TY - JOUR
T1 - Antidepressant activity of anti-cytokine treatment
T2 - A systematic review and meta-analysis of clinical trials of chronic inflammatory conditions
AU - Kappelmann, N.
AU - Lewis, G.
AU - Dantzer, R.
AU - Jones, P. B.
AU - Khandaker, G. M.
N1 - Funding Information:
GMK is supported by an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z), a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (grant no. 80354) and a Gosling Fellowship from the Royal College of Psychiatrists, UK (2015). PBJ acknowledges grant support from the Wellcome Trust (095844/Z/11/Z and 088869/Z/09/Z) and NIHR (RP-PG-0606-1335, Cambridge Biomedical Research Centre and CLAHRC East of England). RD has received grants from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (grants R01 NS073939; R01 NS074999). We would like to thank the following individuals for supplying additional data for meta-analysis: Dr Daphne Guh, Centre for Health Evaluation and Outcome Sciences, Canada; Dr Sara Berkö, BiogenIdec Sweden AB, Sweden; Dr Anders Svenningsson, Umea University and University Hospital of Northern Sweden, Sweden; Dr Eric Simpson, University of Rochester Medical Centre, USA; Dr Catherine Au, Regeneron Pharmaceuticals, USA; Professor Laure Gossec, Pierre and Marie Curie University, France; Dr Tina Bhutani, University of California San Francisco, CA, USA. We would also like to thank Dr Valter Silva, Federal University of São Paulo, Brazil for his correspondence regarding data extraction methodology, and Dr Jan Stochl, University of Cambridge, UK for helpful comments on an earlier version of this manuscript.
Funding Information:
GMK is supported by an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z), a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (grant no. 80354) and a Gosling Fellowship from the Royal College of Psychiatrists, UK (2015). PBJ acknowledges grant support from the Wellcome Trust (095844/Z/11/Z and 088869/Z/09/Z) and NIHR (RP-PG-0606-1335, Cambridge Biomedical Research Centre and CLAHRC East of England). RD has received grants from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (grants R01 NS073939; R01 NS074999). We would like to thank the following individuals for supplying additional data for meta-analysis: Dr Daphne Guh, Centre for Health Evaluation and Outcome Sciences, Canada; Dr Sara Berkö, BiogenIdec Sweden AB, Sweden; Dr Anders Svenningsson, Umeå University and University Hospital of Northern Sweden, Sweden; Dr Eric Simpson, University of Rochester Medical Centre, USA; Dr Catherine Au, Regeneron Pharmaceuticals, USA; Professor Laure Gossec, Pierre and Marie Curie University, France; Dr Tina Bhutani, University of California San Francisco, CA, USA. We would also like to thank Dr Valter Silva, Federal University of São Paulo, Brazil for his correspondence regarding data extraction methodology, and Dr Jan Stochl, University of Cambridge, UK for helpful comments on an earlier version of this manuscript.
Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84991677408&partnerID=8YFLogxK
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U2 - 10.1038/mp.2016.167
DO - 10.1038/mp.2016.167
M3 - Article
C2 - 27752078
AN - SCOPUS:84991677408
SN - 1359-4184
VL - 23
SP - 335
EP - 343
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 2
ER -