This real-world study (n=185) found that oral esketamine (35-210mg/70kg; 6w; 12x) was effective and well-tolerated in severely treatment-resistant depression (TRD) patients, showing significant symptom improvement with minimal dropouts (7.6%), suggesting it could be a viable alternative to intranasal or intravenous administration.
Abstract of Oral esketamine for patients with severe treatment-resistant depression
“Background: Oral esketamine for patients with treatment-resistant depression (TRD) could offer certain advantages over other routes, such as intravenous or intranasal, but it has not been systematically studied in a real-world setting.
Aims: Here we present results from a relatively large naturalistic study to evaluate the effectiveness, tolerability, and safety of oral esketamine in patients with TRD.
Methods: One hundred eighty-five adults with severe TRD (average of 8.1 antidepressant trials plus electroconvulsive therapy in 63% without beneficial outcome) received oral esketamine treatment twice-weekly for 6 weeks with individually titrated doses ranging from 0.5 to 3 mg/kg. Outcome measures included change from baseline to week 6 on the Hamilton Depression Rating Scale (HDRS17), Minimal Clinically Important Difference (MCID), response, remission, self-reported symptom improvement, functioning, and side effects.
Results: Oral esketamine treatment improved depressive symptom severity on the HDRS17 from 21.2 to 15.8 (p < 0.001). MCID, response, and remission rates were 47.1%, 26.8% and 15.6% respectively. In 45.9% of participants, treatment was continued after 6 weeks to maintain initial positive effects. Side effects were reported frequently but were overall well tolerated. The drop-out rate was 7.6%. We found no significant adverse effects associated with urinary tract or cognition.
Conclusions: Repeated treatment with oral esketamine is effective in improving depressive symptom severity in highly treatment-resistant depressive patients. It is safe, well tolerated, and patient-friendly. Considering the level of treatment resistance, outcomes were in the range of studies investigating other routes of (es)ketamine administration.”
Authors: Jolien K. E. Veraart, Sanne Y. Smith-Apeldoorn, Annemarie van der Meij, Jan Spijker, Robert A. Schoevers & Jeanine Kamphuis
Summary of Oral esketamine for patients with severe treatment-resistant depression
Depression that does not respond to several standard treatments—commonly called treatment-resistant depression (TRD)—remains a major clinical challenge. Earlier research has shown that intravenous (IV) racemic ketamine and intranasal esketamine can relieve symptoms, yet most trials enrolled people with only mild-to-moderate resistance and excluded many real-world complexities such as co-occurring illnesses or previous electroconvulsive therapy (ECT) failure. As a result, findings have not always translated to routine practice where patients frequently have a long history of unsuccessful therapies, comorbid psychiatric conditions, and high suicide risk.
The authors note that IV and intranasal routes require on-site medical supervision and can be costly or logistically demanding. Oral esketamine, by contrast, is less invasive, potentially cheaper, and easier to scale, but evidence for its use is sparse and limited to small or tightly controlled studies. Recognising this gap, Veraart and colleagues designed a pragmatic, multicentre, open-label programme to test whether individually titrated oral esketamine could help adults with severe TRD who had exhausted conventional options, including ECT.
The main objective was to evaluate effectiveness, safety, tolerability, and patient-reported functioning during a six-week induction phase in three Dutch tertiary depression centres. An additional aim was to gauge how many participants chose to continue with maintenance treatment, signalling meaningful benefit in everyday life.
Methods
Participants and study design
Find this paper
https://doi.org/10.1177/02698811251332831
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Cite this paper (APA)
Veraart, J. K., Smith-Apeldoorn, S. Y., van der Meij, A., Spijker, J., Schoevers, R. A., & Kamphuis, J. (2025). Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program. Journal of Psychopharmacology, 02698811251332831.
Study details
Compounds studied
Ketamine
Topics studied
Treatment-Resistant Depression
Depression
Study characteristics
Observational
Participants
185
Humans
Compound Details
The psychedelics given at which dose and how many times
Ketamine 35 - 210mg | 12x