ABSTRACT FROM: Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 2014;71:1381–91.
What is already known on this topic
Major depression and depressive symptoms may be associated with an inflammatory state: subgroups of depressed patients show elevated levels of cytokines,1 2 autoimmune diseases and infections are known risk factors for mood disorders3 and treatment with proinflammatory agents induces symptoms of depression.4 This study investigated the promising effects of anti-inflammatory drugs used in addition or instead of traditional antidepressants, which have shown to improve symptoms but where possible adverse side effects are a concern.
Methods of the study
This systematic review evaluated 14 randomised placebo-controlled trials assessing the efficacy and adverse effects of pharmacological anti-inflammatory treatment in 6262 adults with major depression or depressive symptoms. The study included papers published prior to 31 December 2013 and were identified through Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov and relevant review articles. The trials had to allocate participants to: (1) an anti-inflammatory drug or a control group or (2) an anti-inflammatory drug as an add-on treatment to an antidepressant or an antidepressant plus a placebo. Anti-inflammatory drugs considered were non-steroidal anti-inflammatory drug (NSAIDs), COX-2 inhibitors, proinflammatory cytokine inhibitors and minocycline hydrochloride. Data were extracted by two independent reviewers. Pooled SMD and ORs were calculated and the χ2 test for heterogeneity provided an indication of between-trial heterogeneity. Bias risks were assessed by looking at sequence generation, allocation concealment, blinding of outcome assessors, intention to treat and for-profit bias. Outcomes included reduction in depressive symptoms (measured on a continuous scale at the end of an intervention); response (a 50% reduction in depression severity) and remission (a Hamilton Scale for Depression score <7) measured at the end of the intervention, and adverse effects (gastrointestinal and cardiovascular events for NSAIDs and infections for all other drugs, considering that cytokine inhibitors are known to increase the risk for infections).
What does this paper add
This study is the largest evaluation of anti-inflammatory treatments for depressive symptoms, combining data on anti-inflammatory monotherapy and add-on treatment.
Anti-inflammatory treatment reduced depressive symptoms compared with placebo, both for patients with depression and depressive symptoms (standard mean difference, SMD, −0.34; 95% CI −0.57 to 0.11).
The authors found no evidence of an increased number of gastrointestinal (OR 1.04; 95% CI 0.61 to 1.79) or cardiovascular events (OR 2.00; 95% CI 0.25 to 16.08) or infections (OR 1.27; 95% CI 0.89 to 1.82).
Limitations
All trials were associated with a high risk of bias owing to potentially compromised internal validity, which tended to exaggerate treatment effects. Blinded outcome assessment was the only domain in which all studies showed a low risk of bias.
Only 14 out of 53 studies could be included; all had short-term treatment duration, most were small and most of the observed effect sizes were small to medium with high heterogeneity. The possibility of unpublished trial results cannot be excluded.
Not all studies reported on adverse effects (only 6 of them did), so results should be interpreted cautiously, as unfavourable reactions could outweigh any benefits of the treatment.
What next in research
Research to identify subgroups of depressed patients who could benefit from an anti-inflammatory treatment would be useful. Such studies could simultaneously detect levels of several inflammatory molecules in patients at baseline and after treatment, using available screening panels, and correlate changes with response.
Randomised placebo-controlled trials including other anti-inflammatory agents that have shown antidepressant effects, such as aspirin5 and minocycline,6 would be of benefit.
Meta-analysis that includes studies with drugs that improved the effects of antidepressants in randomised placebo-controlled trials, but have speculative anti-inflammatory effects (such as polyunsaturated fatty acids, the antidiabetic pioglitazone, the vigilance-augmenting modafinil) and were therefore not included in this meta-analysis, would also be of benefit.
Do these results change your practices and why?
The results from this study provide a proof-of-concept regarding the use of anti-inflammatory agents as monotherapy or add-on treatment in cases of depressive symptoms. However, adverse side effects have not been appropriately evaluated and it is unclear whether longer term interventions will have any negative consequences. Therefore, care should be taken when considering prescription. It is early days to say whether clinical practice will change. The use of anti-inflammatory drugs could be considered, with caution, in cases of inadequate response to conventional antidepressant treatments.
Acknowledgments
PAZ is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.
Footnotes
Competing interests: PAZ has received speaker's fees from Servier.
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