Table 1.
Characteristics of Previous Trials of One-Off Ketamine in Patients with Severe Mood Disorder
| Trial |
Region,
Country |
Sample Size
b
(N) |
Mean Age (SD),
(y) |
Male (N) | Design | Major Inclusion Criteria | Major Exclusion Criteria | Intervention | Control | Concomitant Treatments | Loss to Follow-Up | Outcome Measures† |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Berman et al., 2000 | Connecticut | 9 | 37 (10) | 4 | Crossover (washout ≥1 week) |
Recurrent unipolar major depression (N=8); Bipolar disorder (N=1) |
Recent alcohol or substance abuse; any other Axis I disorders |
Ketamine i.v. 0.5mg/kg |
Saline placebo i.v. |
Nil and drug free 2 weeks prior |
2 before last treatment (1 placebo, 1 ketamine), attended all previous follow-ups. | HAM-D-25, BDI, (VAS-high), (BPRS) |
| Zarate et al., 2006 | Bethesda, Maryland | 18 | 47 (11) | 6 | Crossover (washout 1 week) |
Major depression disorder, DSM-IV; failed ≥2 antidepressant trials; HAMD-21 ≥ 18 |
Psychotic features; bipolar disorder; history of antidepressant- or substance- induced hypomania/mania |
Ketamine i.v. 0.5mg/kg |
Saline placebo i.v. |
Nil and drug free 2 weeks prior |
4 before last treatment (placebo), attended all previous follow-ups; 1 after first treatment (placebo), didn`t attend follow-up after Day 2. |
HAM-D-21a, BDI, (BPRS), (YMRS), VAS-depression |
| Diazgranados et al., 2010a | Bethesda, Maryland | 18 | 48 (13) | 6 | Crossover (washout 2 weeks) |
Bipolar I or II depression, DSM-IV, failed antidepressant trial and mood stabilizer; MADRS ≥ 20; current major depressive episode ≥4 weeks | Psychotic features; substance abuse or dependence in last 3 months; unstable medical condition; serious risk of suicide; previous treatment with ketamine | Ketamine i.v. 0.5mg/kg |
Saline placebo i.v. |
Lithium/ valproate no other drugs during trial nor in prior 2 weeks (5 for fluoxetine); no psychotherapy |
3 after first treatment (2 ketamine, 1 placebo), didn`t finish follow-ups. 2 after last treatment (both ketamine), didn`t finish follow-ups. |
MADRSa, HAM-D-17, BDI, VAS-depression, VAS-anxiety, HAM-A, (BPRS), (YMRS) |
| Zarate et al., 2012 | Bethesda, Maryland |
15 | 47 (10) | 7 | Crossover (washout 2 weeks) |
Bipolar I or II depression, DSM-IV, failed antidepressant trial and mood stabilizer; MADRS ≥ 20; current major depressive episode ≥4 weeks | Psychotic features; unstable medical condition; substance abuse or dependence in last 3 months; previous treatment with ketamine | Ketamine i.v. 0.5mg/kg |
Saline placebo i.v. |
Lithium/ valproate no other drugs during trial nor in prior 2 weeks (5 for fluoxetine); no psychotherapy |
4 after first treatment (3 ketamine, 1 placebo), didn`t finish follow-ups. | MADRSa
HAM-D-17, BDI, VAS-depression, VAS-anxiety, HAM-A, (BPRS), (CADSS), (YMRS) |
| Murrough et al., 2013 | Houston, Texas and New York City | 72 | 47 (13) Ketamine 43 (12) Midazolam |
35 | Parallel | Major depressive disorder, DSM-IV; failed ≥3 antidepressant trials; ≥1 previous major depressive episode or lasting ≥2 years; ≥32 IDS-C | Psychotic illness or bipolar disorder; alcohol/substance abuse in the previous 2 years; unstable medical illness; serious and imminent suicidal or homicidal risk; <27 on MMSE | Ketamine i.v. 0.5mg/kg (N=47) |
Midazolam i.v. 0.045mg/ kg (N=25) |
Only prn nonbenzodiazepine hypnotic; drug free 1 week before (4 weeks for fluoxetine); no psychotherapy |
2 from ketamine arm: both after 24-hour evaluation; 3 from placebo arm: all after 24-hour evaluation |
MADRSa, QIDS-SR, CGI, (CADSS), (BPRS), (YMRS); |
| Sos et al., 2013 | Prague, Czech Republic | 30 | 42 (15) Ketamine first 45 (11) placebo first |
15 | Crossover (washout 1 week) |
Major depressive disorder, DSM- IV; score of ≥20 on MADRS at baseline | Suicide risk, any other Axis I or II disorders; unstable medical illness or neurological disorder; psychotic symptom/ disorder in 1st/2nd degree relatives; electroconvulsive therapy within 3 months | Ketamine i.v. Loading: 0.27mg/kg Maintenance: 0.27mg/kg |
Saline placebo i.v. |
