This review synthesises methodological lessons from ketamine studies to recommend how clinical trials can be adapted to evaluate rapid reductions in suicidal ideation, emphasising rapid outcome measurement and embedding psychological and neurobiological markers. The authors propose these approaches as a blueprint for testing rapid‑acting pharmacological or psychotherapeutic interventions for suicidal thoughts.
Rapid‐acting treatments for suicidal thoughts are critically needed. Consequently, there is a burgeoning literature exploring psychotherapeutic, pharmacologic, or device‐based brief interventions for suicidal thoughts characterized by a rapid onset of action. Not only do these innovative treatments have potentially important clinical benefits to patient populations, they also highlight a number of methodological considerations for suicide research. First, while most clinical trials related to suicide risk focus on suicide attempts, new clinical trials that use suicidal thoughts as the primary outcome require a number of slight modifications to their clinical trial design. Second, the rapid onset of these new interventions permits an experimental therapeutics approach to suicide research, in which psychological and neurobiological markers are embedded into clinical trials to better understand the underlying pathophysiology of suicidal thoughts. The following review discusses these methodological innovations in light of recent research using the N‐methyl‐D‐aspartate (NMDA) receptor antagonist ketamine, which has been associated with rapid effects on suicidal thoughts. We hope that “lessons learned” from the ketamine literature will provide a blueprint for all researchers evaluating rapid‐acting treatments for suicidal thoughts, whether pharmacologic or psychotherapeutic.
Ballard and colleagues frame a pressing clinical gap: suicide risk is common and current treatments that reduce suicidal behaviour typically take weeks to months to show effects, while clinicians often need interventions that act within hours or days. The authors note that psychotherapies and most pharmacologic or device-based treatments are limited by slow onset, and that there is only one FDA-approved medication specifically linked to reduced suicidal behaviour, with other interventions (lithium, ECT) taking substantial time to act. In response to this gap, the paper uses the literature on ketamine — an N-methyl-D-aspartate (NMDA) receptor antagonist and glutamatergic modulator with rapid antidepressant effects — as an illustrative model to examine how clinical trials should be designed when the primary outcome is rapid changes in suicidal ideation (SI). The review sets out to identify methodological considerations and recommend design features for “next‑generation” randomised clinical trials (RCTs) focused on rapid-acting interventions for SI. Using ketamine studies as a blueprint, the authors address participant selection, outcome measurement, and approaches for probing mechanisms of change, with the broader aim of encouraging standardised methods across disciplines for evaluating interventions that can alter suicide risk within hours to days.
Papers cited by this study that are also in Blossom
Ionescu, D. F., Vande Voort, J. L., Niciu, M. J. et al. · Journal of Psychiatric Research (2014)
Ballard, E. D., Luckenbaugh, D. A., Walls, T. S. et al. · Journal of Psychiatric Research (2015)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Grunebaum, M. F., Ellis, S. P., Keilp, J. G. et al. · Bipolar Disorders (2017)
The extracted text does not describe a formal systematic search strategy or explicit methods for study selection; instead, the paper operates as a narrative review that synthesises findings from published ketamine clinical trials, secondary analyses, and related experimental studies. The authors draw on randomized, double-blind, placebo-controlled ketamine trials (including trials in treatment‑resistant depression, bipolar depression, PTSD and OCD), industry-sponsored esketamine studies, and targeted experimental therapeutics investigations that embedded biomarkers and sleep assessments. Rather than reporting pooled quantitative methods typical of a meta-analysis, the review organises methodological discussion around key trial-design domains relevant to rapid-acting interventions for SI: participant inclusion criteria (severity and chronicity of SI), timing and selection of outcome measures suited to rapid change, and designs that integrate biomarker and mechanistic assessments (experimental therapeutics). Examples from specific ketamine RCTs (e.g. trials by Murrough, Canuso, Ionescu) are used to illustrate how differing inclusion thresholds and outcome instruments have affected findings. The authors also reference analytic possibilities such as ecological momentary assessment (EMA) and cusp catastrophe modelling as tools for future studies, though no new primary data or pooled analyses are presented in the extracted text.
