Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review

This review (2021) evaluates the effect of esketamine and ketamine in patients with suicidal ideation at baseline. The authors find that esketamine trials did not demonstrate antisuicidal effects, while IV ketamine appeared to rapidly decrease the short term severity of suicidal ideation and depressive symptoms in individuals with baseline suicidal ideation.

Abstract

“Suicide accounts for approximately 800,000 deaths per year globally. Previous research has shown that intranasal esketamine and intravenous ketamine can rapidly decrease the severity of depressive symptoms and suicidal ideation. However, the majority of clinical trials excluded individuals with moderate to high baseline suicidality scores (e.g., suicidal ideation with plan/intent at the time of recruitment). The current review aims to evaluate the effect of esketamine and ketamine in patients with suicidal ideation at baseline. A systematic search was conducted on EMBASE, PsychInfo and PubMed from inception to July 2020 following the PRISMA guidelines. 15 studies met inclusion criteria. Results from esketamine trials did not demonstrate antisuicidal effects, as between-group differences were not found. Intravenous ketamine appeared to rapidly decrease the severity of suicidal ideation and depressive symptoms in individuals with baseline suicidal ideation, though retrospective studies suggest that these effects may be short-lasting. During the double-blind treatment phases, 2.4% of patients from the treatment groups and 1.5% of patients from control groups attempted suicide, with zero deaths by suicide in both the treatment and control groups during this phase. Based on the overall pooled samples, studies were assessed to be relatively safe, and the continual inclusion of this study population in future clinical trials is encouraged. Future research should aim to assess the longitudinal efficacy of ketamine in patients with baseline suicidality.“

Authors: Ashley N. Siegel, Joshua D. Di Vincenzo, Elisa Brietzke, Hartej Gill, Nelson B. Rodrigues, Leanna M. W. Lui, Kayla M. Teopiz, Jason Ng, Roger Ho, Roger S. McIntyre & Joshua D. Rosenblat

Summary

Intranasal esketamine and intravenous ketamine can rapidly decrease the severity of depressive symptoms and suicidal ideation in individuals with baseline suicidal ideation. However, the effects of ketamine may be short-lasting and longitudinal studies are needed to assess the efficacy of ketamine in patients with baseline suicidal ideation.

1. Introduction

Suicide accounts for 800,000 deaths globally per year and is linked to mental disorders. Although there are few evidence-based pharmacotherapies for suicidal ideation in patients with Major Depressive Disorder and Bipolar Disorder, clozapine and lithium are two of the only medications that have been demonstrated to reduce suicide rates.

Ketamine, an NMDA receptor antagonist, may be a rapid and effective treatment for depression and SI. It has been found to reduce SI severity within hours of intravenous infusion.

Although numerous studies indicate that esketamine and ketamine are promising interventions in rapidly reducing suicide attempts amongst individuals with depression, most studies exclude participants with suicide attempts due to ethical concerns.

Pharmacological agents that exert rapid antisuicidal effects are imperative, as active suicidal thoughts are a frequent reason for hospitalization. The current systematic review evaluates the extant literature on the use of either IN esketamine or IV ketamine in patients with current SI.

2.1. Search Strategy

A systematic search was conducted on EMBASE, PsychInfo and PubMed using the search terms “ketamine” and depress. A manual citation search was also conducted in the reference list of included articles.

2.2. Study selection and eligibility criteria

Interventional and observational studies were eligible for inclusion if they were original articles, ketamine or esketamine was used to treat symptoms of depression, and all participants had SI at baseline.

2.3. Data extraction

The authors conducted a systematic search to identify special populations not frequently included in clinical trials and divided each population into individual papers. Five supplementary papers were identified after the initial search, which included the terms suicid* OR “suicidal ideation OR suicidal behaviour”.

SI in clinical trials was evaluated by including relevant data on lead author, type of study, sample size, demographic information, suicidality criteria, drug formulation, dose and regimen, and concurrent medications.

2.4. Quality appraisal

All RCTs were assessed for bias based on the Cochrane Handbook for Systematic Review of Interventions. High risk of bias was designated for studies with inadequate protocol descriptions.

