This study (n=60) of randomised, 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.
Papers cited by this study that are also in Blossom
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
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.
Rapid-acting antidepressants such as the NMDA receptor antagonist ketamine can reduce depressive symptoms within hours, and emerging work has suggested they may also reduce suicidal thoughts rapidly. However, most suicide assessment instruments were developed for longer treatment timelines, and there are unresolved methodological questions about measuring suicidal ideation in studies of fast-acting interventions. Key concerns include whether single items drawn from depression scales suffice instead of longer suicide-specific instruments, whether commonly used measures are sensitive to change over hours to days, and whether repeated questioning over a short interval affects validity. Ballard and colleagues used data from two double-blind, randomized, placebo-controlled, crossover ketamine trials to address these issues empirically. By administering several clinician-rated and self-report suicide measures repeatedly over minutes to days after infusion, the study aimed to compare convergent validity across instruments and evaluate their sensitivity to rapid change, with the goal of informing measurement choices in trials of rapid-acting anti-suicidal treatments.
Data were pooled from two inpatient, randomized, crossover, placebo-controlled trials of ketamine for treatment-resistant depression (both unipolar major depressive disorder and bipolar I/II depression) conducted at the NIMH. Sixty participants were included (reported in Results). Diagnosis was confirmed with the SCID-I/P. Eligible participants were aged 18–65, in a current major depressive episode without psychotic features, with minimum severity thresholds (HAM-D 17-item score >= 18, or MADRS >= 20 or 22 at screening and pre-infusion). Patients were medication-free for at least two weeks prior (five weeks for fluoxetine), except bipolar participants who remained on therapeutic lithium or valproate. One of the trials excluded acutely suicidal patients at consent defined as MADRS item 10 > 4 or by clinical judgment; participants whose suicidality increased during taper or trial were not systematically excluded. Ketamine hydrochloride 0.5 mg/kg was administered intravenously over 40 minutes and saline was used as placebo. Four instruments assessed suicidal ideation: the clinician-rated HAM-D 17-item (single suicide item scored 0–4), clinician-rated MADRS (single suicide item scored 0–6), the self-reported Beck Depression Inventory (BDI) suicide item (0–3), and the clinician-administered Scale for Suicide Ideation (SSI). For the SSI the researchers analysed both the first five items (SSI5) and the full 19-item total score (SSITotal). Baseline assessment occurred 60 minutes pre-infusion (covering the last 24 hours). Post-infusion assessments were at 40, 80, 120, and 230 minutes, and Days 1, 2, and 3, with reporting windows covering symptoms since the last assessment. Analyses focused on both static convergent validity at 230 minutes and Day 3 and sensitivity to change from baseline to those time points. Cut-offs for 'any suicidal ideation' were predefined: HAM-D >= 1, BDI >= 1, MADRS >= 2, or SSI5/SSITotal >= 2. Pearson correlations assessed agreement at single time points and for change scores. Linear mixed models evaluated trajectories across seven post-infusion time points, including fixed effects for time, intervention, their interaction, and a fixed intercept; models were restricted to participants endorsing any ideation at baseline on the specific measure and controlled for baseline ideation. A compound symmetry covariance structure and restricted maximum likelihood estimation were used. Cohen's d was calculated for differences between ketamine and placebo at 230 minutes and Day 3. As a post-hoc analysis, the earliest time point showing a significant drug–placebo difference was determined. IBM SPSS v21 was used and significance was set at p < .05, two-tailed.
Sixty participants were analysed: 23 with MDD and 37 with BD. The sample was 62% female (n = 37) with a mean age of 41.6 years (SD 11.3). Lifetime suicide attempts were reported by 48% (n = 28) and 18% (n = 11) reported more than one attempt. Mean illness duration was 25.3 years. At the 230-minute and Day 3 time points, correlations between the suicide assessments were generally high. All pairwise correlations exceeded r = .60, and correlations among the HAM-D suicide item, MADRS suicide item, and SSI5 were particularly strong (r > .80). The BDI item and the SSITotal showed lower correlations overall. Correlations of change from baseline to 230 minutes and Day 3 were all above r = .40, with the strongest change correlation observed between SSI5 and the BDI; correlations between the BDI and other single-item clinician measures were lower. Linear mixed models examining trajectories across the seven post-infusion time points showed significant drug effects of ketamine on suicidal thoughts for all measures except SSITotal (p < .01 for the significant measures). Effect sizes across 230 minutes and Day 3 were largest for the MADRS suicide item, the BDI suicide item, and SSI5, indicating these measures were more sensitive to change. In a post-hoc analysis the first time point at which ketamine differed from placebo was 40 minutes for all assessments (p < .05). Given concerns about ketamine's psychotomimetic effects at 40 minutes, the 80-minute time point was also examined; at 80 minutes all assessments except SSITotal showed a significant ketamine–placebo difference. The SSITotal results diverged from other measures; one participant with an SSITotal score > 20 was identified as an extreme outlier. Excluding that participant did not render the SSITotal model significant (drug effect F(1,314) = 2.02, p = .14; interaction F(6,285) = 1.15, p = .33).
