CoChat
Sign Up
Cited by 55Treatment of Major DepressionElectroconvulsive Therapy StudiesPsychedelics and Drug Studies

Ketamine as a mental health treatment: Are acute psychoactive effects associated with outcomes? A systematic review

Grabski, Meryem, Borissova, Anna, Marsh, Beth, Morgan, Celia J.A., Curran, H.Valerie·2020·Behavioural Brain Research
DOI 10.1016/j.bbr.2020.112629
Open this paper in CoChat — free account

Abstract

Esketamine was recently licensed by the US Food and Drug Administration (FDA) and European Drug Agency (EDA) for use in treatment resistant depression (TRD), and further research indicates ketamine as a possible treatment in other mental health conditions. While the underlying mechanisms remain unclear, it has been hypothesised that ketamine's acute psychoactive effects may be associated with psychiatric treatment efficacy. We systematically reviewed the evidence for this association. The databases Medline, Embase and PsychInfo were searched up to June 2019. Studies were included if they enrolled adults with a psychiatric diagnosis, assessed acute psychoactive effects using a quantitative measure, and reported on the relationship between acute effects and treatment outcome. We included 21 studies, involving 891 patients. Seventeen studies assessed patients with depression (TRD [k = 14]), three assessed substance use disorders, and one assessed social anxiety disorder. Overall, 41 associations were assessed, of which 26 % were significant. The studies reviewed displayed great variability in terms of methodology and quality of reporting. The most commonly assessed effect was dissociation, measured by the CADSS. Our results suggest that the CADSS total is not consistently associated with antidepressant outcomes. Apart from this, the current literature is too limited to draw definite conclusions on the presence of an association between acute psychoactive effects and mental health outcomes. The field would benefit from consistently employing a priori hypotheses, more transparent reporting and sufficiently powered statistical analyses. Furthermore, the use of a broader range of assessments tools of acute psychoactive effects during ketamine administration would be beneficial.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.bbr.2020.112629

