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.”

Authors: T. Kishimoto, J. M. Chawla, K. Hagi, C. A. Zarate, J. M. Kane, M. Bauer & C. U. Correll

Summary

Introduction

Mood disorders and accompanying suicidality result in great personal suffering and public expenditure. Although antidepressants have dominated the treatment of depression, efficacy is often unsatisfactory, and onset of clinically noticeable efficacy usually takes 52 weeks.

Ketamine, a non-selective NMDAR antagonist, has shown antidepressant efficacy in subanesthetic doses within hours of administration in placebo-controlled crossover studies for MDD and BD. Ketamine also reduced suicidal thoughts in open and controlled trials.

Ketamine induces presynaptic glutamate release by activating GABAergic inputs leading to increased glutamatergic neuronal firing. Non-ketamine NMDAR antagonists have been conducted in five randomized trials for depression.

There have been five meta-analyses of ketamine and non-ketamine NMDAR antagonists in patients with depression, but these meta-analyses have some deficits, such as mixing pre-post data comparison with placebo-controlled studies, missing some relevant studies, and/or mixing in electroconvulsive therapy studies.

Search and inclusion criteria

Two investigators independently searched PubMed, PsycINFO, ISI Web of Science, and the US National Institutes of Health clinical trials registry for studies comparing single-dose, intravenous NMDAR antagonist infusion vs. placebo or pseudo-placebo for MDD and/or BD.

Data extraction and outcomes

We assessed symptom change using the Hamilton Depression Rating Scale (HAM-D) or Montgomery – sberg Depression Rating Scale (MADRS) and looked at response, remission, all-cause discontinuation, and adverse effects, including psychotic, manic, and dissociative symptoms. In phase 2 studies of GLYX-13 and AZD6765, multiple doses were combined into one experimental arm, but in the phase IIB study of GLYX-13 the 30 mg dose was excluded because it was a clear outlier.

Risk assessment including publication bias

Two reviewers independently assessed the risk of bias for each study using the Cochrane Collaboration’s risk-of-bias tool.

Meta-analytic calculations

Statistical analysis was performed on continuous and dichotomous outcomes, and heterogeneity was assessed using 2, I2, Q and p values.

Search results

The search yielded 1574 hits; 14 articles were removed based on abstract/title. 12 articles reporting on 14 trials were meta-analysed.

Study design, population, treatment and outcomes

In 14 trials, ketamine was used as the treatment in 234 patients with depression. Five studies used non-ketamine NMDAR antagonists, and one study used midazolam as the active pseudo-placebo.

Ketamine studies

Nine ketamine studies were conducted, including seven independent funded studies, six placebo-controlled cross-over studies, and three parallel-group studies. Five studies 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 studied MDD patients, two trials studied BD patients, and one trial included both BD and MDD patients. Five studies were hospitalized for the duration of the study, and two studies were outpatients treated in a day-hospital setting.

Co-morbid anxiety disorders were permitted in three studies, whereas no study permitted recent substance use, unstable medical illness, serious/imminent suicidal or homicidal risk.

Seven studies used ketamine as a single infusion for 40 min, and patients were crossed over after 7 – 14 days in six studies. Three studies reported remission data, i.e. MADRS 10 or HAM-D 7 550%.

Non-ketamine NMDAR antagonist

In five studies, three non-ketamine NMDAR antagonists were studied: CP-101,600, GLYX-13 and AZD6765. Four RCTs were parallel-group, industry-sponsored RCTs, and one study was a non-industry sponsored, 7-day cross-over study of AZD6765.

In one study, a single infusion of CP-101,606 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. In one cross-over study, one patient who responded to AZD6765 was not crossed over.

Ketamine

Single ketamine infusion resulted in superior reduction of depressive symptoms compared with placebo/pseudo-placebo starting at 40 – 60 min and lasting until days 5 – 8 (Fig. 1).

Non-ketamine NMDAR antagonist

Pooled analysis of 4 studies showed that non-ketamine NMDAR antagonists were superior to placebo in reducing depressive symptoms on days 5 – 8, but not at any other time point.

Ketamine

Ketamine was associated with significantly greater response compared to placebo/pseudo-placebo starting at 40 – 60 min, peaking at 230 – 240 min, and lasting until day 7 (Fig. 3a).

Ketamine was associated with significantly greater remission of pain starting at 80 min, peaking at day 1, and lasting until days 3 – 5 (Fig. 3b).

