Novel Intranasal Ketamine Effective for Resistant Depression

Deborah Brauser

January 09, 2018

Combining an antidepressant with a novel intranasal treatment may provide rapid and sustained benefit for patients with treatment-resistant depression (TRD), new research suggests.

A randomized, multisite, phase 2 study of almost 70 patients with TRD showed that those who received intranasal esketamine hydrochloride (Janssen) at doses of 56 or 84 mg plus an oral antidepressant had significantly greater changes in total score from baseline to day 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS) than those who received matching placebo (the primary endpoint).

The mean differences in MADRS score changes were by more than 7 and 10 points, respectively, for those receiving the 56- and 84-mg doses.

When combining data from both assessment periods, all three dosing groups studied (including patients receiving 28 mg) showed significant improvement, but the patients who received the higher doses showed the greatest changes on the MADRS.

In addition, sustained improvement in depressive symptoms was shown for up to 2 months post treatment.

Common treatment-related adverse events (AEs) included headache, dizziness, and dissociative symptoms. In addition, "transient elevations" in heart rate and blood pressure occurred on dosing days.

Although all three doses provided substantial benefit compared to placebo, "the 56- and 84-mg doses appear to sustain the response longer than the lower dose," lead author Ella J. Daly, MD, Department of Neuroscience, Janssen Research and Development, told Medscape Medical News.

Dr Ella Daly

"For that reason, we brought forward those two doses to study them in phase 3 studies that are underway," she said. Results for the phase 3 trials TRANSFORM-1, -2, and -3 and SUSTAIN-1, -2, and -3 are expected to be released later in 2018.

The current study's findings were published online December 27 in JAMA Psychiatry.

Breakthrough Designation

About 30% of patients with major depressive disorder (MDD) do not respond to treatment, note the investigators.

Although antidepressant efficacy has been shown in past studies with the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, this treatment often requires intravenous administration, "reducing its applicability in outpatient settings," the researchers note.

Esketamine provides intranasal delivery and has a "higher affinity for the NMDA receptor than the R-enantiomer."

In 2013, the US Food and Drug Administration (FDA) granted it breakthrough therapy designation for treating TRD. In 2016, the FDA also granted it breakthrough therapy designation for treating MDD "with imminent risk for suicide."

In the current study, 67 patients with MDD who had a history of not responding to at least two antidepressants were enrolled between January 2014 and September 2015.

All participants were randomly assigned in a 3:1:1:1 fashion to receive placebo (n = 33) or an oral antidepressant plus intranasal esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) for 8 days. To help with masking, the placebo group received an intranasal solution of water that contained a bittering agent.

During the following week, the patients in the placebo group who had moderate to severe symptoms on the 16-item Quick Inventory of Depressive Symptomatology Self-Report were reassigned to any of the treatment groups. The six patients with mild symptoms or no symptoms who had originally been assigned to receive placebo continued doing so during this period.

"This design allowed for a smaller sample size to assess efficacy, dose-response, and safety than a standard parallel-group design," write the investigators.

Significant Improvement

An optional open-label treatment period then followed (n = 57), lasting from days 15 to 74. During this time, dosing was titrated from twice a week to once a week and then once every other week. For all participants in this phase, the starting dose was 56 mg; the range was adjusted to between 28 and 84 mg, according to the investigators' clinical judgement.

Posttreatment follow-up was conducted for up to 8 additional weeks; 51 patients participated in the follow-up, and 41 completed it.

From baseline to day 8, the mean differences in MADRS total scores, in comparison with patients who received placebo, were -7.6 for the esketamine 56-mg group (P = .006) and -10.5 for the 84-mg group (P < .001). There was also greater improvement for the 28-mg group, albeit not statistically significant (difference from placebo, -5.0; P = .05).

Interestingly, change from baseline score at just the 2-hour mark on the first day was significantly different for the 28-mg (-6.7) and 84-mg (-7.9) groups compared to the group receiving placebo (P = .02 and .003, respectively). Change at 24 hours was significantly different for the 56-mg (-10) and 84-mg (-10.7) groups (both comparisons, P < .001).

