A review of ketamine’s role in ECT and non-ECT settings

Figures & data

Table 1 Criteria for level of evidence and line of treatment

Level of evidence	Criteria
1	Meta-analysis with narrow confidence intervals and/or 2 or more RCTs with adequate sample size, preferably PBO controlled
2	Meta-analysis with wide confidence intervals and/or 1 or more RCTs with adequate sample size
3	Small-sample RCTs or nonrandomized, controlled prospective studies or case series or high-quality retrospective studies
4	Expert opinion/consensus

Abbreviations: RCTs, randomized controlled trials; PBO, placebo.

Table 2 iv Ketamine in an ECT setting

Study	Objectives	Participants	Methods	Outcome measures	Results	Level of evidence
Jarventausta et al^Citation7 (2013)	Effect of S-ketamine as an adjuvant to propofol anesthesia in ECT.	Adults (n=32) with recurrent, severe, or psychotic TRD. Baseline MADRS according to treatment group: (1) 36.9; (2) 37.3.	RCT: (1) S-ketamine 0.4 mg/kg iv bolus and then propofol, or (2) NS and propofol.	MADRS; speed of response. Rates of adverse effects.	No differences in magnitude and speed of response, numbers of ECT treatments, seizure thresholds, seizure durations and electrical doses.	3
Wang et al^Citation8 (2012)	Effect of combined ketamine and propofol, for patients receiving a single ECT treatment.	Adults (n=48) with MDD. HDRS≥20. Baseline HDRS-17 according to treatment group: (1) 30.1; (2) 28.9; (3) 29.2.	RCT: (1) propofol 1.5 mg/kg iv; (2) ketamine 0.8 mg/kg iv; or (3) propofol 1.5 mg/kg iv plus ketamine 0.8 mg/kg iv.	HDRS scores 1 day before ECT and days 1, 2, 3, and 7 after ECT.	HDRS scores improved earlier with ketamine and propofol+ketamine, compared with propofol. Fewer adverse events with propofol+ketamine than with ketamine.	3
Yalcin et al^Citation9 (2012)	Effect of ketamine, propofol, and ketofol on hemodynamic profile, duration of seizure activity, and recovery times for patients receiving single ECT treatment.	Adults (n=90) with MDD, and schizophrenia with depression.	RCT: (1) concomitant propofol; (2) ketamine; or (3) ketofol dosed at 10 mg increments until responsiveness to verbal command lost.	Hemodynamic profile, duration of seizure activity, and recovery times.	Motor seizure duration with propofol group was significantly decreased compared to ketamine and ketofol groups (29.3±5.1 s, 37.2±3.2 s, and 34±5.8 s, respectively; P<0.001).	3
Yoosefi et al^Citation10 (2014)	Effects of thiopental and ketamine anesthesia in ECT.	Adult inpatients (n=31) with MDD and HDRS of ≥18. Baseline HDRS according to treatment group: (1) 23.6; (2) 22.86.	RCT: (1) ketamine 1–2 mg/kg iv, or (2) thiopental 2–3 mg/kg iv.	MMSE and HDRS before the 1st and 2nd ECT sessions as well as 3–7 days and 1 month after the 6th session.	Ketamine group showed longer seizure duration and significantly greater improvements in depressive symptoms only before the second ECT session (mean HDRS score: (1) 16.2; (2) 20.0; P=0.002). Significant cognitive improvements were demonstrated in the ketamine group (MMSE score at baseline 25.60 vs 27.82 1-month after 6th ECT).	3
