Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant

This study (n=60) of randomized, placebo-controlled, crossover clinical trials appraises suicidal ideation (SI) with ketamine infusion in persons with treatment-resistant depression (TRD). The results indicated improvement in suicidal thoughts after ketamine infusion and the measures are sensitive to these changes.

Abstract

“Rapid reduction of suicidal thoughts is critical for treating suicidal patients. Clinical trials evaluating these treatments require appropriate measurement. Key methodological issues include: 1) the use of single or multi-item assessments, and 2) evaluating whether suicidal ideation measures can track rapid change over time. The current study presents data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment-resistant depression (n = 60). Participants were assessed for suicidal thoughts using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Scale for Suicidal Ideation (SSI) at eight time points over three days. Assessments were compared using correlational analyses and effect sizes at 230 min and three days after ketamine infusion. Linear mixed models evaluated change in ideation across all time points. The HAM-D and MADRS suicide items demonstrated correlations of r > .80 with the first five items of the SSI (SSI5). On linear mixed models, an effect for ketamine was found for the HAM-D, MADRS, BDI items, and SSI5 (p < .001), but not for the full SSI (p = .88), which suggests a limited ability to assess change over time in patients with low levels of suicidal thoughts. Taken together, the results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo. The MADRS suicide item, BDI suicide item, and SSI5 may be particularly sensitive to rapid changes in suicidal thoughts.“

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

Summary

Researchers present data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment-resistant depression. The results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo.

Introduction

Recent research has shown that rapid-acting antidepressants such as ketamine can reduce depressive symptoms within hours rather than weeks, and that such drugs can reduce suicidal thoughts within two hours of administration.

Rapid-acting antidepressants such as ketamine are evaluated for their potential efficacy in alleviating suicidal thoughts. However, repeated suicide assessment instruments are needed, and the psychometrics of these instruments should be evaluated in direct comparisons as well as tracking responses over time.

In ketamine clinical trials, suicidal thoughts were assessed using a number of different measures. These measures were administered repeatedly within minutes, hours, and days after ketamine infusion, and permit the comparison of correlations and correlated change between single items and longer versions of suicide assessments.

Data were drawn from two randomized, crossover, placebo-controlled trials evaluating the efficacy of ketamine in the treatment of depression. The studies were conducted at the NIMH and involved patients ages 18 – 65 years with a depressive episode without psychotic features.

Ketamine hydrochloride was administered intravenously over 40 minutes as part of two placebo-controlled trials. Participants were required to be medication-free for at least two weeks before ketamine infusion, and were not systematically excluded if their suicidal thoughts increased over the course of the medication taper or clinical trial.

Measurements

The HAM-D, MADRS, BDI, and SSI were used to assess depression severity and suicide risk. The MADRS includes one item assessing suicide risk. The Beck Depression Inventory (BDI) and the Suicide Severity Index (SSI) are two widely used measures of depression severity. The SSI includes one item assessing suicidal thoughts, and the BDI includes 14 items assessing characteristics of suicidal thoughts.

Timing of Measurements

Ketamine infusion was administered 60 minutes before symptoms were assessed. Symptoms were assessed 40, 80, 120, and 230 minutes after the infusion and on Days 1, 2, and 3.

This analysis focused on the 230-minute and Day 3 assessment time points to capture the short-term effects of ketamine infusion after psychotomimetic effects have dissipated. The presence or absence of baseline suicidal ideation was determined using the literature on appropriate cut-off scores.

Linear mixed models were used to evaluate changes in suicidal ideation across the seven time points after ketamine infusion. Cohen’s d effect sizes were calculated for the difference in ideation scores at 230 minutes and Day 3 between ketamine and placebo.

Sixty participants with MDD and 37 with BD were included in the analysis. Correlations between suicide assessments are presented in Table 2, and the HAM-D suicide item, MADRS suicide item, and SSI5 demonstrated higher correlations overall.

The MADRS item, the BDI item, and the SSI5 demonstrated the strongest drug effects on suicidal thoughts across 230 minutes and Day 3. The first time point of significant difference between ketamine and placebo was 40 minutes for all assessments.

Results from the SSITotal differed dramatically from results with the other items, so an outlier analysis was conducted. The results remained non-significant.

Discussion

This study evaluated several measures of suicidal ideation in treatment-resistant depressed patients with either MDD or BD who received ketamine. The SSI5, MADRS item, and BDI item demonstrated particular sensitivity to rapid change.

Our findings suggest that single-item and multi-item measures of suicidal ideation yield comparable assessments. The HAM-D and MADRS suicide items may have convergent validity with other clinician-administered measures in samples of depressed patients with relatively low levels of suicidal thoughts.

To address the second question, we used repeated assessments that captured changes in suicidal ideation over a short period of time. Ketamine had a small to moderate effect on suicidal ideation.

The SSITotal was not sensitive to rapid changes in suicidal thoughts over a short period of time, but the SSI5 was. The 40-minute time point was clinically significant because ketamine’s dissociative effects may not have dissipated at this time point.

This post-hoc analysis of patients who received ketamine for treatment-resistant depression and not for acute suicide risk suggests that the SSF and C-SSRS may be useful suicide-specific measures, but no implicit measures or suicide biomarkers were tracked over the same time period.

Conclusions

With the advent of rapid-acting interventions for suicide risk, instruments that can be quickly administered but are sensitive enough to detect rapid changes in suicidal thoughts are critical.