Intranasal esketamine shows promise for treatment-resistant depression
NEW YORK — Results from two phase-3 studies of esketamine presented here demonstrated clinical significance in treatment-resistant depression.
“This is a very important area of unmet need,” David Hough, MD, esketamine compound development team leader at Janssen Research and Development, told Healio Psychiatry. “About 30% of patients with depression are considered treatment-resistant. There are very few drugs that work well, and we are very excited to debut these two studies.”
The first phase-3, double-blind, active-controlled, multicenter study enrolled adults with moderate-to-severe, non-psychotic, recurrent or persistent depression who did not respond to two or more antidepressants. Researchers conducted the study at 39 sites in Spain, Germany, Czech Republic, Poland and the U.S. from August 2015 to November 2017. Patients (n = 227) were randomly assigned 1:1 to flexibly-dosed intranasal esketamine at 56 mg or 84 mg twice weekly plus an oral antidepressant, or placebo plus an oral antidepressant; 197 patients completed the double-blind period. Primary endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) score; the secondary endpoint was remission rate, defined as MADRS score of 12.
Patients assigned to esketamine plus an antidepressant experienced greater improvement in MADRS total scores at 24 hours, as well as at days 8 and 22 (P = .009) and at day 28 (-4.0 vs. -7.31; P = .010), compared with placebo plus an antidepressant. At day 28, the remission rate was 52.5% for the esketamine group vs. 31.0% for placebo (one-sided P = .001).
The rate of common adverse events (dysgeusia, nausea, vertigo and dizziness) was more than 2-fold higher in the esketamine group compared with placebo.
Esketamine in elderly patients
The second phase-3, double-blind, multicenter, active-controlled study included 138 elderly patients with treatment-resistant depression who were randomly assigned 1:1 to intranasal esketamine at 28 mg, 56 mg or 84 mg plus an oral antidepressant (n = 72), or intranasal placebo plus an oral antidepressant (n = 66). Mean age was 70 years and mean MADRS score at baseline was 35.2. The primary endpoint was change in MADRS total score from baseline to the end of a 4-week double-blind induction phase, according to the abstract.
Mean change in MADRS score from baseline to day 28 was -10 for the esketamine group vs. -6.3 for placebo, with a median unbiased estimate of the difference of -3.6 (P = .029). The study failed to meet its primary endpoint, as it was designed using a one-sided significance level of .025.
Even though the change in MADRS score was not statistically significant, Hough said he is pleased with that result, given the difficult-to-treat population.
“Elderly patients, as a general rule, have more concomitant illnesses and more concomitant medications they’re taking and usually have had depressive illness for a very long time,” he said. “So what ends up happening is that they’re more difficult to treat, and more treatment-resistant even than younger adults.”
The researchers performed pre-specified subgroup analyses of patients aged 65 to 75 years (n = 116), and those 75 years of age or older (n = 21). According to findings, the treatment difference favored the esketamine group in the analysis of patients aged 65 to 74 years, with a difference in LS mean change at 28 days of -4.9 for those aged 65 to 74 years vs. -0.4 for those aged 75 years or older.
Common treatment-related adverse events included dizziness (20.8%), nausea (18.1%), headache (12.5%), fatigue (12.5%), vertigo (11.1%), increased blood pressure (12.5%) and dissociation (11.1%). In the placebo group, the most common adverse events were anxiety, fatigue and dizziness (7.7% for all).
“This is a completely new mechanism of action, a completely new treatment paradigm. We’re seeing very high rates of response and remission, so we’re very excited about the data overall,” Hough said.
Results of three additional studies — an acute fixed-dose study, a long-term safety study of up to 1-year in duration and a relapse prevention study — will be released in the coming weeks at the American Society of Clinical Psychopharmacology Annual Meeting in Miami Beach. - by Stacey L. Adams
Ochs-Ross R, et al. P7-065.
Popova V, et al. P8-054. Presented at: American Psychiatric Association Annual Meeting; May 5-9, 20178; New York.
Disclosures: Hough, Ochs-Ross and Popova are employees of Janssen.