Abstract
Rationale
Major depressive episodes are severe mood episodes which occur both in major depressive disorder and bipolar I and II disorder. Major depressive episodes are characterized by debilitating symptoms that often persist and interfere with typical daily functioning. Various treatments exist for major depressive episodes; however, most primary pharmacologic treatments may take weeks to months to provide relief from depressive symptoms. Ketamine is a demonstrated treatment for major depressive episodes, as relief from depressive symptoms can occur rapidly following treatment.
Objectives
Prior meta-analyses have been conducted to analyze the effectiveness of ketamine for the treatment of major depressive episodes, but at the time of this writing, no meta-analysis had been conducted to observe ketamine treatment efficacy beyond 2 weeks.
Methods
The present meta-analysis evaluated the efficacy of ketamine for the treatment of major depressive episodes; observations of depressive episode severity were analyzed at 2, 4, and 6-weeks post-treatment.
Results
The present meta-analysis observed large effects at 2 weeks (g = −1.28), 4 weeks, (g = −1.28), and 6 weeks (g = −1.36) post-treatment.
Conclusions
The results from the present meta-analysis indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes, with treatment effects lasting up to 6 weeks post-ketamine administration, which has many positive implications for treatment.
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Data availability
The datasets generated during and/or analyzed during the current study are available in the OSF repository, https://osf.io/qwbmh/.
References
*References marked with an asterisk indicate studies included in the meta-analysis. +References marked with a plus symbol indicate studies that were imputed and reported in the Supplement
*aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ (2010) Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67(2):139–145. https://doi.org/10.1016/j.biopsych.2009.08.038
Abdallah CG, Adams TG, Kelmendi B, Esterlis I, Sanacora G, Krystal JH (2016) Ketamine’s mechanism of action: A path to rapid-acting antidepressants. Depress Anxiety 33(8):689–697. https://doi.org/10.1002/da.22501
*+Albott CS, Lim KO, Forbes MK, Erbes C, Tye SJ, Grabowski JG, Thuras P, Batres-y-Carr TM, Wels J, Shiroma PR (2018) Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Clin Psychiatry 79(3):17m11634. https://doi.org/10.4088/JCP.17m11634
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC
*Anderson IM, Blamire A, Branton T, Brigadoi S, Clark R, Downey D, Dunn G, Easton A, Elliott R, Elwell C, Hayden K, Holland F, Karim S, Lowe J, Loo C, Nair R, Oakley T, Prakash A, Sharma PK, Williams SR, McAllister-Williams RH (2017) Randomized controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study). Efficacy Mech Eval 4(2):1–112. https://doi.org/10.3310/eme04020
Andrade C (2017) Ketamine for Depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? J Clin Psychiatry 78(7):e852–e857. https://doi.org/10.4088/JCP.17f11738
Aust S, Gärtner M, Basso L, Otte C, Wingenfeld K, Chae WR, Heuser-Collier I, Regen F, Cosma NC, van Hall F, Grimm S, Bajbouj M (2019) Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder. Eur Neuropsychopharmacol 29(4):529–538. https://doi.org/10.1016/j.euroneuro.2019.02.005
Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, Brutsché NE, Ameli R, Furey ML, Zarate CA (2014) Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety. J Psychiatr Res 58:161–166. https://doi.org/10.1016/j.jpsychires.2014.07.027
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR (2009) Introduction to meta-analysis. John Wiley
Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK (2014) Ketamine as the prototype glutamatergic antidepressant: Pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol 4(2):75–99. https://doi.org/10.1177/2045125313507739
