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Clinical Trial
. 2025 Sep 15:385:119414.
doi: 10.1016/j.jad.2025.119414. Epub 2025 May 15.

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

Brandan K Penaluna  1 , Jennifer L Vande Voort  2 , William V Bobo  3 , Vanessa Pazdernik  4 , Eric D Achtyes  5 , Fernando S Goes  6 , John F Greden  7 , Sagar V Parikh  7 , Mark A Frye  2 , Balwinder Singh  2
Affiliations
Clinical Trial

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

Brandan K Penaluna et al. J Affect Disord. .

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.

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Conflict of interest statement

Declaration of competing interest WVB's research has been supported by NIH, AHRQ, the National Science Foundation, the Myocarditis Foundation, the Watzinger Foundation, the Blue Gator Foundation, and the Mayo Foundation for Medical Education and Research. He has contributed chapters to UpToDate regarding the pharmacological treatment of bipolar disorders. He is co-inventor on US Patent No. 11869633 B2, an analytics and machine learning framework for antidepressive response prediction. EDA has received research support from the following entities in the preceding 12 months: Boehringer-Ingelheim, Janssen, Karuna, Neurocrine Biosciences, and Teva. EDA also has served on advisory boards or consulted with Alkermes, Boehringer-Ingelheim, Clinical Care Options, CMEology, CME Outfitters, Healthcare Global Options, and VML Health. SVP has received research support or consulting income from the Canadian Institutes of Health Research, Ontario Brain Institute, Patient-Centered Outcomes Research Institute, the National Network of Depression Centers, Breakthrough Discoveries for Thriving with Bipolar Disorder, Abbvie, Aifred, Biogen, Boehringer-Ingelheim, Compass, Janssen, Myriad, Otsuka, and Sage. MAF has received research grant support from Assurex Health, Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), Mayo Foundation. MAF is supporterd by Carnot Laboratories, American Physician Institute. MAF has financial interest in Chymia, LLC. BS has received research grant support from Mayo Clinic, the National Network of Depression Centers (NNDC), Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2) and NIH. He is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the National Center for Advancing Translational Science (NCATS). BS has received honoraria (to institution) from Elsevier for editing a Clinical Overview on Treatment-Resistant Depression.

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