Journal Article

Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders

Freeman, Tom, Jagannatha, P S, Henderson, Robert B, Borsini Alessandra, Chandran, David, Wang, Dai, Curran, Mark E, Wittenberg, Gayle M, Hume, David, Regan, Tim, Vértes, Petra E, Chen, Guang, Carvalho Livia, Cardinal Rudolf, Richardson, Sylvia, Stewart, Robert, Khan, Shahid, Leday Gwenael, Gupta, Ashutosh, Jones, Declan, Wu Zhaozong, Bell, Joshua, Drevets, Wayne C, Stylianou, Annie, Zhang, Yun, Pariante Carmine, Sun, Yu, Harrison, Neil, Bullmore, Edward T, Zunszain, Patricia, Souza-Teodoro, Luis Henrique, Hsu, Benjamin, Perry, Hugh, Cattaneo Annamaria

2020

Overview

Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4–16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12–0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20–1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26–0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06–0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.

• Publisher: Nature Publishing Group
• Subject: Antibodies / CD20 antigen / Clinical trials / Cyclooxygenase-2 / Hedonic response / Immune system / Immunomodulation / Immunomodulators / Immunosuppressive agents / Inflammatory diseases / Innate immunity / Interleukin 12 / Interleukin 6 / Mental depression / Mental health / Mood / Patients / Placebos / Tumor necrosis factor-α