Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories
This meta-analysis (2016; 14 RCTs) found that single infusions of ketamine (to a lesser extent, non-ketamine NMDAR antagonists) has rapid anti-depressant effects that can last for up to one week.
Abstract
Background: Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear.Method: We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges’ g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects.Results: A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = −1.00, 95% CI −1.28 to −0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = −0.37, 95% CI −0.66 to −0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant.Conclusions: A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
Research Summary of 'Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories'
Introduction
Kishimoto and colleagues frame the study against a backdrop of substantial unmet need in treating mood disorders: standard monoaminergic antidepressants have delayed onset and only partial efficacy, and fewer proven options exist for bipolar depression. Recent research implicates glutamate-related neuroplasticity in depression and has shown that subanaesthetic doses of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, can produce rapid antidepressant effects and reduce suicidal ideation within hours in both major depressive disorder (MDD) and bipolar depression (BD). Given ketamine's mechanism of NMDAR blockade and consequent glutamate release, the authors note an open question about whether other, non-ketamine NMDAR modulators might produce similar clinical benefits. This meta-analysis aimed to quantify the efficacy, safety and time course of effect after a single intravenous infusion of ketamine or non-ketamine NMDAR antagonists versus placebo or pseudo-placebo in randomized trials of adults with MDD and/or BD. The investigators sought to synthesise randomized evidence across agents, to characterise trajectories of symptom change at specific post-infusion time points, and to compare response, remission and adverse-event profiles between ketamine and non-ketamine NMDAR antagonists.
Methods
The researchers performed systematic searches of PubMed, PsycINFO, ISI Web of Science and the US NIH clinical trials registry from database inception until 25 August 2015. Eligible studies were parallel-group or cross-over randomized controlled trials that compared a single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist against placebo (saline) or a pseudo-placebo (a non-antidepressant anaesthetic). Multiple-injection trials were included only if data prior to the second infusion were available. Trials of oral or intranasal administration were excluded. The electronic search string combined ketamine/NMDA/glutamate terms with depression/bipolar/suicidality and randomisation/placebo terms; reference lists and meeting abstracts were hand-searched to supplement the database search. The primary outcome was change in depressive symptoms measured by the Hamilton Depression Rating Scale (HAM-D) or the Montgomery–Åsberg Depression Rating Scale (MADRS) at study-defined post-infusion time points; when both scales were reported the HAM-D was used. Secondary outcomes comprised response (≥50% reduction in HAM-D/MADRS), study-defined remission, all-cause discontinuation, and adverse effects including psychotic, manic and dissociative symptoms assessed with instruments such as the Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS) and the Clinician Administered Dissociative States Scale (CADSS). When trials reported multiple doses, arms were combined for the primary comparison unless a specific dose was a clear outlier; the authors describe combining certain GLYX-13 and AZD6765 dose arms accordingly. Two or three reviewers independently extracted data, calculating values from graphs when necessary and resolving discrepancies by consensus. Risk of bias was assessed independently by two reviewers using the Cochrane risk-of-bias tool across seven domains, and publication bias was inspected visually with funnel plots for symptom change, response and remission. For meta-analysis, continuous outcomes were pooled as Hedges' g (standardised mean difference) with 95% confidence intervals using random-effects models; dichotomous outcomes were pooled as relative risks (RRs) with 95% CIs and number-needed-to-treat/harm (NNT/NNH) when appropriate. Heterogeneity was reported with τ2, I2, Q and p values. Sensitivity analyses included intent-to-treat assessment of all-cause discontinuation (with and without excluding early dropouts due to marked improvement in cross-over trials) and an analysis focused on the AZD6765 studies.
