Ketamine and other glutamate receptor modulators for depression in adults

Why is this review important?

Depression is one of the most common mental disorders, estimated to affect 350 million people worldwide. Antidepressant medication tends to be given as a first treatment for people with major depression. These drugs are however only effective in about one in four people at one year. Effective alternative medications to treat depression are needed, especially for rapid treatment. A new group of medications is called ‘glutamate receptor modulators’, which act on the glutamergic system. This group includes the medicine ketamine. In this review we examined the evidence for glutamate receptor modulators, including ketamine, as a treatment for depression.

Who will be interested in this review?

- People with depression, their friends and families.

- General practitioners, psychiatrists, psychologists and pharmacists.

- Professionals working in adult mental health services.

What questions does this review aim to answer?

1. Is treatment with ketamine and other glutamate receptor modulators more effective than treatment with placebo (dummy pill) or other drugs?

2. Is treatment with ketamine and other glutamate receptor modulators more acceptable than placebo or other drugs?

Which studies were included in the review?

We searched medical databases to find all relevant studies (specifically randomised controlled trials) completed up to 30 July 2020. To be included in the review, studies had to compare ketamine or other glutamate receptor modulators with placebo, other medicines or electroconvulsive therapy (ECT) for depression in adults (aged 18 and over). The studies also had to be single-blind (the participant does not know which treatment they are receiving) or double-blind (neither the participant or researcher know which treatment the participant is receiving), to attempt to reduce bias. We included 64 studies in the review, involving a total of 5299 people. The studies investigated16 different glutamate receptor modulator medications. The majority of participants had treatment-resistant depression (depression which had not responded to two or more medications) at the start of the studies. Most studies were two-armed, where the glutamate receptor modulator was compared with one other intervention.

What does the evidence from the review tell us?

Among the 16 drugs included in this review, only ketamine and esketamine were more effective than placebo at reducing symptoms of depression. The effects of ketamine lasted no more than one week after treatment and clearly disappeared after two weeks. Ketamine did, however, cause more side effects than placebo. The effects of esketamine were seen at 24 hours and could last up to four weeks with repeated doses. Esketamine caused a lot more side effects than placebo. The certainty of evidence varied considerably.

There was no evidence of a difference between the other glutamate receptor modulators included in this review and placebo or other medications.

What should happen next?

Ketamine and esketamine appear to reduce the symptoms of depression. However, the trials were all short term so we do not know about the long-term effects. It is important to note that in some trials attempts to prevent participants and investigators from knowing what medicine was being given were not successful and this may have inflated the positive effects of the active drugs.

Future studies should examine what happens when people are repeatedly given the drug, with the aim to mimic the real-world practice and assess longer-term effects. More non-inferiority trials should be conducted, where glutamate receptor modulators are compared with other active medications rather than placebo to find out whether they are better than alternative treatments.

In most of the ketamine trials in this review, participants were given the drug by injection into a vein. This restricts the wide-scale application of ketamine in clinical settings, so trials of ketamine by other routes are needed. Esketamine trials usually used nasal sprays, which are easier to use and could potentially be taken at home if further monitoring and trials found that it was safe to do so. Further studies assessing administration are needed in order to draw more reliable and firm conclusions.

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.

Read the full abstract...

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.


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 strategy: 

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 midazolam (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.