In a naturalistic open‑label study of 185 adults with severe treatment‑resistant depression, twice‑weekly individually titrated oral esketamine for six weeks significantly reduced depressive symptoms (HDRS‑17 mean 21.2→15.8, p<0.001) with MCID 47.1%, response 26.8% and remission 15.6%, and a low dropout rate (7.6%). Treatment was generally well tolerated with frequent but manageable side effects and no significant urinary or cognitive adverse effects, suggesting oral esketamine is a safe, patient‑friendly option with effectiveness comparable to other administration routes.
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 (HDRS 17 ), 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 HDRS 17 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.
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.
Questionnaires on outcome measures were assessed over the course of the 6 weeks, with the last measurement prior to the last dosing session in week 6. The level of treatment resistance was assessed with the Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD), evaluating information about clinical conditions, psychiatric comorbidity, and failed treatments for the current episode. The DM-TRD contains 11 items and scores range from 2 to 27 (higher scores indicating worse treatment outcome;. The primary outcomes were depressive symptom severity change from baseline to week 6 measured by the Hamilton Depression Rating Scale (HDRS 17 ), with higher scores indicating greater severity of depressive symptoms, response (⩾50% reduction in HDRS 17 score), remission (HDRS 17 score ⩽ 7) and the minimal clinically important difference (MCID). The MCID is defined as "the minimum change in a measurable outcome in which the patient perceives a difference because of an intervention". Recognition of the use of MCID values for clinical trials and for the decision-making process in clinical practice is increasing. A study with 681 patients with nonpsychotic MDD yielded an MCID of 27.1% decrease in depressive symptom severity measured by the HDRS 17. In addition, we report the percentage of patients suffering from suicidality (an HDRS 17 suicidal ideation item score of >0 at baseline) who achieve a decrease in the severity of suicidality. We analyzed the self-reported depressive symptoms, assessed by the Inventory of Depressive Symptomatology -Self Rated (IDS-SR, with higher scores indicating greater severity of depressive symptoms), prior to treatment session 1 (week 1), session 3 (week 2), session 5 (week 3), session 7 (week 4), session 9 (week 5) and session 11 (week 6). Functioning was assessed with the World Health Organization Disability Assessment Schedule II (WHODAS II, (Epping-Jordan and), a 36-item assessment of health and disability with higher scores indicating greater levels of disability. If a participant does not have work or study, the number of questions is reduced to 32. A possible dose-response relationship was investigated by comparing the mean esketamine dose in week 6 between the groups of patients that did and did not reach MCID.
This open-label study of repeated oral esketamine treatment in 185 patients with high TRD is substantially larger than earlier investigations with oral (es)ketamine, describing patient groups ranging between 1 and 80 participants. We found that twice-weekly dosing for 6 weeks resulted in a significant improvement in depressive symptom severity on the HDRS 17 and IDS-SR, with treatment being well tolerated. Comparing our results with those of other esketamine trials in TRD patients, the response and remission rates in our sample (26.8% and 15.6%, respectively) were lower than those reported in two studies on IN esketamineand similar to the results in one study. In the first two trials, response rates were 54.1% (56 mg), 53.1% (84 mg) and 69.3% (56 or 84 mg) and remission rates were 36.0% (56 mg), 38.8% (84 mg) and 52.5% (56 or 84 mg). However, differences between the outcomes of these IN esketamine RCTs and our off-label program should be interpreted with great caution, as our sample was substantially more treatment resistant. In the three IN esketamine RCTs, the proportion of patients who had failed more than two adequate antidepressant trials in the current depressive episode ranged between 31.6% and 39.7%, whereas in our sample this proportion was 83.9%, with a mean DM-TRD score of 19.6, on average 8.1 failed antidepressant trials and unsuccessful ECT in 63% (DM-TRD item 7 in Supplemental material). The relevance of these differences is illustrated by the fact that even the response and remission rates in the control groups of these RCTs were higher than those found in our sample (response in 38.9% and 52.0%, remission in 30.6%, and 31.0%). As expected, patients with higher levels of treatment resistance have poorer treatment outcomes in both regularand (es)ketamine treatments. However, when comparing our results with the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the response and remission rates we observed exceeded those found in STAR*D (16.3% and 13.0%) in patients who had "only" four unsuccessful treatment steps with regular antidepressants and/or cognitive behavioral therapy. On top of that, the median length of the current depressive episode in the STAR*D study was 7.8 months, compared to 75.6 months in our sample, with longer index episodes generally predicting lower remission rates. The difference in the response and remission rates found in the studies byandcould additionally be explained by the discrepancy between rigorously controlled efficacy studies and real-world effectiveness in clinical practice. This pattern was also shown in off-label IV treatment with racemic ketamine that resulted in underwhelming response (18%-44%) and remission (13%-16%) ratesin comparison to RCTs. The differences can be attributed to differing levels of treatment resistance but also to the exclusion of patients with additional clinical characteristics such as bipolar disorder, psychotic symptoms or suicidality in RCTs. In more than half of the patients with suicidality (55.3%), the score on the suicidal ideation item of the HDRS 17 decreased by at least one level, and almost a third of the patients (31.6%) achieved complete remission of suicidality. These results are in line with the response and remission rates of 44% and 27%, respectively, observed in pooled data from five RCTs (n = 128) with IV racemic ketamine. Meta-analyses, including RCTs investigating the effect of IV racemic ketamine compared to saline or midazolam on suicidal ideation, report a significant reduction within the first 72 h (Jollant, 2023). On the other hand, in four large RCTs, IN esketamine did not differ from placebo. It should be noted that in RCTs investigating suicidal ideation, significant effects are also observed in control groups, particularly in inpatients. Empathetic support and connection can impact suicidal ideation in the short term and may also have played a role in the observed effects on suicidality in our population. Furthermore, the effects on suicidal ideation could also be explained by (es)ketamine's antidepressant effects. Some studies suggest that the effects may be partly independent, though not all research supports this. Despite the gradual dose titration schedule, and literature suggesting a later onset of antidepressant effects with oral administration when compared to IV or, we observed antidepressant effectiveness based on IDS-SR scores after two treatment sessions. Nevertheless, the benefits became more pronounced over the course of 6 weeks, implying that there is merit in extending the duration of treatment beyond these 6 weeks. The benefit of prolonged treatment has also been demonstrated in the study by, reporting increased remission rates after 32 weeks of IN esketamine treatment when compared to the end of the acute treatment phase. In this sample, 45.9% of patients benefited from the treatment and decided, together with their clinician, to continue maintenance treatment. This proportion corresponds to percentages found in previous studies (31%-50 %). Not all patients who wished to continue treatment after the induction phase had reached HDRS 17 response or remission thresholds. We observed that even partial symptom improvement could have significant meaning for patients in the clinical setting. Prior research has demonstrated that patients consider quality of functioning and positive affect to be important in relief from depression. As observed in the WHODAS II outcomes, oral esketamine treatment improved functioning in all domains: cognition, mobility, self-care, getting along, life activities, and participation. Previous trials investigating the antidepressant effects of IV ketamine and IN esketamine also found improvements in functioning. Even when response is not detected on depression-specific instruments such as the HDRS 17 , patients might experience an improvement in functioning or overall wellbeing. In patients with very hard-totreat depression, where treatment protocols are exhausted and offer no alternatives, such improvements are relevant and worthwhile for both patients and carers. Using a 50% decrease in depression symptom severity may underestimate this improvement. RCTs studying oral racemic ketamine in MDD indicated good safety and tolerability, with no or only mild dissociative symptoms and no signs of abuse or dependence. In our study, only 8 of 185 patients (4.5%) dropped out because of side effects. The types and frequencies of reported side effects were, in general, similar to those reported with oral (es)ketamine treatment elsewhere. No clinically relevant symptoms of urinary problems, cognitive impairment, or craving were observed in our study. The noninvasive oral route of administration was acceptable for patients, and they felt confident to change to maintenance treatment at home after the first phase of clinical treatment. However, as the therapeutic potential of (es)ketamine maintenance treatment is becoming increasingly evident (Smith-, implementing monitoring programs with a thorough investigation of the risk of abuse and long-term side effects is warranted. Of note, a moderate or severe increase in sexual dysfunction symptoms was most often reported as a side effect by 13.5% of participants (n = 17/126). In abusers of street ketamine, sexual dysfunction such as female sexual dysfunction and erectile dysfunction has been described. Mechanisms underlying (es)ketamine-related sexual dysfunction remain poorly understood. In rats, long-term ketamine administration caused decreased erectile responses, loss of smooth muscle content in the corpus cavernosum, and corporal apoptosis. It would be interesting to explore how the risk of sexual side effects may differ across various routes of administration, considering their distinct pharmacokinetic profiles. The extensive first-pass metabolism after oral administration influences systemic exposure to metabolites of (es)ketamine. Unfortunately, assessment of sexual dysfunction is uncommon in other studies with (es)ketamine for depression. Given our findings, we would argue for routine, standardized assessment of sexual functioning in (es)ketamine studies, especially in the case of long-term treatment, as relying on the spontaneous report of patients leads to underestimation of such symptoms. Regarding tolerability and safety, the oral route of (es)ketamine administration is the least invasive and has been associated with fewer acute side effects than IV or IN routes, potentially rendering it more suitable for at-home maintenance treatment after a first phase of clinical treatment and dose titration. Although at-home treatment needs to be monitored well, the requirement of clinical application and supervision for IN and IV administration rapidly leads to saturation of (es)ketamine treatment programs and consequently limited access. If efficacy is comparable, implementing at-home treatment with oral (es)ketamine could mitigate scalability issues related to treatment capacity.
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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.