Results
The search returned 1,574 records; after screening and full-text assessment the authors included 12 articles reporting 14 randomized trials in the meta-analysis (total duration of included trials 10.0 ± 8.8 days). The dataset comprised nine ketamine trials (n = 234) and five non-ketamine NMDAR antagonist trials (n = 354), with most participants diagnosed with MDD (n = 554) and a smaller BD sample (n = 34). Seven trials were placebo-controlled cross-over designs and seven were parallel-group; mean participant age was about 46 years, 40.7% male, and studies reported a long current episode duration (mean 45.1 ± 49.0 months) with a history of multiple failed antidepressant trials in many samples. Pooled efficacy for ketamine: Single-dose intravenous ketamine produced significantly greater reduction in depressive symptoms versus placebo/pseudo-placebo beginning at 40–60 minutes (studies = 4, Hedges' g = -0.50, 95% CI -1.00 to -0.00, p = 0.05; I2 = 44.3%), peaking at day 1 (studies = 7, Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001; I2 = 0%), and remaining superior through days 5–8 (studies = 5, Hedges' g = -0.38, 95% CI -0.73 to -0.03, p = 0.036; I2 = 9.4%). Differences were not significant at days 10–12 or days 14–15. Response rates favoured ketamine from 40–60 minutes (studies = 3; ketamine 43.1% v. placebo 0.0%; RR = 13.6, 95% CI 2.67–69.6, p < 0.001; NNT = 3), peaking at 230–240 minutes (studies = 3; RR = 14.7, 95% CI 3.72–58.3, p < 0.001; NNT = 2) and persisting to day 7 (studies = 5; ketamine 34.4% v. placebo 7.77%; RR = 3.43, 95% CI 1.77–6.63, p < 0.001; NNT = 5). Remission also favoured ketamine from 80 minutes onward (e.g. day 1 remission: studies = 4; ketamine 34.0% v. placebo 0.0%; RR = 9.89, 95% CI 2.4–40.5, p < 0.001; NNT = 3). Pooled efficacy for non-ketamine NMDAR antagonists: When combined, non-ketamine agents produced a small-to-moderate advantage over placebo on days 5–8 (studies = 4, Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01; I2 = 0%), but not at other time points. Analyses restricted to the three AZD6765 studies showed no significant differences at any time point. Response rates were higher for non-ketamine agents on day 2 and days 3–5 in pooled analyses (studies = 2; RR = 8.52, 95% CI 1.07–67.9, p = 0.04), though NNTs were described as non-significant and remission did not differ significantly from placebo. Safety, tolerability and symptom-specific measures: All-cause discontinuation did not differ between ketamine and placebo (studies = 6; ketamine 12.1% v. placebo 7.8%; RR = 1.52, 95% CI 0.64–3.58, p = 0.34) and remained non-significant after sensitivity analyses excluding early cross-over dropouts. Non-ketamine agents likewise showed no difference in discontinuation versus placebo. Ketamine produced transient increases in psychotomimetic and dissociative measures: BPRS scores were higher at 40–60 minutes (studies = 5, Hedges' g = 0.90, 95% CI 0.58–1.22, p < 0.001) and CADSS scores were markedly elevated at 40–60 minutes (studies = 5, Hedges' g = 2.42, 95% CI 1.13–3.73, p < 0.001) though CADSS analyses showed high heterogeneity. By day 3 BPRS scores were lower with ketamine than placebo. Other adverse events (e.g. tiredness, nausea, dizziness) did not differ significantly between ketamine or non-ketamine NMDAR antagonists and placebo in pooled reports. Risk-of-bias and publication-bias assessment: Many trials had incomplete outcome reporting relative to registered outcomes. The potential for functional unblinding due to ketamine's acute psychoactive effects was acknowledged; the authors judged this inevitable and generally rated it as low risk, noting one study that used midazolam as an active control. Funnel-plot inspection did not suggest publication bias for the main outcomes.
Discussion
Kishimoto and colleagues interpret their pooled findings as clear evidence that a single intravenous infusion of ketamine produces rapid and substantial antidepressant effects in treatment-resistant MDD and BD, with symptom reduction detectable within an hour, peaking at 24 hours and persisting for up to about one week. Effect sizes for symptom reduction were medium to large (Hedges' g from -0.38 to -1.00), and response and remission outcomes yielded favourable NNTs (response NNT = 2–5; remission NNT = 3–7 at peak). By contrast, pooled non-ketamine NMDAR antagonists showed a smaller and later effect, reaching statistical superiority only on days 5–8 with a Hedges' g of -0.37, and yielding mixed findings for response and non-significant results for remission. The authors suggest several possible explanations for the smaller effects with non-ketamine agents, including differences in NMDAR affinity or distinct pharmacodynamic profiles, and caution that grouping different non-ketamine compounds may have produced conservative estimates for some agents. They note that both ketamine and the non-ketamine agents were generally well tolerated and did not increase overall dropout rates relative to placebo, despite transient dissociative and psychotomimetic effects with ketamine. Functional unblinding due to these acute effects is acknowledged as a potential influence on results, though the presence of antidepressant effects with non-psychotomimetic NMDAR agents and similar effect sizes in the midazolam-controlled trial argue against sole reliance on unblinding to explain efficacy. Key limitations highlighted by the authors include the substantial use of cross-over designs among the included trials (six of 14 trials), heterogeneity in assessment time points and the limited number of studies and participants for some comparisons (notably certain non-ketamine agents). Grouping distinct non-ketamine compounds was another constraint, as was incomplete outcome reporting in several trials. The authors conclude that the rapid but transient benefit observed after single infusions motivates further research: sufficiently powered, effectively blinded, parallel-group RCTs are needed to evaluate single and repeated dosing schedules, to investigate mechanisms (including the relationship between dissociation and antidepressant effect), and to develop safe, easy-to-administer NMDAR-targeted treatments that could be used in refractory and potentially non-refractory clinical contexts such as emergency settings.
