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

Rebecca L Dean, Claudia Hurducas, Keith Hawton, Styliani Spyridi, Philip J Cowen, Sarah Hollingsworth, Tahnee Marquardt, Annabelle Barnes, Rebecca Smith, Rupert McShane, Erick H Turner, Andrea Cipriani, Rebecca L Dean, Claudia Hurducas, Keith Hawton, Styliani Spyridi, Philip J Cowen, Sarah Hollingsworth, Tahnee Marquardt, Annabelle Barnes, Rebecca Smith, Rupert McShane, Erick H Turner, Andrea Cipriani

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 in the studies reduced our certainty in the effect for all outcomes.

Authors' conclusions: Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy.

Trial registration: ClinicalTrials.gov NCT02417064 NCT03039192 NCT00408031 NCT00977353 NCT03097133 NCT01304147 NCT00680433 NCT00610649 NCT02418585 NCT00491686 NCT00781742 NCT00344682 NCT01457677 NCT00986479 NCT03965871 NCT04019704 NCT04210804.

Conflict of interest statement

Rebecca Dean: none known.

Claudia Hurducas: none known.

Sarah Hollingsworth: none known.

Tahnee Marquardt: none known.

Stella Spyridi: none known.

Phil Cowen: PJC has a patent with the University of Oxford on the use of ebselen in treatment‐resistant depression

Keith Hawton: none known.

Rupert McShane: Rupert McShane runs NHS and self‐pay ketamine clinics for Oxford Health NHS Foundation Trust. Rupert has undertaken educational and scientific advisory board work for Janssen Pharmaceuticals to support educational and research activity, no funds are received personally. Janssen supported Rupert's attendance at the APA conference in New York in 2018. Rupert has undertaken scientific advisory board work for Sage pharmaceuticals, no funds are directly received.

Erick Turner: Erick Turner has no financial interest in esketamine, ketamine or competing treatments. Erick previously worked as a Medical Officer for the US Food and Drug Administration (FDA), charged with reviewing applications submitted by pharmaceutical companies and determining whether the evidence on drug efficacy and safety met the FDA’s criteria for US marketing approval. Erick is a former member of the Psychopharmacologic Drugs Advisory Committee which, together with the Drug Safety and Risk Management Advisory Committee, convened in Feb 2019, to advise the FDA on whether to approve esketamine, although Erick did not take part in that particular meeting due to matters related to the government shutdown.

Andrea Cipriani: Andrea Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma.