• A Correction to this article was published on 07 January 2019


Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.


  • Question: What is the optimal, rapid antidepressant dose of intravenous (IV) ketamine, an NMDA receptor antagonist?

  • Findings: Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Most of the effect was due to differences at day 1.

  • Meaning: Our results suggest that there is a range of effective, subanesthetic doses of IV ketamine in TRD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 07 January 2019

    Supplementary Figure 1 and Supplementary Tables 1–4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.


  1. 1.

    Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649–59.

  2. 2.

    Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179–200.

  3. 3.

    Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR* D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.

  4. 4.

    Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28:156–65.

  5. 5.

    Bauer M, El-Khalili N, Datto C, Szamosi J, Eriksson H. A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord. 2010;127:19–30.

  6. 6.

    Tohen M, Case M, Trivedi MH, Thase ME, Burke SJ, Durell TM. Olanzapine/fluoxetine combination in patients with treatment-resistant depression: rapid onset of therapeutic response and its predictive value for subsequent overall response in a pooled analysis of 5 studies. J Clin Psychiatry. 2010;71:451–62.

  7. 7.

    Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76:1224–31.

  8. 8.

    O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–16.

  9. 9.

    Bajbouj M, Merkl A, Schlaepfer TE, Frick C, Zobel A, Maier W, et al. Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol. 2010;30:273–81.

  10. 10.

    Trevino K, McClintock SM, Husain MM. A review of continuation electroconvulsive therapy: application, safety, and efficacy. J ECT. 2010;26:186–95.

  11. 11.

    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.

  12. 12.

    Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.

  13. 13.

    Bobo WV, Voort JLV, Croarkin PE, Leung JG, Tye SJ, Frye MA. Ketamine for treatment-resistant unipolar and bipolar major depression: critical review and implications for clinical practice. Depress Anxiety. 2016;33:698–710.

  14. 14.

    Loo CK, Gálvez V, O’Keefe E, Mitchell PB, Hadzi-Pavlovic D, Leyden J. et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016;134:48–56.

  15. 15.

    Wohleb E, Gerhard D, Thomas A,S, Duman R. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol. 2017;15:11–20.

  16. 16.

    Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134–42.

  17. 17.

    Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.

  18. 18.

    Bech P, Allerup P, Gram L, Reisby N, Rosenberg R, Jacobsen O, et al. The Hamilton depression scale. Acta Psychiatr Scand. 1981;63:290–9.

  19. 19.

    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

  20. 20.

    O’Sullivan RL, Fava M, Agustin C, Baer L, Rosenbaum J. Sensitivity of the six‐item hamilton depression rating scale. Acta Psychiatr Scand. 1997;95:379–84.

  21. 21.

    Bech P, Boyer P, Germain J-M, Padmanabhan K, Haudiquet V, Pitrosky B, et al. HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder. Pharmacopsychiatry. 2010;43:271–6.

  22. 22.

    Fawcett J, Epstein P, Fiester SJ, Elkin I, Autry JH. Clinical management: imipramine/placebo administration manual. Psychopharmacol Bull. 1987;23:309–24.

  23. 23.

    Pedrelli P, Blais MA, Alpert JE, Shelton RC, Walker RS, Fava M. Reliability and validity of the Symptoms of Depression Questionnaire (SDQ). CNS Spectr. 2014;19:535–46.

  24. 24.

    Snaith R, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167:99–103.

  25. 25.

    Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville: US Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug Abuse, and Mental Health Administration; 1976.

  26. 26.

    Drevets WC, Furey ML. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry. 2010;67:432–8.

  27. 27.

    Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63:1121–9.

  28. 28.

    Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035–43.

  29. 29.

    Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, et al. Measurement of dissociative states with the clinician-administered dissociative states scale (CADSS). J Trauma Stress. 1998;11:125–36.

  30. 30.

    Levine J, Schooler N. SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacol Bull. 1986;22:343.

  31. 31.

    Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat Theory Appl. 1979;6:65–70.

  32. 32.

    Luckenbaugh DA, Niciu MJ, Ionescu DF, Nolan NM, Richards EM, Brutsche NE, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014;159:56–61.

  33. 33.

    Su TP, Chen MH, Li CT, Lin WC, Hong CJ, Gueorguieva R, et al. Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology. 2017;42:2482–92.

  34. 34.

    Leon AC, Davis LL, Kraemer HC. The role and interpretation of pilot studies in clinical research. J Psychiatr Res. 2011;45:626–9.