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INTRODUCTION
Mood disorders and accompanying suicidality result in great personal suffering and public expenditure. In 2010, major depressive disorder (MDD) rose from 15th to 11th rank in its contribution to disability-adjusted life years. Although for decades antidepressants that act via monoamine pathways have dominated the treatment of depression, efficacy is often unsatisfactory. For example, in the large, randomized, multi-step National Institute of Mental Health (NIMH)-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 47% of patients responded to standard antidepressant treatment and only 33% achieved remission. Moreover, the onset of clinically noticeable efficacy usually takes 52 weeks. Further, the efficacy of antidepressants in bipolar depression (BD) has been challengedand fewer treatment options are available than for MDD. Thus, interventions with fast efficacy and efficacy for patients not responding to available antidepressants are sorely needed. Recent studies demonstrated the role of glutamatemediated neuroplasticity in the pathophysiology of mood disorders and antidepressant effects of glutamatergic agents. Ketamine, a non-selective N-methyl-D-aspartic acid receptor (NMDAR) antagonist, used for decades as an anesthetic, has shown antidepressant efficacy in subanesthetic doses within hours of administration in placebo-controlled crossover studies for MDDand BD. In these trials, ketamine showed quick and dramatic antidepressant effects for refractory and non-refractory depression. Furthermore, ketamine reduced suicidal thoughts in both openand controlledtrials. Ketamine's primary mechanism of action is NMDAR blockade at the phencyclidine site within the ionotropic channel. Ketamine induces presynaptic glutamate release by activating GABAergic inputs leading to increased glutamatergic neuronal firing). Thus, a relevant question is whether non-ketamine NMDAR antagonists could be similarly efficacious for depression. In this context, five randomized trials of non-ketamine NMDAR antagonists, Traxoprodil CP-101,606, AZD6765) and GLYX-13have been) is a selective antagonist of the NR2B subunit of NMDARs. AZD6765 (lanicemine) is a non-selective NMDAR channel blocker like ketamine, but with lower trapping channel blockade (54% v. 86%). GLYX-13 is a NMDAR glycine site partial agonist, producing NMDA functional antagonism, with long-term efficacy without psychotomimetic effects after a single intravenous dose in animal models. There are systematic and/or narrative reviewsincluding five meta-analyses to date that summarized the efficacy of ketamine and non-ketamine NMDAR antagonists. However these meta-analyses have some deficits, such as not assessing the efficacy change over time for all studiesor for some studies, including only ketamine studies, mixing pre-post data comparison with placebo-controlled studies, mixing intranasal with injection studies, missing some relevant studies, and/or mixing in electroconvulsive therapy studies. Here, we conducted a meta-analysis of ketamine and nonketamine NMDAR antagonists in patients with depression. We included all studies conducted to date that examined the efficacy of NMDAR antagonists compared with placebo in randomized trials and examined the time course of efficacy after a single NMDAR antagonist infusion.
SEARCH AND INCLUSION CRITERIA
Two investigators independently searched PubMed, PsycINFO, ISI Web of Science, and the US National Institutes of Health clinical trials registry (), from database inception until 25 August 2015, for, parallel-group or cross-over randomized controlled trials (RCTs), comparing singledose, intravenous NMDAR antagonist infusion v. placebo (saline infusion) or pseudo-placebo (nonantidepressant anesthetic) for MDD and/or BD. We also included multiple injection studies, but only if data before the second injection were available. We excluded RCTs of NMDAR antagonists administered orally or intranasally. The following search string was used: (ketamine OR N-methyl-D-aspartic acid OR NMDA OR glutamat*) AND (depression OR depressive OR depressed OR bipolar OR suicidal) AND (random* OR placebo), supplementing the electronic search by hand-searching reference lists of identified studies, review articles and major meeting proceedings.