*Cao Z, Lin C-T, Ding W, hen, M.-H., Li, C.-T., & Su, T.-P. (2019) Identifying ketamine responses in treatment-resistant depression using a wearable forehead EEG. IEEE Trans Biomed Eng 66(6):1668–1679. https://doi.org/10.1109/TBME.2018.2877651
*Chen M-H, Li C-T, Lin W-C, Hong C-J, Tu P-C, Bai Y-M, Cheng C-M, Su T-P (2018) Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion. J Affect Disord 241:1–7. https://doi.org/10.1016/j.jad.2018.07.033
*+Chen M-H, Cheng C-M, Gueorguieva R, Lin W-C, Li C-T, Hong C-J, Tu P-C, Bai Y-M, Tsai S-J, Krystal JH, Su T-P (2019a) Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: A double-blind randomized placebo–control study. Neuropsychopharmacology 44(12):2112–2118. https://doi.org/10.1038/s41386-019-0480-y
*Chen M-H, Lin W-C, Wu H-J, Cheng C-M, Li C-T, Hong C-J, Tu P-C, Bai Y-M, Tsai S-J, Su T-P (2019b) Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: Reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD). J Affect Disord 251:162–169. https://doi.org/10.1016/j.jad.2019.03.075
Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Earlbaum Associates
*Costi S, Soleimani L, Glasgow A, Brallier J, Spivack J, Schwartz J, Levitch CF, Richards S, Hoch M, Wade E, Welch A, Collins KA, Feder A, Iosifescu DV, Charney DS, Murrough JW (2019) Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: A randomized controlled trial. Neuropsychopharmacology 44(10):1812–1819. https://doi.org/10.1038/s41386-019-0365-0
Coyle CM, Laws KR (2015) The use of ketamine as an antidepressant: A systematic review and meta-analysis: Ketamine as an Antidepressant. Hum Psychopharmacol Clin Exp 30(3):152–163. https://doi.org/10.1002/hup.2475
*Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji H, Drevets WC (2018) Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiat 75(2):139–148. https://doi.org/10.1001/jamapsychiatry.2017.3739
*Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67(8):793–802. https://doi.org/10.1001/archgenpsychiatry.2010.90
*Domany Y, Shelton RC, McCullumsmith CB (2020) Ketamine for acute suicidal ideation. An emergency department intervention: A randomized, double-blind, placebo-controlled, proof-of-concept trial. Depress Anxiety 37(3):224–233. https://doi.org/10.1002/da.22975
*Dong J, Min S, Qiu H, Chen Q, Ren L (2019) Intermittent administration of low dose ketamine can shorten the course of electroconvulsive therapy for depression and reduce complications: A randomized controlled trial. Psychiatry Res 281:112573. https://doi.org/10.1016/j.psychres.2019.112573
Dore J, Turnipseed B, Dwyer S, Turnipseed A, Andries J, Ascani G, Monnette C, Huidekoper A, Strauss N, Wolfson P (2019) Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs 51(2):29–198. https://doi.org/10.1080/02791072.2019.1587556
Duman RS, Sanacora G, Krystal JH (2019) Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron 102(1):75–90. https://doi.org/10.1016/j.neuron.2019.03.013
Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634. https://doi.org/10.1136/bmj.315.7109.629
*Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI (2018) Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 25:1592–1603. https://doi.org/10.1038/s41380-018-0256-5
FDA (2019) Medication guide: Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf. Accessed 24 Jan 2021
Finnegan M, Galligan T, Ryan K, Shanahan E, Harkin A, Daly L, McLoughlin DM (2019) Ketamine versus midazolam for depression relapse prevention following successful electroconvulsive therapy: A randomized controlled pilot trial. The Journal of ECT 35(2):115–121. https://doi.org/10.1097/YCT.0000000000000560
