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Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension

Molecular Psychiatry (2024)Cite this article

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Abstract

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference −6.0, 95% CI −7.71 to −4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

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Fig. 1: Study design.
Fig. 2
Fig. 3: Change in depression severity over time in patients with treatment-resistant depression treated with a 6-week course of thrice-daily fixed low-dose oral esketamine or placebo in a randomized double-blind design.

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Acknowledgements

This study was funded by the Netherlands Organization for Health Research and Development, ZonMw (grant number 80-83600-98-3074, awarded to prof. dr. Schoevers). The authors gratefully acknowledge the contribution of all study participants, research assistants, healthcare professionals, patient and family associations, and all others who contributed to this study. The authors also acknowledge Klaas J. Wardenaar for statistical assistance.

Author contributions

RS obtained funding for the study and was the chief investigator. SS wrote the trial protocol with input from JV, AvA, MahR, and RS. SS, JV, and RS were responsible for general project management. SS, JV, JK, JS, AvdM, and RS were responsible for recruitment and data collection. SS conducted the statistical analysis with input from MahR. All authors contributed to the interpretation of the data. SS drafted the original manuscript, JV, JK, MahR, and RS contributed to the writing of the original manuscript, and all authors contributed to re-drafts. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Author notes

  1. These authors contributed equally: Sanne Y. Smith-Apeldoorn, Jolien K. E. Veraart.

Authors and Affiliations

  1. Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Sanne Y. Smith-Apeldoorn, Jolien K. E. Veraart, Jeanine Kamphuis & Robert A. Schoevers

  2. Department of Psychiatry, PsyQ Haaglanden, Parnassia Psychiatric Institute, The Hague, The Netherlands

    Jolien K. E. Veraart

  3. Depression Expertise Center, Pro Persona Mental Health Care, Nijmegen, The Netherlands

    Jan Spijker & Annemarie van der Meij

  4. Behavioral Science Institute, Radboud University, Nijmegen, The Netherlands

    Jan Spijker

  5. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Antoinette D. I. van Asselt

  6. Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Antoinette D. I. van Asselt

  7. Department of Psychology, University of Groningen, Groningen, The Netherlands

    Marije aan het Rot

  8. School of Behavioral and Cognitive Neurosciences, University of Groningen, Groningen, The Netherlands

    Marije aan het Rot & Robert A. Schoevers

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Correspondence to Sanne Y. Smith-Apeldoorn.

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Competing interests

JV has received a speakers fee from Janssen Pharmaceuticals, outside the submitted work. RS has received research funding for two randomized clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research & Development and the National Health Care Institute, a speakers fee and an investigator initiated research grant from Janssen Pharmaceuticals, and consultancy fees from Clexio biosciences, GH Research, Beckley PsyTech, and QPS. All other authors declare no competing interests.

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Smith-Apeldoorn, S.Y., Veraart, J.K.E., Kamphuis, J. et al. Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02478-9

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