Remained on antidepressant medications and dosages maintained throughout the duration of the study |
1 before last treatment (ketamine), attended all previous follow-ups. 2 after first treatment (ketamine), didn`t finish follow-ups. 5 after last treatment (3 ketamine, 2 placebo), didn`t finish follow-ups. |
MADRSa
(BPRS) |
| Lapidus et al., 2014 | New York City, USA | 20 | 48 (13) | 10 | Crossover (washout ≥1 week) |
Major depressive disorder, DSM-IV; failed ≥1 trial of adequate dose and duration of antidepressant; IDS-C ≥ 30 | Any other Axis I disorders; suicide risk; substance abuse or dependence in last 6 months; psychotic disorder; bipolar disorder; developmental disorder; previous abuse/ dependence on ketamine | Ketamine intranasal 50 mg | Saline placebo intranasal |
Stable doses of psychotropic medication, including antidepressant treatment | 2 before first treatment (1 ketamine, 1 placebo). | MADRSa, QIDS-SR, HAM-A, (BPRS), (CADSS), (YMRS), (SAFTEE) |
| Lai et al., 2014 | Sydney, Australia | 4 | 51 (17) | 2 | Crossover (washout 1 week) 4 dosages of ketamine |
Major depressive episode ≥4 weeks, DSM-IV; MADRS ≥ 20; failed ≥ 1 trial of antidepressant during current episode | Comorbid Axis I or II disorders (aside from one subject with phobic disorder); | Ketamine i.v. 0.1, 0.2, 0.3, 0.4mg/Kg |
Saline placebo i.v. |
Remain on stable doses of psychotropic medications; no changes in medication dosage and no ECT 4 weeks prior to trial entry |
1 after placebo, 0.1, and 0.2mg/kg (attended all previous follow-ups); 1 after placebo, 0.1, 0.2 and 0.3mg/kg (attended all previous follow-ups). |
MADRSa, CGI, QIDS-SR, (BPRS), (YMRS), (CADSS), (SAFTEE). |
| C. K. Loo, V. Galvez, E. O’Keefe, unpublished data | Sydney Australia | 15 | 49 (11) | 11 | Crossover (washout 1 week) 5 dosages of ketamine (i.v., N=4); (IM, N=5); (SC, N=6) |
Major Depressive Disorder, depression episode of duration ≥ 4 weeks, DSM IV; MADRS ≥ 20; failed to ≥1 trial of antidepressant during current episode | Schizophrenia, rapid cycling bipolar disorder or any current psychotic symptoms | Ketamine i.v., IM or SC; 0.1, 0.2, 0.3, 0.4, 0.5mg/kg |
Midazolam i.v., SC or IM 0.01mg/kg |
Remain on stable doses of psychotropic medications; no changes in medication dosage and no ECT 4 weeks prior to trial entry | 1 after placebo, 0.1, and 0.2mg/kg i.v.; 1 after placebo, 0.1, and 0.2mg/kg IM; 1 after placebo, 0.1, 0.2, and 0.3mg/kg IM; 1 after placebo, 0.1, 0.2, 0.3 and 0.4mg/kg IM; 1 after placebo, 0.1 and 0.2mg/kg SC; 1 after placebo SC; | MADRSa, (BPRS), (YMRS - item 1), (CADSS), (SAFTEE) |
| Total/ average |
201 | 46 | 96(48%) | 129 (64%) patients in crossover | Ketamine:145 (82%) i.v.; 20 (11%) intranasal; 5 (3%) intramuscular; 6 (3%) s.c. | Saline:94 (61%) i.v.; 20 (13%) intranasal; Midazolam:29 (19%) i.v.; 5 (3%) intramuscular; 6 (4%) s.c. |
27 (13%) no concomitant medications;33 (16%) on Lithium/valproate; 72 (36%) only nonbenzodiazepine hypnotic; 69 (34%) on other psychotropic medications |
40 |
Abbreviations: MMSE: Mini-Mental State Examination; IDS-C, the Inventory of Depressive Symptomatology—Clinician Rated. †HAM-D, Hamilton Depression Rating Scale scores; BDI, Beck Depression Inventory; VAS(-high), Visual Analog Scales score (for intoxication “high”); BPRS, Brief Psychiatric Rating Scale;YMRS, Young Mania Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; HAM-A, Hamilton Anxiety Rating Scale; CADSS, Clinician Administered Dissociative States Scale; QIDS-SR,Quick Inventory of Depressive Symptomatology-Self Report; CGI, Clinical Global Impression; SAFTEE, Systematic Assessment for Treatment Emergent Effects.Measures in parentheses indicate the safety and tolerability measures.
aPrimary outcome measures.
bSample size was identified at the time of randomization, with an exception for Murrough et al., 2013. There were 73 patients at the time of randomization and 72 remained after allocation. One patient in the ketamine group did not receive intervention. Characteristics (eg, age and sex) were reported based on the 72 patients.