3.1. Search results

After initial screening, 129 publications were removed due to duplication, 440 were excluded based on the screening of titles and abstracts, and 202 full-text articles were assessed for eligibility. 15 studies met the inclusion criteria.

3.2. Prospective studies assessing the effect of intranasal esketamine in reducing Suicidal Ideation

Three double-blind, placebo-controlled RCTs assessing the antidepressant and antisuicidal effects of IN esketamine were identified. Patients with MDD and active SI with intent were randomized to either receive esketamine (84 mg, 2x/week for 4 weeks) or placebo nasal spray.

Participants from an RCT conducted by Ionescu et al. (2020) were randomized to receive esketamine (2x/week for 4 weeks) or placebo nasal spray. Esketamine significantly reduced depressive symptoms severity in the treatment group compared to placebo, but no significant differences between groups were found in the number of patients that achieved remission.

At day 90, 86.3% of patients in the treatment group and 76.7% of patients in the placebo group were normal/questionably suicidal.

In a smaller study, participants with a DSM-IV-TR diagnosis of MDD were randomly assigned to receive IN esketamine (84 mg, 2x/week for 4 weeks) or placebo. The treatment group had significantly greater improvements on the MADRS suicidal thoughts item only 4 h after the initial dose.

Results suggest that esketamine is effective in reducing depressive symptoms, but not suicidal thoughts, at 4 h and 24 h post-treatment.

Treatment emergent serious events occurred in all studies. One patient in each treatment group attempted suicide during the double-blind phase, three patients from the treatment group had a suicide attempt and one patient died by suicide, and two patients from the placebo group attempted suicide.

3.3. Prospective studies assessing intravenous ketamine for Suicidal Ideation

Five double-blind placebo-controlled RCTs were identified, with the largest RCT including 80 participants and using midazolam as the active comparator. All participants had a DSM-IV diagnosis of MDD and active SI, measured by a score of 4 on the Scale for Suicidal Ideation.

Results showed that patients who received ketamine infusions had a significantly lower suicidal ideation and suicide intention score than patients who received midazolam, and that these effects were seen as soon as 230 min after the first ketamine infusion. SSI and depression symptoms were maintained six weeks after ketamine infusion, suggesting the anti-suicidal and antidepressant effects of ketamine may last beyond the final infusion.

Ketamine had a significant antisuicidal effect in patients with bipolar depression, with 4/7 patients receiving ketamine being classified as responders and 3/7 as remitters, compared to 1/9 remitters and responders in the midazolam group. All non-responders from the midazolam group received an open-label ketamine infusion. The results suggest that ketamine may exert antisuicidal effects in patients with BD, but further studies are needed to confirm these results.

Murrough et al. (2015) conducted an RCT in which 24 patients were randomly assigned to receive either a single infusion of ketamine or midazolam. The treatment group showed a significant reduction in suicidal ideation 48 h post-infusion, but not 24 h post-infusion.

Ionescu et al. (2019) examined the effects of repeat-dose IV ketamine in patients with MDD and current, chronic suicide thoughts. Patients receiving 0.5 mg/kg of ketamine over 45 min, twice weekly for three weeks had similar improvement in symptoms to those receiving placebo. However, only one patient from the treatment group and two from the placebo group continued to have an absence of SI at the end of follow-up.

Ketamine did not show superior antidepressant and antisuicidal effects to placebo, and the dose used in the study did not increase to 0.75 mg/kg after the first infusion.

Ionescu et al. (2016a) conducted an RCT in which patients with anxious depression received ketamine (0.5 mg/kg over 45 min; 6 infusions over 2 weeks) or placebo. Patients with anxious depression had significantly greater decreases in depressive symptoms over the course of treatment.

Serious adverse events related to suicidality and depression were seen in four out of five RCTs. Four patients were hospitalized for worsening depression or suicidality during Murrough et al. (2015)’s study, all of which researchers deemed unrelated to study participation.

