Table 1.
Description of included studies.
| Investigator(s) | Study country | Patientsa | Ketamine protocol | Control condition(s) | Study Design | Minimum ADM treatment failures required for eligibility | Excluded psychiatric diagnoses/conditions | Concurrent psych meds | Eligible Depression Measures Provided |
|---|---|---|---|---|---|---|---|---|---|
| Deakin, Abdallah [53, 54] | UK | MDD outpatients (n = 37) | Single infusion 0.5 mg/kg | Saline; Lanicemineb | Parallel Arm | Unspecified (no requirement) | Lifetime history of psychosis, bipolar disorder, or alcohol/substance use disorder, not right-handed, consuming more than 10 cigarettes or 8 cups of caffeinated beverages per day, positive tox screen | Unmedicated/washout period | MADRS |
| Feder #1 [46] | US | PTSD outpatients (n = 30) | Six infusionsb 0.5 mg/kg | Midazolam | Parallel Arm | Unspecified (no requirement) | Active suicidal/homicidal ideation, lifetime history of psychotic or bipolar disorder, current anorexia or bulimia, alcohol/substance use disorder in previous 3 months, history of recreational ketamine/PCP use >1x or any in the past 2 years, current long-acting benzodiazepine or opioid medication. | Stable meds continued | MADRS |
| Feder #2 [55] | US | PTSD outpatients (n = 41) | Single infusion 0.5 mg/kg | Midazolam | Crossover | Unspecified (no requirement) | Active suicidal/homicidal ideation, lifetime history of psychotic or bipolar disorder, current bulimia or anorexia, alcohol/substance abuse/dependence in previous 3 months. | Unmedicated/washout period | MADRS |
| Grunebaum, Mann [56, 57] | US | Inpatients with MDD or BPI, II, or NOS w/ current MDE and suicidal ideation (n = 96) | Single Infusion 0.5 mg/kg | Midazolam | Parallel Arm | Unspecified (no requirement) | ECG abnormalities, current psychosis, history of drug or alcohol dependence within 6 months, suicidality due to substance use or withdrawal | Stable meds continued | HRSDc |
| Mathew, Murrough [58] | US | MDD outpatients (n = 73) | Single Infusion 0.5 mg/kg | Midazolam | Parallel Arm | 3 | Suicide/homicide risk, history of bipolar disorder, psychotic symptoms, and substance abuse within previous 2 years of enrollment | 1 week unmedicated washout (4 weeks for fluoxetine), except for stable nonbenzodiazepine hypnotics | MADRS |
| McLoughlin, Gallagher [59] | Ireland | MDD or BP inpatients (n = 25) | Four infusionsb 0.5 mg/kg | Midazolam | Parallel Arm | Unspecified (no requirement) | Current involuntary admission, active SI, dementia, history of Axis 1 diagnosis other than a MDE, ECT within 2 months or alcohol/substance dependence within 6 months of enrollment | Stable meds continued | HRSDc |
| Murrough [60] | US |
Any non-exclusionary diagnosis Inpatient and Outpatient (n = 24) |
Single infusion 0.5 mg/kg | Midazolam | Parallel Arm | Unspecified (no requirement) | Outpatients excluded with CSSRS score of 4 or 5, lifetime history of schizophrenia or primary psychotic disorder, current psychotic or manic symptoms, substance use disorder within 1 month of screening or positive urine tox, any lifetime abuse of ketamine or PCP | Stable meds continued | MADRS |
| Muthukumaraswamy, McMillan, Sumner [61, 62] | New Zealand | MDD outpatients (n = 30) | Single infusion as a 0.25 mg/kg bolus followed by a 0.25 mg/kg/hr infusion for 45 minutes for a total dose of 0.4375 mg/kg | Remifentanil | Crossover | 2 | Lifetime history of ketamine or PCP abuse, body weight <50 kg or >120 kg, any relevant psychiatric/neurological comorbidities including schizophrenia, psychosis, epilepsy, substance abuse/dependence, or acute suicidality | Stable meds continued | MADRS |
| Papakostas, Fava [29] | US | MDD Outpatients (n = 61) | Single infusion 0.1d, 0.2d, 0.5, or 1.0 mg/kg | Midazolam | Parallel Arm | 2 | Failure to achieve satisfactory response to >7 adequate ADM trials in the current major depressive episode, primary dx of Axis I disorder other than MDD, substance abuse/dependence within 6 months of screening, any history of ketamine or PCP use | Stable meds continued | MADRS, HRSD |
