant improvement in MADRS until week 3, then showed no difference; among remitters, (3/7) maintained remission until 4 weeks, and (2/7) until 8 weeks |
Response criteria: ≥ 50% in MADRS score from baseline Response rate 50% (8/16) |
Relapse rate (at 8 weeks post-ketamine) 25% (2/8) | Not mentioned |
No control group Limited statistical power due to small sample size Unclear method for monitoring AEs |
Y | Y |
| Yoosefi et al. [36] | RCT, 2 weeks |
Aged 20–50 years MDD with ongoing MDE (HAM-D ≥ 18) History of treatment resistance to previous antidepressant trials |
Patients were randomized to receive thiopental 2–3 mg/kg IV (n = 14) or ketamine 1–2 mg/kg IV (n = 15); patients then received ECT thrice weekly for 2 weeks (n = 29 starting, n = 27 completing) |
Significant antidepressant effect was observed 48 h after first ECT only in ketamine group (P = 0.002); there was no significant difference between HAM-D improvements in treatment groups at end of study Patients in the ketamine group showed significant improvement in cognitive function using a paired t test analysis of MMSE scores (P = 0.004); this was not significant in the thiopental group (P = 0.37) |
Response criteria: 60% reduction in the score of the baseline HAM-D Response rate not reported in study |
Not reported in study | None |
No control group Unable to record seizure duration by EEG Limited statistical power due to small sample size Unclear method for monitoring AEs |
Y | Y |
TRD the study sample was treatment resistant to depression, MADRS Montgomery–Asberg Depression Rating Scale, MDD major depressive disorder, MDE major depressive episode, IV intravenous, BPRS+ Brief Psychiatric Rating Scale, AE adverse effect, Y yes (meets criteria for satisfaction), RCT randomized controlled trial, BP bipolar disorder, HAM-D Hamilton Depression Rating Scale, DCS d-cycloserine, QIDS-SR Quick Inventory of Depressive Symptomatology, Clinician Rating, CGI-S Clinical Global Impression Scale, FU follow-up, IM intramuscular injection, SC subcutaneous injection, CADSS Clinician-Administered Dissociative States Scale, IDS-C30 Inventory of Depressive Symptomatology Clinician Rating, HDRS Hamilton Depression Rating Scale, MMSE Mini-Mental State Examination, SI suicidal ideation
*Intravenously administered racemic ketamine was used unless otherwise specified