Ketamine and depression: a narrative review

Figures & data

Figure 1 Flowchart of the literature review process.

Abbreviations: ECT, electroconvulsive therapy; RCT, randomized controlled trial.

Table 1 Synthesis of Cochrane review and meta-analyses which have included RCT studies in their analyses, concerning ketamine efficacy

Authors	Etiology	Review type [articles included]	n studies (n K studies)	n subjects (n K subjects)	Design	Ketamine efficacy
Ketamine versus placebo
Papadimitropoulou et al, 2017^Citation32	TR MDD	MA^Citation63	31 (1) no ECT	5515 (35)	DB, P, vs PBO	Efficacy at week 2. No data at week 4, 6, and 8
McCloud et al, 2015^Citation30	BD	Cochrane^Citation102,Citation108	5 (2) no ECT	329 (33)	DB, CO, vs PBO	Efficacy at day 1 and 3. No efficacy at week 1 and 2.
Romeo et al, 2015^Citation33	MDD, BD	MA^Citation68,Citation102,Citation108^–^Citation111	6 (6) no ECT	103 (103)	DB, CO, vs PBO	Efficacy at day 1, 2, 3–4 and week 1. No efficacy at week 2.
Caddy et al, 2014^Citation34	MDD, BD	MA^Citation102,Citation108,Citation110^–^Citation112	5 (5) no ECT	66 (66)	DB, CO, vs PBO except [101]: OL, P	Efficacy at 60–80 mins. No efficacy at 4 hrs, week 2.
Ketamine versus other comparators
Kishimoto et al, 2016^Citation35	MDD, BD	MA^Citation63,Citation102,Citation108^–^Citation111,Citation113,Citation114 Lai et al, 2014 (case report)	14 (9) no ECT	588 (234)	DB, CO, P, vs PBO or active PBO	Efficacy at 40–60 mins, day 1, 5–8. No efficacy at week 2.
Xu et al, 2016^Citation36	TR MDD, BD	MA^Citation68,Citation102,Citation108^–^Citation111,Citation113,Citation114 Loo unpublished data	9 (9) no ECT	201 (201)	DB, CO, P, vs PBO or active PBO	Efficacy at day 1 and 3. No efficacy at week 1.
Lee et al, 2015^Citation37	TR MDD, BD	MA^Citation102,Citation108^–^Citation111,Citation113	5 (5) no ECT	125 (125)	DB, CO, P vs PBO or active PBO	Efficacy at day 1 and week 1.
McGirr et al, 2015^Citation38	MDD, BD	MA^Citation68,Citation102,Citation108^–^Citation111,Citation113	7 (7) no ECT	183 (183)	DB, CO, P vs PBO or active PBO	Efficacy at day 1.
Ketamine as pre-ECT anesthetic adjuvant versus placebo or active placebo
Ren et al, 2018^Citation39	MDD, BD	MA^Citation115^–^Citation130	16 (16) ECT	928 (928)	DB, OL, P, vs PBO or active PBO pre-ECT	Efficacy after the 1st, 3rd, 4th, 5th, 6th ECT. No efficacy after the 2nd, 8th, 10th, 12th ECT and at the end of ECT sessions.