*Freeman MP, Papakostas GI, Hoeppner B, Mazzone E, Judge H, Cusin C, Mathew S, Sanacora G, Iosifescu D, DeBattista C, Trivedi MH, Fava M (2019) Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. J Psychiatr Res 110:166–171. https://doi.org/10.1016/j.jpsychires.2019.01.010
*Gálvez V, Li A, Huggins C, Glue P, Martin D, Somogyi AA, Alonzo A, Rodgers A, Mitchell PB, Loo CK (2018) Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomized controlled trial. J Psychopharmacol 32(4):397–407. https://doi.org/10.1177/0269881118760660
Godlewska BR, Harmer CJ (2020). Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment. Psychopharmacology (Berl). https://doi.org/10.1007/s00213-019-05448-0
Goldstein DJ, Potter WZ, Ciraulo DA, Shader RI (2011) Biological theories of depression and implications for current and new treatments. In: Ciraulo DA, Shader RI (eds) Pharmacotherapy of Depression. Humana Press, Totowa, pp 1–32. https://doi.org/10.1007/978-1-60327-435-7_1
Han Y, Chen J, Zou D, Zheng P, Li Q, Wang H, Li P, Zhou X, Zhang Y, Liu Y, Xie P (2016) Efficacy of ketamine in the rapid treatment of major depressive disorder: A meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat 12:2859–2867. https://doi.org/10.2147/NDT.S117146
Higgins JPT (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. https://doi.org/10.1136/bmj.327.7414.557
Horvitz-Lennon M, Normand ST, Frank RG, Goldman HH (2003) “Usual care” for major depression in the 1990s: Characteristics and expert-estimated outcomes. Am J Psychiatr 160:720–726. https://doi.org/10.1176/appi.ajp.160.4.720
*Hu Y-D, Xiang Y-T, Fang J-X, Zu S, Sha S, Shi H, Ungvari GS, Correll CU, Chiu HFK, Xue Y, Tian T-F, Wu A-S, Ma X, Wang G (2016) Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: Results from a randomized, placebo-controlled 4-week study. Psychol Med 46(3):623–635. https://doi.org/10.1017/S0033291715002159
*Ibrahim L, DiazGranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, Moaddel R, Wainer I, Luckenbaugh DA, Manji HK, Zarate CA (2012) Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: Results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology 37(6):1526–1533. https://doi.org/10.1038/npp.2011.338
*Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, Brutsche NE, Zarate CA (2014) Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry 75(09):e932–e938. https://doi.org/10.4088/JCP.14m09049
*Kantrowitz JT, Halberstam B, Gangwisch J (2015) Single-dose ketamine followed by daily d-cycloserine in treatment-resistant bipolar depression. J Clin Psychiatry 76(06):737–738. https://doi.org/10.4088/JCP.14l09527
*Kheirabadi G, Vafaie M, Kheirabadi D, Mirlouhi Z, Hajiannasab R (2019) Comparative effect of intravenous ketamine and electroconvulsive therapy in major depression: A randomized controlled trial. Adv Biomed Res 8(1):25. https://doi.org/10.4103/abr.abr_166_18
*+Kheirkhah F, Tayyebi G, Rabiee SM, Moghadamnia A-A, Bijani A (2018) Efficacy of different doses of ketamine as a bolus in major depressive disorder. Caspian J Intern Med 9(3):220–227. https://doi.org/10.22088/cjim.9.3.220
Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, Correll CU (2016) Single-dose infusion ketamine and non-ketamine N -methyl- d -aspartate receptor antagonists for unipolar and bipolar depression: A meta-analysis of efficacy, safety and time trajectories. Psychol Med 46(7):1459–1472. https://doi.org/10.1017/S0033291716000064
*+Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA (2014) Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4(10):e469–e469. https://doi.org/10.1038/tp.2014.105
*+Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA (2015) Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol 29(5):596–607. https://doi.org/10.1177/0269881114568041
