Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Jun 14.
Published in final edited form as: Suicide Life Threat Behav. 2021 Feb;51(1):27–35. doi: 10.1111/sltb.12663

Clinical trials for rapid changes in suicidal ideation: Lessons from ketamine

Elizabeth D Ballard 1, Jessica Fields 1, Cristan A Farmer 1, Carlos A Zarate Jr 1
PMCID: PMC8201419  NIHMSID: NIHMS1711273  PMID: 33624880

Abstract

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.

1 |. INTRODUCTION

Suicide is a worldwide concern, and its rates have increased since 1999 (Curtin, Warner, & Hedegaard, 2016; Stone et al., 2018). In the United States, an estimated 9.8 million adults reported suicidal thoughts in 2016, with 2.8 million reporting a suicide plan and 1.3 million reporting a suicide attempt (Substance Abuse & Mental Health Services Administration, 2017). One major obstacle to reducing the suicide rate is the dearth of effective treatments linked to declines in suicidal thoughts and behavior. While several psychotherapeutic approaches are used for suicide prevention, including dialectical behavioral therapy (DBT) (Linehan et al., 2006), cognitive behavioral therapy (CBT) (Brown et al., 2005), and collaborative assessment and management of suicidality (CAMS) (Comtois et al., 2011), the implementation and effects of these treatments usually occur over weeks to months. Pharmacologic and device-based interventions are similarly limited. Currently, there is only one FDA-approved medication for the prevention of suicidal behavior—clozapine (Hennen & Baldessarini, 2005)—as well as a longstanding history of using lithium (Baldessarini, Tondo, & Hennen, 1999) and electroconvulsive therapy (ECT) (Kellner et al., 2005) for their potential antisuicidal effects. However, with the exception of ECT, most of these interventions take weeks, months, or even years for effects to manifest. This time gap is difficult for clinicians because emergency evaluation of patients for possible hospitalization often requires the assessment and treatment of individuals for suicide risk within days. In addition, the week after psychiatric admission and discharge is high-risk times for suicidal behavior (Qin & Nordentoft, 2005), 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 attempt (Bryan, May, et al., 2018; Stanley et al., 2018) but may also affect depression levels and suicidal thoughts within hours (Bryan, Mintz, et al., 2018). Similarly, new developments in the nonpsychotherapeutic arenas, including transcranial magnetic stimulation (Croarkin et al., 2018), magnetic seizure therapy (Sun et al., 2018), and chronotherapies (Sahlem et al., 2014), 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 (Murrough, Iosifescu, et al., 2013; Nugent et al., 2019; Zarate et al., 2006). 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 depression (DiazGranados et al., 2010a; Price et al., 2014; Price, Nock, Charney, & Mathew, 2009), and these exploratory findings prompted prospective clinical trials in which ketamine was evaluated in individuals with active SI (Grunebaum, Ellis, et al., 2017; Grunebaum, Galfalvy, et al., 2017; Ionescu et al., 2019; Murrough et al., 2015). 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 (Wilkinson et al., 2018). 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 (Canuso et al., 2018). Ketamine clinics—where intravenous ketamine is administered by clinical providers off-label—have also emerged in community settings (Wilkinson et al., 2017). 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.

2 |. Ketamine as a Rapid-Acting Antidepressant: A Primer

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 depression (DiazGranados et al., 2010a; Ibrahim et al., 2012; Zarate et al., 2006) and bipolar depression (Diazgranados et al., 2010b; Zarate et al., 2012), as well as its usefulness as a treatment for post-traumatic stress disorder (PTSD) (Feder et al., 2014), and obsessive–compulsive disorder (OCD) (Rodriguez et al., 2013). 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 (Zarate et al., 2006); current investigations are evaluating the effects of repeated administrations (Ionescu et al., 2016; Murrough, Perez, et al., 2013). 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 (Niciu et al., 2018); 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 (Nugent et al., 2019). There are also indications that ketamine is associated with bladder dysfunction in individuals who have a long history of ketamine abuse (Niesters, Martini, & Dahan, 2014). Additionally, the long-term impact of ketamine use, particularly repeated usage, is unclear; studies are underway to assess these long-term 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 (Zanos et al., 2016). Biomarkers of antidepressant response are also under investigation. In this context, ketamine has been associated with enhanced gamma power on magnetoencephalography (MEG) (Nugent et al., 2019), changes in plasma brain derived neurotropic factor (BDNF) levels (Haile et al., 2014), alterations in slow-wave sleep (Duncan et al., 2013), and changes in default mode connectivity (Evans et al., 2018) on functional magnetic resonance imaging (fMRI) (for a helpful review, please see (Kraus, Kadriu, Lanzenberger, Zarate, & Kasper, 2019)). Building on the recent FDA approval of esketamine, researchers are also investigating whether ketamine metabolites may also exert antidepressant effects (Zanos et al., 2016).