Cites

13 of 13 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 66

  1. [2]2. Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38(12):2475-83.
  2. [3]3. Jones JL, Mateus CF, Malcolm RJ, Brady KT, Back SE. Efficacy of ketamine in the treatment of substance use disorders: a systematic review. Frontiers in Psychiatry. 2018;9.
  3. [4]4. Ezquerra-Romano II, Lawn W, Krupitsky E, Morgan CJN. Ketamine for the treatment of addiction: Evidence and potential mechanisms. Journal of Neuropharmacology. 2018;142:72-82.
  4. [5]5. Zorumski CF, Izumi Y, Mennerick S. Ketamine: NMDA Receptors and Beyond. Journal of Neuroscience. 2016;36(44):11158-64.
  5. [6]6. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62(1):63-77.
  6. [8]8. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry. 1994;51(3):199-214.
  7. [9]9. Frohlich J, Van Horn JD. Reviewing the ketamine model for schizophrenia. Journal of Psychopharmacology. 2014;28(4):287-302.
  8. [10]10. Leary T, Litwin GH, Metzner R. Reactions to Psilocybin Administered in a Supportive Environment. Journal of Nervous and Mental Disease. 1963;137:561-73.
  9. [12]12. Roseman L, Nutt DJ, Carhart-Harris RL. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Frontiers in Pharmacology. 2017;8:974.
  10. [13]13. Garcia-Romeu A, Griffiths RR, Johnson MW. Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Current Drug Abuse Reviews. 2014;7(3):157-64.
  11. [15]15. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64.
  12. [16]16. Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, et al. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK0657 in patients with treatment-resistant major depressive disorder. Journal of Clinical Psychopharmacology. 2012;32(4):551-7.
  13. [18]18. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry. 2013;74(4):250-6.
  14. [19]19. Murrough JW, Wan L-B, Iacoviello B, Collins KA, Solon C, Glicksberg B, et al. Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response. Journal of Psychopharmacology. 2014;231(3):481-8.
  15. [20]20. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. International Journal of Neuropsychopharmacology. 2010;13(1):71-82.
  16. [21]21. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatmentresistant depression. Depression and Anxiety. 2014;31(4):335-43.
  17. [22]22. Niciu MJ, Shovestul BJ, Jaso BA, Farmer C, Luckenbaugh DA, Brutsche NE, et al. Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression. Journal of Affective Disorders. 2018;232:310-5.
  18. [23]23. Pennybaker SJ, Niciu MJ, Luckenbaugh DA, Zarate CA. Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion. Journal of Affective Disorders. 2017;208:560-6.
  19. [24]24. 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? 2014;159:56-61.
  20. [25]25. Duncan Jr WC, Sarasso S, Ferrarelli F, Selter J, Riedner BA, Hejazi NS, et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. International Journal of Neuropsychopharmacology. 2012;16(2):301-11.
  21. [26]26. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry. 2010;67(8):793-802.
  22. [27]27. Zarate CA, Jr., 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. Archives of General Psychiatry. 2006;63(8):856-64.
  23. [28]28. Carlson PJ, Diazgranados N, Nugent AC, Ibrahim L, Luckenbaugh DA, Brutsche N, et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biological Psychiatry. 2013;73(12):1213-21.
  24. [29]29. Wan L-B, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. 2015;76(3):247-52.
  25. [30]30. Niciu MJ, Shovestul BJ, Jaso BA, Farmer C, Luckenbaugh DA, Brutsche NE, et al. Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression. 2018;232:310-5.
  26. [31]31. Aust S, Gärtner M, Basso L, Otte C, Wingenfeld K, Chae WR, et al. Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder. Journal of European Neuropsychopharmacology. 2019;29(4):529-38.
  27. [34]34. Shiroma PR, Johns B, Kuskowski M, Wels J, Thuras P, Albott CS, et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. Journal of Affective Disorders. 2014;155:123-9.
  28. [35]35. Vidal S, Gex-Fabry M, Bancila V, Michalopoulos G, Warrot D, Jermann F, et al. Efficacy and Safety of a Rapid Intravenous Injection of Ketamine 0.5 mg/kg in Treatment-Resistant Major Depression: An Open 4-Week Longitudinal Study. Journal of Clinical Psychopharmacology. 2018;38(6):590-7.
  29. [36]36. Wilkinson ST, Katz RB, Toprak M, Webler R, Ostroff RB, Sanacora GJTJocp. Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital. Journal of Clinical Psychiatry. 2018;79(4).
  30. [37]37. Zheng W, Zhou YL, Liu WJ, Wang CY, Zhan YN, Li HQ, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression. Journal of Psychiatric Research. 2018;106:61-8.
  31. [38]38. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000;47(4):351-4.
  32. [39]39. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinology Letters. 2013;34(4):287-93.
  33. [40]40. Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS. Psychiatry Research: Neuroimaging. 2011;191(2):122-7.
  34. [41]41. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biological Psychiatry. 2014;76(12):970-6.
  35. [42]42. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. American Journal of Psychiatry. 2019;176(5):401-9.
  36. [43]43. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. American Journal of Psychiatry. 2018;175(12):1205-15.
  37. [44]44. Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS. 2011;191(2):122-7.
  38. [47]47. Vidal S, Gex-Fabry M, Bancila V, Michalopoulos G, Warrot D, Jermann F, et al. Efficacy and safety of a rapid intravenous injection of ketamine 0.5 mg/kg in treatment-resistant major depression: An open 4-week longitudinal study. 2018;38(6):590-7.
  39. [48]48. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. 2019;176(6):42838.
  40. [49]49. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. 2014;76(12):970-6.
