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

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.

SUBMITTER: Kappelmann N

PROVIDER: S-EPMC5794896 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Kappelmann N N Lewis G G Dantzer R R Jones P B PB Khandaker G M GM

Molecular psychiatry 20161018 2

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 an ...[more]

PMID: 27752078

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Project description:Background:There is debate in the literature as to whether inclusion of a placebo arm may alter characteristics of antidepressant trials. However, previous research has focused on response rates of various antidepressants on average only, ignoring potential differences among drugs or other aspects of trial findings. Little is known about the impact of a placebo arm on all-cause dropout and dropout due to adverse events. Methods:We carried out a systematic review of published and unpublished double-blind randomized controlled trials (RCTs) for the acute treatment of unipolar major depression (update: January 2016). The probability of being allocated to placebo (?) was the exposure of interest, and we examined its influence on responders (efficacy), all-cause dropouts (acceptability) and dropouts due to adverse events (tolerability), while accounting for differences in drugs, trials and patient characteristics in multivariate random effects meta-regression. Results:We included 421 studies (68 305 participants) comparing 16 antidepressants or placebo; ? ranged from 20% to 50%. Response rate was lower [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.83, 0.92] and all-cause dropout rate higher (RR 1.19; 95% CI 1.08, 1.31) for the same antidepressants in placebo-controlled trials compared with head-to-head trials. The probability of responding decreased by 3% (95% CI 2-5%) for every 10% increase in ?, whereas the risk of all-cause dropout increased by 4% (95% CI 1-7%). Tolerability was unaffected by ?. Response rate was inversely correlated with dropouts due to any cause (correlation coefficient -0.48; 95% CI -0.58, -0.36) and due to adverse events (-0.34; 95% CI -0.44, -0.23). Conclusions:For the same antidepressant, response rate was on average smaller and dropouts higher when placebo was included; however, no association was found with dropouts due to adverse events. Decreased patient expectations, larger dropout rates and use of inappropriate statistical methods to impute missing data may explain this phenomenon. The findings call for caution in the integration of randomized evidence involving placebo arms.

Project description:Advantages and possible risks associated with steroid injection compared with nonsteroidal anti-inflammatory drugs (NSAIDs) for shoulder pain are not fully understood. To compare the efficiency and safety of steroid injection versus NSAIDs for patients with shoulder pain. PubMed, Embase, and the Cochrane Library were searched through July 2015. Study eligibility criteria, participants, and interventions: randomized controlled trials (RCTs) that assessed steroid injection versus NSAIDs for patients with shoulder pain. Study appraisal and synthesis methods: predefined primary efficacy outcome was functional improvement; and secondary efficacy outcomes included pain relief and complications. Relative risks (RRs) and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using a random-effects model accounting for clinical heterogeneity. Eight RCTs involving 465 participants were included in the meta-analysis. Five trials compared steroid injection with oral NSAIDs, and 3 compared steroids injection with NSAIDs injection. Compared with steroid injection, oral NSAIDs were less effective in 4 or 6 weeks for functional improvement (SMD 0.61; 95% CI, 0.08-1.14; P?=?0.01), while there was no significant difference in pain relief (SMD 0.45; 95% CI, -0.50-1.40; P?<?0.00001) or complication rate (RR 1.10; 95% CI, 0.26-4.58; P?=?0.29). Meta-analysis was not performed for NSAIDs injection due to considerable heterogeneity. Conflicting results were observed in favor of either steroid or NSAIDs injection. Not all diseases that can lead to shoulder pain were included, detailed intervention protocols were inconsistent across studies, and some estimated data were input into comparison while some data were lost, which could exert an influence on pooled results. Steroid injection, compared with oral NSAIDs, provides slightly more improvement in shoulder function without superiority in pain relief or risk of complications at 4 to 6 weeks. Treatment decision should be made based on diseases. NSAIDs injection might be a treatment method for shoulder pain.

Dataset Information

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

Publications

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

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