It is remarkable to consider that we now have more than 30 medications approved by the Food and Drug Administration as monotherapy or augmentation for the treatment of major depressive disorder. And yet, we know very little about how these medications perform for patients at high risk for suicide.

Historically, suicidal patients have been excluded from phase 3 antidepressant trials, which provide the basis for regulatory approval. Even studies in treatment-resistant depression (TRD) have tended to exclude patients with the highest risk of suicide. Further, the FDA does not mandate that a new antidepressant medication demonstrate any benefit for suicidal ideation.

An important milestone for antidepressant drug development was, therefore, achieved in 2016 – when an intranasal spray formulation of esketamine, the S(+)-enantiomer of racemic ketamine – was granted FDA “breakthrough therapy” designation for the indication of major depressive disorder (MDD) with “imminent risk for suicide.” Several years earlier, the drug manufacturer Janssen had initiated studies of esketamine for TRD, which have reported rapid antidepressant effects similar to ketamine^1,2. Esketamine has been used in Europe as an anesthetic agent since the 1990s but was never marketed in the United States. Compared with R-(–) ketamine, it has a three- to fourfold higher affinity for N-methyl-D-aspartate receptors.

Focus on high-risk patients

The recent report by Canuso et al.³ in the American Journal of Psychiatry is a groundbreaking study: To my knowledge, it marks the first published randomized, placebo-controlled, repeated-dose trial of any ketamine formulation in depressed patients at high risk for suicide. Previous placebo-controlled trials of intravenous ketamine in depressed patients with clinically significant suicidal ideation have used only one-time dose administrations^4,5,6.

This phase 2, proof-of-concept trial randomized 68 adults with MDD at 11 U.S. sites, which were primarily academic medical centers. In contrast to previous ketamine studies, which recruited patients via advertisement or clinician referral, patients were identified and screened in an emergency department or an inpatient psychiatric unit. Participants had to voluntarily agree to hospitalization for 5 days following randomization, with the remainder of the study conducted on an outpatient basis. Intranasal esketamine (84 mg) or placebo was administered twice per week over 4 weeks, in addition to standard-of-care antidepressant treatment. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) score from baseline to 4 hours after first dose of study medication.

For the primary MADRS outcome, esketamine statistically separated from placebo at 4 hours and 24 hours, with moderate effect sizes (0.61 to 0.65). There were no significant differences at the end of the double-blind period at day 25 and at posttreatment follow-up at day 81. For the suicidal thoughts item of the MADRS, esketamine’s efficacy was greater than placebo at 4 hours, but not at 24 hours or at day 25. Clinician global judgment of suicide risk was not statistically different between groups at any time point, although the esketamine group had numerically greater improvements at 4 hours and 24 hours. There were no group differences in self-report measures (Beck Scale for Suicidal Ideation or Beck Hopelessness Scale) at any time point.

Regarding safety and tolerability, adverse events led to early termination for 5 patients in the esketamine group, compared with one in the placebo group. The most common adverse events were nausea, dizziness, dissociation, unpleasant taste, and headache, which were more frequent in the esketamine group. Transient elevations in blood pressure and dissociative symptoms generally peaked at 40 minutes after dosing and returned to baseline by 2 hours.

Putting findings in perspective

Several aspects of the trial are noteworthy. First, enrolled patients were markedly depressed, and half required additional suicide precautions in addition to hospitalization. Three patients (all in the placebo group) made suicide attempts during the follow-up period, further evidence that these patients were extremely high risk. Second, the sample was significantly more racially diverse (38% black or African American) than most previous ketamine studies. Third, psychiatric hospitalization plus the initiation of standard antidepressant medication resulted in substantial improvements for many patients randomized to intranasal placebo spray. Inflated short-term placebo responses are commonly seen even in severely depressed patients, making signal detection especially challenging for new drugs. Finally, it is difficult to compare the results of this study with the few placebo-controlled trials of intravenous ketamine for patients with MDD and significant suicidal ideation, because of differences in outcomes measures, patient populations, doses, and route of administration. This study used the Suicide Ideation and Behavior Assessment Tool, a computerized, modular instrument with patient-reported and clinician-reported assessments, which was developed specifically to measure rapid changes in suicidality and awaits further validation in ongoing studies.

Limitations of this study include the absence of reported plasma esketamine levels. Is it possible that higher doses of esketamine, or a different dosing schedule, would have had resulted in greater efficacy? The 84-mg dose used in this trial recently was found to be safe and effective in patients with TRD², and was reported to have similar plasma levels as IV esketamine 0.2 mg/kg². This dose, in turn, corresponds to a racemic ketamine dose of approximately 0.31 mg/kg¹. Future studies will need to examine the antisuicidal and antidepressant effects of the most commonly used racemic ketamine dose (0.5 mg/kg), compared with 84 mg intranasal esketamine. The twice per week dosing schedule was supported empirically from a previous study of intravenous ketamine showing that twice weekly infusions were equally effective to thrice weekly administrations⁷. It is unknown, however, whether even less-frequent administrations (such as once weekly) would have been more effective than twice-weekly over the 4-week, double-blind period. Finally, the authors raise the possibility of functional unblinding, which always is a concern in ketamine studies. Although the placebo solution contained a bittering agent to simulate the taste of esketamine intranasal solution, the integrity of the blind was not reported.

Conclusion

Overall, this study is a promising start. In my view, the risk to benefit ratio for this approach is acceptable, given the morbidity and mortality associated with suicidal depression. The fact that esketamine nasal spray would be administered only under the observation of a clinician in a medical setting, and not be dispensed for at-home use, is reassuring and would mitigate the potential for abuse. In the meantime, our field awaits the results of larger phase 3 studies for patients with MDD at imminent risk for suicide.

Dr. Mathew is affiliated with the Michael E. Debakey VA Medical Center, and the Menninger Department of Psychiatry and Behavioral Sciences at the Baylor College of Medicine in Houston. Over the last 12 months, he has served as a paid consultant to Alkermes and Fortress Biotech. He also has served as an investigator on clinical trials sponsored by Janssen Research and Development, the manufacturer of intranasal esketamine, and as an investigator on a trial sponsored by NeuroRx.

References

1. Biol Psychiatry. 2016 Sep 15;80(6):424-31.

2. JAMA Psychiatry. 2018 Feb 1;75(2):139-48.

3. Am J Psychiatry. 2018 Apr 16. doi: 10.1176/appi.ajp.2018.17060720.

4. Am J Psychiatry. 2018 Apr 1;175(4]):327-35.

5. Psychol Med. 2015 Dec;45(16):3571-80.

6. Am J Psychiatry. 2018 Feb 1;175(2):150-8.

7. Am J Psychiatry. 2016 Aug 1;173(8):816-26.

Ketamine formulation study is ‘groundbreaking’

References