Browsing by Author "Merad, Miriam"

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    Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome.
    Kiraly, D. D.; Horn, S. R.; Van Dam, N. T.; Costi, S.; Schwartz, J.; Kim-Schulze, S.; Patel, M.; Hodes, Georgia E.; Russo, Scott J.; Merad, Miriam; Iosifescu, D. V.; Charney, D. S.; Murrough, J.W. (2017-03-21)
    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.
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    Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice
    Wang, Jun; Hodes, Georgia E.; Zhang, Hongxing; Zhang, Song; Zhao, Wei; Golden, Sam A.; Bi, Weina; Menard, Caroline; Kana, Veronika; Leboeuf, Marylene; Xie, Marc; Bregman, Dana; Pfau, Madeline L.; Flanigan, Meghan E.; Estebam-Fernández, Adelaida; Yemul, Shrishailam; Sharma, Ali; Ho, Lap; Dixon, Richard A.; Merad, Miriam; Han, Ming-Hu; Russo, Scott J.; Pasinetti, Giulio M. (Nature, 2018)
    Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a highthroughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3′-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stresssusceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.