Lee EE, Della Selva MP, Liu A, Himelhoch S (2015) Ketamine as a novel treatment for major depressive disorder and bipolar depression: A systematic review and quantitative meta-analysis. Gen Hosp Psychiatry 37(2):178–184. https://doi.org/10.1016/j.genhosppsych.2015.01.003
*Lenze EJ, Farber NB, Kharasch E, Schweiger J, Yingling M, Olney J, Newcomer JW (2016) Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J Biol Psychiatry 17(3):230–238. https://doi.org/10.3109/15622975.2016.1142607
*Liu W, Zhou Y, Zheng W, Wang C, Zhan Y, Lan X, Zhang B, Li H, Chen L, Ning Y (2019) Repeated intravenous infusions of ketamine: Neurocognition in patients with anxious and nonanxious treatment-resistant depression. J Affect Disord 259:1–6. https://doi.org/10.1016/j.jad.2019.08.012
*Loo CK, Katalinic N, Garfield JBB, Sainsbury K, Hadzi-Pavlovic D, Mac-Pherson R (2012) Neuropsychological and mood effects of ketamine in electroconvulsive therapy: A randomised controlled trial. J Affect Disord 142(1–3):233–240. https://doi.org/10.1016/j.jad.2012.04.032
*+Loo CK, Gálvez V, O’Keefe E, Mitchell PB, Hadzi-Pavlovic D, Leyden J, Harper S, Somogyi AA, Lai R, Weickert CS, Glue P (2016) Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand 134(1):48–56. https://doi.org/10.1111/acps.12572
*Luckenbaugh DA, Ibrahim L, Brutsche N, Franco-Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA (2012) Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression: Bipolar depression and ketamine response. Bipolar Disord 14(8):880–887. https://doi.org/10.1111/bdi.12003
McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW (2015) A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 45(4):693–704. https://doi.org/10.1017/S0033291714001603
*McMillan R, Sumner R, Forsyth A, Campbell D, Malpas G, Maxwell E, Deng C, Hay J, Ponton R, Sundram F, Muthukumaraswamy S (2020) Simultaneous EEG/fMRI recorded during ketamine infusion in patients with major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 99:109838. https://doi.org/10.1016/j.pnpbp.2019.109838
Minichino A, Senior M, Brondino N, Zhang SH, Godwlewska BR, Burnet PWJ, Cipriani A, Lennox BR (2019) Measuring disturbance of the endocannabinoid system in psychosis: A systematic review and meta-analysis. JAMA Psychiat 76(9):914–923. https://doi.org/10.1001/jamapsychiatry.2019.0970
*+Murrough JW, Soleimani L, DeWilde KE, Collins KA, Lapidus KA, Iacoviello BM, Lener M, Kautz M, Kim J, Stern JB, Price RB, Perez AM, Brallier JW, Rodriguez GJ, Goodman WK, Iosifescu DV, Charney DS (2015) Ketamine for rapid reduction of suicidal ideation: A randomized controlled trial. Psychol Med 45(16):3571–3580. https://doi.org/10.1017/S0033291715001506
National Institute of Mental Health (2019) Major depression. https://www.nimh.nih.gov/site-info/citing-nimh-information-and-publications.shtml. Accessed 8 Aug 2019
Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, The APA Council of Research Task Force on Novel Biomarkers and Treatments (2015) Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. Am J Psychiatr 172(10):950–966. https://doi.org/10.1176/appi.ajp.2015.15040465
*Niciu MJ, Luckenbaugh DA, Ionescu DF, Richards EM, Vande Voort JL, Ballard ED, Brutsche NE, Furey ML, Zarate CA (2015) Ketamine’s antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder. Int J Neuropsychopharmacol 18(1):pyu039. https://doi.org/10.1093/ijnp/pyu039
*Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Morrison RL, Hough D, Manji H, Drevets WC, Sanacora G, Steffens DC, Adler C, McShane R, Gaillard R, Wilkinson ST, Singh JB (2020) Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression—TRANSFORM-3. Am J Geriatr Psychiatry 28(2):121–141. https://doi.org/10.1016/j.jagp.2019.10.008
Papadimitropoulou K, Vossen C, Karabis A, Donatti C, Kubitz N (2017) Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: A systematic review and network meta-analysis. Curr Med Res Opin 33(4):701–711. https://doi.org/10.1080/03007995.2016.1277201