Across the ketamine literature synthesised in the review, single subanesthetic infusions (commonly 0.5 mg/kg given intravenously over about 40 minutes) produce rapid reductions in depressive symptoms and reductions in suicidal ideation observable within hours, with the largest antidepressant effect sizes usually reported at one day post‑infusion and effects on SI reported to persist for up to one week in some studies. Initial trials and secondary analyses demonstrated decreases in SI, which prompted prospective RCTs enrolling participants with active SI. Intranasal esketamine (the S‑enantiomer) received FDA approval in March 2019 for treatment‑resistant depression and is being evaluated for treating SI; meanwhile, ketamine is being used off‑label in community clinics. Adverse effects reported across trials include transient dissociation and depersonalisation that typically resolve within about four hours, elevated blood pressure, and nausea or vomiting related to infusion. Long-term safety, particularly with repeated administration, remains unclear and is the subject of ongoing study; chronic recreational ketamine use has been linked to bladder dysfunction. Neurobiological investigations associated ketamine response with markers such as increased gamma power on magnetoencephalography (MEG), changes in plasma brain‑derived neurotrophic factor (BDNF), alterations in slow‑wave sleep, and changes in default mode network connectivity on fMRI, though precise mechanistic pathways remain under active investigation. The review highlights heterogeneous trial designs and measurement approaches as a cause of inconsistent findings. Early ketamine SI signals often came from secondary analyses that used single SI items embedded in broader depression scales (HAM‑D, MADRS, BDI, QIDS), whereas suicide‑specific trials used dedicated instruments (SSI/BSI, C‑SSRS). Discrepancies arose within the same participant samples: some comparisons showed no significant ketamine–placebo difference on the full SSI while single depression‑scale SI items did show differences, a pattern that may reflect measurement structure and suitability for repeated, rapid assessments. Industry‑sponsored esketamine trials developed a novel instrument (SIBAT) to separately assess suicide constructs that change rapidly versus those that do not. Different inclusion criteria across trials also influenced outcomes: for example, Murrough and Canuso found signals of ketamine efficacy for SI in certain samples, whereas Ionescu’s study of individuals with chronic passive SI reported no ketamine–placebo differentiation. On the relationship between SI and depression, evidence is mixed. Some analyses indicate that ketamine’s reduction of SI is mediated by its antidepressant effects, while others suggest direct antisuicidal effects. A latent profile analysis identified three response groups—nonresponders, responders (reduced SI), and remitters (SI near zero)—and reported that mediation by antidepressant effects was partial in the remitter group but not evident in the other groups. Experimental therapeutics studies provided examples of how rapid‑acting designs permit within‑participant biomarker assessment: one sleep study showed nocturnal wakefulness was associated with next‑day suicidal thoughts and with ketamine SI response, such that remitters showed normalized sleep similar to healthy volunteers. Other correlates of SI response explored in the literature include plasma markers, PET imaging findings, and measures of anhedonia.
The authors interpret the ketamine literature as a useful model for designing RCTs that target rapid changes in suicidal ideation, emphasising that trials should be explicitly powered and structured with SI as a primary outcome rather than relying on secondary analyses from depression trials. They recommend careful consideration of participant selection because inclusion criteria (for example, chronic passive SI versus acute severe SI with intent) will determine the population to which results generalise; evidence to date suggests that efficacy may differ across these groups, underscoring the need to evaluate interventions across a range of SI severities and chronicities. Measurement issues receive central attention: the authors caution that many commonly used instruments were not developed to capture rapid within‑day changes in SI, and that discrepancies between single‑item measures embedded in depression scales and full suicide‑specific scales may reflect psychometric and procedural limitations. They note the development of new instruments (e.g. SIBAT) and point to EMA and cusp catastrophe modelling as promising analytic approaches. In discussing mechanisms, the review argues for embedding biomarkers and experimental‑therapeutic strategies into trials so that baseline and post‑treatment markers can be tested as predictors or mediators of rapid SI change; collaborations across groups will be important to determine whether biomarkers are treatment‑specific or SI‑specific. Key limitations acknowledged in the extracted text include the heterogeneity of existing trials (differences in inclusion criteria and outcome measures), the lack of validated instruments for rapid SI change, and incomplete knowledge about long‑term safety and effects of repeated ketamine administration. The authors call for rigorously designed RCTs focused on SI, standardisation and validation of measurement tools for rapid change, replication of biomarker findings, and multi‑site collaboration to improve generalisability and to clarify whether rapid reductions in SI constitute a direct antisuicidal effect or are mediated by improvements in depression. They frame these steps as necessary to translate the promise of rapid‑acting agents into reliable clinical interventions for individuals in acute suicidal crises.
