Cited by 433Treatment of Major DepressionElectroconvulsive Therapy StudiesTryptophan and brain disorders

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Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

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Fava, Maurizio, Freeman, Marlene P., Flynn, Martina, Judge, Heidi, Hoeppner, Bettina B., Cusin, Cristina, Ionescu, Dawn F., Mathew, Sanjay J., Chang, Lee C., Iosifescu, Dan V., Murrough, James, Debattista, Charles, Schatzberg, Alan F., Trivedi, Madhukar H., Jha, Manish K, Sanacora, Gerard, Wilkinson, Samuel T., Papakostas, George I.·2020·Molecular Psychiatry

DOI 10.1038/s41380-018-0256-5PMC PMC6447473

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Abstract

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.

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At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial
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“…study (McInnes et al., 2022) for KIT, however, response and remission rates for this sample are similar to, if slightly stronger than, those previously reported (aan het Rot et al., 2010; Fava et al., 2020; Lara et al., 2013; Lener et al., 2017; McInnes et al., 2022; Phillips et al., 2019).”
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“infusion for 40 min) [2, 3, 44–46], while the dissociative symptoms are usually observed in the same dose range [44, 45], suggesting a possibile correlation between antidepressant and dissociative effects.”
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Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics?
Hashimoto, K. (2024) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01770-7 · Cited by 58
Ketamine as a mental health treatment: Are acute psychoactive effects associated with outcomes? A systematic review
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Pharmacotherapy
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Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis
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Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian rapid treatment center of excellence
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Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression
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Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks
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“These results suggest that in low doses, similar to the ones used in medical practice to treat depression [41], ketamine mainly affects mental representations.”
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“In future clinical practice, the optimal approach for achieving the best antidepressant effect of ketamine with minimal adverse effects remains a major challenge.”
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“For a full description of the original trial design and patient selection, please refer to the main publication of results (Fava et al., 2018).”
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Nuclear factor of activated T cells 4 in the prefrontal cortex is required for prophylactic actions of (R)-ketamine
Ma, L., Zhang, J., Fujita, Y., Qu, Y., Shan, J., Wan, X., Wang, X., Ishima, T., Kobayashi, K., Wang, L., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01803-6 · Cited by 52
Targeting metaplasticity mechanisms to promote sustained antidepressant actions
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Recreational ketamine-related deaths notified to the National Programme on Substance Abuse Deaths, England, 1997–2019
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“The most effective IV dosages for TRD appear to be 0.5 mg/kg and 1.0 mg/kg (Fava et al., 2020).”
BackgroundInfluential
Active mechanisms of ketamine-assisted psychotherapy: A systematic review
Joneborg, I., Lee, Y. L., Vincenzo, J. D. D., Ceban, F., Meshkat, S., Lui, L. M. W., Fancy, F., Rosenblat, J. D., & McIntyre, R. S. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.07.030 · Cited by 48
A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions
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Long-term outcome in outpatients with depression treated with acute and maintenance intravenous ketamine: A retrospective chart review
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“Multiple clinical trials have demonstrated that even a single subanesthetic dose of intravenous ketamine has a rapid-acting antidepressant e ﬀ ect (Cusin et al., 2017; Diamond et al., 2014; Fava et al., 2018; Singh et al., 2016).”
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Harm related to recreational ketamine use and its relevance for the clinical use of ketamine. A systematic review and comparison study
Van Amsterdam, J., & Van Den Brink, W. (2022) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2021.1949454 · Cited by 44
Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder
Freeman, M. P., Hock, R. S., Papakostas, G. I., Judge, H., Cusin, C., Mathew, S. J., Sanacora, G., Iosifescu, D. V., DeBattista, C., Trivedi, M. H., et al. (2020) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001209 · Cited by 44
“The primary study has been reported in detail and demonstrated an acute superior antidepressant response to a single intravenous (IV) ketamine administration compared with active placebo.(14) Planned exploratory analyses did not demonstrate a sex difference in response rates or differences between premenopausal and po…”
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Subcutaneous Ketamine in Depression: A Systematic Review
Cavenaghi, V. B., da Costa, L. P., Lacerda, A. L. T., Hirata, E. S., Miguel, E. C., & Fráguas, R. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.513068 · Cited by 44
A key role of miR-132-5p in the prefrontal cortex for persistent prophylactic actions of (R)-ketamine in mice
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Self-citation
Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder
Dean, R. L., Hurducas, C., Hawton, K., Spyridi, S., Cowen, P. J., Hollingsworth, S., Marquardt, T., Barnes, A., Smith, R., McShane, R., et al. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011612.pub3 · Cited by 95
Neural plasticity and depression treatment
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“…2020) Ketamine CGI-S, HAMD, MADRS and SDQ score↓ PAS score↑ fronto-striatal FC↑ CGI-S, HAMD, MADRS, PAS, SDQ rs functional MRI HumanTRD Increasing frontostriatal FC (Domany et al., 2019; Fava et al., 2020; Mkrtchian et al., 2021) Ketamine MADRS score↓ Subgenual ACC activation↓ MADRS functional…”
Background
Arketamine for cognitive impairment in psychiatric disorders
Hashimoto, K. (2023) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-023-01570-5 · Cited by 42
Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives
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Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study
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“However, given ketamine’s unambiguous dissociative effects, an adequate control condition is challenging (62) and application of GABAergic compounds such as benzodiazepines, as performed in previous trials (2) is particularly questionable when GABA levels are assessed.”
BackgroundMethod
Ketamine for Treatment of Mood Disorders and Suicidality: A Narrative Review of Recent Progress
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“13 Although this was the largest randomized control trial (RCT) of ketamine published to date (N = 99), each dose arm included an average of approximately 20 participants, with some demographic differences across the patient groups.”
Self-citation
A role of microRNA-149 in the prefrontal cortex for prophylactic actions of (R)-ketamine in inflammation model
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Methodological challenges in psychedelic drug trials: Efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE) – Rationale and study design
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“In esketamine and ketamine trials for TRD, placebo response rates ranged from 6 to 15% (Daly et al., 2018; Singh et al., 2016), while response rates to active placebo (midazolam) was 11 and 33% at day one and three respectively (Fava et al., 2018).”

