Background <p>Treatment-resistant depression (TRD) poses a significant therapeutic challenge, with remission often unattainable. Recognition and detection of treatment-emergent adverse events (TEAEs) are essential, as these events may significantly influence the quality of treatment response. This knowledge aids in personalizing care and selecting the best treatment strategy.</p> Methods <p>In a retrospective analysis of an observational study of inpatients (<i>n</i> = 28) with TRD, who were administered 8 ketamine infusions as an add-on therapy, psychiatric TEAEs were assessed using the Inventory of Depressive Symptomatology Self-Report 30 (IDS SR-30) and defined as symptoms that were not present at baseline but emerged during ketamine administration. The protocol was registered at ClinicalTrials.gov on Jan 2, 2020 (NCT04226963).</p> Results <p>Sleep disturbances were the most consistently reported psychiatric TEAEs, with nighttime sleep problems increasing by the 7th infusion and persisting at follow-up (<i>n</i> = 5), and early waking reported across timepoints (<i>n</i> = 3–4). Appetite and weight changes were also observed, with both increased and decreased appetite peaking early in treatment (<i>n</i> = 7 and <i>n</i> = 6 at the 3rd infusion) and persisting at lower levels at follow-up. In contrast, mood, cognitive, and most somatic symptoms were rare (≤ 2–4 participants), and suicidal ideation was minimal (<i>n</i> = 1 at the 3rd infusion and follow-up).</p> Conclusions <p>This study identified sleep disturbances, appetite changes, and weight fluctuations as common patient-reported TEAEs during ketamine use for TRD inpatients. These preliminary results highlight the need for larger, controlled trials to gain a comprehensive understanding of ketamine’s psychiatric safety profile.</p>