Experts Weigh in on Esketamine's Use for People With Suicidal Thoughts

In 2019, Janssen Pharmaceuticals’ esketamine (brand name Spravato), a “chemical cousin” to ketamine, became the first new medication approved to treat clinical depression in three decades. Meant for “treatment-resistant” depression, you take the drug nasal spray in a doctor’s office — meaning esketamine can’t be taken at home — along with your regular antidepressant.

Now, the Food and Drug Administration (FDA) approved a supplemental application to use esketamine with patients who have suicidal thoughts. However, it’s not a treatment for suicidal thoughts. Rather, esketamine can now also be prescribed if you have clinical depression and “acute” suicidal ideation. There’s actually no evidence esketamine reduces suicidal ideation or prevents suicide.

Following the news of its approval, skeptics questioned not having enough data to back up esketamine’s use or safety for people with suicidal thoughts. However, Janssen highlighted that the primary measure for its new indication was reducing underlying depression symptoms until a comprehensive care and safety plan can be put in place for patients who are struggling.

“Clinicians need more options to help quickly address their patients’ underlying depressive symptoms and change the trajectory of an acute episode so a longer-term care plan can be put in place,” Abigail Nash, M.D., Ph.D., medical director, Janssen Pharmaceuticals, told The Mighty via email, adding:

Until now, there have been no FDA-approved antidepressant medications specifically for people who are struggling with major depressive disorder with acute suicidal ideation or behavior. This patient population has been excluded from previous registration trials, yet, represents a group of adults with clear need to quickly improve their depressive symptoms during a depressive episode.

To learn more about the drug’s recent approval for use in patients with suicidal thoughts, The Mighty asked three experts their opinion about esketamine.

Here’s what they shared with us:  

Editor’s note: Comments have been lightly edited for content and clarity.

Bart Andrews, Ph.D. 

Executive committee member, American Association of Suicidology board of directors and chief clinical officer at Behavioral Health Response in St. Louis, Missouri

I am cautiously optimistic about the use of ketamine, which has some psychedelic properties, and other psychedelic drugs in treatment of psychiatric conditions and suicide. The current status of research is quite promising, and I strongly believe we need to be more aggressive and innovative in how we treat emotional pain, psychiatric conditions and especially suicide. To date, I think we have been too risk averse and culturally been resistant to the use of psychedelic medications.

That being said, I am very concerned about the approval of esketamine, the nasal administered version of the medication. Many initial studies have discounted its antidepressant effect, shown no suicide prevention component and some data suggests it could increase the risk of suicide (in several studies, there were no suicides in the control groups but multiple suicides in the treatment group).

Intravenous ketamine has shown the strongest and most positive effects. My biggest concern is that if esketamine is ineffective, or worse, causes deleterious effects, it will damage the good work going on with IV Ketamine and other psychedelics. I would not hesitate to recommend IV ketamine to someone who had refractory depression or suicide thoughts that were not responding to first line treatments, I would not recommend esketamine until I have evidence that it is effective.

Erick Turner, M.D.

Former reviewer of psych drugs for the FDA and associate professor at Oregon Health and Science University Department of Psychiatry

The way the evidence panned out, they took patients with major depressive disorder, who also had suicidal thoughts and a history of suicidal behavior, and customarily patients with recent suicidal behavior might have been excluded from the trials. But there’s nothing unusual about patients with suicidal thoughts. There was no effect of ketamine compared to placebo. There was no advantage. But nevertheless, when you go telling people that the drug has been approved for major depression with suicidal patients, with suicidal thoughts and behavior, it misleads the listener into believing that this is going to help the suicidal thoughts and behavior. But again, there was no effect on that.

People seem to be enamored with the mechanism of action of ketamine and how it supposedly works that they seem blinded to the question as to whether it works, whether the evidence from the randomized controlled trial shows that it works. The data are surprisingly mediocre. There was a statistically significant effect in one of the three trials, but statistical significance and clinical significance are two different things — something can be significant without being clinically significant.

I want to say that the proportion of patients who had a rapid onset of effect and it was a sustained response that helped and held to the end of the trial, which was at four weeks, was in the neighborhood of 10%. And so if you think about it, well, that’s 90% of people who did not have a clinically sustained response. So if you report that there was an effect, they might use that to say it was superior to placebo and rapidity of response. But when you think about the percentage of people that did not have that [effect] puts things in a different light.

Gerard Sanacora M.D., Ph.D.

Esketamine clinical trial investigator, professor of psychiatry at Yale University School of Medicine, director of Yale Depression Research Program, co-director of Yale New Haven Hospital Interventional Psychiatry Service

I believe the studies related to the recent supplemental indication for esketamine in the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior is very important for three reasons.

First, these were the first studies specifically designed to examine the efficacy of a new treatment of depression in patients considered at high risk for imminent suicidal behavior. These patients have traditionally been excluded from clinical trials examining the efficacy of antidepressant treatments. So, we never had good data to tell us how well these treatments actually work in this severely ill population of patients, we had to extrapolate from studies in patients with less severe forms of depression or at least from studies in patients that did not have significant suicidal ideation.

Second, this study was unique, in that the “placebo group” actually were provided with the best level standard of care (including oral antidepressant medications and psychotherapy) the investigators could provide (barring ECT and an MAOIs that were disallowed due to potential drug/drug or drug/treatment interactions). The findings, showing remission rates of approximately 30% for the severely ill patients assigned to placebo nasal spray demonstrates the efficacy of very good high-quality care, as provided in these clinical trials which mandated visits to the clinic at least two times a week after completing an inpatient hospitalization. This is very assuring to me and highlights the need for comprehensive treatment planning for these patients following discharge.

Third, it was very encouraging and satisfying to see the esketamine treatment add approximately an additional 12% on to these very favorable remission rates, and to show rapid improvement in mood symptoms beyond those of the high-level standard of care provided.

In sum, I believe these studies successfully show that the addition of esketamine to comprehensive clinical management plan for patients can produce both rapid and sustainable benefits to patients, with major depressive disorder experiencing acute suicidal ideation. However, it is important to emphasize that all of the data for these studies were collected in the context of the comprehensive clinical management of the patients. I do not believe we can interpret this data to support the use of esketmaine for the treatment of depressed patients at imminent risk for suicide outside of a comprehensive care plan.

Editor’s note: Janssen added the following comment in response to the experts we talked to about esketamine’s new indication. A representative for the company said: 

There were two identical Phase 3 clinical trials – ASPIRE I and ASPIRE II – supporting the FDA approval of this second indication for Spravato. The ASPIRE program enrolled adults with MDD with active suicidal ideation with intent with no restrictions regarding prior treatment of MDD. The primary endpoint of these studies was a reduction in depressive symptoms at 24 hours after the first dose, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Both trials met this endpoint with a statistically significant and clinically meaningful reduction with Spravato plus comprehensive standard of care compared to placebo plus standard of care. There was a secondary endpoint that measured improvement in the severity of suicidality at 24 hours, which did not show a significant difference between the treatment groups.Spravato was not studied as a prevention for suicide. During the double-blind phase of treatment in the ASPIRE trials when patients were actively receivingSpravato or placebo, there were no completed suicides. Both clinical trials and real-world safety monitoring show the rates of suicide in Spravato-treated patients are consistent with the background rate of suicide in the general population of adults with MDD (all of which occurred during open label treatment, without control group data).

Article updated Aug. 19, 2020, with additional comment from Janssen.