Ballard and colleagues interpret their findings to indicate that single-item suicide ratings embedded within depression scales can converge closely with a brief clinician-rated suicide measure, and that some short measures detect rapid reductions in suicidal thoughts after ketamine. In particular, the HAM-D and MADRS suicide items correlated strongly with the first five SSI items, and the MADRS item, the BDI suicide item, and the SSI5 showed moderate sensitivity to rapid change as reflected by effect sizes. The longer SSI total score was less sensitive to short-term change and showed reduced agreement with other measures, a discrepancy the authors attribute to administration variability: the SSI proceeds from five to 19 items only when initial responses are positive, potentially introducing heterogeneity and extra variance. Differences between self-report (BDI) and clinician-rated items were also noted as a possible source of measurement variance. The investigators highlight that trajectories of suicidal ideation over three days differed significantly between ketamine and placebo for most scales, and that no evidence emerged for an iatrogenic increase in suicidal thoughts due to repeated assessment. Several limitations are acknowledged. The sample consisted of treatment-resistant depressed inpatients not selected for acute suicide risk, limiting generalisability to actively suicidal populations. Assessment timeframes varied across the three days so the 230-minute and Day 3 assessments are not strictly comparable, and longer follow-up (for example seven days) was not consistently available in this dataset. All measures relied on patient-reported or clinician-rated items; no implicit measures or biological markers of suicide risk were collected. The authors note that suicidal thoughts are a proxy for suicide risk and that lack of validated biomarkers remains an obstacle. Based on these results, the authors suggest that brief measures such as the MADRS suicide item, the BDI suicide item, and the first five SSI items may be particularly useful for trials of rapid-acting interventions because they balance brevity with sensitivity to change. They recommend further studies that enrol participants for acute suicidality, incorporate additional suicide-specific instruments (for example the Suicide Status Form or Columbia Suicide Severity Rating Scale), and explore implicit or neurobiological measures alongside self-report and clinician-rated tools to better characterise rapid changes in suicide risk.
With the emergence of rapid-acting treatments for suicidal risk, assessment instruments that are quick to administer yet sensitive to change over hours to days are needed. The present analysis indicates that single items from depression scales correlate with longer suicide assessments, and that the MADRS suicide item, the BDI suicide item, and the first five items of the SSI may be particularly well suited to detecting rapid changes in suicidal ideation in clinical trials.
Comparison of single-and multi-item suicide assessments-This analysis focused on the 230-minute and Day 3 assessment time points in order to capture one brief and one more distal time point in relation to a range of time points after ketamine infusion. The 230-minute time point is often used in ketamine analyses because it assesses the shortterm effects of ketamine infusion after psychotomimetic effects have dissipated. The Day 3 assessment was used because it was further removed from the time of ketamine infusion. The presence or absence of baseline suicidal ideation was determined using the literature on appropriate cut-off scores. A score of 1 or more on the HAM-D suicide item, 1 or more on the BDI suicide item, 2 or more on the MADRS suicide item, or 2 or more on the SSITotal or SSI5 were considered to be "any suicidal ideation" (as compared to acute suicidal ideation, which commonly requires higher cutoff scores). Pearson correlations of scales at static points were conducted to assess convergent validity. Change in ideation across time-Pearson correlations of absolute change from baseline to 230 minutes and Day 3 after ketamine infusion were performed to assess sensitivity to change. Linear mixed models were used to evaluate changes in suicidal ideation across the seven time points after infusion. Included in the model were time and intervention status as fixed within-subjects factors, as well as a fixed intercept and the interaction between drug and time. Linear mixed models were limited to participants who reported any ideation at baseline on that specific measure (i.e. the HAM-D model included participants who scored 1 or more on the HAM-D suicide item at baseline) and also controlled for baseline suicidal ideation. A compound symmetry covariance structure and restricted maximum likelihood estimates were used. Cohen's d effect sizes of the difference in ideation scores at 230 minutes and Day 3 between ketamine and placebo were calculated. Due to the use of linear mixed models, all figures include estimated marginal means and standard errors of these mean estimates. As a post-hoc analysis, the first timepoint at which suicidal ideation response to ketamine was determined to be significantly different from placebo was evaluated. IBM SPSS version 21 was used for statistical analyses and significance was considered at p<.05, two-tailed.
