Hostname: page-component-f554764f5-wjqwx Total loading time: 0 Render date: 2025-04-21T04:26:44.664Z Has data issue: false hasContentIssue false
  • English
  • Français

Ketamine for the Treatment of Psychiatric Disorders: A Systematic Review and Meta-Analysis

Published online by Cambridge University Press:  20 November 2024

Angela T.H. Kwan ,
Moiz Lakhani ,
Gurkaran Singh ,
Gia Han Le ,
Sabrina Wong ,
Kayla M. Teopiz ,
Donovan A. Dev ,
Arshpreet Singh Manku ,
Gurnoor Sidhu  and
Roger S. McIntyre Open the ORCID record for Roger S. McIntyre [Opens in a new window]
Angela T.H. Kwan
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
Moiz Lakhani
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
Gurkaran Singh
Affiliation:
Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
Gia Han Le
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada
Sabrina Wong
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
Kayla M. Teopiz
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada
Donovan A. Dev
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada School of Medicine, University College Dublin, Dublin, Ireland
Arshpreet Singh Manku
Affiliation:
Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
Gurnoor Sidhu
Affiliation:
Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
Roger S. McIntyre*
Affiliation:
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
*
Corresponding author: Roger S. McIntyre; Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Inadequate response to first- and second-line pharmacological treatments for psychiatric disorders is commonly observed. Ketamine has demonstrated efficacy in treating adults with treatment-resistant depression (TRD), with additional off-label benefits reported for various psychiatric disorders. Herein, we performed a systematic review and meta-analysis to examine the therapeutic applications of ketamine across multiple mental disorders, excluding mood disorders.

Methods

We conducted a multidatabase literature search of randomized controlled trials and open-label trials investigating the therapeutic use of ketamine in treating mental disorders. Studies utilizing the same psychological assessments for a given disorder were pooled using the generic inverse variance method to generate a pooled estimated mean difference.

Results

The search in OVID (MedLine, Embase, AMED, PsychINFO, JBI EBP Database), EBSCO CINAHL Plus, Scopus, and Web of Science yielded 44 studies. Ketamine had a statistically significant effect on PTSD Checklist for DSM-5 (PCL-5) scores (pooled estimate = ‒28.07, 95% CI = [‒40.05, ‒16.11], p < 0.001), Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores (pooled estimate = ‒14.07, 95% CI = [‒26.24, ‒1.90], p = 0.023), and Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores (pooled estimate = ‒8.08, 95% CI = [‒13.64, ‒2.52], p = 0.004) in individuals with PTSD, treatment-resistant PTSD (TR-PTSD), and obsessive compulsive disorder (OCD), respectively. For alcohol use disorders and at-risk drinking, there was disproportionate reporting of decreased urge to drink, increased rate of abstinence, and longer time to relapse following ketamine treatment.

Conclusions

Extant literature supports the potential use of ketamine for the treatment of PTSD, OCD, and alcohol use disorders with significant improvement of patient symptoms. However, the limited number of randomized controlled trials underscores the need to further investigate the short- and long-term benefits and risks of ketamine for the treatment of psychiatric disorders.

Keywords

ketamineAnxiety disordersBorderline personality disorder (BPD)Eating disordersObsessive compulsive disorder (OCD)Post-traumatic stress disorder (PTSD)Substance/alcohol use disordersSchizophrenia
Type
Review
Information
CNS Spectrums , Volume 29 , Issue 5 , October 2024 , pp. 354 - 361
Copyright
© The Author(s), 2024. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

Footnotes

†

Denotes co-first authorship

This article has been updated since it was originally published. A notice detailing this has been published.

