Early Dose Management and Up-Titration of Esketamine: ECNP Poster Data

CONFERENCE REPORTER

In the double-blind induction phase of the randomized, active-controlled, phase 3 TRANSFORM-2 study (NCT02418585), investigators explored early dose management and up-titration from 56 to 84 mg of esketamine for treatment-resistant depression (TRD). According to the results, both esketamine nasal spray doses resulted in clinically relevant improvement in symptoms severity with no adverse effects, but some patients may benefit from early up-titration during esketamine induction. These results were shared via poster presentations at the 38th European College of Neuropsychopharmacology (ECNP) Annual Congress, on October 11-14, 2025, in Amsterdam.¹

Esketamine nasal spray was first approved by the US Food and Drug Administration for TRD in conjunction with an oral antidepressant on March 5, 2019,² and was recently approved as monotherapy for TRD.³ Results from the phase 3 TRANSFORM-2 study support esketamine’s original approval, showing significant and clinically meaningful reductions in MADRS score and a 7% study drug discontinuation rate with flexibly dosed esketamine (56/84 mg) plus oral antidepressant vs placebo plus oral antidepressant. Long-term trial data and real-world data have since shown that the 84 mg dose is more commonly used.⁴

TRANSFORM-2 included adult participants with major depressive disorder (per DSM-5 criteria) without psychotic features, with moderate-to-severe depression, and with a history of nonresponse to ≥2 OADs in the current episode (N=227). Participants were randomly assigned 1:1 to esketamine plus a new oral antidepressant, or to a new oral antidepressant plus placebo. On day 1, particpants were given esketamine 56 mg with the option to up-titrate to 84 mg on days 4, 8, 11, or 15, twice per week for 4 weeks. The primary endpoint was change from baseline to day 28 in Montgomery Åsberg Depression Rating Scale (MADRS) total score.

On Day 1, 113/114 (99.1%) participants received 56 mg esketamine plus oral antidepressant; 1 participant received esketamine 42 mg on day 1 due to a problem with the intranasal device. With the second administration on day 4, more than half of participants (58/107 [54.2%]) received 56 mg esketamine and the remaining (49/107 [45.8%]) received 84 mg. With the third administration on day 8, approximately a third of participants (40/108 [37.0%]) received 56 mg esketamine and approximately two-thirds (68/108 [63.0%]) received 84 mg. On the subsequent dosing days, this ratio was approximately maintained through the rest of the double-blind induction phase. The mean (SD) change from baseline in MADRS total score at day 28 was -17.0 (13.88) for placebo (n=100), -19.6 (12.62) for esketamine mode dose 56 mg (n=34), and -22.4 (12.16) for mode dose 84 mg (n=67).

Investigators observed numerically greater decreases in mean MADRS total score in all administration sessions in participants receiving modal 84 mg of esketamine vs modal 56 mg. The safety profile between the modal 56 mg and modal 84 mg doses of esketamine was similar, with a low proportion of participants decreasing dose due to treatment-emergent adverse events.

References

1. Santos PM, Lopez TC, Lignugaris A, et al. Early dose management and up-titration of esketamine to 84 mg in the double-blind induction phase of the randomized, active-controlled, phase 3 TRANSFORM-2 study. Poster presented at: 38th European College of Neuropsychopharmacology Annual Congress; October 11-14, 2025; Amsterdam, The Netherlands. Accessed October 13, 2025.

2. Janssen announces U.S. FDA approval of SPRAVATO (esketamine) CIII nasal spray for adults with treatment-resistant depression (TRD) who have cycled through multiple treatments without relief. News release. March 5, 2019. Accessed October 13, 2025. https://www.jnj.com/media-center/press-releases/janssen-announces-u-s-fda-approval-of-spravatotm-esketamine-ciii-nasal-spray-for-adults-with-treatment-resistant-depression-trd-who-have-cycled-through-multiple-treatments-without-relief

3. SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. News release. January 21, 2025. Accessed October 13, 2025. https://www.jnj.com/media-center/press-releases/spravato-esketamine-approved-in-the-u-s-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression

4. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.