Ketamine for Treatment Resistant Depression: Claims are Based on Poor Quality Evidence
- Posted by Alan Eppel
- Posted in Articles, Editorials & Commentary
Vol 11 #5 April 3, 2022
Alan Eppel MB, FRCPC
Department of Psychiatry & Behavioural Neurosciences
McMaster University, Hamilton Ontario
Over the past decade, there has been an accelerated interest in the use of ketamine for the treatment of major depressive disorder. Ketamine was developed in 1964 for use primarily as a veterinary anaesthetic replacing phencyclidine . The number of published articles specifically on the use of ketamine for treatment of depression has risen from five in 2011 to 211 in 2020. This arises in the context of disappointment in the progress of psychopharmacology for major depression over the past decade. In particular, there has been no discernible advantage to the more recently marketed antidepressants. SSRIs and SNRIs have similar effectiveness. Tricyclic antidepressants are still in use and less often monoamine oxidase inhibitors.
Ketamine has aroused interest because, unlike most existing antidepressants, it is unique in its neurotransmitter action. One hypothesis is that ketamine binds to NMDA receptors on GABA secreting inhibitory neurons . This in turn increases release glutamate and of brain derived neurotrophic factor (BDNF). However action on opioid receptors has also been identified .
TREATMENT RESISTANT DEPRESSION?
Claims have been made for ketamine’s effectiveness in “treatment resistant depression”. A major proposed advantage of ketamine is the rapidity of response with lifting of depressed mood and reduction in suicidal ideation . The quality of studies is, however, often poor due to lack of randomization and study controls, heterogeneous populations, lack of standardization of administration procedures, and prescriptions of concurrent medications . Munkholm et al  concluded that the effectiveness of IV ketamine for symptoms in mixed mood states was not substantiated by the data in a paper by McIntyre and colleagues .
A fundamental flaw in research of ketamine is that the definition of “treatment resistant depression” is misleading. In the ketamine studies, treatment resistant depression is taken to mean a failure to respond to a trial of two antidepressants. This is a low threshold for defining treatment resistance. There are multiple other medications and psychotherapeutic options that could be tried prior to embarking on an invasive procedure . Alternative pharmacological treatment strategies are to use drugs from a number of different classes; e.g., selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants, augmentation, combination . Failure to respond to electroconvulsive therapy could also be considered as a criterion.
QUALITY of EVIDENCE
The clinical significance of many ketamine studies remains unclear. Outcome measures require a modest change in depression rating scales; e.g., 4 to 6 points on the Montgomery–Asberg. This is not a large clinical improvement.
To date, there is no convincing evidence of a sustained response to ketamine treatment despite some claims. The effects are transient. The long-term effect of repeated dosages and outcome remains uncertain in normal clinical practice. Corriger and Pickering  analyzed two Cochrane reviews, 14 meta-analyses, and 15 randomized controlled trials (RCTs) of treatment with ketamine in major depressive disorder and bipolar disorder. The results showed a rapid but short-lived effect lasting 1-2 weeks after infusion. Some have concluded that evidence for efficacy remains low and that more RCTs are needed [6-10].
RISK OF BIAS
Risk of bias has been identified as high. Article abstracts or conclusions are often at variance with the data presented. This is known as “spinning”[11,12,13]. While methodological deficiencies may be referred to, they do not prevent overreaching claims for treatment efficacy. Walsh et al  note problems with randomization, allocation concealment, missing data and measurement of outcome in the randomized trials they reviewed. Nonrandomized trials are at serious risk of bias due to lack of controls, and measurement of outcomes, selection bias, and deviation from the planned interventions .
Conflict of interest bias is high among authors who have received honoraria, research grants and other payments from industry. Full conflict of interest disclosure may not always appear in published articles. An example of this is the case of Dr. McIntyre and Dr. Rosenblat which required a correction in their original publication . It was later disclosed that Dr. McIntyre was the director of and Dr. Rosenblat a staff psychiatrist at a clinic that administers intravenous ketamine. Dr. McIntyre also disclosed that he has been on advisory boards and/or received honoraria for educational activities and/or research grants from Takeda, Neurocrine, Allergan, and Sunovion .
The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force on the use of racemic Ketamine concluded that
“There is now Level 1 evidence for efficacy of single-infusion IV ketamine as an antidepressant. The antisuicidal effects of ketamine make it a particularly promising novel treatment. Side effects of ketamine treatment are generally mild, short-lasting, and infrequently require clinical intervention. Unfortunately, however, there is still only Level 3 evidence for efficacy of repeated infusions and Level 4 evidence for relapse prevention. There are also feasibility challenges for access to monitored infusions. For these reasons, we consider IV ketamine to be a third-line recommendation for adults with TRD”. (Emphasis added) .
