Real-world esketamine for treatment-resistant depression: induction outcomes from the enTRD registry

Background

Treatment-resistant depression (TRD) is associated with chronic illness course, suicidality, and substantial clinical burden. Intranasal esketamine offers a mechanistically distinct treatment pathway for TRD, yet real-world data on induction-phase effectiveness, symptom-domain change, suicidality, and tolerability in complex routine-care populations remain limited. We examined outcomes from the Vienna esketamine TRD registry (enTRD), focusing on supervised outpatient induction treatment.

Methods

This monocentric retrospective registry analysis included adults with TRD who initiated intranasal esketamine at the TRD outpatient clinic, Department of Psychiatry and Psychotherapy, Medical University of Vienna. TRD was defined as inadequate clinical response to at least two antidepressants given at adequate dose and duration with verified adherence. Esketamine was administered twice weekly for up to eight sessions over four weeks, up to 84 mg per administration, in combination with oral antidepressant pharmacotherapy. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the pre-treatment visit (PV) to end of induction (EOI). MADRS scores at baseline, PV, and EOI were analysed using a mixed model for repeated measures adjusted for age and sex. Secondary outcomes included MADRS three-factor change, Patient Health Questionnaire-9 course, response, remission, suicidal ideation, and adverse events.

Results

Of 229 referred patients, 224 were eligible, 176 initiated intranasal esketamine, and 156 completed induction. The induction cohort had substantial severity and complexity: mean age was 40.8 years, 54.0% were female, mean baseline MADRS was 31.5, mean PHQ-9 was 18.5, psychiatric comorbidity was present in 79.5%, and 74.9% fulfilled criteria for chronic major depressive disorder. Adjusted mean MADRS changed minimally from baseline to PV, from 31.7 to 30.3, but decreased to 17.7 at EOI. The primary PV-to-EOI contrast was −12.5 points, with a 95% confidence interval of −14.1 to −11.0; p<0.001, corresponding to Hedges’ g=1.8. Findings were robust across prespecified sensitivity analyses, including analysis of covariance, multiple imputation, and delta-adjusted tipping-point analyses. All MADRS factors improved, with the greatest relative change in the affective-anhedonic domain compared with anxiety-vegetative and hopelessness domains. PHQ-9 decreased steadily across the eight induction sessions, with no evidence of attenuation between early and late induction. At EOI, MADRS response was achieved by 57.4% and remission by 27.2% of patients with available data. Suicidal ideation decreased significantly on both MADRS item 10 and PHQ-9 item 9, with no suicide or serious self-harm event recorded during induction. Adverse events were documented in 34.7% of patients and 7.8% of administrations; adverse event-related discontinuation occurred in 3.4%.

Conclusions

In a specialised outpatient setting with routine monitoring, intranasal esketamine induction was associated with clinically meaningful improvement in depressive symptoms and suicidal ideation in a severe, highly comorbid TRD cohort, with acceptable tolerability. Longer-term registry follow-up and controlled comparative studies are needed to further define maintenance outcomes, persistence, and the benefit–risk profile beyond the induction phase.

References

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