*Pérez-Esparza R, Corona T, Ruiz-García RG, Oñate-Cadena N, de la Fuente-Sandoval C, Ramírez-Bermúdez J (2018) Time until relapse after augmentation with single-dose ketamine in treatment-resistant depression: Letters to the Editor. Psychiatry Clin Neurosci 72(8):623–623. https://doi.org/10.1111/pcn.12675
Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, Owoeye O, Batten LA, Blier P (2019) Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: A randomized controlled trial. Am J Psychiatr 176(5):401–409. https://doi.org/10.1176/appi.ajp.2018.18070834
Price RB, Nock MK, Charney DS, Mathew SJ (2009) Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 66(5):522–526. https://doi.org/10.1016/j.biopsych.2009.04.029
R Core Team (2019) R: A language and environment for statistical computing. Retrieved from https://www.R-project.org/
Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor 1A knockout: An animal model of anxiety-related disorder. Proc Natl Acad Sci 95(24):14476–14481. https://doi.org/10.1073/pnas.95.24.14476
Rohatgi A (2019) WebPlotDigitizer. https://automeris.io/WebPlotDigitizer/. Accessed 8 Aug 2019
Romeo B, Choucha W, Fossati P, Rotge J-Y (2015) Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res 230(2):682–688. https://doi.org/10.1016/j.psychres.2015.10.032
Saligan LN, Farmer C, Ballard ED, Kadriu B, Zarate CA (2019) Disentangling the association of depression on the anti-fatigue effects of ketamine. J Affect Disord 244:42–45. https://doi.org/10.1016/j.jad.2018.10.089
Salloum NC, Fava M, Hock RS, Freeman MP, Flynn M, Hoeppner B, Cusin C, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, Debattista C, Ionescu DF, Papakostas GI (2020) Time to relapse after a single administration of intravenous ketamine augmentation in unipolar treatment-resistant depression. J Affect Disord 260:131–139. https://doi.org/10.1016/j.jad.2019.09.017
Schwartz J, Murrough JW, Iosifescu DV (2016) Ketamine for treatment-resistant depression: Recent developments and clinical applications: Table 1. Evid Based Ment Health 19(2):35–38. https://doi.org/10.1136/eb-2016-102355
Shelton R (2016) *A study of ketamine in patients with treatment-resistant depression (Clinicaltrials.gov Identifier NCT01627782). https://clinicaltrials.gov/ct2/show/NCT01627782. Accessed 8 Aug 2019
Shiroma PR (2019) *+Efficacy of repeated ketamine infusions for treatment-resistant depression (Clinicaltrials.gov Identifier NCT02360280). https://clinicaltrials.gov/ct2/show/NCT02360280. Accessed 8 Aug 2019
*Shiroma PR, Johns B, Kuskowski M, Wels J, Thuras P, Albott CS, Lim KO (2014) Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord 155:123–129. https://doi.org/10.1016/j.jad.2013.10.036
Short B, Fong J, Galvez V, Shelker W, Loo CK (2018) Side-effects associated with ketamine use in depression: A systematic review. Lancet Psychiatry 5(1):65–78. https://doi.org/10.1016/S2215-0366(17)30272-9
*Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, Pinter C, Murrough JW, Sanacora G, Shelton RC, Kurian B, Winokur A, Fava M, Manji H, Drevets WC, Van Nueten L (2016) A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatr 173(8):816–826. https://doi.org/10.1176/appi.ajp.2016.16010037
*Sinyor M, Williams M, Belo S, Orser B, Vincent M, Mah L, Zarate C, Castel S, Levitt AJ, Schaffer A (2018) Ketamine augmentation for major depressive disorder and suicidal ideation: Preliminary experience in an inpatient psychiatry setting. J Affect Disord 241:103–109. https://doi.org/10.1016/j.jad.2018.07.073
Sterne JAC, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, Wood AM, Carpenter JR (2009) Multiple imputation for missing data in epidemiological and clinical research: Potential and pitfalls. BMJ 338(9 1):b2393–b2393. https://doi.org/10.1136/bmj.b2393