3.4. Retrospective studies assessing intravenous ketamine for Suicidal Ideation

Ketamine has been shown to have anti-suicidal and antidepressant effects in patients with SI, but these results should be interpreted with caution.

Seven retrospective studies were identified, three of which reported on single case studies and four of which reported on case reports from open-label ketamine trials. All patients had active suicide thoughts for more than 3 months.

Patients received 0.5 mg/kg of ketamine over 45 min for the first 3 infusions, with an increase to 0.75 mg/kg for the last three (2x/week for 3 weeks). After infusion six, 5/12 participants met criteria for response, and 2/12 participants met criteria for remission.

Only 1/5 responders experienced a sustained response after the final infusion, and the remaining four responders relapsed two weeks post-final infusion. One non-responder did continue to improve during the 3-month follow-up.

In another open-label ketamine trial, 51/86 patients with either unipolar or bipolar depressive disorder and current SI experienced a sustained response and 26 sustained remission after receiving 0.5 mg/kg of IV ketamine over 40 min, thrice weekly for two weeks.

Vande Voort et al. (2016) gave ketamine infusions three times per week for the duration of two weeks to 12 patients with TRD. 5/12 patients achieved depression symptom remission, and 7 subjects were positive responders.

A 47-year-old woman who had not responded to pharmacological treatments and had at least 10 suicide attempts was given two infusions of ketamine (2 weeks apart) at a dose of 0.5 mg/kg over 40 min. She then received 5 mg of memantine (adjunct to current medication) and maintained a BDI score of five and HDRS score of seven.

A 45-year-old female patient with treatment-resistant bipolar depression and chronic suicidal thoughts received six ketamine infusions over the course of two weeks. The patient experienced euthymia for four weeks, but at week five the symptoms abruptly re-appeared, leading to a suicide attempt.

A 47-year-old woman with a history of anorexia nervosa, fully remitted alcohol dependence and recurrent depressive disorder was admitted to the hospital after a suicide attempt and received two IV ketamine infusions. Five months after the second infusion, the SI had not returned.

4. Discussion

The current systematic review identified three RCTs, five RCTs, four retrospective, open-label ketamine trials and three case studies assessing the use of ketamine for depression and SI. All studies were of high quality.

Esketamine improved depressive symptoms and reduced suicidality in patients with SI at 24 h post-treatment, but the long-term effects of acute esketamine on suicidality are unclear.

Results from prospective and retrospective studies examining IV ketamine are mixed with regards to the antisuicidal and antidepressant effects. The majority of patients responded within the first 24 h of treatment, though the effects were not sustained post-treatment for the majority of patients.

Inpatient studies of patients at high-risk for suicide often had high placebo response rates, which may explain why differences between treatment and placebo groups were often numerically but not statistically different.

Patients in all studies experienced non-serious adverse events and treatment emergent serious events specifically related to depression and suicidality. The proportion of patients who experienced treatment emergent adverse events ranged from 0 to 3% and 0 – 2%, respectively. Patients with active suicidal thoughts were able to safely complete clinical trials and RCTs, and it may be important to continue to include this subpopulation in clinical research in order to conduct comprehensive research.

The current study has several limitations, including small sample sizes, placebo effects, and a lack of longitudinal evidence. Further research is needed to fully determine the long-term effects of esketamine and ketamine, as well as to investigate the influence that psychotherapy has on treatment.

The current systematic review suggests that ketamine may have antisuicidal and antidepressant effects in patients with active SI with intent, but the effects do not last beyond the course of treatment.

Contributions

Ashley Siegel, Joshua Di Vincenzo, Linas Wilkialis, Yuetong Song, and Jiaqi Xiong contributed significantly to the writing, analysis, and synthesis of this review. Joshua Rosenblat provided supervision and direction.

Conflict of interest disclosures

RSM has received funding from Neurocrine, COMPASS, Sunovion, Janssen, Allergan, Lundbeck, Pfizer, Shire, Purdue, and Otsuka, and JDR has received funding from Allergan, Lundbeck, Sunovion, and COMPASS.