Intranasal esketamine in treatment-resistant depression with and without comorbid borderline personality disorder: A multicenter real-world longitudinal study.

Abstract

<h4>Background</h4>Borderline personality disorder (BPD) often occurs alongside treatment-resistant depression (TRD), but the impact of BPD on real-world outcomes with intranasal esketamine is unclear.<h4>Methods</h4>Consecutive TRD outpatients initiating intranasal esketamine treatment at four Italian centres between 1 September 2024 and 30 September 2025 were enrolled in the study (n = 90): 45 with comorbid BPD and 45 without any personality disorder. The primary outcome was the trajectory of depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline (T0) to 2 weeks (T1), 1 month (T2), 3 months (T3) and 6 months (T4). A response was defined as a ≥ 50% reduction in MADRS score, and remission as a MADRS score of ≤10 at T4. Secondary outcomes (exploratory) included anxiety (HAM-A), impulsivity (BIS-11) and cognitive function (MoCA).<h4>Results</h4>MADRS scores decreased over time (F(2.45, 215.50)=365.10, p < 0.001, ηp²=0.81), with a significant time × BPD interaction (F(2.45, 215.50)=17.31, p < 0.001), indicating faster early improvement in the BPD group. Remission at six months was 53.3%, with no difference by BPD status (48.9%vs. 57.8%, p = 0.398). However, response rates were higher in the BPD group from month one onwards (T4 OR=12.57, p = 0.004). Sensitivity analyses adjusting for baseline psychotherapy/medications and excluding patients with a history of hypomanic episodes yielded consistent results. Across the whole sample, anxiety and impulsivity decreased, and there was no evidence of worsening of the MoCA score over six months, supporting cognitive safety. No serious adverse events occurred and no patients dropped out.<h4>Conclusions</h4>In routine care, intranasal esketamine was associated with sustained improvement in TRD over six months, and comorbid BPD did not affect remission outcomes.

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