Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses

This review (2021) summarizes the current state of research regarding the use of ketamine and esketamine for depression. Across 11 studies it was found that ketamine alleviated symptoms of depression 40 min to 1 week while esketamine improved symptoms at 2 hours to 4 weeks. The methodological quality of most reviews was described as “critically low.”

Abstract

“Purpose: To summarize the evidence of efficacy and safety of the use of ketamine and esketamine for depression.

Methods: A literature search was performed in Medline, the Cochrane Library, LILACS, and CRD until November 2020. We included systematic reviews with meta-analyses of randomized controlled trials on the use of ketamine and esketamine in adult patients with depression. Two authors independently performed the study selection and data extraction. The AMSTAR-2 tool was used to appraise the quality of included reviews.

Results: A total of 118 records were identified, and 11 studies fully met the eligibility criteria. Compared to control, ketamine improved the clinical response at 40 min to 1 week and clinical remission at 80 min to 72 h, and esketamine improved both outcomes at 2 h to 4 weeks. Ketamine and esketamine also had a beneficial effect on the depression scales score and suicidality. For adverse events, oral ketamine did not show significant change compared to control, while intranasal esketamine showed difference for any events, such as dissociation, dizziness, hypoesthesia, and vertigo. Most reviews were classified as “critically low quality,” and none of them declared the source of funding of the primary studies and assessed the potential impact of risk of bias in primary studies.

Conclusion: Ketamine and esketamine showed a significant antidepressant action within a few hours or days after administration; however, the long-term efficacy and safety are lacking. In addition, the methodological quality of the reviews was usually critically low, which may indicate the need for higher quality evidence in relation to the theme.”

Authors: Tácio de Mendoça Lima, Marília Berlofa Visacri & Patricia Melo Aguiar

Summary

To summarize the evidence of efficacy and safety of ketamine and esketamine for depression, we performed a literature search and used the AMSTAR-2 tool to appraise the quality of included reviews.

A total of 118 records were identified, and 11 studies fully met the eligibility criteria. Ketamine and esketamine improved depression scales score and suicidality, but oral ketamine did not show significant change compared to control.

Ketamine and esketamine show significant antidepressant action within hours or days of administration, but long-term efficacy and safety are lacking.

Mental disorders, depression, and ketamine

Introduction

Depression is a complex psychiatric disorder characterized by depressed mood, anhedonia, loss of interest, low energy, fatigue, and other symptoms. Its etiology is not yet fully understood.

According to the World Health Organization, more than 300 million people of all ages suffer from depression, which is a leading cause of disability worldwide. Depression also has an important impact on activities of daily living and quality of life.

Antidepressant medications, such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, can be used for treatment of depression. However, current treatments require a considerable time to induce a response.

Ketamine has been shown to inhibit the N-methyl-d-aspartate (NMDA) receptor and to activate the opioid system, which may explain its antidepressant effect. However, the efficacy and safety of ketamine and esketamine for depression are not yet fully established.

A systematic review with meta-analyses has been published recently on the use of ketamine and esketamine in adult patients with depression. The methodological quality of these systematic reviews is unknown.

Literature search

A comprehensive literature search was performed in the Medline, LILACS, Cochrane Library, and CRD databases until November 29, 2020. Keywords were searched in any fields unless specified.

Study selection

The selection process was performed in three stages: exclusion of repeated records, analysis of the titles and abstracts, and analysis of the full-text articles.

To be included in the present overview, articles had to be systematic reviews with pairwise meta-analysis of randomized controlled trials (RCTs), published in English, Spanish, or Portuguese, and evaluate the use of ketamine or esketamine in adults with major depressive disorder or bipolar disorder.

Data extraction

Data extraction was done using a spreadsheet preformatted in Microsoft Excel® by two independent researchers, and any disagreement was resolved by a third author.

Quality assessment

Methodological quality was assessed using the AMSTAR-2 tool, and the overall rating was based on weaknesses in critical domains. One investigator conducted the evaluation of the studies, and a second one verified this evaluation.

Data synthesis

The characteristics of systematic reviews and their methodological quality were summarized using systematically structured tables.

Search results

The electronic search identified 118 potentially relevant records. Of these, 11 systematic reviews with pairwise meta-analysis on use of ketamine or esketamine or both for treatment depression were found for full-text examination.

Characteristics of systematic reviews

The 11 reviews included in this overview included primary studies evaluating patients with major depression disorder or bipolar disorder. They involved ketamine as monotherapy in the intervention arm, and seven reviews included studies whose comparator was placebo or active-control.

Nine reviews assessed clinical remission or clinical response or both, and all of them assessed the severity of depressive symptoms through validity scales. Six reviews assessed other outcomes, such as suicidality, acceptability, disability, and adverse events.

Results on clinical response

Ketamine produced a significant clinical response compared to placebo at 40 min, 80 min, 2 h, and 4 h after intervention, but not at very-low doses or at 48 h.

In four reviews, ketamine produced a significant clinical response compared to placebo or activecontrol or both, but in one review, it did not show a significant effect for patients with bipolar disorder.

Four reviews showed that ketamine improved the clinical response at 1 week compared to placebo or active-control or both, and one review showed a tendency to significant difference between ketamine and placebo at 2 weeks.

Results on clinical remission

Ketamine produced a significant clinical remission of symptoms compared to placebo at 80 min, 2 h, and 4 h after intervention, but not at 24 h or 48 h.

