Anti-inflammatory drugs for depression

Depression has been studied from many different angles and conclusive evidence suggests that there are likely to be several biological domains involved.

More recently, people have started getting excited by possible deregulation of the immune system in depression. For instance, there are studies that have found higher levels of pro-inflammatory substances in the blood of people with depression and some report that anti-inflammatory drugs may help alleviate symptoms (Dantzer, O’Connor, Freund, Johnson, & Kelley, 2008).

However, to date there are hardly any state-of-the-art meta-analyses that systematically review the efficacy and safety of such drugs in the treatment of depression. To heat up the debate, Köhler et al. (2014) have recently published a paper that has taken a look at this issue.

Methods

The authors screened major medical databases for randomised, placebo-controlled trials that evaluated efficacy and tolerability of anti-inflammatory drugs on both clinically diagnosed depression as well as depressive symptoms. Pooled standard mean differences (SMD), odds ratios (ORs) and 95% confidence intervals (95% CI) are provided.

We all feel tired and irritable when we have viral or bacterial infections, but for some people this can lead to a more serious episode of clinical depression.

Results

Overall, 10 publications based on 14 trials (including a total of 6,262 participants) without psychiatric comorbidities were eligible for inclusion. Of those:

10 trials investigated non-steroidal anti-inflammatory drugs (NSAID, 4,258 participants)
4 trials assessed cytokine inhibitors (2,004 participants)

There was a high risk of bias (e.g. inadequate blinding) in all studies and this casts a long shadow on the results section. Only 1 study provided dichotomous information on response and was not included in SMD calculations.

There was high heterogeneity among primary studies and a generally high risk of bias
Four out of ten trials used NSAIDs as an add-on therapy (combined with serotonergic or noadrenergic drugs) and cytokine inhibitors were the only pharmacological treatment in all four studies
Compared to placebo, any kind of anti-inflammatory drug treatment significantly reduced depressive symptoms (SMD -0.34; 95% CI -0.57 to -0.11)
This was the case for both clinically diagnosed depression (SMD -0.54, 95% CI -1.08 to -0.01) and sub-clinical depressive symptoms (SMD -0.27, 95% CI -0.53 to -0.01)
A similar superiority of anti-inflammatory treatment over placebo was also noted in terms of response (OR 2.41, 95% CI, 1.12 to 5.2) and remission (OR 2.73, 95% CI 1.37 to 5.46)
NSAIDs (SEM -0.27, 95% CI -0.45 to -0.08) and cytokine inhibitors (SEM -0.38, 95% CI -0.88 to 0.12) did not differ in their antidepressant effects (p= 0.67), but only NSAIDs were significantly more effective than placebo
Only six studies investigated adverse effects, but found no increased number of common occurrences like gastrointestinal (OR 1.04, 95% CI 0.61 to 1.79) or cardiovascular events (OR 2.0, 95% CI 0.25 to 16.08) of either NSAIDs or cytokine inhibitors compared to placebo
Add-on celecoxib, a popular NSAID, was associated with a higher response (OR 6.59, 95% CI 2.24 to 19.42) and remission (OR 7.89, 95% CI 2.94 to 21.17) when compared with placebo

The studies included in this review all suffered from inadequate blinding.

Limitations

Overall, the conclusions of this meta-analysis suffer from several draw-backs:

Not all studies report adverse effects and in addition, treatment duration was restricted to 6-12 weeks, which might have been too short to detect more long-term (adverse) effects. As previous studies have warned of significant health threats associated with prolonged NSAID treatment, future studies will need to incorporate longer durations
All studies have a high risk of bias which threatens internal validity and might have inflated efficacy estimations. For instance, the authors suggest a for-profit bias in 12 of the 14 studies
What is more, publication bias might have been at work

Summary

The study concludes that:

…anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risk of adverse effects.

Conclusion

This meta-analysis reports that easily available anti-inflammatory drug treatment (more NSAIDs and less cytokine inhibitors) can have antidepressant effects either on their own or as add-on to standard drug therapy. However, while it seems these drugs are generally well tolerated in the short-term, longer studies are needed to provide adequate safety data.

As the authors suggest, subgroups of patients with raised inflammatory markers or somatic comorbitidies may particularly benefit from such treatment. Specifically, celecoxib may prove to be a useful addition to antidepressant treatment, but more “unbiased” studies are needed to corroborate such an effect.

To what extent these findings will translate into improved patient care, however, depends on careful discussion with health practitioners and patients. Given the high effect sizes reported here, there is some stimulus for further investigation.

This review gives practitioners and researchers something to think about, but more better quality studies are needed before we can use this evidence in practice.

Links

Köhler, O., Benros, M. E., Nordentoft, M., Farkouh, M. E., Iyengar, R. L., Mors, O., & Krogh, J. (2014). Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.1611 [PubMed abstract]

Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews. Neuroscience, 9, 46–56. doi:10.1038/nrn2297