DATA EXTRACTION AND OUTCOMES
The primary outcome was symptom change measured by the Hamilton Depression Rating Scale (HAM-D;or the Montgomery-Åsberg Depression Rating Scale (MADRS;at study-defined time points postinfusion. When both the HAM-D and MADRS were reported, we used HAM-D scores. Secondary outcomes included response (550% reduction in HAM-D/MADRS score), study-defined remission, allcause discontinuation, and adverse effects, including psychotic, manic and dissociative symptoms, assessed by the Brief Psychiatric Rating Scale (BPRS;, the Young Mania Rating Scale (YMRS;) and the Clinician Administered Dissociative States Scale (CADSS;, among others. When assessment time points were similar but not identical, we combined these (e.g. days 3-4). When 52 doses were examined in a single study, we combined multiple doses into one experimental arm, given that the ideal dose of such agents has not been established. However, in one phase 2, dose-finding study of GLYX-13, the mean and S.D. of HAM-D were combined across the 1, 5 and 10 mg doses, but the 30 mg dose was excluded, being a clear outlier, suggesting an inverted U-shaped dose-response curve with an ineffective high GLYX-13 dose. Conversely, in the three-arm phase IIB study) of AZD6765, the mean and S.D. of the MADRS scores were combined for the 100 and 150 mg doses. Data were extracted independently by two or three reviewers (J.M.C., K.H. and T.K.), calculating results from graphs if needed and resolving inconsistencies by consensus.
RISK ASSESSMENT INCLUDING PUBLICATION BIAS
Two reviewers independently assessed risk of bias for each study using the Cochrane Collaboration's risk-of-bias tool, rating studies as having low, high, or unclear risks of bias on seven predefined criteria. Publication bias was assessed inspecting funnel plots for depressive symptom change, response and remission.
META-ANALYTIC CALCULATIONS
For continuous outcomes, standardized mean difference between the intervention and placebo/pseudo-placebo was calculated as Hedges' g with 95% confidence intervals (CIs), using random-effects models. For dichotomous outcomes, relative risk (RR) was calculated with 95% CIs, and with number-needed-to-treat/harm (NNT/ NNH) when appropriate. Heterogeneity is expressed by τ 2 , I 2 , Q and p values. All-cause discontinuation was analysed both in the intent-to-treat sample and in a sensitivity analysis after excluding patients discontinuing due to significant improvement in the first phase of cross-over trials to avoid biasing against the more efficacious treatment. A second sensitivity analysis focused on the three AZD6765 studies.
SEARCH RESULTS
The search yielded 1574 hits. Altogether, 1548 articles were excluded based on abstract/title. Of the remaining 26 full-text articles, 14 articles were removed (for reasons, see online Supplementary Fig.), resulting in 12 articles reporting on 14 trials (ketamine = 9 trials, NMDAR antagonists = 5 trials) that were meta-analysed.
STUDY DESIGN, POPULATION, TREATMENT AND OUTCOMES
Of 14 trials, which lasted 10.0 ± 8.8 days, seven were placebo-controlled cross-over studies (duration = 8.4 ± 4.1 days, interval until crossover = 9.0 ± 3.4 days), and seven were parallel-group studies (duration = 11.6 ± 12.1 days) (online Supplementary Table). Participants were 45.8 ± 3.8 years old, 40.7 ± 8.7% were male, 77.1 ± 9.2% were white (studies = 7). The current episode duration was 45.1 ± 49.0 months (studies = 9), and patients had failed 6.0 ± 1.1 antidepressant trials (studies = 3). Nine studies investigated single-dose intravenous ketamine (n = 234), five used intravenous non-ketamine NMDAR antagonists (n = 354), i.e. CP-101,606 (studies = 1, n = 30), AZD6765 (studies = 3 including one repeated infusion study, n = 158) and . Although technically not an NMDAR antagonist, we included GLYX-13, as it pharmacodynamically reduces NMDA transmission. Placebo was the comparator in all but one parallelgroup ketamine study, which used midazolam, an anesthetic without known antidepressant effect, as active pseudo-placebo.
