Esketamine for Treatment-Resistant Depression
Abstract
To the Editor Janik et al reported a positive trial of esketamine monotherapy for treatment-resistant depression. However, the lead-in design and functional unblinding could have biased treatment estimates. The 4-week double-blind phase was preceded by a lead-in phase of up to 7 weeks, during which time antidepressant medication was discontinued; therefore, the last 2 weeks of prerandomization were antidepressant medication free. Primary efficacy analysis included all participants randomized in the double-blind phase who met nonresponse criteria. These criteria are detailed in the article (ie, Montgomery-Åsberg Depression Rating Scale [MADRS] ≥28 during weeks 1 and 2 and at day 1 prerandomization, and ≤25% improvement in the MADRS score from week 1 to day 1 prerandomization) but not in the protocol, which only mentions that MADRS will be used during the screening phase. A total of 98 participants were excluded from the primary analysis for not meeting nonresponse criteria. Analysis of all randomized participants (eTable 2 in Supplement 2) showed a significant, albeit smaller effect as follows: a difference in least-squares mean (SE) of −5.7 (1.18) vs −6.8 (1.38) for a dose of 84 mg and −4.6 (1.23) vs −5.1 (1.42) for a dose of 56 mg.
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BibTeX
@article{cristea2026esketamine,
title = {{Esketamine for Treatment-Resistant Depression}},
author = {Ioana Cristea and Martin Plöderl and Florian Naudet},
journal = {JAMA Psychiatry},
year = {2026},
month = oct,
doi = {10.1001/jamapsychiatry.2025.3242},
url = {https://hal.science/hal-05802459v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Esketamine for Treatment-Resistant Depression
AU - Ioana Cristea
AU - Martin Plöderl
AU - Florian Naudet
PY - 2026
DA - 2026/10/16
JO - JAMA Psychiatry
DO - 10.1001/jamapsychiatry.2025.3242
UR - https://hal.science/hal-05802459v1
AB - To the Editor Janik et al reported a positive trial of esketamine monotherapy for treatment-resistant depression. However, the lead-in design and functional unblinding could have biased treatment estimates. The 4-week double-blind phase was preceded by a lead-in phase of up to 7 weeks, during which time antidepressant medication was discontinued; therefore, the last 2 weeks of prerandomization were antidepressant medication free. Primary efficacy analysis included all participants randomized in the double-blind phase who met nonresponse criteria. These criteria are detailed in the article (ie, Montgomery-Åsberg Depression Rating Scale [MADRS] ≥28 during weeks 1 and 2 and at day 1 prerandomization, and ≤25% improvement in the MADRS score from week 1 to day 1 prerandomization) but not in the protocol, which only mentions that MADRS will be used during the screening phase. A total of 98 participants were excluded from the primary analysis for not meeting nonresponse criteria. Analysis of all randomized participants (eTable 2 in Supplement 2) showed a significant, albeit smaller effect as follows: a difference in least-squares mean (SE) of −5.7 (1.18) vs −6.8 (1.38) for a dose of 84 mg and −4.6 (1.23) vs −5.1 (1.42) for a dose of 56 mg.
SN - 2168-622X
SN - 2168-6238
ER -