, and these time periods are often too short for interventions to take effect. Therefore, a critical need exists for interventions with a potentially rapid onset of action. Given the clinical need for interventions that bridge gaps in continuity of care, a new set of rapid-acting interventions for suicide risk is being explored. One area of brief interventions includes suicide safety planning or crisis response planning, both of which have been associated with reduced risk of suicide attemptbut may also affect depression levels and suicidal thoughts within hours. Similarly, new developments in the nonpsychotherapeutic arenas, including transcranial magnetic stimulation, magnetic seizure therapy, and chronotherapies, have all demonstrated initial findings of reduced suicidal thoughts. Such interventions were often developed to take specific advantage of the therapeutic window of opportunity during or just after a suicide crisis, meaning that these interventions can demonstrate effects within days. In a similar vein, the N-methyl-D-aspartate (NMDA) receptor antagonist and glutamatergic modulator ketamine have received increasing research, clinical, and media attention over the last few years. In contrast to traditional antidepressants whose effects may take weeks to months to manifest, a single infusion of subanesthetic-dose ketamine rapidly decreases depressive symptoms within hours of administration, with the largest effect sizes observed one day postinfusion. Notably, subanesthetic-dose intravenous ketamine has also been associated with decreased suicide ideation (SI). In particular, secondary analyses of ketamine clinical trials reported reduced SI in individuals with, and these exploratory findings prompted prospective clinical trials in which ketamine was evaluated in individuals with active SI. A recent meta-analysis found that ketamine decreased SI for up to one week, an outcome that appeared to occur independently of its antidepressant effects. In March 2019, the FDA approved intranasal esketamine (U.S. Food & Drug Administration, 2019), the S-enantiomer of ketamine, for use in adults with treatment-resistant depression; this agent is also currently being evaluated for approval in treating SI. Ketamine clinics-where intravenous ketamine is administered by clinical providers off-label-have also emerged in community settings. Therefore, individuals with recent suicidal thoughts and behavior are likely to hear about ketamine as a potential treatment option. This review summarizes the methodological considerations associated with rapid-acting interventions for suicide using ketamine as an illustrative example. Ketamine is a particularly helpful model because a number of published clinical trials have already assessed its effects on suicidal ideation across a range of diagnoses. In addition, a burgeoning literature describes ketamine as a tool for experimental therapeutic investigation into the phenomenology of suicidal thoughts. While this review will focus on ketamine, it is meant to initiate discussion into the design and evaluation of all rapid-acting interventions for suicide, regardless of mechanism, in the hopes that standard methods of design and assessment can be used across scientific disciplines.