Download references


This project was funded by the National Institute of Mental Health (NIMH) under Contract Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID) Number: HHSN271201100006I, to the Massachusetts General Hospital (Maurizio Fava and George Papakostas, co-principal investigators). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. We would like to thank Dr. Matthias Eikermann from MGH who served as a collaborator, and Drs. Mi Hillefors, Steven Zalcman, Adam Haim, and Galia Siegel from NIMH for their support which was absolutely critical to both the planning and the implementation of the study.

Author information


  1. Massachusetts General Hospital, Boston, MA, USA

    • Maurizio Fava
    • , Marlene P. Freeman
    • , Martina Flynn
    • , Heidi Judge
    • , Bettina B. Hoeppner
    • , Cristina Cusin
    • , Dawn F. Ionescu
    •  & George I. Papakostas
  2. Baylor College of Medicine/Michael E. Debakey VA Medical Center, Houston, TX, USA

    • Sanjay J. Mathew
    •  & Lee C. Chang
  3. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Dan V. Iosifescu
    •  & James Murrough
  4. Stanford University School of Medicine, Stanford, CA, USA

    • Charles Debattista
    •  & Alan F. Schatzberg
  5. University of Texas Southwestern, Dallas, TX, USA

    • Madhukar H. Trivedi
    •  & Manish K Jha
  6. Yale University, New Haven, CT, USA

