Abstract
Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti- cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven RCTs involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD) = 0.40, 95% confidence interval (CI), 0.22–0.59). Anti-TNF drugs were most commonly studied (five RCTs); SMD = 0.33 (95% CI, 0.06–0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD = 0.19 (95% CI, 0.00–0.37) and 0.51 (95% CI, 0.34–0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Furthermore, antidepressant effect was associated with depressive symptom severity at baseline (p = 0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects.
Highlights
The association between the immune system and the brain may offer new mechanistic understanding and insights for novel therapies for depression
We report a systematic review and meta-analysis of secondary data from clinical trials of anti-cytokine treatment in chronic inflammatory conditions to address the following key outstanding questions: (1) does blocking-specific inflammatory cytokine pathways lead to improvement in depressive symptoms; (2) what is the relationship between the antidepressant effect and the improve
Additional analyses based on randomised controlled trial (RCT) indicated that the antidepressant effect was associated with severity of depressive symptoms at baseline, but not with improvement in physical illness, sex and age of participants, or study duration
Summary
The association between the immune system and the brain may offer new mechanistic understanding and insights for novel therapies for depression. A meta-analysis of randomised controlled trials (RCTs)[15] of nonsteroidal anti-inflammatory drugs (NSAIDs), given as sole treatment or as adjunct to antidepressants, indicates that they may be more effective than placebo in treating depression (Cohen’s d = 0.27; 95% confidence interval (CI), 0.08–0.45),[16] there are limitations of individual studies included such as attrition. Heterogeneity between studies was investigated by calculating the Cochrane’s heterogeneity statistic Q and the I2 statistic that represents the fraction of variation between studies attributable to heterogeneity.[32] ment in physical illness; (3) is the antidepressant effect related to baseline severity of depressive symptoms; (4) is there any sex or age difference of the antidepressant effect Answers to these questions would provide important clues on whether inflammatory cytokines have a causal role in depression, and whether cytokine modulators may be useful for treating depression. One RCT35 administered adalimumab to all participants for 4 weeks before randomising them to placebo or adalimumab for subsequent 52 weeks, so we included data from
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