507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review

Abstract Background Esketamine, the S-enantiomer of ketamine, is an NMDA receptor antagonist approved for treatment-resistant depression (TRD). Although regulated clinical trials suggest a low risk of misuse, concerns remain that esketamine exposure may facilitate transition to ketamine dependence, particularly in East Asia where illicit ketamine is widely available. Aims & Objectives To describe a clinical case with a temporal association between esketamine treatment and subsequent development of ketamine use disorder, and to discuss potential mechanisms and monitoring implications.

Method: We reviewed the patient’s longitudinal psychiatric and substance-use history to reconstruct a clinical timeline. Depressive symptoms were assessed using standardized instruments. We also conducted a focused narrative review of the literature on ketamine/esketamine and depression.

Results: Mr A, a 41-year-old man with no family history of major psychiatric disorders, was admitted for severe ketamine use disorder. He had experienced depressive symptoms since age 20 with multiple treatment trials and hospitalizations and had a prior diagnosis of zolpidem use disorder. He denied use of other psychoactive substances before initiating ketamine. At ages 35–37, he received two induction courses of intranasal esketamine followed by weekly maintenance (84 mg) for approximately three years, achieving significant improvement in depressive symptoms (CGI-S 7 to 4) with only mild dissociation. Toward the end of treatment, he developed anxiety regarding continued access and initiated illicit ketamine use by snorting, which rapidly escalated to 2–3 g/day, accompanied by tolerance, dissociation, cravings, urinary symptoms, and withdrawal features. Intermittent nitrous oxide and cannabis use was reported, with minimal craving. Depressive symptoms subsequently worsened. At age 41, he attempted suicide in the context of escalating ketamine use and occupational stressors and was hospitalized. Baseline depression severity was high, with a positive ketamine screen. His psychotropic regimen was maintained, naltrexone was initiated, and psychotherapy provided, resulting in marked improvement in depressive symptoms at discharge after three weeks. Discussion & Conclusions Ketamine shows a dose-dependent trade-off between antidepressant efficacy and abuse liability. At subanesthetic doses, NMDA receptor blockade on GABAergic interneurons enhances AMPA receptor activation and downstream mTOR–BDNF signaling, promoting synaptogenesis and rapid antidepressant effects. However higher-dose exposure may suppress BDNF and mTOR signaling by broadly inhibiting neuronal network activity and glutamatergic transmission, thereby attenuate BDNF/mTOR-linked plasticity and diminish antidepressant efficacy. Esketamine, approved for TRD under strict regulatory frameworks, was initially considered to have low addiction risk; however, emerging real-world and pharmacovigilance data report infrequent but notable abuse-related signals, including dissociation and withdrawal-like symptoms. This concern is particularly salient in Asia, including Taiwan, where illicit ketamine remains broadly accessible. The present case is consistent with temporality and biological plausibility linking prolonged esketamine exposure with subsequent ketamine use disorder, although causality cannot be inferred from a single observation. Clinically, these findings emphasize the need for careful patient selection, psychoeducation, and close monitoring for early drug liking, craving, and drug-seeking behaviors during and after esketamine treatment, with extended follow-up in high-risk regions. This case emphasizes the need for careful patient selection, psychoeducation, and close monitoring for reinforcement, tolerance, and craving during and after esketamine treatment, particularly in regions with high ketamine availability.