Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety

This post-hoc meta-analysis (n=133) examined the relationship between the antidepressant efficacy of intravenous ketamine (35mg/70kg) and its effects on suicidal ideation (SI) among patients with depression. Ketamine increased the patient’s wish to live and decreased their wish to die, and these reductions in suicidal ideation independent of reductions in depressive and anxiety symptoms.

Abstract

“Objective: Suicide is a psychiatric emergency. Currently, there are no approved pharmacologic treatments for suicidal ideation. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal ideation as well as depression and anxiety, but the dynamic between these symptoms is not known. The aim of this analysis was to evaluate whether ketamine has an impact on suicidal thoughts, independent of depressive and anxiety symptoms.

Methods: 133 patients with treatment-resistant depression (major depressive disorder or bipolar I/II disorder) received a single subanesthetic infusion of ketamine (0.5mg/kg over 40 minutes). Post-hoc correlations and linear mixed models evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAMA) focusing on 230 minutes post-infusion.

Results: At 230 minutes post-infusion, correlations between changes in suicidal ideation and depression ranged from 0.23 to 0.44 (p <. 05), accounting for up to 19% in the variance of ideation change. Correlations with anxiety ranged from 0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine infusion was associated with significant reductions in suicidal ideation compared to placebo, when controlling for the effects of ketamine on depression (F(1,587)= 10.31, p = .001) and anxiety (F(1,567)= 8.54, p = .004).

Conclusions: Improvements in suicidal ideation after ketamine infusion are related to, but not completely driven by, improvements in depression and anxiety. Investigation of the specific effects of ketamine on suicidal thoughts is warranted.”

Authors: Elizabeth D. Ballard, Dawn F. Ionescu, Jennifer L. Vande Voort, Mark J. Niciu, Erica M. Richards, David A. Luckenbaugh, Nancy E. Brutsché, Rezvan Ameli, Maura L. Furey & Carlos A. Zarate Jr

Summary

Ketamine, an N-methyl-D-aspartate receptor antagonist, reduces suicidal ideation and depression and anxiety, but the dynamic between these symptoms is not known.

1. Introduction

Suicidal ideation is a frequent and potentially life-threatening indication for psychiatric emergency services. Currently, few psychiatric medications have been shown to reduce suicidal ideation, and available antidepressants may take weeks-to-months to achieve the desired effects.

Novel, rapid-acting antidepressants have great potential in the emergent treatment of suicidal patients. Ketamine is a glutamatergic, N-methyl-D-aspartate (NMDA) receptor antagonist that has antidepressant efficacy within hours-to-days with concomitant reductions in suicidal ideation.

Ketamine’s anti-suicidal properties may be explained by its impact on depression and anxiety symptoms. This is supported by studies that show ketamine reduces depression and anxiety symptoms, and a study that shows ketamine reduces suicidal thoughts in patients with treatment-resistant depression.

Many individuals think about, attempt and die by suicide outside the context of a depressive or anxious episode, and ketamine may decrease suicidal thoughts independently from depression and anxiety.

This analysis evaluated the relationship between suicidal ideation, depression and anxiety in a sample of depressed patients and found that ketamine reduced suicidal ideation independent of reductions in depression and anxiety symptoms.

2. Methods

Ketamine hydrochloride was administered intravenously over 40 min and patients were assessed on a variety of psychiatric measures.

2.1. Measures

The Scale for Suicide Ideation (SSI) is a 19-item clinician-administered measure of current suicidal thinking. The first two items, “Wish to Live” and “Wish to Die”, were found to predict later suicide.

2.2. Statistical analysis

To evaluate the relationship between changes in ideation, depression and anxiety, Pearson correlations were performed at 230 min post-infusion. Suicidal items were removed from the total score when assessing for depression.

A series of linear mixed models were conducted in a subset of patients with suicidal thoughts who participated in double-blind, placebo-controlled, crossover studies of ketamine. The effects of ketamine on suicide ideation and depression were evaluated, and the effect of ketamine on wish to live and wish to die were evaluated.

3. Results

Correlations between changes in suicidal ideation, anxiety and depressive symptoms were significant at 230 min post-ketamine infusion. The HAMD depression cluster was significantly associated with change in suicidal ideation, while HAMD anxiety was not.

3.1. Linear mixed models

In a placebo-controlled crossover study, ketamine reduced suicidal ideation in patients who had suicidal ideation at baseline. The intervention by time interaction did not reach significance, but the effect of ketamine on suicidal ideation was significant.

Ketamine infusion increased wish to live and decreased wish to die in participants with suicidal ideation. This effect persisted when controlling for depressive and anxiety symptoms across all time points.

4. Discussion

Ketamine reduced suicidal ideation in depressed patients, independent of depressive and anxiety symptoms, and increased wish to live and decreased wish to die, two cognitive aspects of suicidal ideation that have been shown to predict later death by suicide. Interest in ketamine as a rapid antidepressant has grown, and research has been conducted to better understand its clinical and mechanistic implications. Ketamine reduces suicidal thinking by enhancing neuroplasticity, which is believed to occur in response to NMDA receptor-mediated release of inhibition and concomitant “glutamate surge” from projection neurons.

These findings emphasize the importance of evaluating both anxiety and depression when assessing suicide risk, and the need for further investigation into the role of comorbid anxiety and depression in the development of suicidal thoughts.

This study examined the effects of ketamine on suicidal thoughts in patients with major depression. The effects of ketamine on suicidal thoughts were most robust at 40 min after ketamine infusion, the time point associated with greatest psychotomimetic symptoms, dissociative side effects and hemodynamic changes.

Conflict of interest

Dr. Furey and Dr. Zarate are co-inventors on patent applications for the use of scopolamine and ketamine in major depression. The remaining authors have no conflicts of interest to disclose.