Abdallah et al^Citation11 (2012)	Effect of ketamine on antidepressant effects of ECT.	Adults (n=18) with MDD and BPD. Baseline HDRS according to treatment group: (1) 38.3±2.1; (2) 35.3±2.5.	RCT: (1) thiopental alone, or (2) thiopental plus ketamine 0.5 mg/kg iv for anesthesia before each ECT session.	HDRS at baseline and 24–72 h after the 1st and 6th ECT sessions.	No significant group effect or group-by-time interaction on HDRS scores.	3
Erdil et al^Citation12 (2015)	Effect of an adjunctive sub-anesthetic dose of ketamine to sevoflurane, on seizure duration in ECT.	Adults (n=84) with MDD with no other major medical problems.	RCT: (1) SK, or (2) SS. Ketamine was administered as a 0.5 mg/kg iv bolus.	Duration of the motor seizure and EEG seizure duration.	Motor and EEG seizure durations were similar in both groups. MAP was significantly increased in both groups compared to BL: (1) 95.6 to peak of 119.8 mmHg; (2) 94.8 to peak of 115.6 mmHg. Heart rate increased significantly in both groups: (1) 77.3 to peak of 89.8 bpm; (2) 78.8 to peak of 91 bpm.	3
Salehi et al^Citation13 (2015)	Effect of ketamine and sodium thiopental anesthesia during ECT.	Adults (n=160) with TRD (without other psychiatric disorders). Baseline HDRS according to treatment group: (1) 29.82±7.3; (2) 28.86±7.6.	DB, RCT: (1) ketamine 0.8 mg/kg iv, or (2) sodium thiopental 1–1.5 mg/kg iv. Number of ECT treatments=8.	HDRS-17 at baseline and after the end of ECT sessions 2, 4, 6, and 8.	HDRS score demonstrated a significant decreasing trend in both groups: (1) 8.32±5.17; (2) 10.53±7.87. Response was more rapid with ketamine.	2
Rybakowski et al^Citation14 (2016)	Effect of ketamine anesthesia on antidepressant activity and cognition in ECT.	Adults with TRD (n=45). Mean HDRS-17=32 (no differences between groups). Mean duration of illness was 12.8 years.	DB RCT: (1) thiopental anesthesia only, (2) ketamine (1–1.5 mg/kg) at 2nd and 3rd ECT sessions, or (3) ketamine (1–1.5 mg/kg) at 2nd, 4th, 6th, 8th, and 10th sessions. Mean number of ECT treatments=10.8.	HDRS-17 after each ECT session. Cognitive function assessed with three categories of tests.	HDRS-17 scores decreased by: (1) 16.6, (2) 15.7, and (3) 21.8 points. Difference between groups (1) and (3) was statistically significant (P=0.0006). Verbal memory and phonological fluency in ketamine groups were markedly worsened.	3
Anderson et al^Citation15 (2017)	Effect of adjunctive ketamine on cognitive and depressive symptoms in ECT.	Adult outpatients and inpatients (n=70) with severe MDD or BD (ECT in the previous 3 months was exclusionary). Baseline MADRS according to treatment group: (1) 31.8±7.4; (2) 35.2±8.4.	MC superiority RCT. 1:1 randomization: (1) ketamine (0.5 mg/kg) or (2) saline; with propofol or thiopental anesthesia. Mean number of ECT treatments=11.	Neuropsychological assessment using several tests. MADRS, CAS, CGI-S, CGI-I, QIDS-SR, and EQ-5D-3L.	No significant differences between the treatments in neuropsychological and efficacy measures.	3
Kuscu et al^Citation16 (2015)	Effect of anesthesia with thiopental, ketamine, and ketamine-thiopental on depressive and anxiety symptoms in ECT.	Adults (n=58) with TRD (HDRS>17). Baseline scores according to treatment group: HDRS (1) 17.6±4.9; (2) 20.0±4.0; (3) 19.7±4.3. HAM-A (1) 10.2±4.3; (2) 12.3±4.8; (3) 13.1±5.7.	RCT: (1) thiopental 4 mg/kg iv; (2) ketamine 1 mg/kg; or (3) both administered pre-ECT. Total number of ECT treatments=8.	HDRS and HAM-A at baseline, after 3rd and 6th and last ECT treatments.	No statistical differences between the groups regarding HDRS scores. HAM-A scores were higher in ketamine groups: (1) 1.4±0.8; (2) 2.9±1.8; (3) 3.2±1.9 (P=0.017).	3
