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

Abstract

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.

Fig. 1

High depressive symptoms in clinical trial participants at baseline. a Left panel, percentage of patients meeting criteria for high depressive symptoms at baseline for each trial, grouped by the primary disease treated in the study. Abbreviations: rheumatoid arthritis (RA), multicentric Castleman’s disease (MCD). Right panel, boxplot indicating significantly higher percentage of patients with high depressive symptoms in RA studies compared with other studies combined. The box and whiskers plot indicates median value, interquartile range and extreme values. b Scatterplot of percentage of patients with high depressive symptom scores at baseline vs. mean baseline C-reactive protein (CRP). Each point corresponds to a study

Fig. 2

Effects of immunomodulatory drugs (overall and classified by mechanism of action) on depressive symptoms in high depressive stratum of patients. a Change in depressive symptom scores from baseline to follow-up visit was compared between active treatment and placebo arms. The standardized mean difference (SMD) is a measure of placebo-controlled antidepressant effect size that can be compared and combined across studies. b Immunomodulatory drug effects on depressive symptoms were estimated by a linear model including the primary disease symptom scale appropriate for each study (Table 1) as a covariate to control for drug effects on physical health outcome. c Immunomodulatory drug effects on depressive symptoms were estimated only in the subgroup of high depressive patients who did not respond physically to drug treatment (non-responders)

Fig. 3

Effects of immunomodulatory drugs (overall and classified by mechanism of action) on SF-36 Mental Health Component (MC) scores in the high depressive stratum of patients. a Change in SF-36 MC scores from baseline to follow-up visit was compared between active treatment and placebo arms. The standardized mean difference (SMD) is a measure of placebo-controlled antidepressant effect size that can be compared and combined across studies. b Immunomodulatory drug effects on SF-36 MC scores were estimated by a linear model including the primary disease symptom scale appropriate for each study (Table 1) as a covariate to control for drug effects on physical health outcome

Fig. 4

Effects of immunomodulatory drugs (overall and classified by mechanism of action) on SF-36 Vitality Domain scores in the high depressive stratum of patients. a Change in SF-36 vitality domain scores from baseline to follow-up visit was compared between active treatment and placebo arms. The standardized mean difference (SMD) is a measure of placebo-controlled antidepressant effect size that can be compared and combined across studies. b Immunomodulatory drug effects on SF-36 vitality domain scores were estimated by a linear model including the primary disease symptom scale appropriate for each study (Table 1) as a covariate to control for drug effects on physical health outcome