3 |. Clinical Trial Design Considerations for SI

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 (Hawton et al., 2015, 2016). 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.

3.1 |. Participant selection

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 (DiazGranados et al., 2010a; Price et al., 2009, 2014). 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) (Montgomery & Asberg, 1979) 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 (Murrough et al., 2015). 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 (Canuso et al., 2018). As another example, the RCT of repeated ketamine administrations conducted by Ionescu and colleagues (Ionescu et al., 2019) required that all participants maintain a relatively low level of suicidal thoughts (≥ 1 on the Columbia Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011) 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 another—meaning 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.

3.2 |. Outcome measurement

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 two-hour 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 (Murrough et al., 2015; Wilkinson et al., 2018). However, recent analyses have investigated repeated administrations of ketamine and esketamine with a focus on potentially maintaining response over weeks to months (Canuso et al., 2018; Ionescu et al., 2019).

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) (Hamilton, 1960), the MADRS (Montgomery & Asberg, 1979), the Beck Depression Inventory (BDI) (Beck, Steer, & Brown, 1996), and the Quick Inventory of Depression Symptomatology (QIDS) (Rush et al., 2003). 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) (Beck, Kovacs, & Weissman, 1979; Beck, Steer, & Ranieri, 1988) or the C-SSRS (Posner et al., 2011). 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 (Ballard et al., 2015). 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 (Canuso et al., 2018). 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) (Williamson et al., 2017). 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) (Kleiman, 2017) or cusp catastrophe modeling (Bryan & Rudd, 2018) may potentially provide new insights for future studies of suicide interventions.

3.3 |. Relationship between SI and depression

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 (Price et al., 2014), while others suggest that ketamine has direct effects on SI (Ballard, Ionescu, et al., 2014; Wilkinson et al., 2018). 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) (Ballard et al., 2018). 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.

3.4 |. Summary and recommendations

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 the range of decisions made over the course of designing a clinical trial that have important implications for understanding and interpreting results related to the effectiveness of any intervention for SI. Ignoring the nuances surrounding participant selection, outcome measurement, and data analysis could lead to either overestimating or underestimating the results, thereby setting the stage for implementing large-scale interventions too quickly or else abandoning interventions with clinical promise. Consequently, we encourage all suicide researchers to consider these questions of clinical trial design, regardless of the provenance of their interventions.

Methodological Suggestions for Researchers:

  • Encourage precise participant selection in clinical trial design. This will require careful assessment of SI history. An individual with years of chronic passive SI leading to an attempt may respond differently to an SI-focused intervention than someone who had never previously considered suicide before their current crisis.

  • Expand perspectives beyond traditional suicide assessment measures, including measurements from the EMA literature or returning to visual mood analog scales to capture dynamic variability in symptoms. Integrating current psychological theories of suicidal behavior, particularly ideation-to-action frameworks and fluid vulnerability theory, may help guide the selection of appropriate measurements. It may be that overall mean change in SI may be less meaningful than metrics such as SI variability or reactivity to stressful events.

  • Incorporate clinical and lived experience perspectives to define SI response to a rapid-acting intervention. One fundamental question is as follows: What level of symptom relief would be meaningful in the lives of individuals with suicidal thoughts and behaviors?

  • Because few, if any, SI assessments are validated across rapid changes in symptoms, any clinical trial in this area could consider including additional measures for psychometric evaluations of convergent and divergent validity. The creation of research networks of clinical trials into suicide risk may be beneficial even across treatment types, in order to increase statistical power for such analyses.

4 |. Experimental Therapeutics Perspective on SI

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, Figure 1 depicts the study design for an evaluation of sleep, ketamine, and SI. Sleep difficulties are a known long-term risk factor for suicidal behavior (Bernert, Turvey, Conwell, & Joiner, 2014), 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 (Ballard et al., 2016); (b) ketamine’s ability to improve suicidal thoughts versus improve nocturnal wakefulness (Vande Voort et al., 2017); 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) (Vande Voort et al., 2017). 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 markers (Ballard et al., 2018) and markers of PET imaging (Ballard, Lally, et al., 2014), as well as non-neurobiological markers such as anhedonia (Ballard et al., 2017). 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.

FIGURE 1.

