Intranasal esketamine in treatment-resistant depression: longitudinal changes in anxiety and correlations with depressive symptoms, functioning, and suicidality in real-world practice

Introduction

Treatment-resistant depression (TRD) is often associated with anxiety symptoms, resulting in poorer prognosis, impaired functioning and increased suicidal risk [1, 2]. Currently, real-world evidence regarding the potential of intranasal esketamine (ESK) in reducing anxiety symptoms remains insufficiently characterized [3]. The primary outcome of this study was to evaluate the longitudinal changes in anxiety symptoms among patients with TRD treated with ESK. Moreover, we examined possible correlations with depressive symptoms, functional impairment and suicidal ideation.

Methods

This multicentre, real-world, prospective observational study included 99 adult patients with TRD, treated in augmentation with ESK. Psychometric evaluation was conducted at baseline (T0), after 1 week (T1) and monthly up to 6 months (T2-T5) through Hamilton Anxiety Rating Scale (HAM-A), Montgomery-Åsberg Depression Rating Scale (MADRS), Columbia Suicide Severity Rating Scale (C-SSRS) and Sheehan Disability Scale (SDS). At each time-point, outcomes were assessed through the variation of HAM-A mean scores, compared to baseline. Moreover, we investigated potential correlations between score reductions of HAM-A and variations in MADRS, SDS and C-SSRS.

Results

The study included 99 patients (females: 56.6%, mean age: 49.15 ± 16.88 years). As shown in Table 1, HAM-A mean scores showed a substantial decrease from baseline (20.6 ± 10.8) to T1 (16.8 ± 8.9), reaching mild levels by T3 (9.3 ± 5.1), with sustained improvement up to T5 (8.4 ±5.4).

	T0	T1	T2	T3	T4	T5
HAM-A scores (± SD)	20.6 (± 10.8)	16.8 (± 8.9)*******	11.7 (± 6.1)*******	9.34 (± 5.1)*******	8.3 (± 5.7)*******	8.4 (± 5.4)*******
n	97	78	90	76	70	55

Table 1: *p-value < 0.05; **p-value < 0.01; ***p-value < 0.001.

Linear mixed-effects models demonstrated significant time effects, indicating longitudinal improvement in HAM-A scores following treatment initiation (Estimated Marginal Mean (EMM) from 20.78 to 7.48; F (5, 99.02) = 52.46, p < 0.001).

Significant associations across all clinical outcome domains were observed using Pearson correlation analyses of change scores from baseline (T0) up to month 6 (T5). The strongest association was found between improvements in anxiety and depressive symptoms (r = 0.741, p < 0.001). Anxiety improvement showed moderate associations with changes in functional impairment (r = 0.414, p < 0.001) and suicidal ideation (r = 0.385, p < 0.001). All the aforementioned correlations remained statistically significant after Bonferroni correction for multiple comparisons (p < 0.005).

Conclusions

ESK treatment was associated with a continuous and sustained improvement in anxiety symptoms from baseline up to month 6 (T5), occurring already during the first weeks of treatment. Strong correlations were observed among changes in anxiety symptoms, depressive symptoms, functional impairment and suicidal ideation. However, randomized controlled trials with a larger sample size and longer follow-up periods are needed to confirm these findings and to identify potential predictive factors of response.

No conflicts of interest.

References

1. Lundberg, J., Cars, T., Lööv, S.-Å., Söderling, J., Sundström, J., Tiihonen, J., Leval, A., Gannedahl, A., Björkholm, C., Själin, M., & Hellner, C. (2023). Association of treatment-resistant depression with patient outcomes and health care resource utilization in a population-wide study. JAMA Psychiatry, 80(2), 167.
2. Gaspersz, R., Nawijn, L., Lamers, F., & Penninx, B. W. J. H. (2018). Patients with anxious depression. Current Opinion in Psychiatry, 31(1), 17–25.
3. Masdrakis, V. G., Tebbs, Z., Natsis, V., & Baldwin, D. S. (2025). Ketamine/esketamine pharmacotherapy for treatment of anxiety disorders and anxiety symptoms in depression: Systematic review. Journal of Psychopharmacology.