Abstract
A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg−1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.
Highlights
Major depressive disorder (MDD) is a debilitating condition that can have profound effects on both the mind and the body of individuals who suffer from the disorder
We found that patients who went on to respond to ketamine had significantly lower pretreatment levels of fibroblast growth factor 2 (FGF-2) (P = 0.0001 unadjusted; P = 0.03 in a model correcting for covariates; Figure 3a) and IL-1ra (P = 0.0035 unadjusted; P = 0.033 in a model correcting for covariates)
In performing a broad characterization of inflammatory signaling pathways, we found a unique serum profile not previously described within a group of treatment-resistant depression (TRD) patients
Summary
Major depressive disorder (MDD) is a debilitating condition that can have profound effects on both the mind and the body of individuals who suffer from the disorder. The mechanisms of treatment resistance are not well understood, TRD patients represent a large fraction of patients with MDD2—making the understanding of pathophysiology and alternative treatment strategies a critical research aim. Numerous studies have measured alterations in cytokines in the blood and cerebrospinal fluid (CSF) of patients with major depression,[3,4,5,6] and elevated levels of cytokines in adolescence have been associated with increased susceptibility to depression in adulthood.[7] Some studies point to a role for increased inflammation in patients with TRD.[4,8,9] these findings have been consistently reported, there is considerable variability between individuals, and anti-inflammatory treatments for depression in patients not pre-screened for elevated inflammatory markers have far only limited clinical efficacy.[10,11] This has led to the hypothesis that there is a subset of MDD cases, enriched in TRD populations, driven by inflammatory processes, whereby anti-inflammatory treatments have the potential to be viable alternative treatment strategies.[3,4]
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