At the end of period 2, which assessed the placebo-crossover patients, the score change differed significantly for the 84-mg group compared to the placebo group (difference, -6.9; P = .03).

When data from both 1-week assessment periods were combined, the mean difference was significant for all three dosing groups in comparison with the group receiving placebo.

Table. Dosing Groups vs Placebo Group in MADRS Total Score Change

Esketamine Dose Mean Difference 95% Confidence Interval P Value
28 mg -4.2 -7.67 to -0.79 .02
56 mg -6.3 -9.71 to -2.88 .001
84 mg -9.0 -12.53 to -5.52 < .001


In addition, there was a 7.2-point change in MADRS total score from baseline to day 74 (end of open-label phase) for those receiving active treatment, "despite reduced dosing frequency," write the investigators.

Also, "improvement in mean MADRS ratings persisted over the 8-week follow-up phase (without additional esketamine doses)," they add.

Among those receiving active treatment, three patients in the double-blind phase and one in the open-label phase discontinued treatment because of AEs; none of the patients who received placebo did so. There was one report each of headache, syncope, dissociative syndrome, and ectopic pregnancy.

Treatment-related AEs included dizziness, headache, dissociative symptoms, nausea, and sedation. "Most...occurring on dosing days were transient and either mild or moderate in severity. No death was reported," note the researchers.

Transient elevations in blood pressure were also seen on dosing days (maximum mean change for systolic, 19.0 mm Hg; for diastolic, 10.3 mm Hg), as was increased heart rate (maximum mean change, 9.4 bpm).

Overall, "the results have given us the confidence to further study and evaluate this [treatment] in phase 3, which we're doing in the present," said Dr Daly.

"This will help us fully clarify efficacy and safety in a much larger group of patients," including AEs, she said. The phase 3 studies have a combined patient population of between 1500 and 2000.

"We're working to complete these studies and are hoping to file for an indication [from the FDA] for resistant depression in 2018," she said.

"Considerable Promise"

Daniel S. Quintana, PhD, Oslo University Hospital and Institute of Clinical Medicine, Norway, and colleagues write in an accompanying editorial that this study of "the more potent S-enantiomer of ketamine" provides intriguing findings ― especially in two areas.

First, significant results were seen at 1 week, which is much sooner than results occur using current therapies. Moreover, the improvement in symptoms was sustained up to 2 months, "at least in the open-label phase of the trial," they write.

"As the authors conclude, the findings are encouraging and should lead to investigations in larger trials."

The second interesting aspect of the study is the delivery system itself, note the editorialists.

"Esketamine is a good candidate for intranasal delivery because of its relatively low molecular weight (238 Daltons), providing more favorable nasal mucosa absorption," they write.

"Although the possibility is speculative, a direct nose-to-brain delivery route bypassing the blood-brain barrier is...plausible via olfactory and trigeminal nerve fibers," they add.

However, this same delivery system may also present challenges, including nasal mucosa absorption being limited by such things as nasal polyps or inflammation; poor self-administration practices; or excessive sniffing, which could constrict the nasal valve.

"Regardless of administration modality, esketamine should be used with caution in psychiatric populations, because it can induce psychotic-like symptoms," add Dr Quintana and colleagues.

Although in the current study there were no reports of psychotic symptoms, the editorialists note that the reports of dissociative symptoms should be further clarified.

Still, the overall results "demonstrate the considerable promise of combining a compound with rapid antidepressant effects with intranasal delivery."

The study was funded by Janssen Research and Development, which employs Dr Daly. Dr Quintana is a coinventor on a patent application for an intranasal oxytocin administration delivery device. The original articles contain a full list of relevant financial relationships for the other study authors and editorialists.

JAMA Psychiatry. Published online December 27, 2017. Abstract, Editorial

Follow Deborah Brauser on Twitter: @MedscapeDeb. For more Medscape Psychiatry news, join us on Facebook and Twitter.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.