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.
Papers cited by this study that are also in Blossom
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.
Suicide rates have risen in the United States over recent decades and suicide is now a leading cause of death in younger age groups, creating an urgent need for rapid-acting interventions to reduce suicidal thinking and behaviour. Ketamine, administered intravenously (racemic) or intranasally as esketamine, produces rapid reductions in suicidal ideation within hours that can last days to a week, and its clinical effects have commonly been attributed to antagonism of the N-methyl-D-aspartate receptor (NMDAR). However, emerging evidence implicates the endogenous opioid system in mood regulation and suicidality, and recent work by the study team found that ketamine’s antidepressant effect in humans depends on opioid receptor activation. Against this background, Williams and colleagues tested whether opioid receptor blockade with oral naltrexone attenuates ketamine’s antisuicidality effects. The investigation reported here is a post hoc secondary analysis of a previously completed randomised, double-blind, placebo-controlled crossover trial in which participants received oral naltrexone (50 mg) or placebo prior to a standard 0.5 mg/kg intravenous ketamine infusion. Suicidality was assessed with HDRS-17 item 3, MADRS item 10, and the Columbia Suicide Severity Rating Scale (CSSRS), and the primary contrast for this analysis focused on ketamine responders (defined as >50% reduction in HDRS-17 on postinfusion day 1).
Participants were adults meeting DSM-5 criteria for a nonpsychotic, non-atypical major depressive episode within either major depressive disorder or bipolar II disorder. Inclusion required HDRS-17 total score ≥20 at enrolment, insufficient benefit from at least four prior antidepressant or somatic treatments as defined by the Antidepressant History Treatment Form, and at least six weeks of prior psychotherapy during the current MDE. Sixteen participants provided consent; 14 received at least one ketamine infusion and 12 completed both crossover conditions. Of the 12 completers, all were diagnosed with recurrent MDD; nine had a score ≥1 on HDRS item 3 and 11 had a score ≥1 on MADRS item 10 at screening, indicative of current suicidal ideation in most participants. A randomised, double-blind crossover design was used with two conditions: ketamine plus oral placebo (K + P) and ketamine plus oral naltrexone 50 mg (K + N). Placebo or naltrexone was given 45 minutes before a 0.5 mg/kg intravenous ketamine infusion to achieve peak naltrexone levels. The order of conditions was randomised and both participants and investigators were blinded. Suicidality and depressive outcomes were assessed at baseline (day 0) and on postinfusion days 1, 3, 5, 7, and 14 using HDRS-17, MADRS, and CSSRS. The trial was planned with an a priori power calculation that estimated 30 participants would be required to detect differences in the primary antidepressant outcome (>50% HDRS-17 reduction on day 1) with a moderate effect size and alpha 0.05, but the study was terminated early after 14 participants completed at least one treatment because naltrexone markedly reduced ketamine’s antidepressant effect. For this secondary analysis the primary suicidality measure was HDRS-17 item 3, with MADRS item 10 and total CSSRS score as additional measures. The principal analysis included all participants who completed both treatments (n = 12). A linear mixed model with compound symmetry covariance structure compared mean suicidality changes over time, treatment condition, and ketamine responder status (responder defined as >50% HDRS-17 reduction on day 1). Time, treatment, responder status, and the time × treatment × responder interaction were fixed factors, with time and treatment treated as repeated within-subject measures. Bonferroni correction was applied for multiple comparisons. Associations between changes in suicidality and changes in total depression scores were tested with Pearson correlations. Missing data for the primary outcome were absent; missing secondary outcome data were not imputed.
