Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder.

BACKGROUND: 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. OBJECTIVES: 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 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: 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%). 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.

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

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.