Real-world clinical outcomes under intravenous and subcutaneous esketamine protocols for treatment-resistant depression: a multicenter, retrospective study

Background: Esketamine is a promising therapeutic option for treatment-resistant depression (TRD). Intravenous (IV) administration is the most extensively studied parenteral route. However, subcutaneous (SC) administration may offer simpler, more scalable delivery. Multicenter real-world evidence comparing IV and SC routes of administration remains limited.

Objective: To report clinical outcomes and tolerability of parenteral esketamine protocols for TRD at three Brazilian advanced-care centers.

Methods: This multicenter retrospective chart review study (2023–2025) included 72 outpatients aged 18–65 years who received esketamine 2 to 3 times weekly via IV (n = 26; 6 sessions) or SC (n = 46; 12 sessions) administration. Data were analyzed in RStudio 2026.01.0 Build 392 using R 4.5.2. The primary outcome was categorical response on the Beck Depression Inventory-II (BDI-II) at the shared 6-session milestone and at each protocol-specific endpoint. Secondary outcomes included continuous changes in BDI-II and Beck Anxiety Inventory (BAI) scores in the full sample, tolerability and documented adverse events, and exploratory factor analysis of baseline symptom dimensions.

Results: After six sessions, BDI-II response distribution favored the IV protocol, although the between-group difference was not statistically significant (Pearson’s chi-square = 5.661; p = 0.059; odds ratio, 3.06; 95% CI, 1.22–8.00). At the protocol-specific endpoints, categorical BDI-II response did not differ significantly between groups (Pearson’s chi-square = 1.227; p = 0.541; odds ratio, 1.44; 95% CI, 0.57–3.73). No serious adverse events or adverse-event-related discontinuations were reported; dissociation was more frequent with IV than with SC treatment (53.8% vs. 13.0%; p = 0.001), whereas nausea and mild transient blood pressure increases did not differ significantly. BDI-II factor analysis identified cognitive-affective and somatic-neurovegetative dimensions.

Conclusions: The IV protocol showed a more favorable BDI-II response distribution at the shared 6-session milestone, whereas SC esketamine achieved statistically comparable categorical outcomes at its 12-session protocol-specific endpoint. Route selection should consider speed of response, tolerability, dosing, operational complexity, and access. SC esketamine may be a feasible option where simplicity, tolerability, and access are priorities. Results should be interpreted with caution because of the retrospective, observational study design.