Characterizing the course of suicidal ideation response to ketamine

Abstract

Background: No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine.

Methods: Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers.

Results: The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders.

Limitations: Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used.

Conclusion: The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Depression; Growth mixture modeling; Ketamine; Suicidal ideation; Suicide.

Conflict of interest statement

Declaration of interest

Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government.

All other authors have no conflict of interest to disclose, financial or otherwise.

Published by Elsevier B.V.

Figures

Fig. 1.

Suicidal Ideation (SI) composite scores (Panel A) by SI latent class (Panel B).

Fig. 2.

Suicidal Ideation (SI) latent class assignment by traditional responder groupings at post-ketamine Day 1 (Panel A) and Day 3 (Panel B).

Fig. 3.

Independence of change in Suicidal Ideation (SI) from change in Depressed Mood. Panel A illustrates Depressed Mood composite scores by SI latent class. Panel B illustrates the change from baseline post-ketamine (Cohen’s d with 95% CI) in each class, with or without change in Depressed Mood entered as a covariate.