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5-TR. American Psychiatric Association Publishing; 2022:1050.Google Scholar
McIntyre, RS, Alsuwaidan, M, Baune, BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394–412.CrossRefGoogle ScholarPubMed
Howes, OD, Thase, ME, Pillinger, T. Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry. 2021;27(1):58–72.CrossRefGoogle ScholarPubMed
McIntyre, RS, Rosenblat, JD, Nemeroff, CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–399.CrossRefGoogle ScholarPubMed
Albott, CS, Lim, KO, Forbes, MK, et al. Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Clin Psychiatry. 2018;79(3). http://doi.org/10.4088/JCP.17m11634 CrossRefGoogle ScholarPubMed
Ochs-Ross, R, Daly, EJ, Zhang, Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121–141.CrossRefGoogle ScholarPubMed
Rodriguez, CI, Kegeles, LS, Levinson, A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013 Nov;38(12):2475–2483.CrossRefGoogle ScholarPubMed
Jones, JL, Mateus, CF, Malcolm, RJ, Brady, KT, Back, SE. Efficacy of ketamine in the treatment of substance use disorders: a systematic review. Front Psychiatry. 2018;9:277.CrossRefGoogle ScholarPubMed
Jovaisa, T, Laurinenas, G, Vosylius, S, Sipylaite, J, Badaras, R, Ivaskevicius, J. Effects of ketamine on precipitated opiate withdrawal. Medicina. 2006;42(8):625–634.Google ScholarPubMed
Greenwald, M, Greenstein, D, Park, L, Acevedo-Diaz, E, Cavanaugh, G, Zarate, CA. Do acute experiences during ketamine infusions influence its antidepressant effects? Biol Psychiatry. 2020;87(9):S276.CrossRefGoogle Scholar
Duek, O, Yutong, L, Kelmendi, B, et al. Enhancing trauma-memories reconsolidation with one-time ketamine infusion. Biol Psychiatry. 2021;89(9):S298.CrossRefGoogle Scholar
Feder, A, Norbury, A, Rutter, S, et al. Neural circuitry mechanisms of response to ketamine in ptsd: preliminary findings. Biol Psychiatry. 2022;91(9):S34–S35.CrossRefGoogle Scholar
Duek, O, Levy, I, Yutong, L, Gordon, C, Kelmendi, B, Harpaz-Rotem, I. O40. PTSD augmented psychotherapy with ketamine (KPE) - first results. Biol Psychiatry. 2019;85(10):S122.CrossRefGoogle Scholar
Liriano, F, Hatten, C, Schwartz, TL. Ketamine as treatment for post-traumatic stress disorder: a review. Drugs Context. 2019;8:212305.CrossRefGoogle ScholarPubMed
Stroup, DF, Berlin, JA, Morton, SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–2012.CrossRefGoogle ScholarPubMed
Page, MJ, Moher, D, Bossuyt, PM, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160.CrossRefGoogle ScholarPubMed
Covidence. Covidence - better systematic review management. 2020 [cited 2023 Dec 18]. Available from: https://www.covidence.org/ Google Scholar
Higgins, JPT, Altman, DG, Gøtzsche, PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.CrossRefGoogle ScholarPubMed
Higgins, JPT, Altman, DG. Assessing risk of bias in included studies. In: Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: John Wiley & Sons, Ltd; 2008:187–241.CrossRefGoogle Scholar
Higgins, JPT, Thomas, J, Chandler, J, et al. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons;2019:736 p.CrossRefGoogle Scholar
Chapter 14: Completing “Summary of findings” tables and grading the certainty of the evidence. [cited 2024 Mar 12]. Available from: https://training.cochrane.org/handbook/current/chapter-14 Google Scholar
Feder, A, Costi, S, Rutter, SB, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry. 2021;178(2):193–202.CrossRefGoogle ScholarPubMed
Dakwar, E, Levin, F, Hart, CL, et al. A single ketamine infusion combined with motivational enhancement therapy for alcohol use disorder: a randomized midazolam-controlled pilot trial. Am J Psychiatry. 2020;177(2):125–133.CrossRefGoogle ScholarPubMed
