Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression

Abstract

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher-and sTNFR1 levels were significantly lower-in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Bipolar disorder; Cytokine; Interleukin-6 (IL-6); Ketamine; Major depressive disorder; Soluble tumor necrosis factor receptor 1 (sTNFR1).

Published by Elsevier Ltd.

Figures

Figure 1

Significant but transient changes in cytokine levels in patients with major depressive disorder (MDD) or bipolar disorder (BD) over time. (a) sTNFR1 and (b) IL-6 levels at −60 minutes (pre-treatment), 230 minutes, 1 day, and 3 days post-infusion. *p<.001>

Figure 1

Significant but transient changes in cytokine levels in patients with major depressive disorder (MDD) or bipolar disorder (BD) over time. (a) sTNFR1 and (b) IL-6 levels at −60 minutes (pre-treatment), 230 minutes, 1 day, and 3 days post-infusion. *p<.001>

Figure 2

Differential cytokine profiles by diagnosis, co-varying for baseline level. (a) IL-6 and (b) TNF-α were overall significantly higher in patients with bipolar disorder (BD) versus those with major depressive disorder (MDD). (c) sTNFR1 was significantly lower in BD patients compared to MDD patients at day 1.

Figure 2

Differential cytokine profiles by diagnosis, co-varying for baseline level. (a) IL-6 and (b) TNF-α were overall significantly higher in patients with bipolar disorder (BD) versus those with major depressive disorder (MDD). (c) sTNFR1 was significantly lower in BD patients compared to MDD patients at day 1.

Figure 2

Differential cytokine profiles by diagnosis, co-varying for baseline level. (a) IL-6 and (b) TNF-α were overall significantly higher in patients with bipolar disorder (BD) versus those with major depressive disorder (MDD). (c) sTNFR1 was significantly lower in BD patients compared to MDD patients at day 1.