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Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
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Araújo, D. B., Zeifman, R. J., Palhano-Fontes, F. et al. · Frontiers in Pharmacology (2019)
Vande Voort, J. L., Ballard, E. D., Luckenbaugh, D. A. et al. · Journal of Clinical Psychiatry (2017)
This study evaluated the repeated assessment of several measures of suicidal ideation across three days post-ketamine infusion. In a sample of treatment-resistant depressed patients with either MDD or BD who received ketamine, we found that the HAM-D and MADRS suicide items were strongly correlated with the SSI5. The SSI5, MADRS item, and BDI item demonstrated particular sensitivity to rapid change as demonstrated by moderate effect sizes. In contrast, the longer version of the SSI (SSITotal) was not as sensitive to rapid changes in suicidal thoughts. With regard to which type of assessment of suicidal ideation should be used, our findings suggest that single-item and multi-item measures appear to yield comparable assessments. Correlations demonstrated adequate agreement, particularly when comparing the HAM-D and MADRS suicide items and the SSI5 (r's > .80). It should be noted that, in contrast to the HAM-D, MADRS, and SSI, the BDI is a self-reported measure, which may have led to differences across the measures. In addition, when comparing correlations between the single items, the SSITotal, and the SSI5, the SSITotal demonstrated reduced agreement. It is possible that the differing administration of the SSI (some patients are administered five items and some 19, depending on their level of severity) may have introduced unwanted variability into the correlations, effect sizes, and linear mixed models. Nevertheless, results suggest that 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 posed by this analysis, we used repeated assessments capable of capturing changes in suicidal ideation over a short period of time. As demonstrated by the results from linear mixed models, the trajectory of suicide symptoms over the course of three days differed significantly from the trajectory on placebo for most scales. The MADRS, BDI, and SSI5 also detected a "small to moderate" effect for ketamine on suicidal ideation at 230 minutes and Day 3 post-infusion, as demonstrated by the Cohen's d between drug and placebo. Again, the linear mixed model using SSITotal as the outcome measure found no significant drug effect (p = .88), which may have been due to the increased variability introduced by using the extra items. In contrast, the SSI5 was sensitive to rapid changes in suicidal thoughts over a short period of time. The time point at which a difference between ketamine and placebo was detected was 40 minutes for all measures, although this difference was not found at 80 minutes for the SSITotal. The 40-minute time point is clinically significant because ketamine's dissociative effects may not have dissipated at this time point, which may limit the validity of patient response; this, in turn, led to our decision to focus on the 230-minute time point assessment for correlations and effect sizes. It is important to note that despite the repeated suicide assessment, we found no evidence of a iatrogenic increase in suicidal symptoms, which is consistent with other findings in the literature. In addition, overall suicidal ideation was reduced in the drug condition when compared to the placebo arm, suggesting that this improvement was not simply due to repeated assessments. The most significant limitation of this post-hoc analysis is that patients were selected as part of a clinical trial for treatment-resistant depression and not for acute suicide risk. Further studies of patients selected for suicidal thoughts, with and without depressive symptoms, are indicated. Such investigations may also benefit from additional suicide-specific measurements such as the Suicide Status Form (SSF)or the Columbia Suicide Severity Rating Scale (C-SSRS)in addition to those reported here. Moreover, the present study used several timeframes across the three days of assessment, which means that the assessment at the 230-minute time point is not directly comparable with the Day 3 time point. Similar analyses that lasted for seven days postketamine infusion also repeatedly assessed depressive symptoms, although this time frame was not consistently available with the current dataset. Lastly, it is important to highlight that all suicidal thoughts were reported by the patient. No implicit measuresor suicide biomarkers were tracked over the same time period in this sample. Indeed, the lack of validated suicide biomarkers is a significant obstacle to suicide research, and suicidal thoughts, while clinically significant, are only a proxy for suicide risk. As research expands into the phenomenology and neurobiology of treatment for suicide, further understanding of suicidal ideation measures and implicit/neurobiological measures will be needed.