FIGURE 1

Open in a new tab

An example research design using an experimental therapeutics approach

Methodological Considerations for Research:

  • 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 (Cha, Najmi, Park, Finn, & Nock, 2010; Nock et al., 2010).

  • 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.

4.1 |. Summary and Conclusions

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 ketamine and other potential rapid-acting interventions on SI and suicide risk, such “next-generation” initiatives could help researchers design more useful studies, develop more sensitive psychometric instruments, explore potential biomarkers of response and, ultimately, develop better treatments. In short, any rapid-acting intervention for SI has the potential to lead to new developments in clinical trial design and to generate valuable clinical and research considerations for the field as a whole. While most ketamine research has focused on its neurobiological mechanisms, the field is expanding to encompass important psychological considerations related to ketamine use that warrant discussion, including the best way to measure changes in SI and the treatment of the suicidal individual. We encourage researchers to use these lessons learned from the ketamine literature in the careful design, implementation, and interpretation of “next-generation” clinical trials for SI.

ACKNOWLEDGMENTS

The authors thank the 7SE research unit and staff for their support. Ioline Henter provided invaluable editorial assistance.

CONFLICT OF INTEREST

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857), by a NARSAD Independent Investigator Award to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate. Dr. Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation; as a coinventor 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 coinventor 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.

