IV vs. Subcutaneous Esketamine for TRD: Real-World Outcomes in Brazil

Real-World Evidence: IV and Subcutaneous Esketamine Compared

A multicenter retrospective study conducted at three advanced-care centers in Brazil from 2023 to 2025 compared intravenous (IV) and subcutaneous (SC) esketamine protocols for adults with treatment-resistant depression (TRD). This study, published on October 16, 2026 (OpenAlex W7222434086), included 72 outpatients aged 18–65 years, with 26 receiving IV esketamine (6 sessions) and 46 receiving SC esketamine (12 sessions). The primary outcome was categorical response on the Beck Depression Inventory-II (BDI-II) at both a shared 6-session milestone and at each protocol's endpoint. Secondary outcomes included continuous changes in BDI-II and Beck Anxiety Inventory (BAI) scores, tolerability, adverse events, and exploratory factor analysis of symptom dimensions.

Efficacy and Mechanisms: Speed Versus Simplicity

IV esketamine demonstrated a trend toward faster antidepressant response after six sessions, with a higher proportion of responders compared to SC (odds ratio 3.06; 95% CI, 1.22–8.00), but this difference did not reach statistical significance (p = 0.059). At the respective protocol endpoints (6 sessions for IV, 12 for SC), both routes produced statistically comparable categorical outcomes (p = 0.541). Continuous BDI-II and BAI score improvements were observed in both groups, and factor analysis identified cognitive-affective and somatic-neurovegetative symptom dimensions responding to treatment. The underlying mechanism—N-methyl-D-aspartate (NMDA) receptor antagonism—remains the same for both routes, but pharmacokinetics differ: IV administration yields rapid peak plasma levels, while SC provides a more gradual absorption, potentially explaining the observed difference in speed of response.

Tolerability, Safety, and Operational Considerations

Both IV and SC esketamine protocols were well tolerated, with no serious adverse events or discontinuations due to adverse effects reported. Notably, dissociation—a well-known side effect of ketamine—was significantly more frequent with IV administration (53.8%) than with SC (13.0%; p = 0.001). Nausea and mild, transient blood pressure increases did not differ significantly between groups. The lower dissociation rates and simpler logistics of SC administration may offer advantages in outpatient settings, especially in resource-constrained environments. SC esketamine requires less intensive monitoring, specialized equipment, and staff training compared to IV, potentially increasing scalability and access. A non-obvious operational insight is that SC protocols, while requiring more sessions, may reduce the overall burden on clinical staff due to shorter post-administration monitoring times and fewer acute side effects, a factor not widely addressed in previous literature.

Policy, Access, and Research Implications

Route selection for esketamine in TRD should consider not only efficacy but also tolerability, operational complexity, and patient access. In Brazil and similar jurisdictions, where healthcare resources and psychiatric infrastructure are often limited, SC esketamine may represent a pragmatic alternative to IV protocols. The study's real-world design reflects routine clinical practice, offering valuable data for policymakers and clinicians evaluating scalable models for TRD care. However, the retrospective, observational nature of the study limits causal inference; confounding factors, selection bias, and protocol differences (e.g., number of sessions) must be acknowledged. Prospective, randomized controlled trials directly comparing IV and SC esketamine are needed to establish definitive guidance for clinical and regulatory decision-making.

Risks, Limitations, and the Road Ahead

While both protocols were well tolerated in this study, the long-term safety of repeated esketamine administration—regardless of route—remains incompletely characterized, particularly outside of controlled research settings. Dissociation, though less frequent with SC, may still impact patient acceptability and adherence. The study's relatively small sample size and lack of blinding further constrain generalizability. Importantly, the logistical advantages of SC esketamine must be balanced against the need for careful patient selection, monitoring, and integration with broader mental health services. As regulatory agencies and health systems consider expanding access to esketamine for TRD, robust pharmacovigilance and prospective effectiveness studies will be critical to inform safe, equitable implementation.

Conclusion: Pragmatic Options for Expanding TRD Care

This Brazilian multicenter study provides real-world evidence that both IV and SC esketamine protocols can achieve meaningful outcomes for treatment-resistant depression, with SC administration offering potential advantages in tolerability and scalability. While the findings are promising, they underscore the need for further prospective research and careful policy development to ensure that expanded access to esketamine is both safe and effective for diverse patient populations.

By Dr. Ana Luiza Ferreira, MD, PhD (Federal University of São Paulo). Reviewed by Dr. Rafael S. Mendes on 2026-10-20. Research based on primary data from OpenAlex study W7222434086 and Brazilian clinical protocols.