Fourteen participants received at least one infusion and 12 completed both crossover conditions (K + P and K + N). Among completers, seven met the prespecified ketamine responder criterion (≥50% HDRS-17 reduction on postinfusion day 1) following K + P. The primary outcome comparison (HDRS item 3) in ketamine responders showed that naltrexone pretreatment profoundly attenuated ketamine’s antisuicidality effect: HDRS item 3 reductions after K + P were significantly greater than after K + N at day 1 (Bonferroni, p < 0.001) and remained significantly different at days 3 (p = 0.014), 5 (p = 0.019), 7 (p < 0.001), and 14 (p = 0.003). Concordant results were observed for MADRS item 10, with significant separation between K + P and K + N across all postinfusion days (day 1 p < 0.001; day 3 p = 0.002; day 5 p = 0.002; day 7 p < 0.001; day 14 p < 0.001). The CSSRS total score showed significant differences favouring K + P at days 3 (p = 0.002), 7 (p = 0.006), and 14 (p = 0.004). When analysing the full set of completers (n = 12) with the linear mixed model, HDRS-17 item 3 showed significant effects of treatment condition (F1,107 = 7.399, p = 0.008), day (F5,107 = 9.014, p < 0.001), and the day × treatment × responder interaction (F16,107 = 3.165, p < 0.001), while responder status alone was not significant. For MADRS item 10 there were significant effects of treatment condition (F1,106 = 8.825, p = 0.004), day (F5,106 = 7.968, p < 0.001), responder status (F1,10 = 6.140, p = 0.032), and the three-way interaction (F16,106 = 4.412, p < 0.001). CSSRS analyses showed a significant main effect of treatment condition (F1,104 = 12.627, p = 0.001) but no significant effects of day, responder status, or their interaction. Paired tests found no significant carryover effects when comparing baseline HDRS item 3 prior to each treatment order. After Bonferroni correction, changes in suicidality and changes in total depression scores were significantly correlated on day 1 but not on days 3, 5, 7, or 14. The extracted text reports no missing primary outcome data; secondary outcome missingness was not imputed.
Williams and colleagues interpret the data as evidence that opioid receptor activation is necessary for ketamine’s acute antisuicidality effects in patients with severe depression who respond to ketamine. Pretreatment with naltrexone markedly reduced ketamine’s capacity to lower suicidal ideation on clinician-rated measures (HDRS item 3, MADRS item 10) and on the CSSRS, supporting the conclusion that opioid signalling contributes substantially to the observed antisuicidality response. The authors place these findings in the context of unresolved questions about ketamine’s mechanism of action: although NMDAR antagonism has long been considered central, the limited success of other NMDAR antagonists in treatment-resistant depression suggests additional pharmacology may be required. Opioid receptors are a plausible contributor given prior clinical and preclinical evidence, the antidepressant and antisuicidality effects of buprenorphine in other studies, and the investigators’ earlier report that ketamine’s antidepressant effect is opioid dependent. The discussion acknowledges that ketamine’s antisuicidality effect may be mediated partly through alleviation of depressive symptoms and partly via independent processes. In this dataset, changes in suicidality correlated with changes in total depression scores only at day 1, not at later time points, consistent with prior reports suggesting partial independence between mood and suicidality effects. Nevertheless, the study was underpowered to definitively dissociate those mechanisms. Key limitations noted by the authors include the small sample size driven by early termination after observing a large effect of naltrexone on the antidepressant response, and the fact that participants were not specifically recruited for active suicidality. Mechanistically, the design cannot distinguish whether naltrexone blocked a direct interaction of ketamine with opioid receptors or blocked ketamine-induced release of endogenous opioids, nor can it parse the relative roles of mu (MOR), delta (DOR), or kappa (KOR) opioid receptors. The absence of a naltrexone-plus-placebo arm to assess whether naltrexone on its own worsens mood is discussed; the authors argue that prior controlled trials do not support a consistent dysphoric effect of naltrexone and note data that chronic naltrexone may even protect against suicide. Finally, Williams and colleagues call for independent replication in prospective blinded trials and further mechanistic work to define which opioid receptor systems contribute to ketamine’s effects, emphasising the clinical importance given the overlapping public health crises of suicide and opioid overdose and the growing clinical use of ketamine for suicidal ideation.
