TY - JOUR
T1 - Effects of immunomodulatory drugs on depressive symptoms
T2 - A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders
AU - MRC ImmunoPsychiatry Consortium
AU - Wittenberg, Gayle M.
AU - Stylianou, Annie
AU - Zhang, Yun
AU - Sun, Yu
AU - Gupta, Ashutosh
AU - Jagannatha, P. S.
AU - Wang, Dai
AU - Hsu, Benjamin
AU - Curran, Mark E.
AU - Khan, Shahid
AU - Vértes, Petra E.
AU - Cardinal, Rudolf
AU - Richardson, Sylvia
AU - Leday, Gwenael
AU - Freeman, Tom
AU - Hume, David
AU - Regan, Tim
AU - Wu, Zhaozong
AU - Pariante, Carmine
AU - Cattaneo, Annamaria
AU - Zunszain, Patricia
AU - Borsini, Alessandra
AU - Stewart, Robert
AU - Chandran, David
AU - Carvalho, Livia
AU - Bell, Joshua
AU - Souza-Teodoro, Luis Henrique
AU - Perry, Hugh
AU - Harrison, Neil
AU - Jones, Declan
AU - Henderson, Robert B.
AU - Chen, Guang
AU - Bullmore, Edward T.
AU - Drevets, Wayne C.
PY - 2019/9/19
Y1 - 2019/9/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070810380&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0471-8
DO - 10.1038/s41380-019-0471-8
M3 - Review article
AN - SCOPUS:85070810380
SN - 1359-4184
VL - 25
SP - 1275
EP - 1285
JO - Molecular Psychiatry
JF - Molecular Psychiatry
M1 - 25
ER -