Fernie et al^Citation17 (2017)	Effect of ketamine anesthesia on depressive and cognitive symptoms in ECT vs standard anesthesia.	Adults (n=40) with MDD, receiving ECT. Baseline scores according to treatment group: HDRS (1) 27.19±6.47; (2) 24.79±8.50; MADRS (1) 36.38±8.29; (2) 35.68±8.39.	DB RCT: (1) bolus ketamine up to 2 mg/kg, or (2) propofol up to 2.5 mg/kg.	HDRS-17 and MADRS before 1st, after 4th, at the end of treatment, and 1 month after the end of treatment.	No difference in the number of ECT treatments. No differences in change in symptom severity.	3
Zhong et al^Citation18 (2016)	Effect of anesthetic and sub-anesthetic doses of ketamine on mood and cognitive symptoms in ECT.	Adults (n=90) with treatment resistant MDD or BD (other mental disorders, exclusionary). Baseline scores according to treatment group: HDRS-17 (1) 26.7±1.6; (2) 26.7±2.0; (3) 26.0±2.8. BPRS-18 (1) 35.47±4.167; (2) 36.53±5.164; (3) 36.93±6.142.	RCT: (1) ketamine 0.8 mg/kg iv (K), (2) ketamine 0.5 mg/kg iv plus propofol 0.5 mg/kg iv (KP), or (3) propofol 0.8 mg/kg iv (P). Total number of ECT treatments=8.	HDRS-17, BPRS at baseline, after 1st, 2nd, 3rd, 4th, 6th, and 8th treatments.	K and KP groups showed statistically significant higher response rates after the 3rd ECT (HDRS-17=(1) 13.5±1.2; (2) 15.0±2.1 and (3) 16.5±1.9; P<0.001) and 4th ECT (HDRS-17=(1) 11.0±1.0; (2) 12.5±2.1; (3) 14.1±1.8; P<0.001). K group had a statistically significant higher remission rate compared to the KP and P groups after 8th ECT.	3
Rasmussen et al^Citation19 (2014)	Effect of ketamine as an anesthetic agent for ECT.	Adults (n=38) with non-psychotic MDD, unipolar, or BD. Baseline scores according to treatment group: PHQ-9 (1) 17.57±6.96; (2) 15.98±7.54. HADS (1) 24.45±7.70; (2) 22.08±8.11.	RCT: (1) methohexital; or (2) ketamine as anesthetic during the first six treatments of ECT. Starting doses of 1.0 mg/kg were targeted for both agents and were individually adjusted.	PHQ-9, HADS, MMSE at baseline and after treatments 2, 4, and 6.	No significant difference in scores on either depression rating scale or in MMSE or post-treatment orientation scores.	3
Loo et al^Citation20 (2012)	Effect of ketamine on depressive and cognitive symptoms with ECT.	Adult inpatients (n=51) with TRD, unipolar or bipolar (without current psychotic symptoms). Baseline MADRS according to treatment group: (1) 32.1±4.5; (2) 32.7±7.9.	DB, RCT: (1) ketamine 0.5 mg/kg iv; or (2) a PBO iv at the time of thiopentone anesthesia for ECT, for the whole ECT course.	MADRS prior to ECT, after 6 ECT treatments, 1–3 days after the end of the ECT course, and 1 month later.	No significant difference was found in MADRS scores between the groups over the whole course. A significant time-by-group interaction was found over the first week of treatment (F(1, 40)=4.555, P=0.039, η^2=102), indicating improvement in the ketamine group.	3

