Esketamine monotherapy shows robust, rapid efficacy as treatment for TRD

Intranasal esketamine, administered at two fixed doses as monotherapy for treatment-resistant depression (TRD), has demonstrated robust and rapid efficacy in a phase IV double-blind, placebo-controlled randomized trial.

Patients (n=378) randomized to receive intranasal esketamine monotherapy at either 56 mg (n=86) or 84 mg (n=95) twice weekly for 4 weeks had a significant improvement in depressive symptoms vs those who received a matching intranasal placebo (n=197), as measured by the change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Results were initially observed at 24 hrs after the first dose and were maintained through 4 weeks.

The least-square (LS) mean difference between esketamine and placebo at 4 weeks was −5.1 (1.42) (95 percent confidence interval [CI], −7.91 to −2.33) for the 56-mg dose and −6.8 (1.38) (95 percent CI, −9.48 to −4.07) for the 84-mg dose (two-sided p<0.001 for each). The observed effect sizes were 0.48 and 0.63 for esketamine 56 mg and 84 mg, respectively. [JAMA Psychiatry 2025;doi:10.1001/jamapsychiatry.2025.1317]

For the key secondary efficacy endpoint of the change in MADRS total scores from baseline to day 2, the reduction with either dose of esketamine was significantly greater than that with placebo, with the LS mean difference of −3.8 (95 percent CI, −6.29 to −1.22; p=0.004) for esketamine 56 mg and −3.4 (95 percent CI, −5.89 to −1.00; p=0.006) for 84 mg.

“In this first placebo-controlled, monotherapy randomized clinical trial, esketamine demonstrated  rapid and robust efficacy at both 56- and 84-mg doses,” said lead author Dr Adam Janik from Johnson & Johnson, San Diego, California, US. “Clinically meaningful and statistically significant treatment effects were initially observed 24 hrs after the first dose, representing a substantial benefit vs oral antidepressants, which typically exhibit a delayed onset of effect.”

Standalone treatment

Previous pivotal clinical trials of intranasal esketamine for TRD (eg, TRANSFORM-2, ESCAPE-TRD, SUSTAIN-1) have tested the use of the ketamine S-enantiomer in conjunction with an oral antidepressant. [Am J Psychiatry 2019;176:428-438; N Engl J Med 2023;389:1298-1309; JAMA Psychiatry 2019;76:893-903]

The current trial (n=477) represents the first controlled study to assess the efficacy and safety of esketamine nasal spray as monotherapy for TRD. [ASCP 2024, poster W80]

Although participants were adults presenting with TRD at screening, implying exposure to ≥2 different oral antidepressants in the current depressive episode, any antidepressant and adjunctive antipsychotic treatments they were using had to be discontinued for ≥2 weeks prior to randomization.

From a state of nonresponse to oral antidepressants at baseline, 30.5 percent of patients receiving esketamine 56 mg and 29.2 percent receiving 84 mg responded on day 28 vs 15.1 percent of placebo-treated patients, with response defined as ≥50 percent improvement in MADRS total scores. The corresponding numbers needed to treat (NNTs) were 6.5 for esketamine 56 mg and 7.1 for 84 mg.

“The NNTs with esketamine monotherapy for response after 4-week treatment align with those from phase III studies of adjunctive esketamine treatment of TRD,” said Janik.

Freedom to further individualize treatment plans

Esketamine nasal spray, administered in conjunction with an oral antidepressant, is already approved for TRD. Following a half-year priority review by the US FDA, esketamine nasal spray was granted an expanded indication in the US to include its monotherapy use for TRD in January 2025, based on data from the current trial.

“Now that healthcare providers have the freedom to further personalize treatment plans based on individual needs, patients can experience the efficacy of esketamine without the need for a daily oral antidepressant,” said Dr Gregory Mattingly, an adult and adolescent psychiatrist at Washington University in St Louis, Missouri, US, in a press release announcing the FDA approval.