REFERENCES

  1. Baldessarini RJ, Tondo L, & Hennen J (1999). Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. Journal of Clinical Psychiatry, 60 Suppl, 2, 77–84; discussion 111–116. [PubMed] [Google Scholar]
  2. Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, et al. (2014). Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety. Journal of Psychiatric Research, 58, 161–166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ballard ED, Lally N, Nugent AC, Furey ML, Luckenbaugh DA, & Zarate CA Jr (2014). Neural correlates of suicidal ideation and its reduction in depression. International Journal of Neuropsychopharmacology, 18, pyu069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ballard ED, Luckenbaugh DA, Richards EM, Walls TL, Brutsche NE, Ameli R, et al. (2015). Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant. Journal of Psychiatric Research, 68, 68–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ballard ED, Vande Voort JL, Bernert RA, Luckenbaugh DA, Richards EM, Niciu MJ, et al. (2016). Nocturnal wakefulness is associated with next-day suicidal ideation in major depressive disorder and bipolar disorder. Journal of Clinical Psychiatry, 77, 825–831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ballard ED, Wills K, Lally N, Richards EM, Luckenbaugh DA, Walls T, et al. (2017). Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials. Journal of Affective Disorders, 218, 195–200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ballard ED, Yarrington JS, Farmer CA, Richards E, Machado-Vieira R, Kadriu B, et al. (2018). Characterizing the course of suicidal ideation response to ketamine. Journal of Affective Disorders, 241, 86–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Beck AT, Kovacs M, & Weissman A (1979). Assessment of suicidal intention: the Scale for Suicide Ideation. Journal of Consulting and Clinical Psychology, 47, 343–352. [DOI] [PubMed] [Google Scholar]
  9. Beck AT, Steer RA, & Brown GK (1996). Manual for the beck depression inventory-II. San Antonio, TX. [Google Scholar]
  10. Beck AT, Steer RA, & Ranieri WF (1988). Scale for Suicide Ideation: psychometric properties of a self-report version. Journal of Clinical Psychology, 44, 499–505. [DOI] [PubMed] [Google Scholar]
  11. Bernert RA, Turvey CL, Conwell Y, & Joiner TE Jr, (2014). Association of poor subjective sleep quality with risk for death by suicide during a 10-year period: a longitudinal, population-based study of late life. JAMA psychiatry, 71, 1129–1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brown GK, Ten Have T, Henriques GR, Xie SX, Hollander JE, & Beck AT (2005). Cognitive therapy for the prevention of suicide attempts: a randomized controlled trial. Journal of the American Medical Association, 294, 563–570. [DOI] [PubMed] [Google Scholar]
  13. Bryan CJ, May AM, Rozek DC, Williams SR, Clemans TA, Mintz J, et al. (2018). Use of crisis management interventions among suicidal patients: Results of a randomized controlled trial. Depression and Anxiety, 35, 619–628. [DOI] [PubMed] [Google Scholar]
  14. Bryan CJ, Mintz J, Clemans TA, Burch TS, Leeson B, Williams S, et al. (2018). Effect of crisis response planning on patient mood and clinician decision making: a clinical trial without suicidal US soldiers. Psychiatric Services, 69, 108–111. [DOI] [PubMed] [Google Scholar]
  15. Bryan CJ, & Rudd MD (2018). Nonlinear change processes during psychotherapy characterize patients who have made multiple suicide attempts. Suicide and Life-threatening Behavior, 48, 386–400. [DOI] [PubMed] [Google Scholar]
  16. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. (2018). Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. American Journal of Psychiatry, 175, 620–630. [DOI] [PubMed] [Google Scholar]
  17. Substance Abuse and Mental Health Services Administration (2017) Key substance use and mental health indicators in the United States: Results from the 2016 National Survey on Drug Use and Health (HHS Publication No. SMA 17–5044, NSDUH Series H-52). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/. [Google Scholar]
  18. Cha CB, Najmi S, Park JM, Finn CT, & Nock MK (2010). Attentional bias toward suicide-related stimuli predicts suicidal behavior. Journal of Abnormal Psychology, 119, 616–622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Comtois KA, Jobes DA, O’Connor S, Atkins DC, Janis KC, Chessen C, Landes SJ, Holen A, & Yuodelis-Flores C (2011). Collaborative assessment and management of suicidality (CAMS): feasibility trial for next-day appointment services. Depression and Anxiety, 28, 963–972. [DOI] [PubMed] [Google Scholar]
  20. Croarkin PE, Nakonezny PA, Deng ZD, Romanowicz M, Voort JLV, Camsari DD, et al. (2018). High-frequency repetitive TMS for suicidal ideation in adolescents with depression. Journal of Affective Disorders, 239, 282–290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Curtin SC, Warner M, & Hedegaard H (2016). Increase in suicide in the United States, 1999–2014. Hyattsville, MD: NCHS Data Brief. [PubMed] [Google Scholar]
  22. DiazGranados N, Ibrahim L, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. (2010). Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Journal of Clinical Psychiatry, 71, 1605–1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. (2010b). A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry, 67, 793–802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Duncan WC, Sarasso S, Ferrarelli F, Selter J, Riedner BA, Hejazi NS, et al. (2013). Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. International Journal of Neuropsychopharmacology, 16, 301–311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Evans JW, Szczepanik J, Brutsche N, Park LT, Nugent AC, & Zarate CA Jr (2018). Default mode connectivity in major depressive disorder measured up to 10 days after ketamine administration. Biological Psychiatry, 84, 582–590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry, 71, 681–688. [DOI] [PubMed] [Google Scholar]
  27. Grunebaum MF, Ellis SP, Keilp JG, Moitra VK, Cooper TB, Marver JE, et al. (2017). Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Bipolar Disorders, 19, 176–183. [DOI] [PubMed] [Google Scholar]
  28. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. (2017). Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. American Journal of Psychiatry, 175, 327–335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Haile CN, Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Foulkes A, et al. (2014). Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. International Journal of Neuropsychopharmacology, 17, 331–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hamilton M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hawton K, Witt KG, Taylor Salisbury TL, Arensman E, Gunnell D, Hazell P, et al. (2015). Pharmacological interventions for self-harm in adults. The Cochrane Database of Systematic Reviews, Cd011777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hawton K, Witt KG, Taylor Salisbury TL, Arensman E, Gunnell D, Hazell P, et al. (2016). Psychosocial interventions for self-harm in adults. The Cochrane Database of Systematic Reviews, Cd012189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Hennen J, & Baldessarini RJ (2005). Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia Research, 73, 139–145. [DOI] [PubMed] [Google Scholar]