Abbreviations: iv, intravenous; ECT, electroconvulsive therapy; TRD, treatment resistant depression; MADRS, Montgomery-Asberg Depression Rating Scale; RCT, randomized controlled trial; NS, normal saline; MDD, major depressive disorder; HDRS, Hamilton Depression Rating Scale; MMSE, Mini Mental State Examination; BPD, bipolar disorder; SK, sevoflurane-ketamine; SS, sevoflurane-saline; DB, double-blind; EEG, electroencephalogram; MAP, mean arterial pressure; BL, baseline; bpm, beats per minute; BD, bipolar depression; MC, multi-center; CAS, Clinical Anxiety Scale; CGI-S, Clinical Global Impression-Severity; CGI-I, Clinical Global Impression-Improvement; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Report; EQ-5D-3L, third-level version of the EuroQol five-dimensional questionnaire; HAM-A, Hamilton Anxiety Scale; PHQ, Patient Health Questionnaire; HADS, Hospital Anxiety and Depression Scale; PBO, placebo.

Table 3 iv Ketamine in a non-ECT setting

Study	Research objective	Participants	Methods/intervention	Outcome assessment/analysis	Results	Level of evidence
Kudoh et al^Citation22 (2002)	Effect of ketamine anesthesia on postoperative outcomes following orthopedic surgery.	Adults (n=70) with MDD (Groups A and B on antidepressants for ≥1 year). Controls (n=25) without depression (Group C). All patients had orthopedic surgery. Baseline HDRS according to treatment group: (A) 12.7±5.4; (B) 12.3±6.0; (C) 4.2±1.7.	RCT: Groups A and C received 1.0 mg/kg of iv ketamine, 1.5 mg/kg iv propofol, and 2 mcg/kg iv fentanyl. Group B received 1.5 mg/kg iv propofol and 2 mcg/kg iv fentanyl.	HDRS score: 1 day before, and 1 and 3 days after surgery.	Depressive and pain symptoms decreased significantly in Group A vs B (HDRS=9.9±4.1 and 14.4±3.8; P<0.001).	3
Lenze et al^Citation23 (2016)	Efficacy and safety of the prolonged (96 h) ketamine infusion vs single iv dose of ketamine, with co-administration of clonidine.	Adults (n=20) with TRD, and MADRS≥22 (patients with BD, lifetime psychotic disorder, and medical instability excluded). Baseline MADRS according to treatment group: (1) 31.9±5.9; (2) 34.0±3.8.	DB RCT: clonidine 0.1 mg po BID× 7 days prior to infusion, then 0.2 mg po BID×1 day, 0.3 mg po BID thereafter, and either: (1) ketamine 0.15 mg/kg/h iv×96 h with increases as tolerated BID until a target rate of 0.6 mg/kg/h; or (2) NS iv×95 h and then ketamine 0.5 mg/kg iv×40 min.	BPRS, clinical and adverse events checklist, MADRS, CGI-I.	Average rate of ketamine administration=0.52 mg/kg/h. No difference between arms in MADRS changes. BPRS score remained significantly higher for most of the infusion in prolonged treatment group. Significant relationship demonstrated between ketamine concentration and sustained response at 8 weeks in the prolonged treatment group. Spearman correlation coefficient between S-ketamine concentration and MADRS change from baseline: 0.75 for 96-hour arm and 0.17 for 40-minute arm; p<0.05.	3
Li et al^Citation24 (2016)	Effects of ketamine on TRD.	Adults (n=48) with TRD (patients with major medical or neurological illnesses or SUD excluded). Baseline MADRS according to treatment group: (1) 22.6±5.8; (2) 20.9±5.6; (3) 22.8±3.9.	DB RCT: (1) ketamine 0.5 mg/kg iv; (2) ketamine 0.2 mg/kg iv; or (3) normal saline.	HDRS-17 and BPRS at baseline, 40, 80, 120, and 240 min.	Non-statistically significant HDRS-17 reduction in ketamine groups vs PBO at 240 min: (1) −37.8%, (2) −38.2%, (3) −26.7% (P=0.537).	3

Abbreviations: iv, intravenous; ECT, electroconvulsive therapy; MDD, major depressive disorder; HDRS, Hamilton Depression Rating Scale; RCT, randomized controlled trial; TRD, treatment resistant depression; MADRS, Montgomery-Asberg Depression Rating Scale; BD, bipolar depression; SUD, substance use disorder; DB, double-blind; po, per os; NS, normal saline; BPRS, Brief Psychiatric Rating Scale; CGI-I, Clinical Global Impression-Improvement; PBO, placebo.

