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

Introduction

Major depressive disorder and bipolar disorder are leading causes of disability, with depressive episodes driving most of the burden. A substantial proportion of patients develop treatment resistance, including treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD), both associated with poor outcomes and limited response to conventional therapies [1,2]. Rapid-acting antidepressants such as ketamine have improved symptom relief, but broader outcomes are increasingly emphasized. Life engagement, encompassing emotional, social, cognitive, and functional domains, has emerged as a key patient-centered measure of recovery [3].

Aims

This study examines clinical and sociodemographic correlates of life engagement non-response following short-term ketamine intervention among TRD (unipolar and bipolar) patients.

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). Treatment resistance was defined as clinically unsatisfactory response following at least two adequate lines of treatment in terms of dose and duration. Patients received short-term ketamine (IV:0.5 mg/kg; oral:2.0–2.5 mg/kg) as add-on intervention over four weeks with a subsequent 7-day long follow-up. Patients were stratified as responders or non-responders based on ≥50% Inventory of Depressive Symptomatology Self-Report 10 Life Engagement (IDS-SR 10 LE) score reduction at the 7th ketamine administration compared to baseline. Binary variables were analyzed using Fisher’s exact test. For categorical variables with more than two levels, Fisher’s exact test with the Freeman-Halton extension was applied. Groups were compared to sociodemographic and clinical variables. For statistical analysis, the normality of quantitative variables was assessed using the Shapiro-Wilk test. For normally distributed variables, comparisons were made using the t-test; otherwise, the Mann-Whitney U test was applied. A p-value of 0.05 was considered statistically significant.

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 electroconvulsive therapy (ECT) (40% vs 9.4%; p=0.0084), no comorbid diabetes mellitus (vs 21.9%; p=0.0048), and differed in employment status (p=0.0171). No significant differences were found for primary diagnosis (57.6% of TRD and 42.4% of TRBD patients among non-responders; p=0.4603), any psychiatric comorbidities such as: personality disorder, substance use disorder, anxiety disorder, history of trauma. Suicidality current or prior, history of benzodiazepine use and family history of psychiatric disorders were also not associated with responder status. These findings are preliminary and require confirmation in larger samples.

Conclusions

In this post-hoc analysis self-assessed life engagement non-response among TRD and TRBD patients was associated with later onset of depression, higher incidence of prior ECT, absence of diabetes, and higher occupational inactivity. These results 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 life engagement, underscoring the need to integrate psychosocial and behavioral interventions.

References

1. McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry 2023;22:394–412. https://doi.org/10.1002/wps.21120.
2. Vieta E, McIntyre RS, Suppes T, Van Rheenen TE, Singh B, Miskowiak KW, et al. Defining Treatment‐Resistant Bipolar Depression: Recommendations From the ISBD Task Force. Bipolar Disord 2025;27:411–23. https://doi.org/10.1111/bdi.70048.
3. McIntyre RS, Ismail Z, Watling CP, Weiss C, Meehan SR, Musingarimi P, et al. Patient-reported outcome measures for life engagement in mental health: a systematic review. J Patient Rep Outcomes 2022;6:62. https://doi.org/10.1186/s41687-022-00468-5.