Non-ketamine NMDAR antagonists

Compared with placebo, non-ketamine NMDAR antagonists were associated with significantly greater response on day 2 and days 3 – 5, but not on days 3 – 5.

Ketamine

All-cause discontinuation was not significantly different between ketamine and placebo, and remained non-significant after removal of five patients ‘dropping out’ during the first cross-over phase for marked improvement to ketamine.

Non-ketamine NMDAR antagonists

All-cause discontinuation did not differ between placebo and non-ketamine NMDAR antagonists, even when one patient on AZD6765 ‘dropped out’ due to marked response to AZD6765 during the firstcross-overphasewasexcluded.

Ketamine

The BPRS score was significantly higher in the ketamine group than with placebo at 40 – 60 min, the YMRS score was significantly lower in the ketamine group than with placebo at all time points until day 14, and the CADSS score was only significantly higher at 40 – 60 min.

Non-ketamine NMDAR antagonists

Non-ketamine NMDAR antagonists significantly reduced BPRS and YMRS scores, whereas CADSS scores were higher in non-ketamine NMDAR antagonists than placebo at 230 – 240 min and day 1, whereas CADSS scores were lower in non-ketamine NMDAR antagonists at day 3 and day 7.

Non-ketamine NMDAR antagonists

Adverse events were not significantly different between non-ketamine NMDAR antagonists and placebo: tiredness/fatigue, dizziness/faintness, anxiety, nausea, drowsiness/sedation, irritability, stomach/ abdominal discomfort, muscle/bone/joint pain, tingling, diarrhea, headache, insomnia/interrupted sleep, and vomiting.

Risk assessment including publication bias

The majority of studies had incomplete outcome data, and Lai et al.(2014) 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. This study was rated as having a high risk of bias.

Discussion

In this meta-analysis of randomized, placebo/ pseudo-placebo-controlled trials, single-dose, intravenous ketamine was significantly superior to placebo/ pseudo-placebo regarding antidepressant efficacy. The superior reduction in depressive symptoms started as early as within 40 – 60 min, peaking on day 1, and lasting until days 5 – 8. Ketamine was significantly superior to placebo at one assessment time point, but non-ketamine NMDAR antagonists had smaller effect sizes and did not lead to greater drop-out than placebo.

Ketamine and non-ketamine NMDAR antagonists improve depressive symptoms in patients with treatment-resistant depression, and compare favorably with first-line antidepressants in acute, non-refractory depression and second-generation antipsychotic augmentation of patients with suboptimal response to antidepressants.

Ketamine infusions have been shown to have a transient antidepressant effect lasting 1 week post-infusion, and to have an extended median time to recurrence of depressive symptoms.

Treatment resistance occurs in approximately 15 – 20% of depressed patients. A fast-acting antidepressant could be used to speed up response and remission while the first-line antidepressant unfolds its efficacy.

Despite these highly favorable results, several important questions remain: can NMDAR antagonists be developed that have similarly large effect sizes as ketamine?, can NMDAR antagonists be safely repeated/chronic administered?, and can NMDAR antagonists be useful anti-suicidal treatments? Several limitations of this meta-analysis deserve mentioning, such as the cross-over design of six studies and the grouping of three different non-ketamine NMDAR antagonists that have different mechanisms. Nonetheless, results were homogeneous, suggesting similar results even with a larger database. Ketamine’s significant sedative, euphoric or dissociative effects could have unblinded patients and/or raters, but the antidepressant effects lasted until days 5 – 7, and non-ketamine NMDAR antagonists also had antidepressant effects, supporting the NMDA hypothesis of depression.

Results from this meta-analysis indicate that single-dose intravenous ketamine and non-ketamine NMDAR antagonists are effective in rapidly reducing depressive symptoms in patients with unresponsive/refractory MDD and BD.

Acknowledgements

This study was funded in part by the NIMH. The NIMH had no role in study design, data collection, analysis, interpretation, or publication.

Declaration of Interest

T.K. has received consulting fees from Sumitomo Dainippon, Novartis, Otsuka and Taisho, and has received speaker’s honoraria from Abbvie, Banyu, Eli Lilly, Dainippon Sumitomo, Janssen, Mochida, Novartis, Otsuka Pfizer and Shionogi.

C.A.Z. has been awarded a patent for the use of ketamine in major depression.

M.B. has received grant/research support from The Stanley Medical Research Institute, NARSAD, Deutsche Forschungsgemeinschaft, European Commission (FP7), American Foundation for Suicide Prevention, and BMBF.