Ketamine was familiar to physicians long before the present focus on its rapid-acting antidepressant effects, both as an anesthetic and as a drug of abuse. Over the last two decades, multiple double-blind, placebo-controlled, randomized trials have established the rapid antidepressant efficacy of subanesthetic-dose (0.5 mg/kg) ketamine for treatment-resistant depressionand bipolar depression, as well as its usefulness as a treatment for post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). In contrast to other psychiatric medications, which are associated with a gradual dissipation of symptoms, ketamine is usually associated with a rapid reduction in depressive symptoms just after administration. The antidepressant effects of a single ketamine infusion-which include reduced SI-can last for up to one week; current investigations are evaluating the effects of repeated administrations. In most of these studies, ketamine was administered intravenously, often over the course of 40 min. Individuals have reported a range of side effects during ketamine infusion and shortly thereafter, including dissociation and depersonalization; these usually dissipate within four hours postinfusion. It should be noted, however, that individuals with schizophrenia or other active psychotic disorders are often excluded from ketamine trials due to concerns of exacerbation of symptomatology. In addition to dissociative experiences, additional side effects associated with ketamine include high blood pressure and potential nausea or vomiting associated with the infusion itself. Somewhat surprisingly, subanesthetic administration of ketamine to individuals with no psychiatric diagnoses may cause transient dysphoric symptoms and anhedonia, suggesting that ketamine may affect potential homeostatic mechanisms. There are also indications that ketamine is associated with bladder dysfunction in individuals who have a long history of ketamine abuse. Additionally, the long-term impact of ketamine use, particularly repeated usage, is unclear; studies are underway to assess these longterm outcomes, particularly outside of the context of clinical trials. Ketamine's underlying neurobiological mechanisms of action are complex and outside of the scope of this review. Broadly, ketamine is a glutamatergic modulator and NMDA receptor antagonist. Ketamine-related research has primarily focused on the neurotransmitter glutamate and postsynaptic receptors such as the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (in contrast to research into selective serotonin reuptake inhibitors (SSRIs), which has largely focused on presynaptic receptors and the neurotransmitter serotonin). The specific neurobiological pathway underlying ketamine's antidepressant effects is still an area of active research, but recent findings suggest that antidepressant effects do not primarily depend on NMDA receptor antagonism but rather on enhanced AMPA throughput. Biomarkers of antidepressant response are also under investigation. In this context, ketamine has been associated with enhanced gamma power on magnetoencephalography (MEG), changes in plasma brain derived neurotropic factor (BDNF) levels, alterations in slow-wave sleep, and changes in default mode connectivityon functional magnetic resonance imaging (fMRI) (for a helpful review, please see). Building on the recent FDA approval of esketamine, researchers are also investigating whether ketamine metabolites may also exert antidepressant effects.
Until recently, the bulk of the literature into suicide-focused interventions centered around suicide attempts, particularly on preventing reattempt over the 6-to 12-month period after the index attempt. In such trials, SI is usually tracked as a secondary outcome measure. In contrast, evaluating rapid-acting interventions for SI requires randomized clinical trials (RCTs) that focus on SI as a primary outcome. Taking principles of good clinical trial design into account, "next-generation" RCTs for SI would need to differ from previous RCTs examining suicide attempt in small but substantial ways. Notably, even within longer-term psychotherapy trials, it is possible that rapid effects on SI after the first session are not being captured because the trials were not designed to assess such outcomes. Using the ketamine literature as a blueprint, we highlight potential changes that could be made to clinical trials for SI in the specific areas of participant selection, outcome measurement, and mechanisms of change.
