Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression

This meta-analysis (2015) of six randomized, double-blind, placebo-controlled trials (n=101) examined the short-and mid-term efficacy of ketamine (bipolar) to depression. Ketamine effectively reduced symptoms in unipolar depression for seven days, , whereas the maintenance of its efficacy in bipolar depression failed to reach significance after 4 days.

Abstract

“Introduction: Among treatments currently assessed in major depression, ketamine, has been proposed of great interest, especially because of its very rapid action. However, the time-course of the antidepressive action of ketamine remained unclear. In the present meta-analysis, we provided a clear and objective view regarding the putative antidepressive effect of ketamine and its time-course.

Methods: We searched the MEDLINE and PsycINFO databases through December 2013, without limits on year of publication, using the key words ketamine and synonyms for mood disorder or episode. Six randomized, double-blind and placebo-controlled trials of ketamine in major depression (n=103 patients) were thus identified. Authors were contacted and they all provided original data necessary for this meta-analysis. Standardized mean differences (SMD) were calculated between the depression scores in ketamine and placebo groups at days 1, 2, 3–4, 7 and 14.

Results: Ketamine showed an overall antidepressive efficacy from day 1 to day 7. However, the maintenance of its efficacy over time failed to reach significance in bipolar depression after day 3–4. Significant SMDs were not explained by demographic or clinical characteristics of included samples.

Discussion: The present meta-analysis provides a high level of evidence that ketamine has a rapid antidepressive action during one week, especially in unipolar disorder.”

Authors: Bruno Romeo, Walid Choucha & Philippe Fossati Jean-YvesRotge

Summary

A meta-analysis of six randomized, double-blind and placebo-controlled trials of ketamine in major depression was performed. Ketamine showed an overall antidepressive efficacy from day 1 to day 7, but the maintenance of its efficacy over time failed to reach significance in bipolar depression.

1. Introduction

Major depression is a highly frequent and disabling disorder, with important functional and health consequences. Pharmacological treatments contribute to improve the depressive symptomatology, but the improvement may occur several weeks after the pharmacological administration.

Ketamine, a N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, has been proposed of major interest in depression since many reports showed a marked antidepressive effect in the very hours following the administration of a single dose. However, a quantitative analysis of the putative antidepressive effect of ketamine and its time-course is now required.

Three meta-analyses on the antidepressive effects of ketamine were published this year, but none of them assessed the time-course of ketamine’s effects. The present meta-analysis addresses these issues and explores the influence of demographic and clinical characteristics on the meta-analysis effect sizes.

2.1. Data sources and study selection process

We searched the MEDLINE and PsycINFO databases for studies on ketamine and depression, and excluded studies controlled by an active drug, ECT or midazolam. An email alert was created after December 2013 to detect putative publications of interest, but no unpublished data were found.

2.2. Data extraction

We systematically contacted all corresponding authors of each included trial and obtained all available data. This includes depression scores on the Hamilton Depression Scale, Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory.

We extracted the means and SD of age, gender, years of illness, duration of the current episode, comorbid anxiety disorder, substance use disorder and alcohol use disorder, and data extraction was performed by one author.

2.3. Data analyses

Data analyses were performed using RevMan, version 5.3 (Copenhagen, Denmark); effect sizes were calculated using Cohen’s method (Cohen 1988); and a random-effects model was used to estimate the overall effect size at each time (baseline, day-1, day-2, day-3, day-4, day-7, day-14).

3. Results

Six double blind, randomized, placebo-controlled, cross-over trials were included in the present meta-analysis, which included 110 patients with a major depressive episode. Among these 110 patients, 103 patients were included in the final analyses described in the selected studies and thus included in the present meta-analysis.

Individual SMDs for each included study at each period of measurements are described in details in Supplementary Material. Overall SMDs are calculated at baseline, day 1 and day 2 and are presented in Table 1. Ketamine showed an antidepressive effect at day 3 – 4 and day 7 in comparison with placebo. The efficacy of ketamine on depression was shown to be major at day 1, day 2, day 3, day 4, day 7, and day 14.

When sensitivity analyses were performed on individual studies, no significant differences were found. However, when meta-regression models were performed, the significance of SMD at day 7 was lost.

4. Discussion

This meta-analysis showed that ketamine was effective in treating treatment-resistant major depressive episode. It was also relatively safe and possible induced-positive symptoms tend to disappear in the minutes following its administration.

Ketamine, an antiglutamatergic drug, was rapidly effective in major depression, as demonstrated by several brain imaging, genetic or post-mortem studies. Ketamine might contribute to antidepressive effects by different mechanisms, including increasing synaptic connections, relieving inhibition of BDNF synthesis, and increasing dendritic spines.

A recent meta-analysis showed that ketamine contributed to a rapid improvement in both unipolar and bipolar depression, but this effect was sustained over time only in unipolar depression. This difference may be due to the involvement of the glumatergic system in both disorders.

The present meta-analysis found that ketamine’s antidepressive effect was not affected by the route of administration, and that the increase in psychotic symptoms occurred 40 min after ketamine administration, but disappeared 80 min after ketamine administration.

The main limitation of this meta-analysis was the limited number of trials and data included in the analyses. This could explain the poor statistical power.

The present meta-analysis of randomized and controlled trials shows that ketamine is relatively safe and contributes to a rapid antidepressive action.