KETAMINE STUDIES
Of nine ketamine studies (n = 234, range = 4-73/study), seven were independently funded, six were placebocontrolled cross-over studies (duration = 8.7 ± 4.4 days, interval before cross-over = 9.5 ± 3.5 days), and three were parallel-group studies (duration = 4.0 ± 2.6 days)) (online Supplementary Table). There were three monotherapy studies and six add-on studies (to lithium or valproate = 2, to antidepressants = 3, to tranylcypromine and second-generation antipsychotics = 1). Of nine studies, five washed out antidepressants for 512.6 ± 3.1 days, while prior antidepressants were maintained throughout the study in the add-on ketamine studies. Seven RCTs, two trialsstudied BD patients (n = 25), and one trial included both BD and MDD patients (n = 9). In five studies with information, subjects were hospitalized for the duration of the study. In thestudy, subjects were hospitalized for the first 24 h after infusion only. In the remaining two studies, the treatment setting was either unclearor subjects were outpatients treated in a day-hospital setting. Co-morbid anxiety disorders were permitted if not requiring current treatment in three studies; no study permitted recent substance use, unstable medical illness, serious/imminent suicidal or homicidal risk. Five of seven MDD studies included patients with inadequate response to antidepressants (the number of prior failed trials varied); whereas in BD studies, patients had to have failed 51 adequate antidepressant trial plus one prospective open trial of either lithium or valproate for 54 weeks at therapeutic levels (lithium = 0.6-1.2 mEq/l; valproic acid = 50-125 µg/ml)) (online Supplementary Table). Seven studies randomized patients to ketamine single infusion at 0.1-0.5 mg/kg per h for 40 min or saline; in one study, patients received 0.27 mg/ kg for the first 10 min using the same dose over next 20 min. Patients were crossed over after 7-14 days in six studies, except that five patients were not crossed over because of marked responses. Response was defined as a 550% decrease in either HAM-D
NON-KETAMINE NMDAR ANTAGONIST
In five studies (n = 354, range = 22-168/study), three non-ketamine NMDAR antagonists (n = 354) were studied: CP-101,600 (n = 30), GLYX-13 (n = 116)and AZD6765 (n = 208)) (online Supplementary Table). Four RCTs were parallel-group, industry-sponsored RCTs (n = 332); one was a non-industry sponsored, 7-day cross-over study of AZD6765). There were three monotherapy studies and two add-on studies [paroxetine = 1, non-tricyclic antidepressants = 1]. All patients had MDD and had failed either 51 antidepressant in the current episode, 52 antidepressant trials; or 51 selective serotonin reuptake inhibitor trial, without non-responsiveness to adequate trials of 53 different antidepressant classes, plus failure to a 6-week prospective paroxetine lead-in treatment). In the three monotherapy studies, antidepressants were washed out for 11.7 ± 4.0 days. One adjunctive study added CP-101,600 to paroxetine after a 6-week lead-in trial) and a second study added AZD6765 to antidepressant, sedative and hypnotic treatment (study 9). Single CP-101,606 infusion was added to paroxetine at 0.75 mg/kg per h for 1.5 h followed by 0.15 mg/kg per h for 6.5 h for the first seven patients. Due to dissociative symptoms, the infusion dose and duration were lowered to 0.5 mg/kg per h for 1.5 h for the remaining 23 patients (online Supplementary Table). AZD6765 was given as a single fixed dose of 100 mgand/or 150 mg) over 60 min. In the one cross-over study, one patient who responded to AZD6765 was not crossed over. In one study, response was defined as a 550% decrease in HAM-D score from baseline at day 5 and remission was defined as an HAMD score of 47). In the second study, response was defined as a 550% MADRS score decrease and remission was defined as a MADRS score of <10. Two studies did not report response or remission resultsand data from the last studycould not be used, as information for the individual included study arms was not available.
KETAMINE
Pooled together, single ketamine infusion resulted in superior reduction of depressive symptoms compared with placebo/pseudo-placebo starting at 40-60 min (studies = 4, Hedges' g = -0.50, 95% CI -1.00 to -0.00, p = 0.05; heterogeneity: τ 2 = 0.11, I 2 = 44.3, Q = 5.39, p = 0.15), peaking at day 1 (studies = 7, Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 2.14, p = 0.91) and lasting until days 5-8 (studies = 5, Hedges' g = -0.38, 95% CI -0.73 to -0.03, p = 0.036; heterogeneity: τ 2 = 0.02, I 2 = 9.38, Q = 4.41, p = 0.35), with non-significant group differences on days 10-12 and days 14-15 (Fig.).
NON-KETAMINE NMDAR ANTAGONIST
Pooled together, non-ketamine NMDAR antagonists resulted in superior reduction of depressive symptoms compared with placebo on days 5-8 (studies = 4, Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 2.28, p = 0.52), without significant group differences at any other time point (Fig.). Repeating the analyses for the three AZD6765 studies yielded no significant group differences at any time points (data not shown).
KETAMINE
Compared with placebo/pseudo-placebo, ketamine was associated with significantly greater response starting at 40-60 min (studies = 3, ketamine = 43.1% v. placebo = 0.00%; RR = 13.6, 95% CI 2.67-69.6, p = 0.00; NNT = 3; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.63, p = 0.73), peaking at 230-240 min (studies = 3, ketamine = 58.8% v. placebo = 2.00%; RR = 14.7, 95% CI 3.72-58.3, p < 0.001; NNT = 2; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.20, p = 0.91) and lasting until day 7 (studies = 5, ketamine = 34.4% v. placebo = 7.77%; RR = 3.43, 95% CI 1.77-6.63, p < 0.001; NNT = 5; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 1.19, p = 0.88) (Fig.). Similarly, ketamine was associated with significantly greater remission starting at 80 min (studies = 3, ketamine = 17.6% v. placebo = 0.00%; RR = 6.63, 95% CI 1.23-35.7, p = 0.03; NNT = 7; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.19, p = 0.91), peaking at day 1 (studies = 4, ketamine = 34.0% v. placebo = 0.00%; RR = 9.89, 95% CI 2.4-40.5, p = 0.00; NNT = 3; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.30, p = 0.96) and lasting until days 3-5 (studies = 3, ketamine = 19.6% v. placebo = 1.96%; RR = 5.22, 95% CI 1.20-22.6, p = 0.03; NNT = 7; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.26, p = 0.88) (Fig.).
