Real‐World Effectiveness and Cost‐Differential of Intranasal Esketamine Versus Intramuscular Ketamine

Objective This study evaluated whether intramuscular (IM) ketamine is non‐inferior to intranasal (IN) esketamine for treatment‐resistant depression (TRD) and assessed differences in safety and healthcare costs. Methods In a retrospective, observational sequential cohort at the VA San Diego, 179 Veterans with TRD received eight treatments of either IN esketamine ( n = 89) or IM ketamine ( n = 90). The primary outcome was change in depressive symptoms (PHQ‐9) analyzed via linear mixed‐effects models with a non‐inferiority margin of −1.25 points. Secondary outcomes included Post‐Traumatic Stress Disorder (PTSD) Checklist for DSM‐5 symptoms, adverse events, and a cost‐difference analysis. Results IM ketamine was non‐inferior to IN esketamine for depression, with a baseline‐adjusted estimated marginal mean PHQ‐9 difference of 0.04 points (95% CI: −1.21 to 1.29). Reductions in PTSD symptoms were also non‐inferior. Incidence of sentinel adverse events were comparable, with no significant differences in emergency department visits or hospitalizations. Cost analysis revealed a significant disparity: the total cost per eight‐treatment course was $6069 for IN esketamine versus $647 for IM ketamine, with this difference driven primarily by the cost of IN esketamine. Conclusions IM ketamine demonstrated comparable clinical effectiveness and safety to FDA‐approved IN esketamine while offering a significant reduction in cost. These findings suggest IM ketamine may be a high‐value alternative to IN esketamine that could significantly expand access to psychiatric care for individuals with TRD. Relevance to Clinical Practice These findings provide real‐world evidence supporting the use of IM ketamine for TRD, and suggests that this formulation could offer a pathway for improving access to ketamine treatment by lowering the cost to healthcare systems.