According to clinical trial data published in the American Journal of Geriatric Psychiatry, intranasal esketamine combined with oral antidepressants did not significantly improve depression symptoms in a cohort of older adults with severe depression. Although esketamine has demonstrated promising outcomes previously, this study brings attention to some potential concerns for a drug approved by the US Food and Drug Administration this year.
Rachel Ochs-Ross, MD, a director at Janssen Research & Development in Titusville, New Jersey, and colleagues led a phase 3 double-blind randomized active-controlled multicenter trial of older adults (≥65 years) with treatment-resistant depression. For 4 weeks, patients were randomly assigned 1:1 to receive either biweekly flexibly dosed esketamine nasal spray (28, 56, or 84 mg) with a newly initiated oral antidepressant (n=72) or placebo nasal spray with a newly initiated oral antidepressant (n=66).
The primary endpoint was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28. Treatment response was defined as a ≥50% reduction from baseline in total MADRS score. Adverse events were assessed throughout the 4-week treatment phase. Patients who completed treatment were offered the option to roll over into a long-term open-label study. A mixed model for repeated measures was used to assess treatment efficacy.
Of 138 randomly assigned patients, 122 (88.4%) completed the double-blind phase. Change in MADRS total score from baseline to day 28 was not statistically significant between the 2 groups. Treatment response was observed in 27.0% and 13.3% of the esketamine and placebo groups, respectively. Furthermore, remission rates were 17.5% for the esketamine group and 6.7% for the control group.
In post hoc analyses, change in MADRS score between treatment groups was significant among patients aged 65 to 75 years (least squares mean difference [LSMD], −4.9; 95% CI, −8.96 to −0.89; P =.017), but not patients ≥75 years old. For patients with depression onset before age 55 years, esketamine facilitated greater improvement (LSMD, −6.1; 95% CI, −10.33 to −1.81; P =.006). For those who entered the long-term open-label stage (n=111; 80.4%), continued improvement with esketamine after 4 additional weeks was observed.
During the double-blind phase, 70.8% and 60.0% of patients in the esketamine and control groups, respectively, experienced treatment-emergent adverse events. The most common safety events in the treatment group were dizziness (20.8%), nausea (18.1%), elevated blood pressure, fatigue, headache, and dissociation (each 12.5%). Most adverse events were mild or moderate and resolved on the dosing day; discontinuation resulting from adverse events occurred in 4 patients receiving esketamine and 2 receiving placebo.
Although esketamine nasal spray combined with an antidepressant did not induce a significant reduction in depression symptoms overall, younger patients (ages 65-74 years) and patients with an earlier age of depression onset (<55 years) displayed some improvements with esketamine over placebo. Investigators noted that although the double-blind status was largely maintained in patients who experienced significant adverse events, unblinding occasionally occurred. “Further studies are required to better evaluate esketamine in elderly patients given several factors that potentially influenced the efficacy of esketamine in this study,” the investigators wrote.
Disclosure: This clinical trial was supported by Janssen Research & Development, LLC. Please see the original reference for a full list of authors’ disclosures.
Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression–TRANSFORM-3 [published online October 17, 2019]. Am J Geriatr Psychiatry. doi:10.1016/j.jagp.2019.10.008