Intranasal Esketamine for Treatment-Resistant Depression: A Practical Clinical Guide to Patient Selection, Dosing, Combination Strategies and Adverse-Event Management
Domenico de Berardis, Tommaso Barlattani, Alessandro Carano, Valentina di Ludovico, Matteo Lupi, Giuseppe Maina, Giovanni Martinotti, Fabiola Raffone, Valerio Ricci, Cinzia Silvestrini, Carmine Tomasetti, Antonio Ventriglio, Vassilis Martiadis
Preprints.org October 14, 2026 preprint DOI: 10.20944/preprints202610.1252.v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review |
|---|---|
| Intervention | Intranasal esketamine |
| Topics | Depression Esketamine |
| Key findings | Argues that the esketamine approval trials excluded many patients commonly seen in practice and leave key prescribing questions unresolved. The authors state that evidence does not show 84 mg is more effective than 56 mg, that comorbidity has seldom predicted non-response in real-world cohorts, that standing benzodiazepine doses should be reviewed before induction, and that response is often judged too early. |
Abstract
Intranasal esketamine has been available for treatment-resistant depression (TRD) since 2019, but the trials that led to its approval answer only some of the questions prescribers face. About 97% of trial participants had failed only one or two antidepressant classes, and patients with bipolar disorder, psychosis, obsessive–compulsive disorder, four personality disorders, moderate-to-severe substance use disorder, or recent suicidal intent were excluded, although such patients are common in practice. This review is meant as a practical guide for prescribers. We discuss the mechanism of action and its clinical implications, ideal and real-world candidates, patients with suicidal ideation, psychiatric comorbidity (including borderline personality disorder), dosing, concomitant medications, prevention and management of adverse effects, comorbid substance use disorder, treatment duration in responders and non-responders, and contraindications. Six tables summarise the drug’s characteristics, receptor pharmacology, patient selection, concomitant medications, adverse-event management and contraindications, including differences between the US and European labels. For each recommendation, we indicate whether it comes from the label, from expert consensus, or from untested practice. The evidence does not show that 84 mg is more effective than 56 mg; comorbidity has seldom predicted non-response in real-world cohorts; the standing benzodiazepine dose should be reviewed before induction; and response is often judged too early.
In the evidence
This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.
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Argues that approval trials excluded many real-world patients and leave prescribing questions unresolved, and states the evidence does not show 84 mg is more effective than 56 mg.
Synthesized
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Argues that esketamine approval trials excluded many real-world patients and leave prescribing questions unresolved, and that evidence does not show 84 mg is more effective than 56 mg.
Synthesized
Comparable studies
Other narrative reviews on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Long-term safety of ketamine and esketamine in treatment of depression | 2022 | Review | |
| Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. | 2024 | Review | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review | |
| The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease | 2022 | Review |