Lack of relationships between ketamine treatment and peripheral neurotrophic and inflammatory factors in a randomized controlled ketamine trial of major depressive disorder.
Manivel Rengasamy, Benjamin Panny, Zakary Hutchinson, Anna L. Marsland, Tessa Kovats, Angela Griffo, Crystal Spotts, Robert H Howland, Meredith L Wallace, Sanjay J. Mathew, Shabnam Hossein, Rebecca B Price
Brain, behavior, and immunity April 4, 2025 DOI: 10.1016/j.bbi.2025.04.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 133 |
| Population | Adults with treatment-resistant depression |
| Interventions | Ketamine Saline |
| Dose | 0.5 mg/kg |
| Duration | Single-dose infusion, five-day post-infusion period |
| Topics | Ketamine Depression Esketamine |
| Keywords | Antidepressant Bdnf Cytokines Inflammation Rct Depression treatment Ketamine administration Biomarkers biological markers Blood markers |
| Citations | 3 |
| Key findings | No differences were found between ketamine and saline groups in peripheral neurotrophic and inflammatory factor levels, their association with depression trajectories, or baseline levels predicting depression outcomes, except that in low-BMI participants, increasing IL-1RA was linked to less early improvement. |
Abstract
Ketamine is a rapid-acting treatment for treatment-resistant depression (TRD), though mechanisms related to ketamine's effects remain unclear. Blood-based neurotrophic and inflammatory factors (NIFs; e.g., brain-derived neurotrophic factor, interleukin-6) have emerged as markers potentially linked to ketamine and ketamine treatment response. In this secondary analysis of a randomized controlled trial (RCT), 133 adults with TRD received a single-dose infusion of ketamine (n = 89; 0.5 mg/kg) or saline (n = 44) and provided measures of peripheral blood NIF levels and depression severity across a five-day post-infusion period. Differences between ketamine and saline groups were examined for (1) NIF levels, (2) associations between NIF trajectories and depression score trajectories, and (3) associations between baseline NIF levels and depression score trajectories. Subgroup sensitivity analyses examined identical relationships within many (n = 28) discrete subgroups of individuals. No differences were found between ketamine and saline cohorts for NIF trajectories, associations of NIF and depression trajectories, or associations of baseline NIF levels and depression trajectories. On subgroup analyses, in participants with lower BMI (BMI < 25; n = 66), increasing interleukin-1 receptor antagonist (IL-1RA) trajectories post-ketamine were associated with less improvement in depression in the first day post-infusion. Associations between ketamine treatment and peripheral neurotrophic/inflammatory factors were not detected in our RCT of 133 adults with TRD. The sole exception across exhaustive sensitivity analyses was that, in individuals with low BMI, increases in IL-1RA levels may be linked to worse immediate treatment response. Future research investigating CNS-specific NIF activity is needed to more definitively test the posited role of NIFs in ketamine's antidepressant mechanisms.