Table 4 Ketamine with adjunctive agents in non-ECT setting

Study	Research objective	Participants	Methods/intervention	Outcome assessment/analysis	Results	Level of evidence
Ibrahim et al^Citation25 (2012)	Effect of a single iv dose of ketamine in TRD, and effect of riluzole on depressive symptoms.	Adult inpatients (n=42) with MDD without psychotic features, MADRS>22 (patients with history of substance/antidepressant induced hypomania or mania excluded). Baseline MADRS according to treatment group: (1) 32.7±3.7; (2) 32.7±5.7.	DB, RCT: all patients received a single open-label infusion of 0.5 mg/kg ketamine. At 4–6 h post-infusion, patients randomized to receive: (1) riluzole 100–200 mg po daily or (2) PBO for 4 weeks.	MADRS; HAM-D, BDI, VAS-depression, HAM-A, BPRS-positive symptoms, CADSS, YMRS, and SSI. Subjects were rated 60 min prior to infusion, at 40, 80, 120, and 230 min post-infusion, and then daily for the next 28 days.	No significant differences in all rating scales between riluzole and placebo groups.	3
Mathew et al^Citation26 (2010)	Effect of riluzole in preventing post-ketamine relapse; and effect of pre-treatment with lamotrigine on ketamine’s psychotomimetic adverse effects and antidepressant efficacy.	Adults (n=26) with TRD (IDS-C30>32). Baseline MADRS=36.9±5.4; QIDS-SR16=18.6±3.9; CGI-I=5.3±0.8.	RCT: two hours prior to iv ketamine, patients received lamotrigine 300 mg po or PBO po. Bolus ketamine 0.5 mg/kg iv infusion was administered 2 h later. Responders were randomized to: (1) riluzole 100–200 mg po daily or; (2) PBO for up to 32 days.	Efficacy: MADRS and QIDS-SR16. CGI-I rating was used to guide riluzole dose adjustment.	Average improvement of 60%±32% (P<0.001) in MADRS at 24 h; average improvement of 62%±28% in QIDS-SR16 (P<0.001). Lamotrigine and placebo pre-treatment groups did not significantly differ in any efficacy measure at the 24-, 48-, or 72-h rating. Riluzole did not protect against post-ketamine relapse in the first month. Lamotrigine did not attenuate psychotomimetic adverse effects, or improve antidepressant response.	3
Hu et al^Citation27 (2016)	Effect of single-dose iv ketamine on escitalopram in MDD.	Adults (n=30) with severe MDD (HDRS-17≥24). Mean total MADRS=34.3±7.3; QIDS-SR=17.1±4.6.	DB RCT: (1) escitalopram 10 mg po daily and single dose of ketamine 0.5 mg/kg iv (EK); or (2) escitalopram 10 mg po daily and single dose of NS iv (E).	MADRS, QIDS-SR, BPRS, YMRS, CADSS at baseline, 1, 2, 4, 24, and 72 h, and 7, 14, 21, and 28 days.	At 4 weeks, EK group had a significantly higher response rate (≥50% in MADRS score reduction) (92.3% vs 57.1%; P=0.04), remission rate (MADRS score≤10) (76.9% vs 14.3%; P=0.001), shorter time to response (HR=0.04 95% CI=0.01–0.22, P<0.001) and remission (HR=0.11, 95% CI=0.02–0.63, P=0.01). YMRS scores increased significantly with ketamine augmentation at 1 (0.4±0.7; P=0.01) and 2 h (0.4±0.7; P=0.02).	3

Abbreviations: ECT, electroconvulsive therapy; iv, intravenous; TRD, treatment resistant depression; MDD, major depressive disorder; MADRS, Montgomery-Asberg Depression Rating Scale; DB, double-blind; RCT, randomized controlled trial; PBO, placebo; HAM-D, Hamilton Depression Rating Scale; BDI, Beck Depression Inventory; HAM-A, Hamilton Anxiety Scale; BPRS, Brief Psychiatric Rating Scale; CADSS, Clinician Administered Dissociative States Scale; YMRS, Young Mania Rating Scale; SSI, Scale for Suicidal Ideation; IDS, Inventory of Depressive Symptomatology; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Report; CGI-I, Clinical Global Impression-Improvement; po, per os; NS, normal saline; HDRS, Hamilton Depression Rating Scale.

