Rapid Antidepressants and Suicide Risk: What Do We Really Know?

Suicide remains an urgent challenge in psychiatry.¹ For clinicians treating a patient with active suicidal ideation, that urgency highlights the need for interventions that can act in the moment. Traditional antidepressant medications typically produce their effects over several weeks and are less suited to situations where rapid intervention is required.² Electroconvulsive therapy (ECT) has long provided an important treatment option in these circumstances, with the potential to produce substantial symptom improvement within the first several treatments.³ More recently, ketamine and esketamine have expanded treatment options for patients experiencing severe depression and suicidal ideation.

Reducing suicidal ideation is not necessarily the same as preventing suicide attempts, and neither outcome is equivalent to preventing suicide deaths. Although these interventions can rapidly reduce suicidal ideation, whether they reduce suicide attempts or suicide deaths remains much less certain. Understanding what available treatments have actually demonstrated and where the evidence remains uncertain is essential to using them appropriately.

Why the Evidence Is Complicated

Suicide is an unusually difficult outcome to study.⁴ Patients at the highest acute risk cannot simply be randomly assigned to treatment and observed without intensive clinical intervention. Contemporary trials involving patients at risk of suicide necessarily incorporate safety planning, frequent monitoring, rescue interventions, concomitant medications, and hospitalization or other higher levels of care. These safeguards are ethically important, but they can make it more difficult to isolate the effect of the intervention itself.

Furthermore, most clinical trials of conventional antidepressants have excluded those with imminent suicide risk, a history of recent attempts, or severe suicidal ideation or intent. As a result, the patients who clinicians may be most concerned about are underrepresented in the trials that establish the evidence base for antidepressant treatment. Finally, suicide death remains a relatively uncommon outcome, with an estimated prevalence of 13 to 14 suicide deaths per 100,000 person-years.⁵ To demonstrate a difference in suicide deaths in a randomized, prospective trial would therefore require a very large sample and prolonged follow-up. Hence, for practical reasons, most prospective studies instead rely on more frequent outcomes such as suicidal ideation or suicidal behavior.

Ketamine and Esketamine

Ketamine has emerged as an important intervention for rapidly reducing suicidal ideation. In a randomized controlled trial of patients with major depressive disorder (MDD) and clinically significant suicidal ideation, ketamine reduced suicidal ideation within hours of administration, with effects emerging before substantial improvement in other depressive symptoms.⁶ Multiple meta-analyses support this rapid effect and suggest that ketamine’s antisuicidal effects may be independent from its antidepressant effects.^7-11 This rapidity makes ketamine particularly relevant to the acute suicidal state. However, effectiveness for preventing suicide attempts or suicide deaths has not been established.

With respect to esketamine, the ASPIRE I and II trials were registrational phase 3, double-blind, randomized, placebo-controlled studies that enrolled more than 450 total participants with MDD and active suicidal ideation and intent.^12,13 Both trials demonstrated rapid improvement in depressive symptoms, with effects evident within 24 hours. However, between-group differences in clinician-rated suicidal ideation were not statistically significant and were more modest than the differences in depressive symptoms, despite substantial reductions in suicidal ideation in both groups. All participants received intensive standard-of-care treatment, including hospitalization and comprehensive psychiatric care. This aspect of the trial design, combined with the relatively fleeting nature of suicidal crises, may have limited the ability to detect an additional effect of esketamine on suicidal ideation.

The ASPIRE trials did not establish an effect of esketamine on suicidal behavior or suicide deaths. The 2020 FDA approval of esketamine in patients with MDD and acute suicidal ideation or behavior addresses depressive symptoms in this population; it should not be interpreted as evidence that esketamine prevents suicide. Accordingly, the FDA labeling for Spravato (esketamine) specifically states that its effectiveness in preventing suicide or reducing suicidal ideation or behavior has not been demonstrated.¹⁴ There is currently insufficient evidence that ketamine or esketamine reduces suicide attempts or suicide deaths. The evidence that ketamine rapidly reduces suicidal ideation compared with placebo or other control has been shown in several trials^7-11; however, the participants in these trials have generally less severe illness compared with the participants in the esketamine trials and the trial designs are fundamentally different.

ECT

ECT occupies a somewhat different position among rapid antidepressant interventions. It has decades of evidence supporting rapid improvement in severe depressive illness and remains particularly valuable when suicidal ideation occurs in the context of psychotic depression, catatonia, refusal to eat, or severe treatment-resistant depression.³ Unlike ketamine and esketamine, however, much of the evidence connecting ECT with suicide death prevention comes from observational studies rather than randomized controlled trials. Large registry studies, including data from Sweden,¹⁵ Denmark,¹⁶ and the United States,¹⁷ as well as a study within the Veterans Health Administration,¹⁸ have reported associations between ECT and reductions in suicide attempts and suicide deaths. However, patients who receive ECT may differ systematically from those who do not, and observational studies cannot establish causality in the same way as randomized trials.¹⁹ Nonetheless, the consistency and magnitude of those findings make ECT an important consideration when discussing treatments associated with lower suicide risk.

Interpreting Suicide Risk Reduction

A practical way to interpret the current evidence is to distinguish among 3 outcomes: suicidal ideation, suicide attempts, and suicide deaths. The Table summarizes the strength of evidence for each outcome.

Implications for Clinical Practice

Rapid antidepressants have changed the therapeutic landscape for patients experiencing severe depression and acute suicidal ideation. While ECT offers a highly effective and rapidly acting treatment for severe depression, including presentations characterized by substantial suicidal ideation, access and utilization can be limited by stigma, requirements for medical clearance that may delay initiation, particularly in outpatient settings, and by legal frameworks for involuntary treatment that differ by state and locality. Ketamine and esketamine can produce rapid reductions in suicidal symptoms and may represent more accessible alternatives to ECT in some clinical settings.

These interventions should nevertheless be viewed as components of comprehensive suicide risk management rather than stand-alone treatments for suicide prevention. Immediate stabilization, assessment and mitigation of access to lethal means, safety planning, appropriate monitoring, psychotherapy, and treatment of the underlying psychiatric disorder remain essential. Treatment decisions should account for both immediate and longer-term suicide risk. Lithium, for example, has been associated with reduced suicide risk over longer periods, although a recent meta-analysis did not find a statistically significant reduction in suicide.²⁰

Rapid antidepressants represent an important advance in the treatment of acute suicidal states. The next challenge is determining whether, and under what circumstances, those rapid effects translate into fewer suicide attempts and suicide deaths. For now, clinicians should remain appropriately cautious about what the evidence does and does not show.

Dr Hughes is an assistant professor of psychiatry at Yale School of Medicine and an attending psychiatrist on the interventional psychiatry service. Dr Wilkinson is an associate professor of psychiatry at the Yale School of Medicine, where he also serves as associate director of the Yale Depression Research Program.

References

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