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Cited by 95Treatment of Major DepressionElectroconvulsive Therapy StudiesTranscranial Magnetic Stimulation Studies

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

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Dean, Rebecca L, Hurducas, Claudia, Hawton, Keith, Spyridi, Styliani, Cowen, Philip J, Hollingsworth, Sarah, Marquardt, Tahnee, Barnes, Annabelle +4 more·2021·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd011612.pub3PMC PMC8434915
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Abstract

BACKGROUND: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression. OBJECTIVES: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. SELECTION CRITERIA: Double- or single-blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression. DATA COLLECTION AND ANALYSIS: Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE. MAIN RESULTS: Thirty-one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Forty-eight studies were placebo-controlled, and 48 were two-arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild-to-moderate depression. Nineteen studies recruited only patients with treatment-resistant depression, defined as inadequate response to at least two antidepressants. The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes. The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence). When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low-certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low-certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and placebo (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low-certainty evidence). Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate-certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD -0.31, 95% CI -0.45 to -0.17; n = 824, studies = 4, moderate-certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low-certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate-certainty evidence). We found very little evidence for the remaining glutamate receptor modulators. We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment

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Authors
Dean, R. L., Hurducas, C., Hawton, K., Spyridi, S., Cowen, P. J., Hollingsworth, S., Marquardt, T., Barnes, A., Smith, R., McShane, R., Turner, E. H., & Cipriani, A.
Affiliations
  • Oxford Health NHS Foundation Trust (GB)
  • Oxford Health NHS Foundation Trust; Oxford UK
  • University of Oxford (GB)
  • Cyprus University of Technology (CY)
  • Oregon Health & Science University (US)
ORCID
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2021-09-12
Volume
2021
Issue
11
Pages
CD011612-CD011612
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd011612.pub3
PMC
PMC8434915
OpenAlex
W3201351307
Cited by
95
References
183
Citations by year
2026: 8 · 2025: 19 · 2024: 24 · 2023: 30 · 2022: 12 · 2021: 2
FWCI
2.15
Type
journal article
Language
en
Open access
Locations
  • Cochrane Database of Systematic Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Ktisis at Cyprus University of Technology (Cyprus University of Technology) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute for Health and Care Research (RP-2017-08-ST2-006)
  • Medical Research Council (MR/S003037/1)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
ketamine, esketamine, memantine, unipolar major depression, treatment-resistant depression, antidepressant efficacy, response rate, tolerability, adverse events, electroconvulsive therapy, NMDA receptor antagonists, NMDA receptor partial agonist, NMDA receptor modulators
MeSH terms
Adult, Antidepressive Agents, Depression, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Receptors, Glutamate

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