Stockmeier C (1997) Serotonin receptors in suicide victims with major depression. Neuropsychopharmacology 16(2):162–173. https://doi.org/10.1016/S0893-133X(96)00170-4
*Su T-P, Chen M-H, Li C-T, Lin W-C, Hong C-J, Gueorguieva R, Tu P-C, Bai Y-M, Cheng C-M, Krystal JH (2017) Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology 42(13):2482–2492. https://doi.org/10.1038/npp.2017.94
*Thakurta R, Ray P, Kanji D, Das R, Bisui B, Singh OP (2012) Rapid antidepressant response with ketamine: Is it the solution to resistant depression? Indian J Psychol Med 34(1):56–60. https://doi.org/10.4103/0253-7176.96161
Wampold BE, Minami T, Baskin TW, Tierney SC (2002) A meta-(re)analysis of the effects of cognitive therapy versus ‘other therapies’ for depression. J Affect Disord 618:159–165. https://doi.org/10.1016/s0165-0327(00)00287-1
*Wilkinson ST, Sanacora G, Bloch MH (2017a) Hippocampal volume changes following electroconvulsive therapy: A systematic review and meta-analysis. Biol Psychiatry Cogn Neurosci Neuroimaging 2(4):327–335. https://doi.org/10.1016/j.bpsc.2017.01.011
*Wilkinson ST, Wright D, Fasula MK, Fenton L, Griepp M, Ostroff RB, Sanacora G (2017b) Cognitive behavior therapy may sustain antidepressant effects of intravenous ketamine in treatment-resistant depression. Psychother Psychosom 86(3):162–167. https://doi.org/10.1159/000457960
*Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, Hawkins J, Birnbaum J, Lyons DM, Rodriguez CI, Schatzberg AF (2018) Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatr 175(12):1205–1215. https://doi.org/10.1176/appi.ajp.2018.18020138
World Health Organization (2015) Ketamine (INN) Update Review Report. https://www.who.int/medicines/access/controlledsubstances/6_1_Ketamine_Update_Review.pdf. Accessed 8 Aug 2019
World Health Organization (2018) Depression. https://www.who.int/news-room/fact-sheets/detail/depression. Accessed 16 Jan 2021
Xu Y, Hackett M, Carter G, Loo C, Gálvez V, Glozier N, Glue P, Lapidus K, McGirr A, Somogyi AA, Mitchell PB, Rodgers A (2016) Effects of low-dose and very low-dose ketamine among patients with major depression: A systematic review and meta-analysis. Int J Neuropsychopharmacol 19e(4):pyv124. https://doi.org/10.1093/ijnp/pyv124
*Yanni Z, Zhang B, Zhou Y, Zheng W, Liu W, Wang C, Li H, Chen L, Yu L, Walter M, Li M, Li MD, Ning Y (2019) A preliminary study of anti-suicidal efficacy of repeated ketamine infusions in depression with suicidal ideation. J Affect Disord 251:205–212. https://doi.org/10.1016/j.jad.2019.03.071
*Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:9
*Zarate CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial. Biol Psychiatry 71(11):939–946. https://doi.org/10.1016/j.biopsych.2011.12.010
*Zhang M, Rosenheck R, Lin X, Li Q, Zhou Y, Xiao Y, Huang X, Fan N, He H (2018) A randomized clinical trial of adjunctive ketamine anesthesia in electro-convulsive therapy for depression. J Affect Disord 227:372–378. https://doi.org/10.1016/j.jad.2017.11.034
Zheng W, Cai D-B, Zheng W, Sim K, Ungvari GS, Peng X-J, Ning Y-P, Wang G, Xiang Y-T (2019a) Brexanolone for postpartum depression: A meta-analysis of randomized controlled studies. Psychiatry Res 279:83–89. https://doi.org/10.1016/j.psychres.2019.07.006
Zheng W, Zhou Y-L, Liu W-J, Wang C-Y, Zhan Y-N, Li H-Q, Chen L-J, Li MD, Ning Y-P (2019b) Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder. J Psychopharmacol 33(4):494–501. https://doi.org/10.1177/0269881119827811
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Conley, A.A., Norwood, A.E.Q., Hatvany, T.C. et al. Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis. Psychopharmacology 238, 1737–1752 (2021). https://doi.org/10.1007/s00213-021-05825-8
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DOI: https://doi.org/10.1007/s00213-021-05825-8