Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression–TRANSFORM-3

ABSTRACT Background Elderly patients with major depression have a poorer prognosis, are less responsive to treatment and show greater functional decline compared with younger patients, highlighting the need for effective treatment. Methods This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly-dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery–Asberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a pre-planned analysis by age (65-74 vs ≥75 years) and post-hoc analyses including age at depression onset. Results For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z=1.89, 2-sided p=0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t= -2.4, df=127; 2-sided nominal p=0.017) for patients 65-74 years vs -0.4 (-10.38, 9.50; t= -0.09, 2-sided nominal p=0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t= -2.8, df=127; 2-sided nominal p=0.006) for patients with depression onset Conclusions Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms was seen for younger patients (65-74 years) and patients with earlier onset of depression (