OBJECTIVE: Oral esketamine has relatively low and variable bioavailability, which may complicate broader use as an antidepressant. This study aimed to investigate associations between different pharmacokinetic outcomes and change in depressive symptoms following oral esketamine administration in patients with treatment-resistant depression. Understanding such associations may inform dosing and administration strategies in clinical practice. METHODS: Oral esketamine was administered twice weekly for six weeks using a titration approach in 17 patients. Esketamine and noresketamine serum levels were measured 30 min and 60 min after esketamine administration. Change in depression severity was plotted against the serum levels of esketamine and noresketamine, their sum and their ratios. RESULTS: We observed high inter-individual variability in oral esketamine pharmacokinetics, and we found no association between depressive symptom change and the pharmacokinetic outcomes. The small sample size and flexible-dose regimen complicate definitive conclusions. DISCUSSION: In the treatment of depression, clinical response may not correspond to esketamine pharmacokinetic outcomes. Individually-based titration strategies based on clinical antidepressant effects appear to be the optimal approach moving forward.