Ketamine and other glutamate receptor modulators for bipolar depression

Why is this review important?

Bipolar disorder is one of the most severe mental health conditions characterised by episodes of mania (abnormally high mood or irritability amongst other symptoms for a short time), or hypomania (the same symptoms lasting for a shorter time) and major depression (low mood). The depressive phase of the illness is linked with a greatly increased risk of self-harm and suicide. Current treatments for depression in bipolar disorder are not always effective and can be slow to work. Among the most promising new and alternative treatments are drugs called glutamate receptor modulators. These drugs work in a different way to the drugs usually used, such as antidepressants. This is an update of a review published in 2015. As more clinical studies have been published since then, it is important to update this review with the most recent evidence.

Who will be interested in this review?

- People with bipolar disorder, 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. Are ketamine and other glutamate receptor modulators better at treating bipolar depression than placebo (dummy pill) or other antidepressants?
2. Do patients prescribed ketamine or other glutamate receptor modulators experience fewer side effects than people who take placebo or other antidepressants?

Which studies were included in the review?

We searched medical databases to find all relevant studies completed up to 30 July 2020. These studies had to be randomised controlled trials (where people in the study are randomly assigned to receive either the drug being tested or a different drug or placebo to compare the results). To be included in the review, studies had to compare ketamine or other glutamate receptor modulators with placebo or other medicines in adults with bipolar depression. We included 10 studies (647 participants). The studies investigated five different glutamate receptor modulator drugs: ketamine (three trials), memantine (two trials), cytidine (one trial), N-acetylcysteine (three trials), and riluzole (one trial). Nine studies compared glutamate receptor modulators with placebo, and one study compared ketamine with another drug. Most of the trials in the review included participants who were also receiving another medication (either lithium, valproate, or lamotrigine). We rated the certainty of the evidence 'very low' to 'low' across different comparisons, meaning that we cannot be confident that the results are a close representation of the truth.

What does the evidence from the review tell us?

The effectiveness of glutamate receptor modulators was measured primarily as the number of patients whose symptoms of depression were reduced by 50% with treatment. A single dose of ketamine injected into a vein proved to be better than placebo, but this was based on very limited evidence (two studies with 33 participants), and its effect only lasted for up to 24 hours. No differences were found in side effects between ketamine and placebo, despite common reports of trance-like states or dissociation (a dream-like state in which body and mind are experienced separately). The small number of participants included in this review means that we cannot say for certain whether ketamine or glutamate receptor modulators work better than other antidepressants. No differences were found between memantine, cytidine, N-acetylcysteine and placebo for numbers of people who responded to treatment or who experienced side effects, and no data were available for riluzole.

What should happen next?

Ketamine may or may not be an effective medication as an add-on treatment to mood stabilisers in people with bipolar depression, but because the amount of data was small, we are unable to draw any firm conclusions. The data suggests that ketamine may work very quickly in bipolar depression, but that the effects only last for a short amount of time. All trials examined the effectiveness of ketamine when injected, which is less practical than other options such as taking a pill. Future research should focus on longer-term use of ketamine compared with placebo and other drugs, so that we can draw confident conclusions about which treatments are more effective. More research is needed on the long-term side effects, as some studies have shown that long-term ketamine use is linked to memory problems.

Authors' conclusions: 

It is difficult to draw reliable conclusions from this review due to the certainty of the evidence being low to very low, and the relatively small amount of data usable for analysis in bipolar disorder, which is considerably less than the information available for unipolar depression. Nevertheless, we found uncertain evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours, however ketamine did not show any better efficacy for remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. We did not find conclusive evidence on adverse events with ketamine, and there was insufficient evidence to draw meaningful conclusions for the remaining glutamate receptor modulators.

However, ketamine's psychotomimetic effects (such as delusions or delirium) may have compromised study blinding in some studies, and so we cannot rule out the potential bias introduced by inadequate blinding procedures. To draw more robust conclusions, further methodologically sound RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine, and to study different methods of sustaining antidepressant response, such as repeated administrations.

Read the full abstract...

Glutamergic system dysfunction has been implicated in the pathophysiology of bipolar depression. This is an update of the 2015 Cochrane Review for the use of glutamate receptor modulators for depression in bipolar disorder.


1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder.
2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing depressive symptoms.

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: 

RCTs comparing ketamine or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression.

Data collection and analysis: 

Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. The GRADE framework was used to assess the certainty of the evidence.

Main results: 

Ten studies (647 participants) were included in this review (an additional five studies compared to the 2015 review). There were no additional studies added to the comparisons identified in the 2015 Cochrane review on ketamine, memantine and cytidine versus placebo. However, three new comparisons were found: ketamine versus midazolam, N-acetylcysteine versus placebo, and riluzole versus placebo. The glutamate receptor modulators studied were ketamine (three trials), memantine (two), cytidine (one), N-acetylcysteine (three), and riluzole (one). Eight of these studies were placebo-controlled and two-armed. In seven trials the glutamate receptor modulators had been used as add-on drugs to mood stabilisers. Only one trial compared ketamine with an active comparator, midazolam. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for riluzole, memantine, cytidine, and N-acetylcysteine (with a follow-up of eight weeks, 8 to 12 weeks, 12 weeks, and 16 to 20 weeks, respectively). Six of the studies included sites in the USA, one in Taiwan, one in Denmark, one in Australia, and in one study the location was unclear. All participants had a primary diagnosis of bipolar disorder and were experiencing an acute bipolar depressive episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (IV) or fourth edition text revision (IV-TR).

Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after infusion for response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; participants = 33; studies = 2; I² = 0%, low-certainty evidence). Ketamine seemed to be more effective in reducing depression rating scale scores (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005; participants = 32; studies = 2; I2 = 0%, very low-certainty evidence). There was no evidence of ketamine's efficacy in producing remission over placebo at 24 hours (OR 5.16, 95% CI 0.51 to 52.30; P = 0.72; participants = 33; studies = 2; I2 = 0%, very low-certainty evidence).

Evidence on response, remission or depression rating scale scores between ketamine and midazolam was uncertain at 24 hours due to very low-certainty evidence (OR 3.20, 95% CI 0.23 to 45.19). In the one trial assessing ketamine and midazolam, there were no dropouts due to adverse effects or for any reason (very low-certainty evidence).

Placebo may have been more effective than N-acetylcysteine in reducing depression rating scale scores at three months, although this was based on very low-certainty evidence (MD 1.28, 95% CI 0.24 to 2.31; participants = 58; studies = 2). Very uncertain evidence found no difference in response at three months (OR 0.82, 95% CI 0.32 to 2.14; participants = 69; studies = 2; very low-certainty evidence). No data were available for remission or acceptability.

Extremely limited data were available for riluzole vs placebo, finding only very-low certainty evidence of no difference in dropout rates (OR 2.00, 95% CI 0.31 to 12.84; P = 0.46; participants = 19; studies = 1; I2 = 0%).