Table 5 Oral ketamine

Study	Research objective	Participants	Methods/intervention	Outcome assessment/analysis	Results	Level of evidence
Jafarinia et al^Citation28 (2016)	Effect of ketamine po vs diclofenac monotherapy on depressive symptoms in patients with chronic pain.	Adults (n=40) with chronic, persistent mild-to-moderate headache≥6 months, MDD with HDRS<19. (Patients with any antidepressant or ECT treatment in past 2 months, other mental disorders, substance dependence, severe depression, suicidal ideation excluded). Baseline scores according to treatment group: HDRS (1) 15±2.36; (2) 14.95±2.72. HADS (1) 9.05±1.60; (2) 9.45±1.47.	DB RCT: (1) ketamine 50 mg po TID; or (2) diclofenac 50 mg po TID for 6 weeks.	HDRS and HADS at baseline, week 3, and week 6.	Difference in HDRS scores not significant at week 3, significant at week 6 (reduction of (1) 6.95±3.86 and (2) 4.10±3.34; mean difference=2.85, 95% CI 0.54–5.16, P=0.017). Significant improvement in difference in HADS score at week 3 (decreased by: (1) 2.10±0.72 and (2) 1.05±1.10; mean difference=1.05, 95% CI 0.45–1.64, P=0.001) and week 6 (decreased by: (1) 2.85±1.04 and (2) 2.10±0.72; mean difference=0.75, 95% CI 0.18–1.32, P=0.012).	3

Abbreviations: po, per os; MDD, major depressive disorder; HDRS, Hamilton Depression Rating Scale; ECT, electroconvulsive therapy; HADS, Hospital Anxiety and Depression Scale; DB, double-blind; RCT, randomized controlled trial.

Table 6 Intranasal ketamine

Study	Research objective	Participants	Methods/intervention	Outcome assessment/analysis	Results	Level of evidence
Daly et al^Citation29 (2016)	Effect of intranasal esketamine in patients with TRD.	Medically stable adults (n=67) with TRD, without psychotic features. IDS-C30≥34 (patients with BD, ID, Cluster B PD, psychotic disorder, PTSD, OCD, suicidality; history of non-response to esketamine, ketamine or ECT excluded). Baseline MADRS according to treatment group: (1) 35.0±5.2; (2) 31.3±3.8; (3) 33.2±6.3; (4) 35.0±4.2.	DB, MC, RCT. DB phase, randomized to receive: (1) intranasal PBO, (2) intranasal esketamine 28 mg; (3) intranasal esketamine 54 mg; or (4) intranasal esketamine 84 mg on days 1, 4, 11, and 16. OL phase, started with intranasal esketamine 56 mg every 3 days, with dose decrease or increase thereafter.	MADRS at BL, at the end of DB and OL endpoints. TEAEs, CADSS pre-dose, at 40 min and 2 h post dose.	All three esketamine doses superior to PL in DB phase, mean MADRS reduction compared to PBO: (2) 4.2±2.09, P=0.021; (3) 6.3±2.07, P=0.001; (4) 9.0±2.13, P<0.001. At the end OL phase (74 days), 64.7% of patients were responders (decrease in MADRS total score≥50%), 32.4% of patients met remission criteria (MADRS total score≤10).	3
Canuso et al^Citation30 (2015)	Effect of intranasal esketamine and standard of care against intranasal PBO in MDD with suicidal symptoms.	Adults (n=68) with MDD and current suicidal ideation with intent, at imminent risk of suicide; MADRS≥22 pre-dose (patients with BPD, ID, antisocial, histrionic, and borderline PD, psychotic symptoms, OCD, or SUD excluded). Baseline MADRS according to treatment group: (1) 38.5±6.17; (2) 38.8±7.02.	DB, MC, RCT: (1) intranasal esketamine 84 mg; or (2) intranasal PBO administered twice weekly for 4 weeks (DB phase, days 1–25). Follow-up phase, weekly visits until day 53, then once every 2 weeks through day 81.	Efficacy: MADRS and CGJ-SR 4 h post-dose, day 2 and day 25. Safety: TEAEs, vital signs, and CADSS total score.	Esketamine treatment superior to PBO with significantly greater change from BL in MADRS at day 1 (mean difference=5.3±2.10, P=0.015) and day 2 (mean difference=7.2±2.85, P=0.015). Difference at day 25 was not significant (P=0.159). No statistically significant differences were observed in CGJ-SR.	3

