Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review

Abstract

Background: More than 2% of the general population experience suicidal ideas each year and a large number of them will attempt suicide. Evidence-based therapeutic options to manage suicidal crisis are currently limited. Objectives: The aim of this study was to overview the findings on the use of ketamine and esketamine for the treatment of suicidal ideas and acts. Design: Systematic review. Data Sources and methods: PubMed, article references, and Clinicaltrials.gov up to June 30, 2022. Meta-analyses published within the last 2 years were also reviewed. Results: We identified 12 randomized controlled trials with reduction of suicidal ideation as the primary objective and 14 trials as secondary objectives. Intravenous racemic ketamine was superior to control drugs (placebo or midazolam) within the first 72 h, in spite of large placebo effects. Adverse events were minor and transient. In contrast, intranasal esketamine did not differ from placebo in large-scale studies. Limitations, clinical considerations, and opportunities for future research include the following points: large placebo effects when studying suicidal ideation reduction; small concerns about blinding quality due to dissociative effects; no studies on the risk/prevention of suicidal acts and mortality; lack of studies beyond affective disorders; no studies in adolescents and older people; lack of knowledge of long-term side effects, notably liability for abuse; no robust predictive markers; limited understanding of the mechanisms of ketamine on suicidal ideas; need for improved assessment of suicidal ideation in clinical trials; need for studies in outpatient settings, emergency room, and liaison consultation; need for research on ketamine administration; limited knowledge on the positive and negative effects of concomitant treatments. Conclusion: Overall, there is compelling evidence for a favorable short-term benefit-risk balance with intravenous racemic ketamine but not intranasal esketamine. The place of ketamine will have to be defined within a multimodal care strategy for suicidal patients. Caution remains necessary for clinical use, and pharmacovigilance will be essential.

Psychiatric and legal considerations for ketamine treatment within prison settings

“…With regard to ketamine, a nasal spray for application of esketamine, the S(+) enantiomer of ketamine, has recently been approved for therapeutic use in several countries, minimizing the risk of substance misuse and side effects such as dissociation ( 75 , 76 ). Although there is strong evidence supporting the positive benefit related to suicide ideation for intravenous racemic ketamine, studies investigating intranasal esketamine did not yet show the same favorable profile ( 77 , 78 ). Given the current lack of empirical evidence, it therefore seems too early to draw conclusions regarding potential effects of esketamine in prison settings.…”

Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review

“…Recently, intravenous (IV) ketamine has been shown to reduce, within hours, the suicidal ideation in MDE and BD [11,42,43] (see below).…”

“…We recently published a review article concerning the interest of ketamine in the prevention of suicidal ideation, specifying its clinical interest [11]. It is difficult to model TRD in rodents.…”

Predicting non-response to ketamine for depression: a symptom-level analysis of real-world data

“…Although many studies have reported on ketamine's effects specifically on suicidality [20], we are aware of only a few studies that have compared how ketamine affects different depression symptoms or symptom clusters [21][22][23]. None of those studies have modeled trajectories of symptoms over time.…”