Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms

A third of patients receiving Interferon-alpha (IFN-alpha) treatment for Hepatitis-C develop major depressive disorder (MDD). Conversely, anti-Tumor Necrosis Factor (TNF) therapies improve depression providing key empirical support for the inflammatory theory of depression. Heightened amygdala reactivity (particularly to negatively valanced stimuli) is a consistent finding within MDD; can predict treatment efficacy and reverses following successful treatment. However, whether IFN-alpha and anti-TNF enhance/attenuate depressive symptoms through modulation of amygdala emotional reactivity is unknown. Utilizing a prospective study design, we recruited 30 patients (mean 48.0 +/- 10.5 years, 21 male) initiating IFN-alpha treatment for Hepatitis-C and 30 (mean 50.4 +/- 15.7 years, 10 male) anti-TNF therapy for inflammatory arthritis. All completed an emotional face-processing task during fMRI and blood sampling before and after their first IFN-alpha (4-h) or anti-TNF (24-h) injection and follow-up psychiatric assessments for 3 months of treatment. IFN-alpha significantly increased depression symptoms (Hamilton Depression Rating Scale HAM-D) at 4 weeks (p < 0.001) but not 4-h after first dose (p > 0.1). Conversely, anti-TNF significantly improved depressive symptoms (Hospital Anxiety and Depression Rating Scale HADS) at both 24-h (P = 0.015) and 12 weeks (p = 0.018). In support of our a-priori hypothesis, both IFN-alpha and anti-TNF significantly modulated amygdala reactivity with IFN-alpha acutelyenhancingright amygdala responses to sad (compared with neutral) faces (p = 0.032) and anti-TNF converselydecreasingright amygdala reactivity (across emotional valence) (p = 0.033). Furthermore, these changes predicted IFN-induced increases in HAM-D 4 weeks later (R-2 = 0.17,p = 0.022) and anti-TNF-associated decreases in HADS at 24-h (R-2 = 0.23,p = 0.01) suggesting that actions of systemic inflammation on amygdala emotional reactivity play a mechanistic role in inflammation-associated depressive symptoms.

Automated summary

Patients receiving IFN-α treatment for Hepatitis-C showed significant increase in depressive symptoms at 4 weeks, whereas those receiving anti-TNF therapy for inflammatory arthritis exhibited marked improvement in depressive symptoms at 24 hours and 12 weeks. The study found that both IFN-α and anti-TNF significantly modulated amygdala reactivity, with IFN-α enhancing right amygdala responses to sad faces and anti-TNF decreasing right amygdala reactivity.