McGirr et al, 2017^Citation40	MDD, BD	MA^Citation115^–^Citation118,Citation120,Citation122^–^Citation125,Citation131	10 (10) ECT	602 (602)	DB, P, vs PBO or active PBO pre-ECT	No efficacy at the end of ECT sessions.
Fond et al, 2016^Citation41	MDD, BD	MA^Citation115^–^Citation119	14 (5) ECT	610 (84)	DB, P, vs active PBO pre-ECT	No efficacy after the 6th ECT.
McGirr et al, 2015^Citation42	MDD, BD	MA^Citation115^–^Citation119	5 (5) ECT	182 (182)	DB, P, vs active PBO pre-ECT	No efficacy at the end of ECT sessions.
Ketamine alone and as pre-ECT anesthetic adjuvant versus placebo or active placebo
Caddy et al, 2015^Citation31	MDD, BD	Cochrane -^Citation113 -^Citation116 -^Citation109,Citation110,Citation111,Citation115,Citation117 -^Citation64	25: - 1 no ECT - 1 ECT - 5 no ECT+ECT - 1 no ECT	1242: - 73 no ECT - 29 ECT - 130 no ECT + ECT - 18 no ECT	DB - P, vs midazolam (no ECT) - P, vs thiopental (pre-ECT) - CO (no ECT), P (pre-ECT), vs PBO - SB, P, vs ECT	No and pre-ECT: efficacy at day 1 (vs PBO, midazolam, ECT), day 3 (vs PBO, thiopental, ECT), week 1 (vs PBO, ECT). No efficacy at day 3 (vs midazolam), week 1 (vs midazolam), week 2 (vs PBO, thiopental, ECT), week 4 (vs thiopental).
Coyle and Laws, 2015^Citation43	MDD, BD	MA^Citation59,Citation68,Citation102,Citation108^–^Citation110,Citation113,Citation117,Citation118,Citation120,Citation132^–^Citation141	21 (21) no ECT and ECT	437 (437)	RCT, no RCT, DB, OL, no ECT, pre-ECT	No and pre-ECT: efficacy at 4 hrs, day 1, week 1 and 2.
Newport et al, 2015^Citation44	MDD, BD	MA -^Citation68,Citation102,Citation108^–^Citation111,Citation113^–^Citation119	12: - 7 no ECT - 5 ECT	236: - 147 no ECT - 89 ECT	DB, CO, P vs PBO or active PBO	No ECT: efficacy at day 1 and week 1. Pre-ECT: efficacy after the 1st ECT; no efficacy at the end of ECT sessions.
Fond et al, 2014^Citation45	MDD, BD	MA -^Citation64,Citation90,Citation108^–^Citation113,Citation142 -^Citation115,Citation117^–^Citation119	12: - 9 no ECT - 4 ECT	310: - 192 no ECT - 118 ECT	DB, CO, P - vs PBO or active PBO or vs ECT - vs PBO or active PBO pre-ECT	No ECT: efficacy at day 1. Pre-ECT: efficacy at day 1.