NON-KETAMINE NMDAR ANTAGONISTS
Compared with placebo, non-ketamine NMDAR antagonists were associated with significantly greater response on day 2 and days 3-5 (studies = 2, non-ketamine NMDAR antagonists = 27.0%, placebo = 0.00%; RR = 8.52, 95% CI 1.07-67.9, p = 0.04; NNT = non-significant; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.75, p = 0.39) (Fig.). However, remission was not significantly different from placebo on days 3-5 (studies = 2, non-ketamine NMDAR antagonists = 16.2%, placebo = 0.00%; RR = 6.18, 95% CI 0.76-50.3, p = 0.089; NNT = non-significant; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.36, p = 0.55) (Fig.).
KETAMINE
All-cause discontinuation was not significantly different between ketamine and placebo (studies = 6, ketamine = 12.1% v. placebo = 7.8%; RR = 1.52, 95% CI 0.64-3.58, p = 0.34; NNT = non-significant; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 4.38, p = 0.50), remaining non-significant after removal of five patients 'dropping out' during the first cross-over phase for marked improvement to ketamine (studies = 6, ketamine = 8.66% v. placebo = 6.86%; RR = 1.14, 95% CI 0.42-3.10, p = 0.81; NNT = non-significant; heterogeneity: τ 2 = 0.14, I 2 = 8.83, Q = 5.48, p = 0.36) (online Supplementary Fig.).
NON-KETAMINE NMDAR ANTAGONISTS
All-cause discontinuation did not differ between placebo and non-ketamine NMDAR antagonists (studies = 2, non-ketamine NMDAR antagonists = 12.3% v. placebo = 20.0%; RR = 0.92, 95% CI 0.11-8.09, p = 0.94; NNT = non-significant; heterogeneity: τ 2 = 1.47, I 2 = 52.6, Q = 2.11, p = 0.15). When one patient on AZD6765 'dropping out' due to marked response to AZD6765 during the first cross-over phase was excluded, results did not change (studies = 2, non-ketamine NMDAR antagonists = 11.1% v. placebo = 20.0%; RR = 0.62, 95% CI 0.14-2.66, p = 0.52; NNT = non-significant; heterogeneity: τ 2 = 0.35, I 2 = 19.2, Q = 1.24, p = 0.27) (online Supplementary Fig.).
KETAMINE
The BPRS score was significantly higher in the ketamine group than with placebo at 40-60 min (studies = 5, Hedges' g = 0.90, 95% CI 0.58-1.22, p < 0.001; heterogeneity: τ 2 = 0.02, I 2 = 10.8, Q = 4.48, p = 0.35), becoming significantly lower on day 3 (studies = 3, Hedges' g = -0.48, 95% CI -0.86 to -0.09, p = 0.015; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.23, p = 0.89) (online Supplementary Fig.). The YMRS score was significantly lower in the ketamine group than placebo at all time points until day 14, except at 40-60 min (studies = 3, Hedges' g = 0.29, 95% CI -0.10 to 0.68, p = 0.15; heterogeneity: τ 2 = 0.03, I 2 = 22.5, Q = 2.58, p = 0.28), 80 min (studies = 2, Hedges' g = -0.59, 95% CI -1.24 to 0.06, p = 0.076; heterogeneity: τ 2 = 0.10, I 2 = 44.1, Q = 1.79, p = 0.18) and day 7 (studies = 2, Hedges' g = -0.57, 95% CI -1.43 to 0.30, p = 0.20; heterogeneity: τ 2 = 0.27, I 2 = 68.3, Q = 3.15, p = 0.08) (online Supplementary Fig.). The CADSS score was only significantly higher in the ketamine group than with placebo at 40-60 min post-ketamine infusion (studies = 5, Hedges' g = 2.42, 95% CI 1.13-3.73, p < 0.001; heterogeneity: τ 2 = 1.96, I 2 = 92.3, Q = 52.1, p < 0.001) (online Supplementary Fig.).