Authors: Fava, M., Freeman, M. P., Flynn, M., Judge, H., Hoeppner, B. B., Cusin, C., Ionescu, D. F., Mathew, S. J., Chang, L. C., Iosifescu, D. V., Murrough, J., Debattista, C., Schatzberg, A. F., Trivedi, M. H., Jha, M. K., Sanacora, G., Wilkinson, S. T., & Papakostas, G. I.
Affiliations: Massachusetts General Hospital (US)
Michael E. DeBakey VA Medical Center (US)
Icahn School of Medicine at Mount Sinai (US)
Stanford Medicine (US)
The University of Texas Southwestern Medical Center (US)
Yale University (US)
ORCID: Freeman, Marlene P.
Hoeppner, Bettina B.
Cusin, Cristina
Mathew, Sanjay J.
Chang, Lee C.
Iosifescu, Dan V.
Murrough, James
Debattista, Charles
Schatzberg, Alan F.
Trivedi, Madhukar H.
Jha, Manish K
Sanacora, Gerard
Wilkinson, Samuel T.
Papakostas, George I.
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2018-10-03
Volume: 25
Issue: 7
Pages: 1592-1603
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-018-0256-5
PMC: PMC6447473
OpenAlex: W2895197076
Cited by: 433
References: 35
Citations by year: 2026: 28 · 2025: 69 · 2024: 79 · 2023: 54 · 2022: 54 · 2021: 59 · 2020: 60 · 2019: 28 · 2018: 1
FWCI: 23.88
Type: journal article
Language: en
Update notices: correction (2019-01-07)
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Molecular Psychiatry (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (HHSN271201100006I)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: treatment-resistant depression, intravenous ketamine, rapid-acting antidepressants, dose-response relationship, NMDA receptor antagonists, active placebo, antidepressant efficacy, depression severity, outpatients, antidepressant safety, CGI-S, CGI-I, adjunctive therapy, suicidal ideation
MeSH terms: Adult, Antidepressive Agents, Depression, Double-Blind Method, Female, Humans, Infusions, Intravenous, Ketamine, Male, Middle Aged, Treatment Outcome, Depressive Disorder, Treatment-Resistant

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Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

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