This double-blind placebo-controlled clinical trial (n=12) examined the effects of naltrexone and ketamine on suicidal ideation (SI) and found that naltrexone attenuates (blocks) the effects of ketamine. It’s proposed, just as with the antidepressant effect of ketamine, that it requires opioid receptor activation.

Abstract

“We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine’s antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery–Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.”

Authors: Nolan R. Williams, Boris D. Heifets, Brandon S. Bentzley, Christine Blasey, Keith D. Sudheimer, Jessica Hawkins, David M. Lyons & Alan F. Schatzberg

Summary

Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism

We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, and here we test whether naltrexone attenuates antisuicidality effects of ketamine. The results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

Introduction

Suicide rates have been steadily increasing in the United States over the past two decades, and the number of psychiatric beds has been decreasing. A durable, rapid-acting intervention to treat suicidal thinking and behavior remains unavailable.

Ketamine, given intravenously or intranasally, is a potential rapid-acting intervention for the treatment of suicidal ideation. Its antidepressant effects are opioid receptor dependent and may be due to pharmacological antagonism of the N-methyl-D-aspartate receptor (NMDAR).

We performed a post hoc secondary analysis of our recently completed placebo-controlled, randomized, double-blinded crossover clinical trial to determine the role of opioid receptors in the anti-suicidality effects of ketamine.

Participants

Potential study participants were required to have a score of 20 on the HDRS-17 and to have tried at least four different antidepressant medications or other somatic treatments without success.

Sixteen participants were eligible for the study, of which 12 completed both conditions. All had recurrent MDD, 6 were women, 5 were unemployed, and 2 continued to receive disability.

Design

A randomized, double-blinded crossover design was used with 2 treatment conditions: oral placebo preceding a 0.5 mg/kg intravenous infusion of ketamine and oral naltrexone preceding a 0.5 mg/kg intravenous infusion of ketamine.

Data analyses

In this two-condition crossover study, 30 participants were required to detect significant differences between treatment conditions in the primary outcome. However, the study was terminated early after 14 participants completed at least one treatment.

In this report we tested the secondary hypothesis that naltrexone would attenuate the antisuicidality response to ketamine. The primary outcome was restricted to those who had responded to ketamine treatment.

All statistical analyses were performed using SPSS Statistics (Version 22). A linear mixed model with compound symmetry covariance structure was used to compare mean changes in suicidality across time, treatment condition, and ketamine responder status.

Participants were compared with those pretreated with placebo first and those pretreated with naltrexone first on suicide items and depression symptoms.

Results

Fourteen participants received at least one ketamine infusion; seven responded to ketamine plus placebo (K + P) with a 50% reduction in total HDRS-17 scores. The reduction in suicidality was significant on day 1, 3, 5, 7, and 14 compared with the K + N condition.

The HDRS-17 and MADRS-17 had significant effects of treatment condition, day, responder status, and day treatment responder interaction, but not of responder status. The CSSRS had a significant effect of treatment condition, day, and responder status.

There were no significant carryover effects between groups with paired t-test testing, and nonparametric Wilcoxon signed-rank testing.

The associations between suicidality and depression were significant on day 1, but not on days 3, 5, 7, or 14.

Discussion

Here we show that naltrexone blocks the anti-suicidality effects of ketamine in responders with severe depression and varying degrees of suicidality, indicating that the anti-suicidality effect of ketamine may depend on opioid receptor signaling.

Ketamine’s antisuicidality effect may be mediated directly through its effects on depression and/or through an independent mechanism. Although the time courses of ketamine’s antidepressant and antisuicidality effects are similar, past reports have found partial independence of these effects.

Suicide and opioid dependence are significant public health problems in the United States, and treatments that release endogenous opioids from the prefrontal cortex have been shown to be effective in reducing suicidality.

Although some opioid agonists are associated with a reduction in suicidality, chronic opioid exposure with some full mu agonist agents has been associated with increased risk of depression onset, relapse, and reduced responsiveness to classic anti-depressants.

Our study has several weaknesses, including a small sample size, early termination due to the large effect size of naltrexone on blocking the effect of ketamine, and no specifically recruited suicidal patients. Further mechanistic studies are necessary to replicate and define the contribution of these opioid receptor systems to affective disorders.

We did not include a naltrexone plus placebo group to control for the possibility that naltrexone worsens affective ratings on its own, attenuating the effect of ketamine. Furthermore, naltrexone is not associated with a higher rate of depression in patients with a history of opioid use.

The antisuicidality effects of ketamine depend, at least in part, on opioid system activation. This finding adds to the growing evidence base on the role of the endogenous opioid system in suicidality.