Intranasal esketamine in treatment-resistant depression: longitudinal response and remission in real clinical practice

Introduction

Treatment-resistant depression (TRD) remains a major unmet clinical challenge, with a substantial proportion of patients failing to respond to multiple antidepressant strategies. Intranasal esketamine (IN-ESK), a glutamatergic modulator targeting N-methyl-D-aspartate receptors, has demonstrated rapid antidepressant effects in clinical trials. However, such trials typically include highly selected populations under controlled conditions, often excluding patients with comorbidities or concomitant treatments. In contrast, real-world evidence provides complementary information on effectiveness in broader, more heterogeneous populations, better reflecting routine clinical practice. Long-term real-world outcomes, particularly remission rates, remain insufficiently characterised.

Objectives

To report longitudinal response and remission rates (1, 3, 6, 12 months) in a cohort of 58 TRD patients treated with IN-ESK in routine clinical practice.

Methods

This longitudinal observational cohort study included 58 patients with treatment-resistant major depressive disorder, defined as non-response to at least three antidepressant strategies, including at least one combination or augmentation approach. All patients received intranasal esketamine for a resistant depressive episode. Doses ranged from 56 mg to 140 mg, adjusted according to clinical response and tolerability. All patients received acute courses of treatment (induction) lasting at least 2 months, followed by maintenance treatment for at least 6 months. Depressive symptoms were assessed prospectively using the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline and at 1, 3, 6, and 12 months. Response was defined as a reduction greater than 50% in MADRS score, and remission as a score ≤10. Demographic, clinical, and treatment-related variables were collected. Descriptive analyses were performed, and response and remission rates were calculated for evaluable patients at each time point.

Results

The mean age was 54.9 years (range 18–73), with 20% older than 65 years, and 62% were female. Comorbidities were present in 46% of patients, most frequently autism spectrum disorder. Melancholic symptoms were observed in 57% of patients. The mean duration of the depressive episode was 35 months, with a mean of 6 failed antidepressant treatments and a mean Maudsley Staging Method score of 10, indicating high treatment resistance. The mean esketamine dose was 80.14 mg (56 mg: 15%; 84 mg: 77%; 112 mg: 8%; >84 mg: 30%). Mean MADRS score decreased from 37.5 at baseline to 17.5 at 1 month, 10.5 at 3 months, 8.7 at 6 months, and 4.0 at 12 months. Remission rates were 29%, 64%, 71%, and 92%, respectively. Treatment with IN-ESK was safe and well tolerated, with side effects comparable with those reported in the literature.

Conclusions

In a real world clinical sample, composed by a highly treatment-resistant population, response and remission rates where higher than those reported in clinical trials [1][2]. These results may be related to a personalised treatment, the use of a flexible dosing enabling dosis superior to 84 mg and longer acute and maintenance treatments

References

1. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–438
2. Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu DJ, Ito T, et al.; ESCAPE-TRD Investigators. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;388(1):32–44.