Ketamine for suicidality: an umbrella review

This review (2022) investigated the role of ketamine in suicidal ideation (SI) and behaviours. Of 27 studies that addressed ketamine for SI, only four reported mixed or negative results. Out of nine reviews, esketamine was significantly beneficial in five. Despite the majority of reviews being of critically low quality, the short-term efficacy of ketamine in suicidality was noted in most.

Abstract

“The urgent need for appropriate treatment for suicide, the tenth leading cause of death, has led to numerous studies. This study aims to systematically identify and appraise systematic reviews with or without meta-analyses investigating ketamine in suicidal ideation and behaviours. The study protocol was published in PROSPERO (CRD42021285320). Scopus, ISI, Embase, PubMed, CINAHL, PsycINFO, Cochrane Library, Google Scholar, and two registries were searched on October 29 without any restrictions for systematic reviews investigating the efficacy of ketamine on suicidal ideation and behaviours. The primary outcome was the final inference of ketamine effectiveness. A formal narrative synthesis was conducted, and the AMSTAR-2 tool was used to evaluate the quality of the studies. No funding was received. Of 27 studies that addressed ketamine for suicidal ideation, only four reported mixed or negative results, and out of nine reviews, esketamine was significantly beneficial only in five. A transient rise in pulse rate and blood pressure, dissociation, confusion, blurred vision, nausea, and vertigo were the most common adverse effects; however, most were mild. More than two-thirds of the included studies qualified as low or critically low quality. Preliminary evidence for the short-term efficacy of ketamine in suicidality was noted by the majority of reviews; however, long-term effects remained unknown. Due to the non-high quality of many studies and the limitations of core studies, further studies are required.”

Authors: Ahmad Shamabadi, Ali Ahmadzade & Alireza Hasanzadeh

Summary

1 | INTRODUCTION

Despite a one-third drop in suicide rates worldwide, suicides are still relatively prevalent in the United States. Suicides cost the health system $70 billion in 2019.

The present study aimed to systematically identify and appraise systematic reviews with or without meta-analyses investigating ketamine in suicidal ideation and suicidal behaviours. The effects of ketamine on suicidality have been proposed to involve glutamate neurotransmission, inflammation and neurotrophic pathways, pain processing, sleep ability and reward system.

2.1 | Search

This study was designed as a systematic review of systematic reviews and was published in PROSPERO under the code CRD42021285320. The first author searched Scopus, Web of Science, Embase, PubMed, CINAHL, PsycINFO, Cochrane Library, and Google Scholar databases for primary study data.

All terms were searched in Scopus, Embase, Cochrane Library, Web of Science and PubMed. MeSH-based terms were not used in the search.

Additional sources included searches on registries of systematic reviews, Google and Bing searches, and reviewing references of included studies.

2.2 | Eligibility

The following criteria were necessary for the inclusion of the studies: systematic review or meta-analysis, published as a full paper in a peer-reviewed journal.

The exclusion of studies was based on the following criteria: being in animals or in vitro, not being published as a full paper, lack of clear reporting of study methodology, and including less than two core studies with the required characteristics.

2.3 | Extraction

The required data were extracted from each study, and the results were summarized in a table. The primary outcome was the final inference of ketamine effectiveness in suicidal ideation and suicidal behaviours.

2.4 | Quality assessment

All authors independently used the second version of the AMSTAR-2 tool to appraise the quality of the included systematic reviews. The quality of a review is determined by the scores of 16 items, of which seven are major and nine are minor.

3.1 | Search and selection

A total of 274 citations were obtained, of which 131 were included. Of these, 62 were excluded because they were editorials, commentaries, non-clinical studies, clinical trials, protocols of systematic reviews or clinical trials, conference abstracts, non-systematic reviews, retracted, or corrigendum of systematic reviews.

3.2 | Methodological quality

The quality of 17 systematic reviews was critically low, 2 were low, 2 were moderate, and 6 were high. Item number 10 was the lowest scoring item.

3.3 | Overlap

15 reviews were conducted on ketamine to reduce suicidal ideation in adults with major depressive disorder and/or bipolar depression, with or without treatment-resistant depression. Five studies were of high or moderate quality, and the remaining had critically low quality.

Ketamine

Ketamine can significantly reduce suicidal ideation (SI) within 40 minutes and the effect may last up to 10 days. Several studies have demonstrated ketamine’s efficacy in lowering SI scores at 4, 2, 4, and 24 hours post-treatment.

In a study by Bahji et al., racemic ketamine and esketamine were compared with respect to their potency. The results showed that racemic ketamine was more promising than esketamine for depressive symptoms, but there was no significant difference in regard to suicidality.

Siegel et al. reported that hospital admission of patients with a high risk for suicide can be considered a potent intervention in itself, and that only three RCTs reported significant differences between trial arms.

Esketamine

Six of the above-mentioned studies also reviewed esketamine effects on SI reduction, and both were effective for acute management of SI. However, only one esketamine RCT was included in the Witt et al. review, and two studies suggested that esketamine does not reduce suicidal ideation.

3.4.2 | Suicidal ideation as a secondary outcome

Twelve studies explored the effects of ketamine on suicidal ideation in MDD and/or BD populations with or without TRD, but most studies used single items from depression questionnaires to assess SI.

Ketamine

Ketamine has been found to reduce SI in three RCTs and one open-label study, suggesting a possible role for ketamine in the acute management of suicidal patients.

Kim et al. found that ketamine reduced suicidal ideation in adolescents and that one patient experienced sustained anti-suicidal effects after multiple infusions. However, Dean et al. did not find any superiority for ketamine over placebo regarding suicidal ideation in subgroup or overall analyses and at any time point.

Esketamine

Esketamine has been shown to have significant effects on SI reduction, but a meta-analysis found that these effects were comparable to placebo.

reviews

Eight studies were assessed to have medium or high quality in AMSTAR-II, of which five investigated suicidality as a primary outcome. However, no significant association between mean age or gender and ketamine efficacy was observed.

Three papers examined ketamine and esketamine for suicidality, but found no significant efficacy at any time point. One paper examined ketamine effectiveness in adolescents and older adults, but found no significant efficacy.

4 | DISCUSSION

Twenty-seven systematic reviews were included in this study. The majority concluded that there is preliminary evidence for the short-term efficacy of ketamine (especially as IV administration) in suicidal patients, although there were mixed results regarding esketamine efficacy.

Ketamine has been shown to be effective in treating suicidal ideation in patients with unipolar or bipolar depression, although it has been suggested that these effects are actually a continuation of the antidepressant effects.

Most studies investigated ketamine’s effectiveness in the short term, and long-term use would be challenging. It is also associated with psychomimetic effects, neurotoxicity, cognitive dysfunction and cardiovascular adverse events, which may increase discontinuation due to intolerability.

Pharmacotherapy for suicidal ideation and behaviours is selected based on the underlying disease after establishing the patient’s safety. Ketamine is effective in depressed, bipolar and psychotic patients.

Ketamine can be prescribed through different formulations and delivery routes, and the study of formulations and routes in different disorders can be the subjects of further research.

This study has some limitations, but it is comprehensive and included studies that investigated suicidal ideation and behaviours as secondary outcomes and in a smaller number of studies. The study’s quality was assessed using AMSTAR-2, and it is recommended that other studies consider AMSTAR-2.

5 | CONCLUSION

Most studies have highlighted ketamine efficacy in acutely suicidal patients. However, data on esketamine is mostly inconclusive, and more than two-thirds of the included studies qualified as low or critically low quality.