Utilizing depression symptom-based phenotypes to explore ketamine treatment response in major depression: The Bio-K multicenter trial

Abstract

Background: Previous work has identified four correlated factors (depression phenotypes) using the Montgomery-Åsberg Depression Rating Scale (MADRS)- Sadness, Negative Thoughts, detachment/Interest and Activity (IA), and Neurovegetative. We explored treatment responses to ketamine based on these 4 phenotypes in treatment resistant depression (TRD).

Methods: This is a secondary analysis of data from an open-label multi-center, clinical trial (BioK) examining biomarkers of treatment response, that enrolled 75 patients (ages 18-65 years old) with treatment-resistant unipolar or bipolar depression, excluding those with an active substance use disorder, psychosis, and unstable medical conditions. Pre-existing treatments were continued. Participants received 3 IV ketamine infusions over an 11-day period (acute phase). Depressive symptoms were measured using MADRS, with the four phenotypes assigned as positive or negative based on the total subset MADRS score. Change in depressive symptoms and odds of remissions (MADRS<10 after infusion #3) were analyzed for all 4 phenotypes.

Results: 53 % of all participants achieved remission by the end of the acute phase. All MADRS phenotypes had significant decreases from baseline in their respective mean factor scores. Negative Thoughts was the least improved after infusion #3. Higher baseline scores for Sadness were associated with lower rates of remission. Neurovegetative was the least responsive to treatment. Males showed significantly greater improvement than females for Sadness phenotype post-infusion #1 that did not persist through the end of the acute phase. A positive Sadness phenotype was associated with reduced odds of remission at the end of the acute phase (OR = 0.32, 95 % CI, 0.10-0.97; p = 0.04).

Conclusion: IV ketamine was associated with improvement across four factor-based depression phenotypes after 3 acute-phase infusions. No meaningful sex differences in antidepressive responses were observed at the end of treatment. A positive Sadness phenotype may be less likely to achieve remission with acute IV ketamine.

Keywords: Bio-K; Ketamine; Phenotypes; Treatment-resistant depression.