Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program

Research on the antidepressant effects of ketamine and its S-enantiomer esketamine has predominantly focused on intravenous and intranasal routes of administration, both of which have demonstrated efficacy in treatment-resistant depression (TRD) but present significant barriers to widespread clinical implementation, including the need for specialist clinical settings, anaesthetic monitoring, and the requirement for supervised administration. Oral esketamine offers a potentially more accessible and cost-effective alternative, but prior studies in this modality have been limited to small samples — ranging from 1 to 80 participants — with relatively low levels of treatment resistance and limited comorbidity. This study aimed to assess the real-world effectiveness, safety, and tolerability of repeated twice-weekly oral esketamine in a large, clinically representative sample of patients with severe TRD treated under a compassionate use protocol across multiple centres.

A multicenter, 6-week open-label study was conducted under an off-label compassionate use protocol, evaluated as exempt from the Dutch Medical Research Involving Human Subjects Act. One hundred and eighty-five patients with severe TRD received 12 doses of oral esketamine in a liquid formulation over six weeks, administered twice weekly. Patients continued their regular antidepressant and other psychiatric medications throughout; benzodiazepine use was tapered to a maximum of 2 mg/day prior to treatment initiation where possible. The level of treatment resistance was quantified using the Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD). Primary depression outcomes were assessed with the Hamilton Depression Rating Scale 17-item (HDRS-17) and the Inventory of Depressive Symptomatology — Self-Report (IDS-SR). Functional outcomes were assessed using the WHODAS II. Adverse events were monitored systematically using the Systematic Assessment for Treatment Emergent Events (SAFTEE) and the Interstitial Cystitis Symptom Index for urinary symptoms.

The 185 included patients had a mean current depressive episode duration of more than six years and a high comorbidity burden: 67.1% had psychiatric comorbidities including personality disorder (38.2%), anxiety disorder (24.9%), and PTSD (13.9%). Overall attrition was low at 7.6%. Significant improvements in depressive symptom severity were observed on both HDRS-17 and IDS-SR from baseline to week 6. Functional outcomes on the WHODAS II also improved significantly, with a mean change of 17.4% in the total score. No significant dose-response relationship was identified — the mean final esketamine dose did not differ between those who reached and those who did not reach the minimum clinically important difference threshold. Side effects were common but predominantly mild to moderate and transient: the most frequently reported included dissociative symptoms, weight loss, sleep disturbance, headache, dry mouth, and urinary symptoms. Severe increases in symptoms were documented 24 times across the sample, primarily sexual dysfunction. No cases of persistent cognitive impairment or serious bladder toxicity were identified. Following the 6-week course, 45.9% of patients showed sufficient benefit to warrant continuation with maintenance oral esketamine treatment.

This open-label study is substantially larger than prior oral esketamine investigations and extends previous findings to a more clinically severe and comorbid TRD population than typically enrolled in controlled trials. The significant antidepressant and functional improvements observed, and the 45.9% maintenance continuation rate, are interpreted as clinically meaningful in a population for whom most conventional treatment options had been exhausted. The authors acknowledge that the open-label design — without a placebo control — is a major limitation, and that expectancy bias may have inflated the observed effects, particularly given that many patients regarded oral esketamine as a treatment of last resort. The absence of a detectable dose-response relationship is noted as a potential concern for dose optimisation in clinical practice. Long-term safety monitoring, particularly for urinary tract effects associated with ketamine at higher recreational doses, is highlighted as an important consideration for future maintenance protocols. The authors compare their response rates favourably with intranasal esketamine trial data whilst noting that direct comparisons are confounded by differing patient selection and trial designs.

This real-world open-label study demonstrates that repeated twice-weekly oral esketamine is associated with significant antidepressant and functional improvements in a large, severely treatment-resistant clinical sample, with a broadly acceptable tolerability profile and a low dropout rate. The findings support the potential clinical utility of oral esketamine as an accessible alternative administration route in TRD, particularly for patients with severe and chronic illness, whilst underscoring the need for randomised placebo-controlled trials to confirm efficacy and establish evidence-based dosing protocols for long-term maintenance treatment.