Prospective association of psychological pain and hopelessness with suicidal thoughts

This study (n=108) used the data from three clinical trials where ketamine was used to treat treatment-resistant depression (TRD) or bipolar disorder (BD) to assess the interaction between hopelessness and psychological pain was associated with future suicidal ideation (SI). Psychological pain and hopelessness were not associated with SI in short-term or long-term analyses yet long-term analyses found that SI was associated with later psychological pain and hopelessness.

Abstract

Background: Early markers preceding suicide ideation (SI) may provide valuable information for both assessment and treatment. The glutamatergic modulator ketamine has rapid, transient effects on SI, creating an opportunity to observe potential antecedents of the re-emergence of SI. This analysis evaluated whether the interaction between two suicide risk factors-psychological pain and hopelessness-were prospectively associated with SI post-ketamine administration.

Methods: Data were drawn from three ketamine clinical trials of participants with treatment-resistant major depressive disorder or bipolar disorder (n = 108) with short- and/or long-term follow-up (three or 11 days). A random intercept cross-lagged panel model evaluated the longitudinal relationship between the correlated concepts, specifically whether the interaction between hopelessness and psychological pain was associated with future SI.

Results: Psychological pain and hopelessness were not prospectively associated with SI in short-term or long-term analyses; rather, long-term analyses found that SI was associated with later psychological pain and hopelessness. Similarly, no relationship was observed for other suicide risk factors, including anhedonia, depressed mood, and impaired sleep.

Limitations: Secondary analysis of clinical trial data not collected for this purpose; hopelessness and psychological pain were assessed via proxy measures from existing depression rating scales; the small sample size required a restricted statistical model.

Conclusions: Psychological pain and hopelessness were not associated with the re-emergence of SI post-ketamine. These results may be due to limited variability in the data. The re-emergence of SI post-ketamine may also not follow patterns typically seen in non-pharmacologic contexts. Individuals with a history of SI warrant careful monitoring post-ketamine administration.”

Authors: Elizabeth D. Ballard, Cristan A. Farmer, Jessica Gerner, Bartholt Bloomfield-Clagett, Lawrence T. Park & Carlos A. Zarate

Summary

Ketamine, a glutamatergic modulator, has rapid, transient effects on suicide ideation, and may provide valuable information for both assessment and treatment.

  1. Introduction

Although research on suicide risk factors has been of limited benefit in lowering overall suicide rates, new psychological theories of suicide have focused on an “ideation-to-action” framework, which can be used to develop targeted treatments for the suicidal crisis.

Researchers have a limited ability to determine which individuals will experience suicide symptoms across a short period of time. However, clinical trials of the glutamatergic modulator ketamine provide a unique opportunity to evaluate the antecedents of suicide symptoms.

Psychological pain and hopelessness are key psychological constructs associated with suicide risk that could be associated with short-term changes in suicidal thoughts. These constructs have also been evaluated using neuroimaging paradigms.

This project sought to determine the antecedents associated with suicide re-emergence after ketamine administration. It also sought to determine whether these effects were unique to these constructs.

2.1. Participants and study design

Data were drawn from four inpatient, randomized, controlled trials conducted at the National Institutes of Health Clinical Center in Bethesda, Maryland between 2006 and 2018. The trials included the bipolar disorder (BP) trial, the major depressive disorder (MDD) trial, the mechanism of action (MOA) trial, and the riluzole (RIL) trial.

All four studies followed very similar methodology, and participants were drug-free for the entirety of their respective study except for participants in the BP study who received therapeutic lithium or valproate.

Participants with MDD or bipolar disorder received a ketamine infusion and completed the Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, and Beck Depression Inventory. The Negative Cognitions score was computed using the three rating scales.

2.2. Measures

The MADRS suicidal thoughts item, the BDI discouragement about future item, and the Negative Cognitions score were used to operationalize SI, hopelessness, and psychological pain. Three other empirically derived scores were used in the secondary analyses.

2.3. Design

Participants responded to questionnaires at 40, 80, 120, and 230 min post-ketamine infusion, as well as at Days 1, 2, 3, 7, and 11 post-infusion. Two sets of analyses were performed: short-term and long-term.

2.4. Analytic plan

A random intercept CLPM (RI-CLPM) was used to analyze within-subject longitudinal relationships among correlated constructs. The RI-CLPM assumes that individuals vary around their own mean and that a positive autoregressive parameter indicates that individuals would expect to score higher than their personal overall mean.

A multiple-group analysis was initially planned, but did not reliably converge due to the small sample size. A primary analysis was performed for the full sample and sensitivity analyses were performed separately within each study.

The RI-CLPM was simplified by constraining the lagged and autoregressive parameters to equality over time, but the effect on model fit could not be determined.

Some data were missing, and these were assumed to be missing at random. Structural equation modeling was performed in Mplus Version 8.4 and processed in R version 4.0.2.

  1. Results

The intraclass correlation coefficient (ICC) for SI was 0.71 for the short-term data and 0.62 for the long-term data.

3.3. Secondary outcomes

All three models were good for predicting secondary outcomes, but cross-lagged parameters did not differ from zero.

  1. Discussion

In this secondary analysis of ketamine clinical trial data, hopelessness and psychological pain were not associated with the re-emergence of SI.

This study of ketamine trial data suggests that psychological theory regarding the development of suicidal thoughts may not be applicable to the re-emergence of suicidal thoughts post-ketamine administration, particularly because ketamine may have independent effects on SI and depressive symptoms.

The experience of re-emerging SI after a few days without it may be upsetting, leading to psychological pain and pessimism about the future. Ketamine may be associated with dramatic, but transient, relief from SI and depressive symptoms.

While repeated assessment of symptoms during the day using smartphone devices can be used to predict short-term changes in symptoms, these analyses have shown limited ability to predict short-term changes in symptoms regardless of setting.

This analysis was limited by the fact that it was a secondary analysis of clinical trial data not collected for this purpose, by the fact that all assessments were proxy measures obtained from existing depression rating scales, and by the fact that no a priori sample size was calculated.

In conclusion, this analysis suggests that hopelessness and psychological pain were not prospectively associated with the re-emergence of next-day SI post-ketamine.

Role of funding source

This work was supported by the National Institute of Mental Health. The NIMH had no role in study design, data collection, analysis, or interpretation.

CRediT authorship contribution statement

CAF, JG, BB-C, LP, and CAZ helped conceptualize the study, conducted the statistical analysis, interpreted the statistical analysis, helped draft the manuscript, and edited the manuscript for critical intellectual content.

Conflict of interest

Dr. Zarate is listed as a co-inventor on several patents for the use of ketamine in the treatment of depression, suicidal ideation, and neuropathic pain. All other authors have no conflict of interest to disclose.

Study details

Compounds studied
Ketamine

Topics studied
Safety Suicidality Depression Bipolar Disorder

Study characteristics
Meta-Analysis Longitudinal

Participants
108 Humans