NON-KETAMINE NMDAR ANTAGONISTS
The BPRS score was significantly lower in the nonketamine NMDAR antagonists than placebo at 110 min (studies = 2, Hedges' g = -0.37, 95% CI -0.72 to -0.03, p = 0.035; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 0.38, p = 0.54) and 230-240 min (studies = 3, Hedges' g = -0.32, 95% CI -0.63 to -0.02, p = 0.04; heterogeneity: τ 2 = 0.00, I 2 = 0.00, Q = 1.40, p = 0.50) (online Supplementary Fig.). Regarding YMRS scores, there was no difference between non-ketamine NMDAR antagonists and placebo at any post-baseline time points. The CADSS score was significantly higher in non-ketamine NMDAR antagonists than placebo at 230-240 min (studies = 1, Hedges' g = -0.66 95% CI -1.26 to -0.07, p = 0.03; heterogeneity: not applicable) and at day 1 (studies = 1, Hedges' g = -0.69, 95% CI -1.29 to -0.09; heterogeneity: not applicable), whereas the CADSS score was lower than placebo at day 3 (studies = 1, Hedges' g = 0.67, 95% CI 0.07-1.26, p = 0.03; heterogeneity: not applicable) and day 7 (studies = 1, Hedges' g = 0.68, 95% CI 0.08-1.28, p = 0.03; heterogeneity: not applicable).
KETAMINE
Among adverse events reported by 52 studies, no significant differences emerged between ketamine and placebo: tiredness/fatigue (p = 0.37), feeling 'woozy/loopy' (p = 0.95), dizziness/faintness (p = 0.22), nausea (p = 0.30) and vivid dreams (p = 0.23) (online Supplementary Fig.).
NON-KETAMINE NMDAR ANTAGONISTS
Adverse events were not significantly different between non-ketamine NMDAR antagonists and placebo: tiredness/fatigue (p = 0.65), dizziness/faintness (p = 0.054), anxiety (p = 0.70), nausea (p = 0.12), drowsiness/sedation (p = 0.40), irritability (p = 0.36), stomach/ abdominal discomfort (p = 0.65), muscle/bone/joint pain (p = 0.96), tingling (p = 0.96), diarrhea (p = 0.75), headache (p = 0.72), insomnia/interrupted sleep (p = 0.38) and vomiting (p = 0.60) (online Supplementary Fig.).
RISK ASSESSMENT INCLUDING PUBLICATION BIAS
Out of seven risk-of-bias categories, most studies had incomplete outcome data; i.e. they did not report results for all outcomes listed in the clinical trial registrations. Moreover,used ascending doses to which participants were blinded, and a placebo infusion was inserted at some point to which both raters and participants were blinded. We considered that these procedures might have compromised blinding, rating this study as being at high risk for multiple risk of bias categories. Although there has been concern of functional unblinding due to the euphorogenic and dissociative effects of sub-anesthetic doses of ketamine, we considered this effect as inevitable and regarded this fact as low risk, similar to many other agents that have substantial side effects that could be noticed by participants and raters (e.g. sedation, weight gain, muscle stiffness, restlessness, etc.) and that are generally regarded as having low risk of bias in clinical trials (online Supplementary Table). Inspecting funnel plots did not indicate publication bias regarding depressive symptom reduction, response or remission.
DISCUSSION
In this meta-analysis of randomized, placebo/ pseudo-placebo-controlled trials of single-dose, intravenous ketamine or non-ketamine NMDAR antagonists for patients with MDD and BD refractory/ unresponsive to trials with standard antidepressants, we examined the time trajectory of efficacy in greater detail than previous meta-analyses. Pooling six crossover trials and three parallel-group studies, single ketamine infusion was significantly superior to placebo/ pseudo-placebo regarding antidepressant efficacy. The significantly greater reduction in depressive symptoms started as early as within 40-60 min, peaking on day 1, and lasting until days 5-8, with maintenance of superior remission and response status until days 3-5 and 7, respectively. Effect sizes ranged from medium to large (-0.38 to -1.00) for the reduction in depressive symptoms, being large for response (NNT = 2-5, peaking at 230-240 min) and remission (NNT = 3-7, peaking at 1 day). At 24 h, 54.1% responded and 34.0% remitted on ketamine compared with only 7.8% and 0% on placebo. Furthermore, the findings were homogeneous throughout. In contrast to ketamine, single infusion of non-ketamine NMDAR antagonists was only significantly superior to placebo at one assessment time point (days 5-8) with a small to medium effect size (-0.37). Although non-ketamine NMDAR antagonists had significantly higher response rates on days 2 and 3-5 (NNT = non-significant), remission was not significantly superior to placebo. Like with ketamine, results were homogeneous throughout. The reason for non-ketamine NMDAR antagonists having smaller effect sizes than ketamine remains unknown. However, lower NMDAR affinity may be one of the mechanisms that also explains their reduced side effect potential. Nevertheless, both single infusion of ketamine and non-ketamine NMDAR antagonists was well tolerated, not leading to greater drop-out than placebo/pseudo-placebo. The magnitude as well as speed of effect of NMDAR antagonists are remarkable. Despite long suffering during a