Clinical correlates of anhedonia non-response to ketamine in treatment-resistant depression

Anhedonia, a core symptom of major depressive disorder (MDD), is associated with illness severity, suicide risk, poor functioning, and predicts poor response to antidepressants. While no treatments are approved, ketamine and esketamine show promise in reducing anhedonia. This study examines clinical and sociodemographic features linked to anhedonia treatment response in treatment-resistant depression (TRD) inpatients receiving short-term ketamine as an add-on to standard care.

A retrospective analysis using data from naturalistic, observational registries of 34 inpatients with treatment-resistant major depressive disorder (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% Snaith-Hamilton Pleasure Scale (SHAPS) score reduction. Groups were compared on sociodemographic and clinical variables.

16 patients (47.1%) were non-responders. No significant differences were detected among sociodemographic and clinical features beyond the lower prior substance use disorder, fewer depressive episodes and differed in marital status. Non-responders were more prone to be single. A multivariable logistic regression model including these three predictors was globally significant (p = 0.024), with all predictors retaining consistent direction of association. The distribution of IV and oral ketamine administration was balanced between groups (p = 0.68).

In this exploratory study, anhedonia non-response was associated with fewer lifetime depressive episodes, lower rates of substance use disorder, and single marital status. These characteristics underscore the demographic context of psychosocial factors in determining anhedonia treatment outcomes among ketamine non-responders and the importance of adopting a personalized approach to treatment in mood disorders.