| Phillips [47] | Canada | MDD outpatients (n = 43) | Single infusion 0.5 mg/kg; followed by up to 10 open-label infusionsb | Midazolam | Crossover | 2 ADMs plus 2 augmentation strategies | History of substance abuse/dependence, BMI ≥ 35, history of mania/hypomania | Stable meds continued | MADRS |
| Shiroma [48] | US | MDD outpatients (n = 54) | One or six infusionsb 0.5 mg/kg | Midazolam | Parallel Arm | 2 | PTSD, mild to moderate TBI, psychosis-related disorder, bipolar disorder, and Axis 1 disorder other than MDD as primary presenting problem, history of alcohol/substance abuse within 6 months of screening, imminent suicide/homicide risk | Stable meds continued | MADRS |
| Šóš [63] | Czech Republic | MDD inpatients (n = 27) | Single infusion; loading dose of 0.27 mg/kg for the first 10 min, followed by a maintenance infusion of 0.27 mg/kg within 20 min | Saline | Crossover | Unspecified (no requirement) | Suicide risk, any current psychiatric comorbidity on Axis I and II, lifetime history of psychotic symptoms and psychotic disorder in first- or second-degree relatives | Stable meds continued | MADRS |
| Su, Chen [30] | Taiwan | MDD outpatients (n = 48) | Single Infusion 0.5 mg/kg or 0.2 mg/kgd | Saline | Parallel Arm | 2 | History of bipolar disorder, psychotic symptoms, and substance dependence | Stable meds continued | MADRS, HRSD |
| Tiger, Lundberg [13] | Sweden | MDD outpatients (n = 30) | Up to four infusionsb 0.5 mg/kg | Saline | Parallel Arm | 1 | No medications taken for current MDE, any antidepressant treatment response, BP disorder, psychosis, neurodevelopmental disorders, any comorbid primary diagnoses, body weight >100 kg, substance abuse, current suicidality | Unmedicated/washout period | MADRS |
| Zarate, Ballard #1 [39, 64] | US | Bipolar (I or II) depressed inpatients (n = 39) | Single infusion 0.5 mg/kg | Saline | Crossover | 1 | Current psychotic symptoms or lifetime psychotic disorder, active suicidal ideation (MADRS Suicide item > 4), substance abuse/dependence within 3 months of enrollment | 2 weeks unmedicated washout period, except for one mood stabilizer at stable dose | MADRS, HRSD |
| Zarate, Ballard #2 [40] | US | MDD inpatients (n = 22) | Single infusion 0.5 mg/kg | Saline | Crossover | 1 | Current psychotic symptoms or lifetime psychotic disorder, active suicidal ideation (MADRS Suicide item > 4), substance abuse/dependence within 3 months of enrollment | 2 weeks unmedicated washout period | HRSDc |
| Zarate, Ballard #3 [65] | US | MDD or bipolar (I or II) depressed inpatients (n = 40) | Single infusion 0.5 mg/kg | Saline | Crossover | 1 | Current psychotic symptoms or lifetime psychotic disorder, active suicidal ideation (MADRS Suicide item > 4), substance abuse/dependence within 3 months of enrollment | 2 weeks unmedicated washout period, except for one mood stabilizer at stable dose (bipolar patients only) | MADRS, HRSD |
MADRS Montgomery-Åsberg Depression Rating Scale, HRSD Hamilton Rating Scale for Depression (17-item version).
aN = number of unique patients with data provided and used in current primary analyses. Values may differ from those reported in original publications due to the eligible treatment conditions used in the pooled patient-level meta-analysis.
bFor “rapid” timepoint, datapoint was approximately 1 day following the first infusion in the sequence of infusions. For “post-rapid” timepoint, the datapoint that was as close as possible to 7 days after the first infusion was used, even if subsequent serial infusions had been given within the ~7-day post-infusion period.
cTo harmonize outcomes for primary analyses, MADRS scores were estimated from HRSD-17 scores according to a published conversion table.
dData not included in analyses.