Abbreviations: TRD, treatment resistant depression; IDS, Inventory of Depressive Symptomatology; BD, bipolar depression; ID, intellectual disability; PD, personality disorder; PTSD, post-traumatic stress disorder; OCD, obsessive compulsive disorder; ECT, electroconvulsive therapy; MADRS, Montgomery-Asberg Depression Rating Scale; DB, double-blind; MC, multi-center; RCT, randomized controlled trial; PBO, placebo; OL, open-label; BL, baseline; TEAE, treatment-emergent adverse event; CADSS, Clinician Administered Dissociative States Scale; PL, placebo; MDD, major depressive disorder; BPD, bipolar disorder; SUD, substance use disorder; CGJ-SR, Clinical Global Judgment of Suicide Risk.

Table 7 Clinical predictors of response to ketamine

Study	Research objective	Participants	Methods/intervention	Outcome assessment/analysis	Results	Level of evidence
Niciu et al^Citation34 (2014)	Effect of a single ketamine infusion in subjects with FHP of an AUD in a 1st degree relative.	Adult patients (n=52) with a diagnosis of TRD without psychotic features; MADRS score of >22. Baseline rating scale scores: MADRS, FHP 31.4±4.6; FHN 34.1±4.7. HDRS, FHP 19.4±4.1; FHN 21.7±4.0.	RCT: all patients received a single 0.5 mg/kg ketamine infusion; 4–6 h later subjects were randomized to: (1) riluzole 100–200 mg po daily or (2) PBO twice daily for 4 weeks. Patients then divided to: FHP riluzole, FHP placebo, FHN riluzole, FHN placebo groups.	MADRS (daily), HDRS-17, BDI, SSI, YMRS.	FHP subjects had less depression when randomized to PBO (F(1,50)=9.69, P=0.003), but not to riluzole (F(1,48)=0.003, P=0.95).	3
Ionescu et al^Citation35 (2014)	Effect of anxious depression on ketamine response.	Adults (n=26) from Ibrahim et al^Citation25 study randomized to PBO; divided into anxious depression (baseline HDRS 22.5±4.9; MADRS 33.8±6.1) and non-anxious depression (baseline HDRS 19.6±2.8; MADRS 32.7±5.1).	As per Ibrahim et al.^Citation25	MADRS and HDRS daily; HDRS, anxiety/somatization factor score.	Patients with anxious depression had significantly lower scores on depression rating scales, and longer time to relapse. All significant time points had at least moderate differences (d>0.51). Similar analysis with the HDRS showed a significant main effect of group (F(1,23)=6.80, P=0.02), but no significant interaction between group and time (F(31,560)=1.39, P=0.08).	3
Murrough et al^Citation36 (2015)	Effect of ketamine on cognition 7 days post-treatment, and baseline neurocognitive predictors of the antidepressant response to ketamine.	Adult inpatients (n=62) with recurrent TRD; current episode length of ≥2 years; score of ≥32 on IDS-C30; and no other psychotropic medications. Baseline MADRS according to treatment group: (1) 32.5±6.0; (2) 31.0±5.1.	DB, RCT: (1) single iv infusion of ketamine at 0.5 mg/kg or (2) midazolam at 0.045 mg/kg.	MADRS at 48 and 72 h and 7 days post-infusion. Neurocognitive battery at baseline and at 7 days post-treatment.	Ketamine responders had significantly slower processing speed at baseline compared with ketamine non-responders (F(1,45)=4.36, P=0.043).	3

Abbreviations: FHP, family history positive; AUD, alcohol use disorder; TRD, treatment resistant depression; MADRS, Montgomery-Asberg Depression Rating Scale; FHN, family history negative; HDRS, Hamilton Depression Rating Scale; RCT, randomized controlled trial; PBO, placebo; BDI, Beck Depression Inventory; SSI, Scale for Suicidal Ideation; YMRS, Young Mania Rating Scale; IDS, Inventory of Depressive Symptomatology; DB, double-blind; iv, intravenous.

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