457. Intensive longitudinal monitoring of symptoms in response to treatment with intranasal esketamine

Abstract Background Esketamine is a NMDA receptor antagonist that has been approved as treatment for treatment-resistant depression (TRD). Unlike serotoninergic therapies requiring weeks for effect, intranasal esketamine modulates glutamate neurotransmission, often yielding symptom relief within hours and significant response rates within one month [1]. This rapid action is particularly critical for mitigating suicide risk, as many of TRD patients experience persistent suicidal ideation [2]. However, its therapeutic dynamics is associated with unique complexities: dosing requires biweekly-to-weekly clinic visits under supervision due to acute dissociation risks, and long-term maintenance protocols dynamically adjust treatment frequency. Aims & Objectives The aim of the present study is thus to demonstrate a protocol of intensive longitudinal monitoring of patients treated with esketamine. We hypothesize that improvement will be observed in four symptom domains: dysphoria, anxiety, ruminating, and functional disability.

Method: Fifteen patients (four women) with treatment-resistant depression were included in the study. All the patients satisfied the criteria for treatment-resistant depression; that is, they underwent treatment with two antidepressants with different mechanisms of action in the same depressive episode with unsatisfactory treatment response [3]. The patients underwent the standardised protocol of esketamine treatment with an induction, continuation and maintenance phase. On a weekly basis, the patients self-reported their symptoms expression in line with the International Consortium for Health Outcomes Measurement. They provided self-report measures of symptoms of depression, anxiety, the presence of ruminating and depression-related functional disability. Due to the nonlinear nature of the data, we divided the time series into early and late phase. The division was determined on an empirical basis by analyzing each time point to the previous ones. Goodness of fit measures were used to determine the optimal breakpoint. The breakpoint was empirically determined to be at 15 weeks. Afterwards, the self-reports were analyzed within the general linear model framework.

Results: Results from linear mixed models examining symptom trajectories over time across 15 patients (202 observations) revealed domain-specific patterns: There was a significant trend toward reduced rumination over time (β = 0.33, SE = 0.10, t(7.21) = 3.47, p = 0.0099). Depression symptoms increased significantly over time (β = 0.25, SE = 0.10, t(5.81) = 2.62, p = 0.041). No significant change was observed for measures of anxiety or functional disability. Discussion & Conclusions Intensive longitudinal monitoring of patients treated with esketamine for treatment-resistant depression demonstrated a non-linear change in symptoms over time. Somewhat surprisingly, no significant changes were observed in measures of anxiety or functional disability. While depression symptoms even worsened with some patients in the empirically-determined late phase of the treatment (likely due to returning to work after longer sick leaves), we nonetheless observed a promising reduction in the severity of symptoms of ruminating. Given the persistent nature of ruminations and their emergent status as an important maintaining factor of psychopathology, intranasal esketamine may prove to be a valuable pharmacological intervention for tackling this often therapeutically resistant symptom. Encore abstract: abstract was presented at ECNP 2025, Oct. 11-14th, Amsterdam, Netherlands.