Five reviews showed that ketamine produced a significant clinical remission compared to placebo or active-control or both in most of them. However, very-low-dose ketamine for patients with major depression disorder did not show significant difference in the clinical remission at the same time compared to placebo and active-control.

Results on depression scales

Four reviews showed significant beneficial effects of ketamine in the HAM-D/HDRS and MADRS scores at 24 h compared to placebo or active-control or both. However, one systematic review did not show significant effect.

Three reviews showed data of HAM-D/HDRS and MADRS scores at 1 week, and all showed significant beneficial effects of ketamine compared to placebo or active-control or both. However, Lee et al. (2015) did not show significant difference between ketamine and placebo for patients with bipolar depression.

Two reviews assessed the use of ketamine through BPRS and CADSS scores and one reviewed the use of esketamine through PHQ-9 score.

Results on suicidality, acceptability, disability, and adverse events

One review observed a significant difference between ketamine and placebo and active control at 4 h and 24 to 72 h, but not at 1 week.

Three reviews showed no significant difference between ketamine and placebo in terms of acceptability, disability, or adverse events. One review showed a significant difference between esketamine and placebo in terms of dissociation, dissociative disorder, dizziness postural, feeling abnormal, feeling drunk, hypoesthesia, oral hypoesthesia, and vomiting.

Methodological quality of systematic reviews

The methodological quality of 11 systematic reviews based on the AMSTAR-2 tool is shown in Table 6. Three reviews presented “low quality” and eight reviews presented “critically low quality”.

No review reported on the sources of funding for the studies included in their review, and only five reviews provided a list of excluded studies and justified their exclusions. Four reviews conducted an adequate investigation of publication bias.

Overlap of primary studies across the systematic reviews

There are two pairs of systematic reviews on ketamine that included the same RCT, but they performed different meta-analyses and showed slightly distinct results. It was not possible to identify whether there was an error in data extraction by the review authors or whether data were extracted from different sources.

Main findings

This is the first overview of systematic reviews with meta-analyses evaluating efficacy and safety of ketamine and esketamine in adult patients with depression. Ketamine showed a significantly greater clinical response compared to control in most results.

Ketamine showed significant superiority to control in clinical remission in most results between 80 min and 72 h post-intervention, and esketamine showed significant superiority to placebo in clinical remission at all results evaluated between 2 h and 4 weeks.

A recent systematic review and network meta-analysis compared the efficacy of 21 antidepressants for the acute treatment of adults with major depressive disorder. Ketamine and its isomer produced a rapid, powerful, and persistent action in adult patients with depression.

Ketamine and esketamine can reduce suicidal ideation, but not at longer time points compared to control. The use of suicide risk assessment tools can complement the clinical assessment and be the starting point of the suicide prevention process.

Only two systematic reviews with meta-analysis reported adverse events. The use of oral ketamine did not cause more adverse events, while intranasal esketamine showed significantly more dropouts due to adverse events and any events, such as dissociative disorder, dizziness, oral hypoesthesia, and vertigo.

Methodological quality of systematic reviews

This overview of systematic reviews on depression treatments is consistent with previous reviews.

All reviews did not report on the sources of funding for the studies included in their study, and no review assessed how their results varied in relation to the inclusion or exclusion of individual studies with a high risk of bias.

The AMSTAR-2 considers the development of a research protocol prior to conducting a review to be a critical item, but few reviews have fully adhered to this item.

Opportunities for future research

The evidence summarized in this review is from 20 RCTs including ketamine and 4 RCTs including esketamine. More evidence is needed on the effects of these drugs on a treatment period longer than 2 – 4 weeks.

Future systematic reviews with meta-analyses on this theme should be appropriately designed and conducted, including reporting on the sources of funding, assessing the potential impact of risk of bias in RCT, and investigating publication bias.

Strengths and limitations of the overview

This study summarized evidence on the use of ketamine and esketamine in adult patients with depression, using the validated AMSTAR-2 tool. However, the study also presented some limitations, including the exclusion of reviews including simultaneous use of ECT and ketamine or esketamine.

Conclusion

Ketamine and esketamine showed significant superiority in most results for clinical response, clinical remission, depression scales scores, and suicidal ideation compared to control. However, long-term efficacy and safety are lacking, and more primary studies are needed.

A comprehensive literature search will be performed until October 2019 in the Medline, LILACS, Cochrane Library, and CRD databases, and the reference lists of appraised articles will be screened for additional studies. The studies will be independently selected by two authors, and the disagreements will be resolved by a third author. They must be published in English, Spanish or Portuguese, and have evaluated the use of ketamine in patients with major depressive disorder or bipolar disorder.

We will exclude studies that are narrative reviews, systematic reviews without meta-analysis, meta-analyses not from systematic reviews, systematic reviews with use concomitant of ECT and ketamine as intervention, or systematic reviews that did not have the full-text article available.

The methodological quality of included systematic reviews will be assessed using the AMSTAR-2. This is a 16-item questionnaire with the majority of questions being judged as “yes”, “partial yes”, or “no”. The review authors must have performed a comprehensive literature search strategy, performed study selection in duplicate, performed data extraction in duplicate, provided a list of excluded studies and justified the exclusions, described the included studies in adequate detail, and assessed the risk of bias in individual studies. Item 14: Did the review authors provide a satisfactory explanation for heterogeneity in the results? Item 15: Did the review authors carry out an adequate investigation of publication bias? The overall confidence in the results of the review will be rated as high, moderate, low, or critically low. The characteristics of systematic reviews and their methodological quality will be descriptively summarized using systematically structured tables.