Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions

N Kappelmann, G Lewis, R Dantzer, P B Jones, G M Khandaker, N Kappelmann, G Lewis, R Dantzer, P B Jones, G M Khandaker

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 randomised controlled trials (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-tumour necrosis factor 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. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (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. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.

Conflict of interest statement

The authors have no competing financial interests in relation to the work described. PBJ received an honorarium that he donated to his department, from Roche (UK) for taking part in an advisory board to advise on education about schizophrenia for psychiatrists. RD received consulting fee and honorarium from Ironwood Pharma (USA) and Pfizer (France).

Figures

Figure 1
Figure 1
PRISMA Flow diagram of study selection for systematic review.
Figure 2
Figure 2
Meta-analysis of antidepressant activity of anti-cytokine treatment. (a) Meta-analysis of RCTs of anti-cytokine drug vs. placebo. (b) Meta-analysis of RCTs of anti-cytokine drug plus DMARD vs. DMARD. (c) Meta-analysis of other trials (non-randomised and/or non-placebo). CI, confidence interval; DMARD, Disease Modifying Anti-rheumatoid Drug; RCT, randomised controlled trial.
Figure 3
Figure 3
Antidepressant activity of anti-TNF treatment: meta-analysis of RCTs. CI, confidence interval; RCT, randomised controlled trial; TNF, tumor necrosis factor.
Figure 4
Figure 4
Meta-regression of the association between antidepressant effects and improvements in physical illness. P-value for meta-regression slope indicates no statistically significant association between antidepressant effect of anti-cytokine treatment and improvement in physical illness. The Figure shows that the antidepressant effect does not change significantly (that is, increase or decrease) across the range of effect estimates for physical illness. SMD, standardised mean difference.

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