Ketamine and esketamine for suicidal ideation: Recent progress and practical issues

Over the last decade, there has been a growing interest in ketamine, an antagonist of N-methyl-D-aspartate (NMDA), as a rapid-acting agent for treatment-resistant depression and suicidal ideation. Despite findings of different meta-analyses showing antidepressant and antisuicidal effects of ketamine (e.g., Wilkinson et al., 2018), quality of evidence needs to be carefully judged to interpret results, draw conclusions and generate appropriate recommendations. The meta-analysis of Witt and colleagues (2020) tested the efficacy of ketamine for suicidal ideation in adults with major depressive or bipolar disorders. The authors estimated a moderate reduction in suicidal ideation 4 hours after ketamine’s infusion, which persisted until 72 hours. However, intravenous ketamine and intranasal esketamine may behave differently with respect to both short- and long-term outcomes. To date, no head-to-head trial of esketamine versus ketamine in depression or suicidal ideation has been conducted. Notably, the single trial based on esketamine included in the meta-analysis of Witt et al. (2020) estimated a significant improvement in suicidal ideation at 4 hours, but not at subsequent endpoints (Canuso et al., 2018). The different protocols and comparator treatments used in each trial may limit strict comparisons across trials.

Intranasal esketamine (the S-enantiomer of ketamine) has been recently approved by Food and Drug Administration (FDA) as an adjunctive therapy for treatment-resistant depression. FDA approval was based on data from five phase III clinical trials, two of which were positive, two of which narrowly missed their primary outcome measures and one of which is a long-term open-label study. The manufacturer recently filed a Supplemental New Drug Application to FDA for esketamine for the indication of a rapid reduction of depressive symptoms in adults with active suicidal ideation, following the announcement of positive results from two phase III clinical trials (ASPIRE I [clinicaltrial.gov identifier: NCT03039192] and ASPIRE II [clinicaltrial.gov identifier: NCT03097133], including 226 and 230 participants, respectively). Because of the timing of these trials, they were not able to be included in the meta-analysis of Witt et al. (2020). Results for both trials revealed a significant effect on depression scores at 24 hours though not on suicidal ideation. It is important to note that some of the trials included in the Witt et al. meta-analysis and the ASPIRE trials actively recruited patients with suicidal ideation, a population that has historically been excluded from antidepressant clinical trials.

Several key issues and unresolved questions regarding the clinical use of ketamine or esketamine in the treatment of patients with suicidal ideation remain. Despite showing possible efficacy on suicidal ideation, thus far no study has investigated the drug’s effects on fatal and non-fatal suicide attempts even though concern has been raised regarding the number of suicide deaths in the development programs of esketamine, with at least one expert suggesting that this could be possibly due to a protracted withdrawal reaction (Schatzberg, 2019). In addition, the ideal healthcare setting treatment of patients with suicidal ideation who are going to receive rapid-acting antidepressants is unclear; the provision of ketamine or esketamine in the emergency department settings may lead to an influx of patients who would be inappropriate for treatment. In addition, it remains possible that the combination of premature discharge combined with the potential for rapid rebound of suicidal ideation, if treatment is not continued, may result in poor patient outcomes. Finally, open questions remain regarding the possible impact of ketamine/esketamine-related addictive behaviors and the safety of long-term exposure on cognitive function.

Although dissociative side effects are generally well tolerated and short lived (60–90 minutes generally), they pose logistical barriers given the length of administration time (roughly 2 hours) and the prohibition on driving on the same day of treatment. Interestingly, psychoactive effects, in particular dissociative ones, may share neurobiological mechanisms with antidepressant and antisuicidal response attributable to ketamine, possibly involving glutamatergic enhancement.

Notably, it has been hypothesized that the effects of ketamine on depression and suicidal ideation may at least partially occur via procognitive mechanisms targeting neural circuits involved in executive function and cognitive emotional processing (Lee et al., 2016). Nevertheless, findings on cognition are controversial considering that, even though low and single doses of ketamine infusion may favor cognitive function in the short term, long-term use of ketamine at high doses and high frequencies may lead to cognitive impairment. All these clinical considerations further complicate the interpretation of mechanisms through which ketamine induces antidepressant and antisuicidal effects.

In short, ketamine seems a promising therapeutic option considering findings on its efficacy, but prudence dictates a cautious approach to its implementation, considering relevant clinical and practical issues.