Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Antidepressive Agents/*therapeutic use ; Antirheumatic Agents/*therapeutic use ; Biomarkers/*blood ; Bipolar Disorder/*drug therapy ; Cytokines/*metabolism ; Extracellular Vesicles/*immunology ; Infliximab/*therapeutic use; Adolescent ; Adult ; Aged ; Antidepressive Agents/pharmacology ; Antirheumatic Agents/pharmacology ; Double-Blind Method ; Female ; Humans ; Infliximab/pharmacology ; Male ; Middle Aged ; Young Adult

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants ( n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ ² = 9.275, p = 0.026), NF-κB (χ ² = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα) (χ ² = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ ² = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

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K08 CA237528 United States CA NCI NIH HHS

Keywords: bipolar disorder; childhood trauma; cytokines; depression; inflammation

0 (Antidepressive Agents)
0 (Antirheumatic Agents)
0 (Biomarkers)
0 (Cytokines)
B72HH48FLU (Infliximab)

Date Created: 20200410 Date Completed: 20210316 Latest Revision: 20210316

20231215

PMC7226726

10.3390/cells9040895

32268604