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

This review (2021) examines methodological innovations within clinical trials investigating ketamine as a rapid-acting treatment option for depression or suicidal ideation (SI). The authors emphasize that the fast-acting dynamic of this treatment will enable the next generation of clinical trial designs to focus more on the development of better psychometric instruments, and more reliable biomarkers for assessing the efficacy of suicidal ideation treatment.

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.

Authors: Elizabeth D. Ballard, Jessica Fields, Cristan A. Farmer & Carlos A. Zarate

Summary

1 | INTRODUCTION

Suicide is a worldwide concern and has increased since 1999. In the United States, 9.8 million adults reported suicidal thoughts in 2016. The implementation and effects of most psychotherapeutic interventions for suicide prevention take weeks to months, or even years. Pharmacologic and device-based interventions are similarly limited, and a critical need exists for interventions with a potentially rapid onset of action.

Rapid-acting treatments for suicidal thoughts are critically needed. These treatments require several methodological innovations, including modifying clinical trial design and embedding psychological and neurobiological markers into clinical trials to better understand the underlying pathophysiology of suicidal thoughts.

New rapid-acting interventions for suicide risk are being explored, including suicide safety planning, crisis response planning, and transcranial magnetic stimulation. These interventions may also reduce depression levels and suicidal thoughts within hours.

Ketamine, an NMDA receptor antagonist and glutamatergic modulator, rapidly decreases depressive symptoms and has the largest effect sizes observed one day postinfusion. Subanesthetic-dose intravenous ketamine has been associated with decreased suicide ideation in individuals with depression. Ketamine clinics have also emerged in community settings, and the S-enantiomer of ketamine is currently being evaluated for use in adults with treatment-resistant depression.

This review will focus on ketamine as an illustrative example of rapid-acting interventions for suicide, but the 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 its present focus on its rapid-acting antidepressant effects, both as an anesthetic and as a drug of abuse. Multiple double-blind, placebo-controlled, randomized trials have established the rapid antidepressant efficacy of subanesthetic-dose ketamine for treatment-resistant depression and bipolar depression.

Ketamine may cause dissociation, depersonalization, high blood pressure, nausea, and anhedonia, but these side effects usually dissipate within four hours postinfusion. Ketamine may also cause bladder dysfunction in individuals with a long history of ketamine abuse.

Ketamine is a glutamatergic modulator and NMDA receptor antagonist. It has been shown to have antidepressant effects by enhancing AMPA throughput, changing plasma brain derived neurotropic factor levels, and altering slow-wave sleep.

3 | Clinical Trial Design Considerations for SI

Until recently, most literature on suicide-focused interventions focused on preventing suicide attempts. However, rapid-acting interventions for suicide intention (SI) require randomized clinical trials that focus on SI as a primary outcome.

3.1 | Participant selection

Researchers may modify the inclusion criteria of an RCT according to the intervention or outcome of interest, but studies focused on preventing reattempt are usually limited to individuals with a history of recent suicide attempt.

Within the ketamine literature, initial findings were reported in the context of treatment-resistant ketamine trials for depression. Later, criteria became more rigorous when SI was the primary outcome, and participants had to maintain a relatively low level of suicidal thoughts for three months. The ketamine literature highlights a range of potential participant samples via which to evaluate impact on suicide attempt.

Clinical trials for suicide intervention are a new area of research, and there is little to no evidence that interventions for one level of suicide intervention will be directly translatable to interventions for another level of suicide intervention.

3.2 | Outcome measurement

Ketamine is a rapid-acting antidepressant, and initial clinical trials evaluated participants at 40, 80, 120, and 230 min after ketamine administration. However, the clinical utility of ketamine for suicidal thoughts depends on the underlying goals of any given intervention.

The ketamine literature offers a range of perspectives, with some trials focusing on repeated administrations of subanesthetic-dose ketamine and esketamine with a focus on maintaining response over weeks to months.

With all of these clinical considerations in mind, the question of measurement selection remains. The HAM-D, MADRS, BDI, QIDS, and C-SSRS are all valid measures of suicide ideation, but none 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.

The underlying structure of the SSI could be related to differences in items administered to participants depending on their level of suicide risk, and patient/clinician fatigue may be an issue when several scales are administered at once.

In light of concerns over rapidly occurring changes in suicide ideation and behavior, researchers have developed a new scale to assess suicide risk. However, it is important to understand the ketamine and SI literature in light of the variety of measurements used as outcome measures.

3.3 | Relationship between SI and depression

The question of whether ketamine’s antisuicidal effects are due to its antidepressant effects or whether these occur independently of one another is relevant to “next-generation” clinical trials investigating ketamine for SI.

Ketamine may have different effects on SI depending on the participant. The study mentioned previously suggested that SI may be more readily separable from depression among participants recruited primarily for SI versus those recruited for depression (with incidental SI).

3.4 | Summary and recommendations

This section has focused on a key underlying question: How will we know if a treatment is effective for suicide intervention? The overview of the ketamine literature demonstrates the importance of considering participant selection, outcome measurement, and data analysis when designing clinical trials.

To improve the effectiveness of interventions for individuals with suicidal thoughts and behaviors, researchers should encourage precise participant selection in clinical trial design, expand perspectives beyond traditional suicide assessment measures, and incorporate clinical and lived experience perspectives to define SI response to a rapid-acting intervention.

4 | Experimental Therapeutics Perspective on SI

Rapid-acting interventions for suicide can be used to evaluate real-time markers of response, such as markers of the active disease state. This allows researchers to better understand the mechanism of action of the intervention and the nature of its effects on the symptomatology itself. The evaluation of rapid-acting treatments makes this type of study design more realistic, because environmental factors can be held constant over days to weeks.

Researchers conducted a sleep study on individuals who took ketamine and were assessed before and after the study. They found that ketamine reduced nocturnal wakefulness and increased risk of next day suicidal thoughts.

Ketamine is a rapid-acting intervention that has been shown to improve suicidal thoughts and nocturnal wakefulness in individuals with psychiatric diagnoses. These results suggest that nocturnal wakefulness may be a potential short-term indicator of suicidal thoughts.

A clinical trial can use an experimental therapeutics approach to suicide research, and can include measures of anhedonia, social connection, hope, or positive affect.

Timing of assessments is critical in such studies, and collaboration across research groups will be critical to determining whether biomarkers of interest are specific to certain treatments.

4.1 | Summary and Conclusions

Ketamine as a rapid-acting antidepressant with antisuicidal effects presents an important opportunity for framing “next-generation” studies in suicide research. These studies could help researchers design more useful studies, develop more sensitive psychometric instruments, explore potential biomarkers of response, and ultimately develop better treatments.

CONFLICT OF INTEREST

This work was supported by the Intramural Research Program at the National Institute of Mental Health, the NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. The authors have no conflicts of interest to disclose.

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