  34. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, et al. (2012). Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology, 37, 1526–1533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ionescu DF, Bentley KH, Eikermann M, Taylor N, Akeju O, Swee MB, et al. (2019). Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. Journal of Affective Disorders, 243, 516–524. [DOI] [PubMed] [Google Scholar]
  36. Ionescu DF, Swee MB, Pavone KJ, Taylor N, Akeju O, Baer L, et al. (2016). Rapid and sustained reductions in current suicidal ideation following repeated doses of intravenous ketamine: secondary analysis of an open-label study. Journal of Clinical Psychiatry, 77, e719–725. [DOI] [PubMed] [Google Scholar]
  37. Kellner CH, Fink M, Knapp R, Petrides G, Husain M, Rummans T, et al. (2005). Relief of expressed suicidal intent by ECT: a consortium for research in ECT study. American Journal of Psychiatry, 162, 977–982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kleiman EM (2017). Examination of real-time fluctuations in suicidal ideation and its risk factors: Results from two ecological momentary assessment studies. Journal of Abnormal Psychology, 126, 726–738. [DOI] [PubMed] [Google Scholar]
  39. Kraus C, Kadriu B, Lanzenberger R, Zarate CA Jr, & Kasper S (2019). Prognosis and improved outcomes in major depression: a review. Translational Psychiatry, 9, 127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Linehan MM, Comtois KA, Murray AM, Brown MZ, Gallop RJ, Heard HL, et al. (2006). Two-year randomized controlled trial and follow-up of dialectical behavior therapy vs therapy by experts for suicidal behaviors and borderline personality disorder. Archives of General Psychiatry, 63, 757–766. [DOI] [PubMed] [Google Scholar]
  41. Montgomery SA, & Asberg M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382–389. [DOI] [PubMed] [Google Scholar]
  42. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry, 170, 1134–1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan Het Rot M, Collins KA, Mathew SJ, Charney DS, & Iosifescu DV, (2013). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry, 74, 250–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Murrough JW, Soleimani L, DeWilde KE, Collins KA, Lapidus KA, Iacoviello BM, et al. (2015). Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychological Medicine, 45, 3571–3580. [DOI] [PubMed] [Google Scholar]
  45. Niciu MJ, Shovestul BJ, Jaso BA, Farmer C, Luckenbaugh DA, Brutsche NE, et al. (2018). Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression. Journal of Affective Disorders, 232, 310–315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Niesters M, Martini C, & Dahan A (2014). Ketamine for chronic pain: risks and benefits. British Journal of Clinical Pharmacology, 77, 357–367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Nock MK, Park JM, Finn CT, Deliberto TL, Dour HJ, & Banaji MR (2010). Measuring the suicidal mind: implicit cognition predicts suicidal behavior. Psychological Science, 21, 511–517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Nugent AC, Ballard ED, Gould TD, Park LT, Moaddel R, Brutsche NE, & et al. (2019). Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Molecular Psychiatry, 24, 1040–1052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. (2011). The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. American Journal of Psychiatry, 168, 1266–1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, et al. (2014). Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depression and Anxiety, 31, 335–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Price RB, Nock MK, Charney DS, & Mathew SJ (2009). Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biological Psychiatry, 66, 522–526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Qin P, & Nordentoft M (2005). Suicide risk in relation to psychiatric hospitalization: evidence based on longitudinal registers. Archives of General Psychiatry, 62, 427–432. [DOI] [PubMed] [Google Scholar]
  53. Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, et al. (2013). Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology, 38, 2475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. (2003). The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biological Psychiatry, 54, 573–583. [DOI] [PubMed] [Google Scholar]
  55. Sahlem GL, Kalivas B, Fox JB, Lamb K, Roper A, Williams EN, et al. (2014). Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study. Journal of Psychiatric Research, 59, 101–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Stanley B, Brown GK, Brenner LA, Galfalvy HC, Currier GW, Knox KL, et al. (2018). Comparison of the safety planning intervention with follow-up vs usual care of suicidal patients treated in the emergency department. JAMA Psychiatry, 75, 894–900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Stone DM, Simon TR, Fowler KA, Kegler SR, Yuan K, Holland KM, et al. (2018). Vital Signs: Trends in State Suicide Rates - United States, 1999–2016 and Circumstances Contributing to Suicide - 27 States, 2015. Morbidity and Mortality Weekly Report, 67, 617–624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Sun Y, Blumberger DM, Mulsant BH, Rajji TK, Fitzgerald PB, Barr MS, et al. (2018). Magnetic seizure therapy reduces suicidal ideation and produces neuroplasticity in treatment-resistant depression. Translational Psychiatry, 8, 253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. U.S. Food & Drug Administration (2019). FDA approves new nasal spray medication for treatment-resistant depression. Retrieved from https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm.
  60. Vande Voort JL, Ballard ED, Luckenbaugh D, Bernert RA, Richards EM, Niciu MJ, et al. (2017). Antisuicidal response following ketamine infusion is associated with decreased nighttime wakefulness in major depressive disorder and bipolar disorder. Journal of Clinical Psychiatry, 78, 1068–1074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. (2018). The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. The American Journal of Psychiatry, 175, 150–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, & Sanacora G (2017). A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. American Journal of Psychiatry, 174, 695–696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Williamson D, Canuso C, Fu D-J, Lane R, May R, Bossaller N, et al. (2017). 862. Patient report with the Suicide Ideation and Behavior Assessment Tool (SIBAT): acceptability and sensitivity to rapid change. Biological Psychiatry, 81, S349. [Google Scholar]
  64. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533, 481–486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. (2012). Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biological Psychiatry, 71, 939–946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 63, 856–864. [DOI] [PubMed] [Google Scholar]

RESOURCES