    • Gerard Sanacora
    •  & Samuel T. Wilkinson


  1. Search for Maurizio Fava in:

  2. Search for Marlene P. Freeman in:

  3. Search for Martina Flynn in:

  4. Search for Heidi Judge in:

  5. Search for Bettina B. Hoeppner in:

  6. Search for Cristina Cusin in:

  7. Search for Dawn F. Ionescu in:

  8. Search for Sanjay J. Mathew in:

  9. Search for Lee C. Chang in:

  10. Search for Dan V. Iosifescu in:

  11. Search for James Murrough in:

  12. Search for Charles Debattista in:

  13. Search for Alan F. Schatzberg in:

  14. Search for Madhukar H. Trivedi in:

  15. Search for Manish K Jha in:

  16. Search for Gerard Sanacora in:

  17. Search for Samuel T. Wilkinson in:

  18. Search for George I. Papakostas in:

Conflict of interest

LCC, MF, BBH, and HJ declare that they have no conflict of interest. CD: Dr. DeBattista has received grant support from Janssen, Neuronetics, St. Jude, and Biolite. He has served on the Advisory Board of Alkermes. CC: Dr. Cusin receives funding from NIMH (R01MH102279) and has received consulting fees from Janssen Pharmaceuticals, Takeda, Boehringer, Lundbeck. She has also participated in research funded by Janssen, Medtronic, Otsuka, Takeda. MF: reports 3-year disclosures as below: all lifetime disclosures can be viewed online at: http://mghcme.org/faculty/faculty-detail/maurizio_fava; research support: Alkermes, Inc., Johnson & Johnson, Axsome, Acadia Pharmaceuticals, Cerecor, Lundbeck Inc., Neuralstem, Otsuka, Taisho, Marinus Pharmaceuticals, BioHaven, Takeda, Vistagen, Relmada Therapeutics Inc., Stanley Medical Research Institute (SMRI), National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH), and PCORI. Dr. Fava has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital. Stock/Other Financial Options: Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd. MPF: over the past 3 years, Dr. Freeman has received research support from: Takeda, JayMac, and Sage; she has served in advisory boards of: Janssen, Sage, JDS therapeutics, Sunovion, and Takeda; she has served in the Independent Data Safety and Monitoring Committee of Janssen (Johnson&Johnson); she has served as a medical editor for the GOED newsletter. Dr. Freeman is an employee of Massachusetts General Hospital, and works with the MGH National Pregnancy Registry [Current Registry Sponsors: Teva, Alkermes, Inc. (2016-Present); Otsuka America Pharmaceutical, Inc. (2008-Present); Forest/Actavis (2016-Present), Sunovion Pharmaceuticals, Inc. (2011-Present)]. As an employee of MGH, Dr. Freeman works with the MGH CTNI, which has had research funding from multiple pharmaceutical companies and NIMH. DFI: Dr. Ionescu is an employee of Janssen Pharmaceuticals and, within the past year, has received grant funding with salary support from the Brain and Behavior Research Foundation and the NIMH for ketamine research. DVI: In the past 3 years, Dr. Iosifescu has received consultation fees from Alkermes, Axsome, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, Sunovion, and has received research support (through his academic institutions) from Alkermes, Astra Zeneca, Brainsway, LiteCure, Neosync, Roche, Shire. MJ: Dr. Jha has obtained contracted research support from Acadia Pharmaceuticals and Janssen Research & Development. SJM: over the past 3 years, Dr. Mathew has received consulting fees from Acadia, Alkermes, Allergan, Bracket, Cerecor, Fortress Biotech, Otsuka, and Valeant; he has received research support from: Janssen and NeuroRx; he has also received support from facilities and resources of the Michael E. Debakey VA Medical Center and the Johnson Chair for Research from Baylor College of Medicine. JM: in the past 3 years, Dr. Murrough has provided consultation services to Allergan, Fortress Biotech, Novartis, Janssen Research and Development, Genentech, and ProPhase, and has received research support from Avanir Pharmaceuticals. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders as well as on patents pending for lithium to extend the antidepressant effect of ketamine and ketamine plus lithium as a treatment for suicidal ideation. The Icahn School of Medicine (employer of Dr. Murrough) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine if it is approved for the treatment of depression. Dr. Murrough is not named on this patent and will not receive any payments. GIP: over the past 3 years, Dr. Papakostas has consulted to: Lundbeck, Sunovion, Brainsway, Pfizer, Boston Pharmaceuticals*, Novartis*, Acadia*, Axsome*, Genomind*, and Mylan* (*on behalf of Massachusetts General Hospital). He has received honoraria from: Lundbeck, Grunbiotics-Mylan, Takeda, Alkermes, Pfizer, Pharma Trade SAS, Asofarma, Sunovion, Brainsway, and Unilab Philippines. He has received research support from Neuralstem Inc and Tal Medical. GS: Dr. Sanacora has received consulting fees form Allergan, Alkermes, AstraZeneca, Biohaven Pharmaceuticals, Genentech, Janssen, Lundbeck, Merck, Navitor pharmaceuticals, Noven pharmaceuticals, Sage Pharmaceuticals, Takeda, Taisho Pharmaceuticals, Teva Pharmaceuticals and Vistagen Therapeutics over the last 36 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Johnson & Johnson, Hoffman La-Roche, Merck & Co., Naurex and Servier over the last 36 months. Free medication was provided to Dr. Sanacora for an NIH-sponsored study by Sanofi-Aventis. In addition, he holds shares in Biohaven Pharmaceuticals and is a co-inventor on a patent “Glutamate agents in the treatment of mental disorders” Patent number: 8778979. AFS: Dr. Schatzberg has served as a consultant for Alkermes, Avanir, Bracket, Lundbeck/Takeda, McKinsey, Myriad Genetics, Neuronetics, and Owl and as a speaker for Merck and Pfizer; he holds equity in Corcept (co-founder), Gilead, Incyte, Intersect ENT, Merck, Owl, Seattle Genetics, Titan, and Xhale; he has research funding from Janssen; and he is listed as an inventor on pharmacogenetic and mifepristone patents from Stanford University. MHT: Consulting/Advisory Board: Alkeremes Inc., Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education Inc, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research & Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck & Co. Inc, Mitsubishi Pharma, MSI Methylation Sciences–Pamlab Inc., Navitor, Otsuka America Pharmaceutical Inc., One Carbon Therapeutics, Otsuka America Pharmaceutical Inc., Pfizer Inc, Takeda Global Research. Royalties: Janssen Research and Development LLC. Author Agreement: Janssen Asia Pacific, Oxford University Press. Honoraria: American Psychiatric Association. Grants: Agency for Healthcare Research and Quality (AHRQ), Cancer Prevention and Research Institute of Texas (CPRIT), National Institute of Mental Health (NIMH), National Institute of Drug Abuse (NIDA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Center for Advancing Translational Sciences (NCATS), Johnson & Johnson, PCORI. STW: Dr. Wilkinson acknowledges support from the Agency for Healthcare Research and Quality (AHRQ; K12HS023000), the NIMH (T32MH062994), the Brain and Behavior Research Foundation (formerly NARSAD), the Robert E. Leet and Clara Guthrie Patterson Trust, the American Foundation for Suicide Prevention and the Yale Department of Psychiatry. Dr. Wilkinson has received consulting fees from Janssen Research & Development and from Guidepoint.

Corresponding author

Correspondence to Maurizio Fava.

Electronic supplementary material

About this article

Publication history







Further reading