Abbreviations: RCT, randomized controlled trial; TR, treatment-resistant; MDD, major depressive disorder; BD, bipolar depression; MA, meta-analysis; ECT, electroconvulsive therapy; K, ketamine; PBO, placebo; DB, double-blind; SB, single-blind; OL, open-label; P, parallel; CO, cross-over.

Table 2 Synthesis of additional RCT not including in the Cochrane reviews and the meta-analyses, concerning ketamine efficacy

Authors	Etiology	n subjects	Design	Rating scale	Ketamine efficacy
Ketamine versus placebo
Ionescu et al, 2019^Citation46 Single center	TR MDD	26	(a) K: 6 IV infusions 0.5 mg/kg over 45 mins, twice weekly for 3 weeks (n=13) (b) PBO (n=13)	HDRS	No efficacy across infusions at week 1, 2, and 3.
Popova et al, 2019^Citation47 Multicenter	TR MDD	223	(a) Intranasal (S)-K, 56 or 84 mg twice weekly+AD for 4 weeks (n=114) (b) PBO+AD for 4 weeks (n=109)	MADRS	Efficacy at week 4. No efficacy at day 1, week 1, 2, and 3.
Arabzadeh et al, 2018^Citation48 Single center	MDD	90	(a) Oral K, 25 mg twice daily for 6 weeks (n=45) (b) PBO (n=45)	HDRS-17	Efficacy at week 2, 4, and 6.
Canusco et al, 2018^Citation49 Multicenter	TR MDD	66	(a) Intranasal (S)-K, 84 mg twice weekly for 4 weeks (n=35) (b) PBO (n=31)	MADRS	Efficacy at 4 hrs and day 1. No efficacy at day 25.
Daly et al, 2018^Citation50 Multicenter	TR MDD	67	(a) Intranasal (S)-K, 28 (n=11), 56 (n=11) or 84 mg (n=12) administered twice weekly for 2 weeks (double-blind period) (b) PBO (n=33)	MADRS	Efficacy at day 1 and 2, week 1 and 2.
Domany et al, 2018^Citation51 Single center	MDD	41	(a) K (n=22): 1 mg/kg thrice weekly for 21 days by oral route (b) PBO (n=19)	MADRS	Efficacy at 40 mins, 4 hrs, day 3, week 1, 2, and 3.
Chen et al, 2018^Citation52 Single center	TR MDD	24	(a) Ketamine (n=8): 1 IV infusion 0.5 mg/kg over 40 mins (b) Ketamine 0.2 mg/kg (n=8): 1 IV infusion 0.2 mg/kg over 40 mins (c) PBO (n=8)	HDRS-17	Efficacy (0.5 mg/kg) at 4 hrs and day 1. No efficacy at 40 mins, 80 mins and 2 hrs.
Su et al, 2017^Citation53 Single center	TR MDD	71	(a) K (n=24): 1 IV infusion 0.5 mg/kg over 40 mins (b) K (n=23): 1 IV infusion 0.2 mg/kg over 40 mins (c) PBO (n=24)	HDRS-17	Efficacy (0.5 mg/kg) from 40 mins to 4 weeks post-infusion.
Hu et al, 2016^Citation54 Single center	TR MDD	23	(a) K: 1 IV infusion 0.5 mg/kg over 40 mins+escitalopram: 10 mg/day for 4 weeks (n=13) (b) PBO+escitalopram (n=14)	MADRS	Efficacy at 2 hrs, 4 hrs, day 1, 3, week 1 and 2. No efficacy at 60 mins, weeks 3 and 4.
Li et al, 2016^Citation55 Single center	TR MDD	48	(a) K (n=16): 1 IV infusion 0.5 mg/kg over 40 mins (b) K (n=16): 1 IV infusion 0.2 mg/kg over 40 mins (c) PBO (n=16)	HDRS-17	Efficacy (both groups) at 40 mins. No efficacy at 80 mins, 2and 4 hrs.
Singh et al, (a) 2016^Citation56 Multicenter	TR MDD	30	(a) (S)-K (n=11): 1 IV infusion 0.4 mg/kg over 40 mins (b) (S)-K (n=9): 1 IV infusion 0.2 mg/kg over 40 mins (c) PBO (n=10)	HDRS-17	Efficacy (both groups) at 2 hrs, 4 hrs, days 2 and 3.
Ketamine as pre-ECT anesthetic adjuvant versus active placebo
Carspecken et al, 2018^Citation57 Single center	TR MDD	50	(a) K (n=23): 1–2 mg/kg (b) Methohexital (n=27): 1–2 mg/kg ECT: 3 consecutive sessions/week (right unilateral)	HDRS-21	No efficacy post-ECT (with a total of 3 ECT sessions).
Gamble et al, 2018^Citation58 Single center	TR MDD	27	(a) K (n=14): IV infusion 0.75 mg/kg (b) Propofol (n=13): 1 mg/kg 4–8 ECT (uni or bilateral): 2 or 3 sessions/week	MADRS	Faster improvement of depressive symptoms with ketamine.

Abbreviations: RCT, randomized controlled trial; TR, treatment-resistant; MDD, major depressive disorder; BD, bipolar depression; MA, meta-analysis; ECT, electroconvulsive therapy; K, ketamine; PBO, placebo; DB, bouble-blind; SB, single-blind; OL, open-label; P, parallel; CO, cross-over; MADRS, Montgomery–Asberg Depression Rating Scale; HDRS, Hamilton Depression Rating Scale; IV, intravenous; AD, antidepressant.

Figure 2 (A) Ketamine efficacy with time (versus placebo or other comparators). (B) Ketamine efficacy with the number of electroconvulsive therapies (ECT) (ketamine given as an anesthetic adjuvant pre-ECT).

Notes: Numbers represent references. Bold red: Cochrane review; bold purple: meta-analyses; others: randomized controlled trials.

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