Why is this review important?
Bipolar disorder is one of the most severe psychiatric disorders, which is characterised by a chronic pattern of relapse into mania (abnormally elevated mood or irritability and related symptoms with severe functional impairment or psychotic symptoms for seven days or more), or hypomania (same symptoms with decreased or increased function for four days or more) and major depression. The depressive phase of the illness is associated with a greatly increased risk of self harm and suicide. Current treatments for depressive symptoms are of limited efficacy and onset of action is generally slow. Among the most promising alternatives with a different mechanism of action, is a new class of drugs, called glutamate receptor modulators. New compounds have been tested, mainly in unipolar depression, but recent studies have focused on bipolar depression. There are some recent reviews that have tried to summarise the evidence about glutamate receptor modulators, but they either focused only on ketamine or did not include relevant data from the most recent trials. For these reasons, a comprehensive and updated synthesis of all the available studies is needed.
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. Is treatment with ketamine and other glutamate receptor modulators more effective than placebo or other antidepressants?
2. Is treatment with ketamine and other glutamate receptor modulators more acceptable than placebo or other antidepressants?
Which studies were included in the review?
We searched medical databases to find all relevant studies (specifically randomised controlled trials) completed up to 9 January 2015. To be included in the review, studies had to compare ketamine or other glutamate receptor modulators with placebo or other medicines in adults. We included five placebo-controlled studies, involving a total of 329 participants. The studies investigated three different glutamate receptor modulators: ketamine (two trials), memantine (two trials) and cytidine (one trial). All trials in the present review included participants who were also receiving another medication (either lithium, valproate, or lamotrigine). In the majority of studies, the included participants were already taking (and showing an inadequate response to) these treatments. We rated the quality of the evidence 'very low' to 'low' across different comparisons.
What does the evidence from the review tell us?
Efficacy was measured primarily as the number of patients who responded to treatment. A single intravenous dose of ketamine 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. This finding was based on evidence rated as low quality. In terms of adverse events, no differences were found between ketamine and placebo, despite common reports of trance-like states or hallucinations. The very small population under investigation in this review could have limited the ability to detect any real difference. No differences were found between memantine or cytidine and placebo in terms of number of people who responded to treatment or who experienced adverse effects.
What should happen next?
Ketamine may be an effective medication as add-on therapy to mood stabilisers in people with acute bipolar depression, but due to the small amount of data usable for analysis we are unable to draw any firm or reliable conclusions. The effects of ketamine may be very quick, but they are likely to last for less than three days. All trials that examined the efficacy of ketamine used only intravenous administration, which could potentially restrict its applicability in clinical settings. Future research should focus on studies which compare long-term use of ketamine (also with other active interventions), in order to draw reliable conclusions about comparative efficacy between treatments. Unfortunately, the present review did not find any reliable information about tolerability of glutamate receptor modulators; however adverse effects, particularly of repeated exposure to ketamine, still remain a major concern in this area.
Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited 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; ketamine did not show any better efficacy in terms of 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. Ketamine's psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.
We did not find conclusive evidence on adverse events with ketamine. To draw more robust conclusions, further 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. There was not enough evidence to draw meaningful conclusions for the remaining two glutamate receptor modulators (memantine and cytidine). This review is limited not only by completeness of evidence, but also by the low to very low quality of the available evidence.
There is emerging evidence that glutamatergic system dysfunction might play an important role in the pathophysiology of bipolar depression. This review focuses on 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 acute depression symptoms.
We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR, to 9 January 2015). This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We cross-checked reference lists of relevant papers and systematic reviews. We did not apply any restrictions to date, language or publication status.
Randomised controlled trials (RCTs) comparing ketamine, memantine, or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression.
At least two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes for this review were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. We contacted study authors for additional information.
Five studies (329 participants) were included in this review. All included studies were placebo-controlled and two-armed, and the glutamate receptor modulators - ketamine (two trials), memantine (two trials), and cytidine (one trial) - were used as add-on drugs to mood stabilisers. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for memantine and cytidine (8 to 12 weeks, and 12 weeks, respectively). Three of the studies took place in the USA, one in Taiwan, and in one, the location was unclear. The majority (70.5%) of participants were from Taiwan. All participants had a primary diagnosis of bipolar disorder, according to the DSM-IV or DSM-IV-TR, and were in a current depressive phase. The severity of depression was at least moderate in all but one study.
Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after the infusion for the primary outcome, response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; I² = 0%, 2 studies, 33 participants). This evidence was rated as low quality. The statistically significant difference disappeared at three days, but the mean estimate still favoured ketamine (OR 8.24, 95% CI 0.84 to 80.61; 2 studies, 33 participants; very low quality evidence). We found no difference in response between ketamine and placebo at one week (OR 4.00, 95% CI 0.33 to 48.66; P = 0.28, 1 study; 18 participants; very low quality evidence).
There was no significant difference between memantine and placebo in response rate one week after treatment (OR 1.08, 95% CI 0.06 to 19.05; P = 0.96, 1 study, 29 participants), two weeks (OR 4.88, 95% CI 0.78 to 30.29; P = 0.09, 1 study, 29 participants), four weeks (OR 5.33, 95% CI 1.02 to 27.76; P = 0.05, 1 study, 29 participants), or at three months (OR, 1.66, 95% CI 0.69 to 4.03; P = 0.26, I² = 36%, 2 studies, 261 participants). These findings were based on very low quality evidence.
There was no significant difference between cytidine and placebo in response rate at three months (OR, 1.13, 95% CI 0.30 to 4.24; P = 0.86, 1 study, 35 participants; very low quality evidence).
For the secondary outcome of remission, no significant differences were found between ketamine and placebo, nor between memantine and placebo. For the secondary outcome of change scores from baseline on depression scales, ketamine was more effective than placebo at 24 hours (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005, 2 studies, 32 participants) but not at one or two weeks after treatment. There was no difference between memantine and placebo for this outcome.
We found no significant differences in terms of adverse events between placebo and ketamine, memantine, or cytidine. There were no differences between ketamine and placebo, memantine and placebo, or cytidine and placebo in total dropouts. No data were available on dropouts due to adverse effects for ketamine or cytidine; but no difference was found between memantine and placebo.