Clinical correlates of non-responders to ketamine in terms of self-assessed life engagement among treatment-resistant depression patients.

Background: Major depressive and bipolar disorders are leading causes of disability, with many patients developing treatment-resistant depression (TRD/TRBD). Ketamine offers rapid symptom relief, yet recovery extends beyond symptoms. Life engagement (LE) is a key patient-centered outcome encompassing the ability to experience pleasure, function effectively, and participate in meaningful activities but remains understudied. This study examines clinical and sociodemographic correlates of LE non-response following short-term ketamine intervention.

Methods: A retrospective analysis using data from naturalistic, observational registries of 65 inpatients with treatment-resistant major depressive disorder or bipolar depression (NCT04226963 and NCT05565352). Patients received short-term ketamine (IV:0.5 mg/kg; oral:2.0-2.5 mg/kg) as add-on intervention over four weeks. Patients were stratified as responders or non-responders based on ≥50% Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10 LE score reduction. Groups were compared on sociodemographic and clinical variables.

Results: 33 patients (50.8%) were classified as non-responders. Sociodemographic and baseline clinical variables were similar between groups. Non-responders had later depression onset (39.5 vs 24.5 years; p = 0.0257), more frequent prior ECT (40% vs 9.4%; p = 0.0084), no comorbid diabetes (vs 21.9%; p = 0.0048), and differed in employment status (p = 0.0171). These findings are preliminary and require confirmation in larger samples.

Conclusions: In this post-hoc analysis LE non-response among TRD patients was associated with depression later onset, prior ECT, absence of diabetes, and occupational inactivity. This may reflect greater illness severity, psychosocial burden, and a lack of potential neuroplasticity enhancement through metabolic pharmacotherapy. Pharmacological treatment alone may be insufficient to improve LE, underscoring the need to integrate psychosocial and behavioral interventions.