Tolerance-inducing effect and properties of innate immune stimulation on chronic stress-induced behavioral abnormalities in mice

Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants. To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. Double-blind, placebo-controlled, randomized clinical trial. Outpatient infusion center at Emory University in Atlanta, Georgia. A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial. The 17-item Hamilton Scale for Depression (HAM-D) scores. No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups. This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. clinicaltrials.gov Identifier: NCT00463580.

A novel test procedure for antidepressants was designed in which a mouse is suspended by the tail from a lever, the movements of the animal being recorded. The total duration of the test (6 min) can be divided into periods of agitation and immobility. Several psychotropic drugs were studied: amphetamine, amitriptyline, atropine, desipramine, mianserin, nomifensine and viloxazine. Antidepressant drugs decrease the duration of immobility, as do psychostimulants and atropine. If coupled with measurement of locomotor activity in different conditions, the test can separate the locomotor stimulant doses from antidepressant doses. Diazepam increases the duration of immobility. The main advantages of this procedure are the use of a simple, objective test situation, the concordance of the results with the validated "behavioral despair" test from Porsolt and the sensitivity to a wide range of drug doses.

‘Innate immune memory’ is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished, training and tolerance, which are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages, microglia, that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis while tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.