  41. [50]50. Moaddel R, Luckenbaugh DA, Xie Y, Villaseñor A, Brutsche NE, Machado-Vieira R, et al. D-serine plasma concentration is a potential biomarker of (R, S)-ketamine antidepressant response in subjects with treatment-resistant depression. 2015;232(2):399-409.
  42. [51]51. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, repeated, and maintenance ketamine Infusions for treatment-resistant depression: a randomized controlled trial. 2019;176(5):401-9.
  43. [52]52. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. 2000;47(4):351-4.
  44. [54]54. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek TJNL. Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. 2013;34(4):287-93.
  45. [56]56. Shiroma PR, Johns B, Kuskowski M, Wels J, Thuras P, Albott CS, et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. 2014;155:123-9.
  46. [57]57. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. 2018;175(12):1205-15.
  47. [58]58. Aust S, Gärtner M, Basso L, Otte C, Wingenfeld K, Chae WR, et al. Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder. 2019;29(4):529-38.
  48. [59]59. Ionescu DF, Swee MB, Pavone KJ, Taylor N, Akeju O, Baer L, et al. Rapid and sustained reductions in current suicidal ideation following repeated doses of intravenous ketamine. 2016;77(6):e719-e25.
  49. [60]60. Zheng W, Zhou Y-L, Liu W-J, Wang C-Y, Zhan Y-N, Li H-Q, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression. 2018;106:61-8.
  50. [62]62. Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry. 1960;23(1):56-62.
  51. [63]63. Carlson PJ, Diazgranados N, Nugent AC, Ibrahim L, Luckenbaugh DA, Brutsche N, et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. 2013;73(12):1213-21.
  52. [64]64. Hamilton M. A rating scale for depression. 1960;23(1):56.
  53. [66]66. Overall JE, Gorham DRJPr. The brief psychiatric rating scale. Psychological Reports. 1962;10(3):799-812.
  54. [68]68. Dakwar E, Nunes E, Hart C, Hu M, Foltin R, Levin FJN. 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. 2018;142:270-6.
  55. [70]70. Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Journal of Psychoactive Drugs. 1997;29(2):165-83.
  56. [71]71. Krupitsky E, Grinenko AJJopd. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. 1997;29(2):165-83.
  57. [72]72. Dakwar E, Anerella C, Hart C, Levin F, Mathew S, Nunes EJD, et al. Therapeutic infusions of ketamine: do the psychoactive effects matter? 2014;136:153-7.
  58. [74]74. 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). 1998;11(1):125-36.
  59. [75]75. van Schalkwyk GI, Wilkinson ST, Davidson L, Silverman WK, Sanacora G. Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale. Journal of Affective Disorders. 2018;227:11-6.
  60. [76]76. Neehoff S, Glue PJJoad. Dissociation after ketamine dosing: Is the CADSS fit for purpose? Journal of Affective Disorders. 2019;244:239-40.
  61. [77]77. Castle C, Gray A, Neehoff S, Glue P. Effect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders. Journal of Psychopharmacology. 2017;31(10):1306-11.
  62. [78]78. Taylor JH, Landeros-Weisenberger A, Coughlin C, Mulqueen J, Johnson JA, Gabriel D, et al. Ketamine for social anxiety disorder: A randomized, placebo-controlled crossover trial. 2018;43(2):325.
  63. [79]79. Overall JE, Gorham DRJPr. The brief psychiatric rating scale. 1962;10(3):799-812.
  64. [80]80. Frohlich J, Van Horn JDJJop. Reviewing the ketamine model for schizophrenia. 2014;28(4):287-302.
  65. [81]81. Mason OJ, Morgan CJ, Stefanovic A, Curran HV. The psychotomimetic states inventory (PSI): measuring psychotic-type experiences from ketamine and cannabis. Schizophrenia Research. 2008;103(1-3):138-42.
  66. [82]82. van Schalkwyk GI, Wilkinson ST, Davidson L, Silverman WK, Sanacora GJJoad. Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale. 2018;227:11-6. Figure 1. PRISMA Flow Chart of Study Selection <!-- image --> Table 1. Studies included in Systematic Review % f: percentage female, MDD: Major Depressive Disorder, BD: Bipolar Disorder, DB: double-blind, rand: randomized, MADRS: Montgomery Asberger Depression Rating Scale, HDRS: Hamilton Depression Rating Scale, HDRS-I: Hamilton Depression Rating Suicide Subscale, C-SSRS: Columbia Suicide Severity Rating Scale, C-SSRS In: Columbia Suicide Severity Rating Intensity Subscale, CSSRS Id: Columbia Suicide Severity Rating Ideation Subscale, 5D-ASC: 5-Dimensional Altered State of Consciousness Rating Scale, VAS: Visual Analogue Scale, BPRS: Brief Psychiatric Rating Scale , CADSS: Clinician Administered Dissociative States Scale, R: Responders, NR: Non-responders M: Mean, SD: Standard Deviation, * number of participants used to calculate key relevant findings

Cited by

Sorted by citations

Authors
Grabski, M., Borissova, A., Marsh, B., Morgan, C. J. A., & Curran, H. V.
Affiliations
  • University of Exeter (GB)
  • University College Hospital (GB)
  • University College London (GB)
ORCID
Venue
Behavioural Brain Research
Publisher
Elsevier BV
Published
2020-08
Volume
392
Pages
112629
ISSN
0166-4328 (ISSN-L)
DOI
10.1016/j.bbr.2020.112629
OpenAlex
W3029786173
Cited by
55
References
13
Citations by year
2026: 11 · 2025: 9 · 2024: 15 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 2
FWCI
0.66
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Behavioural Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Medical Research Council (NCT02649231)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
Keywords
ketamine, esketamine, dissociation, treatment-resistant depression, antidepressant efficacy, substance use disorders, social anxiety disorder, psychiatric treatment outcomes
MeSH terms
Adult, Antidepressive Agents, Mental Disorders, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Ketamine, Male, Mental Health, Middle Aged, Psychotropic Drugs, Treatment Outcome, Substance-Related Disorders, Depressive Disorder, Treatment-Resistant

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review