The inclusion criteria of an RCT define the population that the investigator is interested in studying more broadly; researchers may modify these according to the intervention or outcome of interest. By definition, trials focused on preventing reattempt include participants with a history of recent suicide attempt (usually within 6 months); as a result, the population targeted for these studies is in some ways circumscribed. However, as trials begin to move towards SI as the primary outcome, myriad options for inclusion criteria are available, and any option the researcher makes will dictate how the results are interpreted. For example, a "next-generation" RCT could select individuals with longstanding passive SI or, alternatively, severe SI in the context of an active crisis. Within the ketamine literature, for example, the initial SI findings were reported in the context of treatment-resistant ketamine trials for depression; these secondary analyses often included participants with any level of SI, including passive thoughts, but often excluded subjects with more severe forms of SI. Criteria subsequently became more rigorous when SI was the primary outcome; for instance, an RCT by Murrough and colleagues investigating this issue required a rating of 4 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS)suicide item ("Probably better off dead. Suicidal thoughts are common, and suicide is considered as a possible solution, but without specific plans or intention") at the time of screening. Similarly, the RCT of esketamine conducted by Canuso and colleagues required "current SI with intent to act" in the last 24 hours and the need for immediate psychiatric hospitalization. As another example, the RCT of repeated ketamine administrations conducted by Ionescu and colleaguesrequired that all participants maintain a relatively low level of suicidal thoughts (≥ 1 on the Columbia Suicide Severity Rating Scale (C-SSRS)SI score) for three months in order to be included in the study. Thus, the ketamine literature highlights a range of potential participant samples via which to evaluate impact on SI. While selecting an RCT participant sample according to severity or chronicity of symptoms is not a new methodological concept, the presence of many choices where there were-until recently-relatively few may be new terrain for suicide researchers who have previously focused on attempters. In this context, both researchers and consumers of the research literature should pay close attention to the inclusion criteria for these types of trials. In addition, because clinical trials for SI are such a new area of research, there is little to no evidence that interventions for one level of SI will be directly translatable to interventions for anothermeaning that a treatment for chronic passive SI may or may not be appropriate for the treatment of an active suicide crisis. For instance, in the RCTs by Murrough and colleagues and Canuso and colleagues mentioned above, there was a signal that ketamine was effective for SI; in contrast, in the study by Ionescu and colleagues of individuals with chronic passive SI, there was no differentiation between ketamine and placebo. Therefore, as with the broader ketamine literature, it will be important to evaluate-and replicate-impact on SI across a range of participant samples.
Outcome selection is another key issue. Ketamine is a rapid-acting antidepressant, meaning that its effects are usually observed within minutes to hours. Therefore, initial clinical trials evaluated participants at 40, 80, 120, and 230 min after ketamine administration, with many primary outcomes focusing on 24 hr postinfusion. This dramatically shortened timeframe introduces the key methodological issue of identifying an outcome measure that is both appropriate and valid for this type of repeated administration. This distinction, in turn, raises a number of questions about clinical utility. For example, from a clinical perspective, is a twohour alleviation of SI clinically meaningful? What about a day? A week? Similarly, what constitutes an "SI response"? Is the goal complete remission of suicidal thoughts? A 50% reduction? All of these decisions depend on the underlying goals of any given intervention-for instance, if the treatment in question is meant to be implemented in an emergency setting as a way to divert psychiatric hospitalization, it may be focused on decreasing SI levels to near-zero for the crucial first few hours to days after administration. In contrast, an intervention conducted over the course of repeated outpatient visits in individuals with longstanding SI may focus on a gradual reduction in SI that can be maintained over weeks to months. The involvement of clinicians and individuals with lived experience will be key to defining these endpoints and treatment goals. In this context, the ketamine literature also offers a range of perspectives. Most of the initial trials focused on single infusions of subanesthetic-dose ketamine and on the first 24 hours postadministration, with primary outcome measures of either a 50% reduction or complete remission of SI. However, recent analyses have investigated repeated administrations of ketamine and esketamine with a focus on potentially maintaining response over weeks to months. With all of these clinical considerations in mind, the question of measurement selection remains. As noted above, the initial