Grabski, M, McAndrew, A, Lawn, W, et al. Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder. Am J Psychiatry. 2022 Feb;179(2):152–62.CrossRefGoogle ScholarPubMed
Krupitsky, E, Burakov, A, Romanova, T, Dunaevsky, I, Strassman, R, Grinenko, A. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Subst Abuse Treat. 2002;23(4):273–283.CrossRefGoogle ScholarPubMed
Dakwar, E, Levin, F, Foltin, RW, Nunes, EV, Hart, CL. The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol Psychiatry. 2014;76(1):40–46.CrossRefGoogle ScholarPubMed
Davis, MT, DellaGiogia, N, Maruff, P, Pietrzak, RH, Esterlis, I. Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder. Transl Psychiatry. 2021;11(1):205.CrossRefGoogle ScholarPubMed
Krystal, JH, Petrakis, IL, Limoncelli, D, et al. Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients. Neuropsychopharmacology. 2003;28(11):2020–2028.CrossRefGoogle ScholarPubMed
Glue, P, Neehoff, S, Sabadel, A, et al. Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study. J Psychopharmacol. 2020;34(3):267–72.CrossRefGoogle ScholarPubMed
Bloch, MH, Wasylink, S, Landeros-Weisenberger, A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012;72(11):964–970.CrossRefGoogle ScholarPubMed
Shadli, SM, Kawe, T, Martin, D, McNaughton, N, Neehoff, S, Glue, P. Ketamine effects on eeg during therapy of treatment-resistant generalized anxiety and social anxiety. Int J Neuropsychopharmacol. 2018;21(8):717–724.CrossRefGoogle ScholarPubMed
Abbar, M, Demattei, C, El-Hage, W, et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022;376:e067194.CrossRefGoogle ScholarPubMed
Murrough, JW, Soleimani, L, DeWilde, KE, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015 Dec;45(16):3571–3580.CrossRefGoogle ScholarPubMed
Daly, EJ, Turkoz, I, Salvadore, G, et al. The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder. Depress Anxiety. 2021;38(11):1120–1130.CrossRefGoogle ScholarPubMed
Dadabayev, AR, Joshi, SA, Reda, MH, et al. Low dose ketamine infusion for comorbid posttraumatic stress disorder and chronic pain: a randomized double-blind clinical trial. Chronic Stress (Thousand Oaks). 2020;4:2470547020981670.CrossRefGoogle ScholarPubMed
Dakwar, E, Nunes, EV, Hart, CL, Hu, MC, Foltin, RW, Levin, FR. A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: results from a randomized, controlled laboratory study. Neuropharmacology. 2018;142:270–276.CrossRefGoogle Scholar
Dakwar, E, Nunes, EV, Hart, CL, et al. A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: a randomized clinical trial. Am J Psychiatry. 2019;176(11):923–930.CrossRefGoogle ScholarPubMed
Das, RK, Gale, G, Walsh, K, et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun. 2019;10(1):5187.CrossRefGoogle ScholarPubMed
Duek, O, Korem, N, Li, Y, Kelmendi, B, Amen, S, Gordon, C, et al. Long term structural and functional neural changes following a single infusion of Ketamine in PTSD. Neuropsychopharmacology. 2023;48(11):1648–1658.CrossRefGoogle ScholarPubMed
Feder, A, Parides, MK, Murrough, JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681–688.CrossRefGoogle ScholarPubMed
Fineberg, SK, Choi, EY, Shapiro-Thompson, R, et al. A pilot randomized controlled trial of ketamine in Borderline Personality Disorder. Neuropsychopharmacology. 2023;48(7):991–999.CrossRefGoogle ScholarPubMed
Lahti, AC, Weiler, MA, Tamara Michaelidis, BA, Parwani, A, Tamminga, CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25(4):455–467.CrossRefGoogle ScholarPubMed
Malhotra, AK, Pinals, DA, Adler, CM, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology. 1997;17(3):141–150.CrossRefGoogle ScholarPubMed
Noppers, I, Niesters, M, Swartjes, M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. 2011;15(9):942–949.CrossRefGoogle Scholar