current depressive episode lasting 45.1 ± 49.0 months that was not relieved by 6.0 ± 1.1 treatment trials, NMDAR antagonism promptly and dramatically improved depressive symptoms. Effect sizes for symptom reduction were much higher for ketamine (-0.38 to -1.00) and similar for non-ketamine NMDAR antagonists (-0.37) in patients with treatment-resistant depression compared with first-line antidepressants in acute, non-refractory depression (-0.31), although effect sizes are lower when patients with milder depression are included due to greater placebo response. Effect sizes for response with ketamine (NNT = 2-5) and non-ketamine NMDAR antagonists (NNT = 4)) also compare very favorably to antidepressants in nonrefractory depression (NNT = 7) and to secondgeneration antipsychotic augmentation of patients with suboptimal response to antidepressants (NNT = 7-10). The transient efficacy lasting 1 week post-infusion have stimulated multi-infusion studies, which have yielded encouraging results. Repeated ketamine infusions resulted in significant antidepressant effect with an extended median time to recurrence of depressive symptoms in a 4-week open-label study (Aan het Rot et al. 2010), 18-day open-label study) and 12-month, naturalistic three-patient case series. Furthermore, a placebo-controlled RCT (n = 152) comparing three infusions of 100 or 150 mg AZD6765 within the first week with placebo showed superior antidepressant effects starting at week 2 and lasting until week 5. Treatment resistance occurs in approximately 15-20% of depressed patients. If safe, using a fast-acting antidepressant for non-refractory depression that could speed up response and remission while the first-line antidepressant unfolds its efficacy, as shown recently, would be an important treatment option. Such strategy could be used during emergency room visits to shorten or, even, prevent admissions. A related question includes whether patients will be able to maintain the response if standard antidepressants are started concurrently in non-refractory depression, or if repeated NMDAR antagonist doses would be necessary. Despite Several limitations of this meta-analysis deserve mentioning. First, six studies applied a cross-over design. Clearly, parallel-group trials are needed; yet, at least, the one parallel-group ketamine studyshowed very similar effects as the cross-over studies. Second, we grouped three different non-ketamine NMDAR antagonists together that have different mechanisms and that were studied to find optimal doses. Thus, findings may be a conservative estimate for some or all of the non-ketamine NMDAR antagonists. Further, although fewer nonketamine NMDAR antagonists studies reported outcomes at the same time point as ketamine studies, RCTs were larger with one and a half times as many participants (n = 354). Moreover, effect sizes in nonketamine NMDAR antagonist studies were homogeneous and approximately two-to four-fold lower than those observed after ketamine infusion. Third, the number of studies and patients was still limited, and assessment time points differed across studies. Therefore, some effect sizes were based on one study, especially for non-ketamine NMDAR antagonists. Nevertheless, study results were homogeneous, suggesting similar results even with a larger database. Finally, significant sedative, euphoric or dissociative effects of ketamine could have unblinded patients and/or raters. In fact, a recent post-hoc analysis suggested that higher dissociation ratings were associated with greater antidepressant efficacy of ketamine. While this result could have bolstered concerns about functional unblinding, it was interpreted as a lead toward a mechanisms of ketamine's efficacy. This interpretation is supported by our meta-analysis. Dissociative symptoms and BPRS scores were significantly higher with ketamine at 40-60 min, but BPRS scores became significantly lower at day 3, and antidepressant effects lasted until days 5-7. Moreover, non-ketamine NMDAR antagonists, not causing any psychogenic effects, also had antidepressant effects, supporting the NMDA hypothesis of depression. Finally, in the midazolamcontrolled study, midazolam sub-anesthetic doses that could also have unblinded treatment did not diminish ketamine's effect sizes. However, considering that such unblinding effects of ketamine could have influenced the results, we have used the score of 'unclear' in the risk-of-bias assessment table for studies not using midazolam as the control. In conclusion, results from this meta-analysis indicate that single-dose intravenous ketamine and, less so, non-ketamine NMDAR antagonists are effective in rapidly reducing depressive symptoms in patients with unresponsive/refractory MDD and BD. While these findings are highly encouraging and important for patients, clinicians, researchers and drug developers, several questions outlined above call for the conduct of sufficiently large, effectively blinded, parallel-group RCTs with single-dose and repeateddose ketamine and, ideally, additional NMDAR antagonists.
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