Ketamine Spray Effective for Suicidality, but Abuse Concerns Linger

Megan Brooks

April 17, 2018

Intranasal esketamine, when added to standard antidepressant therapy, rapidly reduces symptoms of major depression and suicidality in patients at imminent risk for suicide, but experts are concerned about its potential for abuse.

"The results of this proof-of-concept study reinforce the potential of esketamine as an acute treatment for patients with major depressive disorder and suicidal ideation, a condition for which there is an urgent public health need and currently no approved treatment," lead investigator Carla Canuso, MD, from Janssen Research and Development, LLC, which funded the study, told Medscape Medical News.

The study was published online April 16 in the American Journal of Psychiatry.

In an accompanying editorial, members of the editorial board of the journal, led by Robert Freedman, MD, of the University of Colorado School of Medicine in Aurora, note that "if positive, longer-duration results emerge for intranasal esketamine, it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies."

However, "a framework to ensure the safe use of the drug will be critical, as the potential for abuse and diversion are real," they write.

The study involved 66 adults aged 19 to 64 years with major depressive disorder who presented to an emergency department or inpatient psychiatric unit and were assessed as being at imminent risk for suicide.

All participants were severely depressed at enrollment, as evidenced by a high total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (mean score, 38.6). They were assessed as having current active suicide ideation with intent to act on those thoughts. Forty-four (66.7%) participants reported having thoughts about suicide that were "severe," and 36 (54.5%) reported having such thoughts "very often." Half of the participants required suicide precautions in addition to hospitalization.

Participants were randomly allocated to receive intranasal esketamine 84 mg (35 patients) or placebo (31 patients) twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment.

The primary efficacy outcome was change in MADRS total score from baseline to 4 hours after initial dose. The MADRS score decreased (indicating improvement of symptoms) from baseline to 4 hours after the first dose in both the esketamine group (mean, -13.4) and the placebo group (mean, -9.1). There was significantly greater improvement in the esketamine group (least-square mean difference, -5.3; effect size, 0.61).

A statistically significant difference in the MADRS total score favoring esketamine over placebo was also seen at 24 hours (least-square mean difference, -7.2; effect size, 0.65), but not at day 25 (least-square mean difference, -4.5; effect size, 0.35).

Intranasal esketamine also showed a rapid and statistically significant effect on suicidal ideation, as measured by the MADRS suicidal thoughts item at 4 hours after initial dosing (effect size, 0.67), but not at 24 hours (effect size, 0.35) or at day 25 (effect size, 0.29).

Analysis of clinician global judgment of suicide risk rating using a ranked analysis of change from baseline showed numerically greater, but not statistically significant, decreases in ratings in the esketamine group compared with the placebo group at 4 hours (effect size, 0.31) and 24 hours after the first dose (effect size, 0.56).

In a post hoc analysis, a greater number of participants in the esketamine group compared with the placebo group achieved resolution of suicide risk (clinician global judgment of suicide risk scores of 0 - 1) at 4 hours (21.2% and 9.7%, respectively) and 24 hours after the first dose (40.0% and 6.5%, respectively). This suggests that esketamine "may be an important treatment to bridge the efficacy gap created by the delayed onset of action of standard antidepressants," write the investigators.

The acute effects of intranasal esketamine seen in this study are similar to those achieved with intravenous ketamine.

Intranasal esketamine was generally well tolerated, the researchers report. Common adverse events were nausea, dizziness, dissociation, unpleasant taste, and headache.

Janssen is developing esketamine nasal spray for both treatment-resistant depression and major depressive disorder with imminent risk for suicide. "Esketamine nasal spray is currently being evaluated in two global phase 3 clinical studies for patients with major depressive disorder who are at imminent risk for suicide. There is also a phase 2 clinical study for adolescents with major depressive disorder who are at imminent risk for suicide," Canuso told Medscape Medical News.

Drug-Seeking Already an Issue

In their editorial, Freedman and colleagues note that ketamine "drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. Some patients use the intravenous formulation intranasally repeatedly without supervision," they point out. In addition, diversion of ketamine is occurring already.

"Nonetheless, as in the case of oxycodone, the onus remains on individual physicians to assess appropriate use and to avoid creating dependence and abuse," they write.

Last year, as reported by Medscape Medical News, the American Psychiatric Association issued a consensus statement on ketamine for mood disorders. "Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder," the statement reads.

Although physicians have the responsibility to provide a suicidal patient with the "fullest range" of effective interventions, "the protection of the public's health is part of our responsibility as well, and as physicians, we are responsible for preventing new drug epidemics," write Freedman and colleagues.

Janssen's Canuso is confident that a framework for the safe use of esketamine can be developed. If approved, "several measures will be in place to help ensure the safe and appropriate use of esketamine," she told Medscape Medical News.

Esketamine nasal spray would be administered under the observation of a healthcare professional in a medical setting. It will not be accessed by patients at their pharmacy, Canuso said.

"Esketamine nasal spray will be delivered through a metered, single-use, disposable nasal spray device that does not require priming, preventing multiuse and leaving minimal remaining drug in the device container after administration, minimizing potential for abuse," she noted.

"We have generated comprehensive long-term safety data and will be discussing our safety profile and any mitigation plans with regulatory authorities in the coming months," said Canuso.

The study was funded by Janssen Research and Development, LLC. Several authors have disclosed financial relationships with the company. The original article has a complete list of authors' relevant financial relationships.

Am J Psychiatry. Published online April 16, 2018. Abstract, Editorial

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