reports of ketamine's impact on SI were secondary analyses of depression clinical trials, and those studies therefore operationalized SI as single items from longer depression scales, particularly the Hamilton Depression Rating Scale (HAM-D), the MADRS, the Beck Depression Inventory (BDI), and the Quick Inventory of Depression Symptomatology (QIDS). Suicide-specific clinical trials used longer scales dedicated to measuring SI, such as the Beck Scale for Suicide Ideation (SSI or the self-report version, BSI)or the C-SSRS. However, none of these measures were developed to evaluate rapid changes in SI. The absence of psychometric validation may have led to inconsistent findings in the ketamine literature-even within the same participants. For example, across one group of ketamine RCTs at a single institution, all participants were administered the HAM-D, MADRS, BDI, and SSI. When comparing statistical outcomes between ketamine and saline placebo, no significant differences were observed between ketamine and saline placebo using the full-length SSI, but statistical differences were found using single items from the various depression rating scales. Although a difference in statistical significance does not necessarily mean a difference in effect, it is instructive to consider what might explain the apparent discrepancy, such as the suitability of the scale (or items) for repeated assessment. These differences could be related to the underlying structure of the SSI, which has 21 items, including an initial five items administered to all participants; the remaining 17 items are only administered if the participant receives a particular score on the first five items. Therefore, with repeated assessment over the course of a day, participants may be administered differing items depending on their level of SI. These concerns are not limited to the SSI and arise when using the C-SSRS and likely many other suicide risk assessments, particularly because the scales were meant to assess predictive suicide risk, rather than rapid changes in suicidal state. In contrast, SI items from depression rating scales are embedded in a long form; as a result, when several scales are administered at once in the context of repeated assessments, patient/clinician fatigue may be an issue. In light of these assessment concerns, researchers evaluating esketamine (sponsored by industry) developed new scales to address rapidly occurring changes in SI. In an efficacy and safety study of esketamine, Canuso and colleagues implemented a novel instrument, the Suicide Ideation and Behavior Assessment (SIBAT) to assess outcome measures of suicide risk. This tool uses both participant-and clinician-reported information relevant to suicide risk to assess suicide constructs that are prone to rapid change (e.g., SI) separately from constructs that are not prone to change (e.g., history of suicidal behavior). Within this framework, it is important to understand the ketamine and SI literature in light of the variety of measurements used as outcome measures. However, it would also be a mistake to assume that such concerns are limited to the ketamine literature, particularly as additional rapid-acting interventions emerge. Instead, this may be an opportunity for collaboration and discussion between experts in suicide assessment, a moment to think carefully about use and validation of suicide assessment instruments across clinical trials, particularly those focused on rapid interventions for SI. In this regard, new analytic methods using ecological momentary assessment (EMA)or cusp catastrophe modelingmay potentially provide new insights for future studies of suicide interventions.
One issue of particular relevance to "next-generation" clinical trials investigating ketamine for SI surrounds whether ketamine's antisuicidal effects are due to its antidepressant effects or whether these occur independently of one another. This question echoes a concern plaguing most suicide studies; that is, should suicide be considered an outcome specific to a particular psychiatric diagnosis or as a distinct clinical entity? From a clinical perspective, if a suicidal individual is in need of effective treatment, the specific psychological mechanism may be a secondary concern. However, at a more systematic level, this question gets at the heart of whether an intervention truly has "antisuicidal" effects. For ketamine, initial analyses have been mixed. Some studies suggest that ketamine's effects on SI are fully mediated by its antidepressant effects, while others suggest that ketamine has direct effects on SI. One latent profile analysis of SI response to ketamine suggests that the answer is nuanced; the analysis identified three potential responses to ketamine: "nonresponders," "responders" (reduced SI), and "remitters" (SI to near-zero levels). Interestingly, that study found that SI reductions in the "remitter" group were partially mediated by ketamine's antidepressant effects but that the other groups (the nonresponders and responders) showed no such mediation. The design features mentioned previously are relevant here. SI may be more readily separable from depression among participants recruited primarily for SI versus those recruited for depression (with incidental SI), and in order to disentangle unique effects on SI and depression, each must be measured with a precision not currently available in existing instruments.