It is of note that eleven of the authors of this document had received honoraria or research funding from the pharmaceutical company Janssen, a manufacturer of ketamine.
The Canadian Journal of psychiatry published a correction to this article as the declaration of conflict of interests statement for one of the authors, Dr. Roger McIntyre, was incomplete in the original article. The full disclosures indicated that Dr. Roger McIntyre is CEO of Braxia Scientific Corp (previously known as Champignon), which owns The Canadian Rapid Treatment Center of Excellence (CRTCE), a group of medical clinics that provide ketamine/esketamine for persons with treatment-resistant depression.
The promotion of ketamine for the sustained treatment of depression is not supported by current evidence. Editors of psychiatric journals need to raise their standards for assessing the quality of evidence in published articles. In particular where the data do not support conclusions that are made in the abstract or title of an article this should be corrected. Editors need to be more transparent about potential conflicts of interest to indicate how funding received by authors could impact conclusions. Systems for rating the quality of evidence should be required for all psychiatric journals.
The author has no conflicts of interest.
1.Walsh Z, Mollaahmetoglu OM, Rootman J, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych Open. 2021 Dec 23;8(1):e19. doi: 10.1192/bjo.2021.1061.
- Williams NR(1), Heifets BD(1), Williams NR et al.Williams NR, Heifets BD, Blasey C et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry. 2018 Dec 1;175(12):1205-1215. doi: 10.1176/appi.ajp.2018.18020138. Epub 2018 Aug 29.
- Munkholm K, Jørgensen KJ. No evidence for the effectiveness of IV ketamine for treatment resistant mood disorders in retrospective study. Bipolar Disord. 2020 Dec;22(8):860-861. doi: 10.1111/bdi.13006. Epub 2020 Oct 8. PMID: 32981094.
- McIntyre RS, Lipsitz O, Rodrigues NB, et al. The effectiveness of ketamine on anxiety, irritability, and agitation: implications for treating mixed features in adults with major depressive or bipolar. Bipolar Disord. 2020 May 13;22(8):831-840. https://doi.org/10.1111/bdi.12941.
- Mattes JA. Ketamine After Two Antidepressants? Am J Psychiatry. 2021 Dec;178 (12):1129. doi: 10.1176/appi.ajp.2021.21060576
- Corriger A, Pickering G. Ketamine and depression: a narrative review. Drug Des Devel Ther. 2019 Aug 27;13:3051-3067. doi: 10.2147/DDDT.S221437.
- Gastaldon C, Papola D, Ostuzzi G, Barbui C. Esketamine for treatment resistant depression: A trick of smoke and mirrors? Epidemiol Psychiatr Sci. 2020 Dec 16;29:e79. doi:10.1017/S2045796019000751.
- Canadian Agency for Drugs and Technologies in Health (CADTH). Esketamine Hydrochloride Common Drug Review [Internet]. CADTH.ca. 2020. Available from: https://www.cadth.ca/esketamine-hydrochloride
- National Institute for Health and Care Excellence (NICE). Esketamine for treating treatment-resistant depression [Internet]. 2020. https://www.nice.org.uk/guidance/GID- TA10371/documents/129-2
- Gastaldon C, Papola D, Ostuzzi G, Barbui C. Esketamine clinical trials: reply to Maju et al. Epidemiol Psychiatr Sci. 2020 Apr 29;29:e122. DOI: 10.1017/S204579602000027X.
- Bero L (2018) Meta-research matters: Meta-spin cycles, the blindness of bias, and rebuilding trust. PLoS Biol 16(4): e2005972.
12.Chiu K, Grundy Q, Bero L. ‘Spin’ in published biomedical literature: A methodological systematic review. PLoS Biol. 2017;15(9):e2002173. Published 2017 Sep 11. doi:10.1371/journal.pbio.2002173
- Mahtani KR. ‘Spin’ in reports of clinical research. Evid Based Med December 2016; 21:201-202.
14. Rosenblat JD, Carvalho AF, Li M, Lee Y, Subramanieapillai M, McIntyre RS. Correction. J Clin Psychiatry. 2020 Apr 22;81(2):20lcx13315.
doi: 10.4088/JCP.20lcx13315. Erratum for: J Clin Psychiatry. 2019 Apr 16;80(3): Erratum for: J Clin Psychiatry. 2020 Jan 28;81(1).
- Swainson J, McGirr A, Blier P, et al The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Can J Psychiatry. 2021 Feb;66(2):113-125. doi: 10.1177/0706743720970860. Epub 2020 Nov 11. Erratum in: Can J Psychiatry. 2021 Dec;66(12):1102.