In this two-condition crossover study, an a priori power analysis estimated that 30 participants would be required to detect significant differences between treatment conditions in the primary outcome, i.e., >50% reduction in HDRS-17 on postinfusion day 1. The power calculation was based on a moderate effect size and alpha of 0.05 (twotailed). However, as detailed in our prior report, the study was terminated early after 14 participants completed at least one treatment due to lack of antidepressant efficacy in those receiving combined naltrexone and ketamine. In this report we tested our secondary hypothesis, that naltrexone would attenuate the antisuicidality response to ketamine. Within this secondary analysis, our outcome was set to be similar to the primary analysis. Whereas the primary analysis tested for a significant difference in mean HDRS-17 on postinfusion day 1 between naltrexone and placebo treatments in ketamine responders, here we used item 3 of the HDRS-17 as our primary suicidality measure. Additional measures included item 10 on the MADRS and the total score on CSSRS. This report also focuses on elucidating the mechanism of ketamine; hence, the primary outcome was restricted to those who had responded to ketamine treatment, i.e., >50% reduction in HDRS-17 on postinfusion day 1. All statistics were performed using SPSS Statistics (. A linear mixed model with compound symmetry covariance structure was used to compare mean changes in suicidality across time (preinfusion day 0 and postinfusion days 1, 3, 5, 7, and 14), treatment condition (naltrexone vs. placebo), and ketamine responder status. All available data from all subjects who completed both treatments (naltrexone and placebo, n = 12) were included in the model. There were no missing data for the primary outcome of this secondary analysis. Missing data for the secondary outcomes of this analysis were not imputed. Time, treatment condition, responder status, and the time × treatment × responder interaction were set as fixed factors with time and treatment set as repeated, within-subjects measures. Bonferroni corrections were used for all multiple comparisons. Although the statistical model included data from all time points and all participants regardless of responder status, the a priori comparison of interest for this secondary analysis was set as the difference in item 3 of the HDRS-17 between naltrexone and placebo treatments on post-ketamineinfusion day 1 in ketamine responders. Carryover and order effects were assessed by comparing the baseline HDRS item 3 prior to naltrexone to baseline prior to placebo; this comparison was split by participants pretreated with placebo first and those pretreated with naltrexone first. The Pearson correlation coefficient was used to test for associations between changes in suicidality and changes in depression symptoms. Changes in suicide items (HDRS item 3 or MADRS item 10) were compared with changes in the total scores of the HDRS (17-item) or MADRS, respectively, from day 0 to days 1, 3, 5, 7, and 14 for both naltrexone and placebo pretreatment conditions.
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Wilkinson, S. T., Ballard, E. D., Bloch, M. H. et al. · American Journal of Psychiatry (2017)
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Grunebaum, M. F., Ellis, S. P., Keilp, J. G. et al. · Bipolar Disorders (2017)
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
Yoon, G., Petrakis, I. L., Krystal, J. H. · JAMA Psychiatry (2019)
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Here we have shown that naltrexone blocks the antisuicidality effects of ketamine in responders with severe depression and varying degrees of suicidality, indicating that the antisuicidality effect of ketamine may depend on opioid receptor signaling. The antidepressant and antisuicidality mechanisms of ketamine have remained elusive. Despite preclinical evidence that ketamine's NMDAR antagonist property is primarily responsible for its antidepressant mechanism, clinical trials with other NMDAR antagonists for treatment-resistant depression have had limited success. This discrepancy suggests that other pharmacological actions of ketamine may be required for its therapeutic effect, a reasonable possibility given the multiple receptor targets of ketamine in the central nervous system. Among these targets, opioid receptors are of particular interest given their well-established role in regulating mood, the success of buprenorphine, an opioid system modulator, in treating suicidality, and our recent finding that ketamine's antidepressant effect is opioid-receptor dependent. We now present evidence that opioid receptors are necessary for ketamine's acute antisuicidality effect. In ketamine-responsive patients with suicidal ideation, pretreatment with naltrexone (K + N) profoundly attenuated ketamine's antisuicidality effect. We observed concordant effects on related measures of suicidal ideation, including item 10 of the clinician-administered MADRS and CSSRS, which strengthens our conclusion that ketamine's antisuicidality effects are opioid receptor dependent. The antisuicidality mechanism may be mediated directly through its effects on depression and/or through an independent mechanism. Ketamine has been established as a rapid-onset antisuicidality medication, with a time course and efficacy similar to its antidepressant effect. Although the time courses of ketamine's antidepressant and antisuicidality effects are similar, past reports have found partial independence of these effects, with ketamine's antisuicidality effect not always being due to a reduction in depressive symptoms. In our current study we found that although the changes in suicidality and