Norbury, A, Rutter, SB, Collins, AB, et al. Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence. Neuropsychopharmacology. 2021 Dec;46(13):2266–2277.CrossRefGoogle ScholarPubMed
Pradhan, B, Mitrev, L, Moaddell, R, Wainer, IW. d-Serine is a potential biomarker for clinical response in treatment of post-traumatic stress disorder using (R,S)-ketamine infusion and TIMBER psychotherapy: A pilot study. Biochim Biophys Acta: Proteins Proteomics. 2018;1866(7):831–839.CrossRefGoogle ScholarPubMed
Rodriguez, CI, Kegeles, LS, Levinson, A, et al. In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: proof of concept. Psychiatry Res. 2015;233(2):141–147.CrossRefGoogle ScholarPubMed
Rodriguez, CI, Wheaton, M, Zwerling, J, et al. Can exposure-based CBT extend the effects of intravenous ketamine in obsessive-compulsive disorder? an open-label trial. J Clin Psychiatry. 2016;77(3):408–409.CrossRefGoogle ScholarPubMed
Ross, C, Jain, R, Bonnett, CJ, Wolfson, P. High-dose ketamine infusion for the treatment of posttraumatic stress disorder in combat veterans. Ann Clin Psychiatry. 2019;31(4):271–279.Google ScholarPubMed
Rothberg, RL, Azhari, N, Haug, NA, Dakwar, E. Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial. J Psychopharmacol. 2021;35(2):150–158.CrossRefGoogle ScholarPubMed
Taylor, JH, Landeros-Weisenberger, A, Coughlin, C, et al. Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2018;43(2):325–333.CrossRefGoogle ScholarPubMed
Terasaki, D, Loh, R, Cornell, A, Taub, J, Thurstone, C. Single-dose intravenous ketamine or intramuscular naltrexone for high-utilization inpatients with alcohol use disorder: pilot trial feasibility and readmission rates. Addict Sci Clin Pract. 2022;17(1):64.CrossRefGoogle ScholarPubMed
Albott, CS, Lim, KO, Erbes, C, et al. Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder. J Affect Disord. 2022;308:289–297.CrossRefGoogle ScholarPubMed
Shiroma, PR, Thuras, P, Wels, J, et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl Psychiatry. 2020;10(1):206.CrossRefGoogle ScholarPubMed
Abdallah, CG, Roache, JD, Gueorguieva, R, et al. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology. 2022;47(8):1574–1581.CrossRefGoogle ScholarPubMed
Kelson, M, Burnett, JM, Matthews, A, Juneja, T. Ketamine treatment for alcohol use disorder: a systematic review. Cureus. 2023;15(5):e38498.Google ScholarPubMed
Krupitsky, EM, Grineko, AY, Berkaliev, TN, et al. The combination of psychedelic and aversive approaches in alcoholism treatment. Alcohol Treat Q. 1992;9(1):99–105.CrossRefGoogle Scholar
Arizona, P. ACNP 61st annual meeting: poster abstracts p271-P540. Neuropsychopharmacology. 2022;47(Suppl 1):220–370.Google Scholar
Whittaker, E, Dadabayev, AR, Joshi, SA, Glue, P. Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders. Ther Adv Psychopharmacol. 2021;11:20451253211056743.CrossRefGoogle ScholarPubMed
Hartland, H, Mahdavi, K, Jelen, LA, Strawbridge, R, Young, AH, Alexander, L. A transdiagnostic systematic review and meta-analysis of ketamine’s anxiolytic effects. J Psychopharmacol. 2023;37(8):764–774.CrossRefGoogle ScholarPubMed
Du, R, Han, R, Niu, K, et al. The multivariate effect of ketamine on PTSD: systematic review and meta-analysis. Front Psychiatry. 2022;13:813103.CrossRefGoogle ScholarPubMed
Nikayin, S, Murphy, E, Krystal, JH, Wilkinson, ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf. 2022;21(6):777–787.CrossRefGoogle ScholarPubMed
ClinicalTrials.Gov. [cited 2024 Jul 22]. Available from: https://clinicaltrials.gov/search?cond=Psychiatric%20Disorders&intr=Ketamine.Google Scholar
Higgins, JPT, Green, S. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: Wiley; 2008:672.CrossRefGoogle Scholar
Supplementary material: File

Kwan et al. supplementary material

Kwan et al. supplementary material
Download Kwan et al. supplementary material(File)
File 142 KB