This section has focused on a key underlying question: How we will know if a treatment is effective for SI? The simple answer is that we will know what works for SI when there are data from rigorously designed clinical trials conducted for this purpose. However, within this larger goal, the overview of the ketamine literature demonstrates
Another major implication of rapid-acting interventions for SI is the ability to build in evaluations of real-time markers. Most suicide research focuses on cross-sectional or longitudinal risk factors-that is, whether a certain clinical (or neurobiological) characteristic is associated with lifetime, current, or future suicidal thoughts and behavior. A rapid-acting intervention such as ketamine allows for another research strategy-broadly termed an "experimental therapeutics" model. In experimental therapeutics, additional measures or potential biomarkers of response are embedded into the course of the clinical trial. These measures can be evaluated at baseline-that is, before the intervention-in order to later assess which individuals might be most likely to respond to treatment. Other biomarkers can be investigated after the intervention or placebo to determine potential effects on treatment response. This design allows researchers to evaluate within-participant markers of the active disease state, for example, markers of a depressed versus a nondepressed mood state. Findings drawn from such studies have important implications for both the mechanism of action of the intervention and the nature of its effects on the symptomatology itself. While this type of study design has always been feasible over the course of a clinical trial, the evaluation of rapid-acting treatments makes its implementation more realistic. For example, because ketamine's impact is so rapid (and, given its short half-life, dissipates so quickly), these studies can be conducted over the course of days to weeks, often in psychiatric inpatient environments where many other environmental factors can be held constant. In contrast, it would be difficult to control environmental effects over months to years when studying an intervention with long-term effects. To draw an example from the ketamine literature, Figuredepicts the study design for an evaluation of sleep, ketamine, and SI. Sleep difficulties are a known long-term risk factor for suicidal behavior, but few studies have evaluated the relationship between sleep quality and risk of suicidal thoughts. In the study, individuals participated in a sleep study the nights before and after ketamine administration, with repeated assessments in between. This study design permitted investigators to evaluate: (a) the relationship between nocturnal wakefulness and next day suicidal thoughts; (b) ketamine's ability to improve suicidal thoughts versus improve nocturnal wakefulness; and (c) patterns of nocturnal wakefulness in individuals who experienced complete remission of SI postketamine compared to individuals who continued to have SI postketamine (i.e., responders versus nonresponders). The study design allowed researchers to use ketamine as a probe to evaluate correlates of the absence or presence of SI within the same individual. Notably, in this example, nocturnal wakefulness was associated with next-day suicidal thoughts as well as SI response to ketamine, meaning that individuals who had complete remission of SI postketamine also demonstrated normalized sleep patterns that were similar to those in healthy volunteers with no psychiatric diagnoses. While the findings require replication, they underscore ketamine's potential effects on the sleep and circadian systems and highlight nocturnal wakefulness as a potential short-term indicator of suicidal thoughts. Similar studies have been conducted to examine correlates of SI response to ketamine with plasma markersand markers of PET imaging, as well as non-neurobiological markers such as anhedonia. Taken together, these results illustrate the way that rapid-acting interventions such as ketamine have set the stage for exploring rapid changes in SI, ideally to better understand its neurobiological and psychological underpinnings.
• An experimental therapeutics approach to suicide research can be used across any clinical trial and does not require in-depth neurobiological measures. Other potential measures include clinical assessments of anhedonia, social connection, hope, or positive affect, as well as cognitive measures, including suicide-specific measures such as the Suicide Implicit Association Task (S-IAT) or the suicide Stroop task. • In such an approach, the timing of the assessments is a critical variable; these studies require precise standards for when markers are collected as related to the intervention (e.g., within 5 hr or one day after treatment). • Collaboration across research groups will be critical to determining whether biomarkers of interest are specific to certain treatments. For example, would reductions in SI after a safety planning intervention also be linked to sleep changes? Understanding which biomarkers are linked to mechanisms of treatments as compared to SI more generally will help further our understanding of both the nature of SI and the future treatment targets.
In conclusion, the excitement surrounding ketamine as a rapid-acting antidepressant with antisuicidal effects presents an important opportunity for framing "next-generation" studies in suicide research. In addition to offering an opportunity to evaluate the effects of
Create a free account to open full-text PDFs.
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Ionescu, D. F., Bentley, K. H., Eikermann, M. et al. · Journal of Affective Disorders (2019)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Niciu, M. J., Shovestul, B. J., Jaso, B. A. et al. · Journal of Affective Disorders (2018)
Nugent, A. C., Ballard, E. D., Gould, T. D. et al. · Molecular Psychiatry (2018)
Vande Voort, J. L., Ballard, E. D., Luckenbaugh, D. A. et al. · Journal of Clinical Psychiatry (2017)
Wilkinson, S. T., Ballard, E. D., Bloch, M. H. et al. · American Journal of Psychiatry (2017)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)