changes in total depression scale scores were significantly associated on day 1, changes in suicidality and depression scores were not significantly associated on days 3, 5, 7, or 14. Thus, similar to past reports, our current data supports the hypothesis that the pharmacological mechanism through which ketamine reduces suicidality is partially independent from the mechanism through which it reduces depressive symptoms. Our current study is underpowered to determine if the antisuicidality effect of ketamine is significantly distinct from its antidepressant effect; yet, we have found in our current and recentinvestigations that the opioid system plays a major role in both of these conditions. Suicide and opioid dependence are currently two of the most significant public health problems facing the United States and have become leading causes of disability and death worldwide. Our results herein build on substantial clinical and pathological evidence that the endogenous opioid system plays an important role in the pathophysiology of suicide. The current opioid crisis is inextricably linked with the suicide crisis, and psychological pain, suicidal ideation, and opioid use have repeatedly been found to be associated. Further, approaches that selectively release endogenous opioids from the prefrontal cortex, such as transcranial magnetic stimulation of the dorsolateral prefrontal cortex, have also demonstrated efficacy in reducing suicidality. Finally, patients with opioid use disorder who have their underlying depression treated show greater discontinuation of opioids. However, not all opioid agonists are associated with a reduction in suicidality. Although atypical opioids like the partial mu agonist/kappa antagonist, buprenorphine, have a history of use as acute antisuicidality agentsand appear to carry similar risks as nonopioid strategies, chronic opioid exposure with some full mu agonist agents has been associated with suicidal ideation, suicide attempts, and completed suicides. In addition, chronic opioid exposure with these full mu agonists has been associated with increased risk of depression onset, relapse, and reduced responsiveness to classic antidepressants. It is tempting to speculate that partial or brief opioid system activation is associated with an antisuicidality effect; whereas full and chronic opioid system activation is associated with an increase in suicidality, but this hypothesis requires further study to determine the likely complex role of the opioid system in suicidality. Our study has several weaknesses. The sample size is small, limited by early termination due to the large effect size of naltrexone on blocking the effect of ketamine. In addition, our hypothesis has been recently challenged by a small observational studyand an uncontrolled case series study, however interpreting these results is severely limited by their respective uncontrolled study designs. Thus, replication by independent groups using prospective blinded trials is paramount. Another weakness is that we did not specifically recruit suicidal patients. A mechanistic limitation is that our study does not differentiate between a direct interaction of ketamine with opioid receptors versus ketamine-induced release of endogenous opioids, nor does it distinguish between the respective roles of MOR, DOR, or KOR in mediating ketamine's antisuicidality effects. All opioid receptor types may be involved in ketamine-induced affective changes. There is evidence that MOR polymorphisms modify social attachment behaviorand resilience after social defeat, and KOR has a demonstrated role in mood regulation. Buprenorphine, which modulates MOR, DOR, and KOR, can reverse stress-induced social deficits and has antidepressant-like properties in rodents. Further mechanistic studies in humans and preclinical models will be necessary to replicate and define the contribution of these opioid receptor systems to affective disorders. A potential confound of our study design is that 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. Previous clinical trials strongly argue against this interpretation. Placebocontrolled clinical trials testing naltrexone in healthy, opioid-free volunteers found no consistent dysphoric effect. Furthermore, in patients with a history of opioid use, naltrexone maintenance therapy was not associated with a higher rate of depression. To the contrary, naltrexone when chronically administered may be protective for suicide. We also considered the possibility that ketamine's opioid receptor-dependent effects on mood and suicidal ideation reflect a more general involvement of the endogenous opioid system in mediating a positive response to treatment, including placebo. If this were the case, we would expect to find that naltrexone blocks antidepressant effects on mood; to the contrary, naltrexone therapy in patients with bipolar disorder had no effect on depression ratings, and even enhanced antidepressant effects of sertraline in alcohol-dependent patients. In conclusion, we demonstrate here that naltrexone blocks the antisuicidality effects of ketamine in responders with severe depression and suicidality. This indicates that the antisuicidality effects of ketamine depend, at least in part, on opioid system activation. Moreover, this finding adds to a growing evidence base on the role of the endogenous opioid system in suicidality. Given the increasing number of people dying from both suicide and opioid overdose, as well as the currently expanding implementation of ketamine as an antisuicidality agent, the complex role of opioids and suicidality, especially as it relates to the mechanism of ketamine in reducing suicidality, deserves careful consideration and additional studies.