Bai S, Guo W, Feng Y, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2019 Oct 28. pii: jnnp-2019-320912. doi: 10.1136/jnnp-2019-320912. (Systematic review)

OBJECTIVES: To systematically review the efficacy and safety of anti-inflammatory agents for patients with major depressive disorders.

METHODS: We searched the literature to identify potentially relevant randomised controlled trials (RCTs) up to 1 January 2019. The primary outcome was efficacy, measured by mean changes in depression score from baseline to endpoint. Secondary outcomes included response and remission rates and quality of life (QoL). Safety was evaluated by incidence of classified adverse events. Heterogeneity was examined using the I2 and Q statistic. Pooled standard mean differences (SMDs) and risk ratios (RRs) were calculated. Subgroup meta-analyses were conducted based on type of treatment, type of anti-inflammatory agents, sex, sponsor type and quality of studies.

RESULTS: Thirty RCTs with 1610 participants were included in the quantitative analysis. The overall analysis pooling from 26 of the RCTs suggested that anti-inflammatory agents reduced depressive symptoms (SMD -0.55, 95% CI -0.75 to -0.35, I2=71%) compared with placebo. Higher response (RR 1.52, 95% CI 1.30 to 1.79, I2=29%) and remission rates (RR 1.79, 95% CI 1.29 to 2.49, I2=41%) were seen in the group receiving anti-inflammatory agents than in those receiving placebo. Subgroup analysis showed a greater reduction in symptom severity in both the monotherapy and adjunctive treatment groups. Subgroup analysis of non-steroidal anti-inflammatory drugs, omega-3 fatty acids, statins and minocyclines, respectively, disclosed significant antidepressant effects for major depressive disorder (MDD). For women-only trials, no difference in changes of depression severity was found between groups. Subanalysis stratified by sponsor type and study quality led to the same outcomes in favour of anti-inflammatory agents in both subgroups. Changes of QoL showed no difference between the groups. Gastrointestinal events were the only significant differences between groups in the treatment periods.

CONCLUSIONS: Results of this systematic review suggest that anti-inflammatory agents play an antidepressant role in patients with MDD and are reasonably safe.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
FM/GP/Mental Health 5 / 7
Psychiatry 5 / 7
Internal Medicine 5 / 7
Comments from MORE raters

FM/GP/Mental Health rater

Interesting lack of signal in the female population. Not an article applicable to practice at this point.

FM/GP/Mental Health rater

Really interesting study that adds useful information. Occasionally, patients may refuse or wish to avoid typical antidepressants or pharmaceuticals for many reasons, but they may be willing to consider "natural" alternatives such as omega-3 fatty acids. This gives us some data to help patients make informed decisions.

General Internal Medicine-Primary Care(US) rater

I have not heard of this effect and the agents that were useful were relatively safe. I am not a psychiatrist or a geriatric specialist, but I think this information would be useful to know if you treat that population.

General Internal Medicine-Primary Care(US) rater

There may be possible beneficial effects of anti-inflammatory drugs as adjuncts or monotherapy in major depressive disorder, but it's not clear the reported benefits outweigh the multitude of side effects of these drugs over long time periods.

General Internal Medicine-Primary Care(US) rater

This well done meta-analysis shows that the preponderance of evidence is pointing toward efficacy in NSAID use for major depression. There are issues, however, that are appropriately pointed out: short follow-up, no effect on quality-of-life, adverse effect potential. The article may stimulate larger more robust trials. In my interpretation of the analysis, an NSAID may be chosen as an adjunct to usual care for refractory patients.

Internal Medicine rater

I only skimmed the methods of this paper, but these results are not plausible. For example, an SMD of 0.76, three quarters of an effect size, for remission of depression treating patients with celecoxib? Those are big effects that, if true, would be the kind clinicians should notice in uncontrolled clinical observations. I cannot imagine encouraging primary care physicinss to use celecoxib or omega-3 or minocycline or whatever in place of SSRIs or similar meds. These results need a large degree of verification before any change in practice can be recommended.

Psychiatry rater

Interesting. There is, however, always the possibility of "confounding by indication." Anti-inflammatories are usually taken for painful conditions and pain is strongly associated with depression, so successfully treating the pain may reduce depression without a direct antidepressant effect for these agents.

Psychiatry rater

Interesting if true.

Psychiatry rater

We all want new treatments for depression. To fully assess the utility of anti-inflammatory drugs for depression, we would need to know more about the severity of depression in the trials. It would be ethically problematic to withhold standard treatment if prospective trial participants had more severe depression, suggesting these trials were in less depressed patients. Limitations of the small sample sizes for all tested agents and very short duration of trials were understated.
Comments from EvidenceAlerts subscribers

Dr. Gabriel Symonds (12/1/2019 6:55 AM)

RCTs of empirical treatment on mechanistic lines for the treatment of the symptom of depression. The basis for these trials was presumably because some depressed patients have raised levels of inflammatory markers. What about the majority of depressed patients who don’t have raised inflammatory markers? I cannot see that this study will be of the slightest value in treating a depressed patient sitting in front of you.

Dr. Ahmed Elaghoury (11/16/2019 3:44 AM)

Some patients with depressive disorders have high blood inflammatory markers, like high CRP. It happens also with melancholic depression. I think they might get benefits from NSAIDs in the short term, but we cannot generalize these results for all types of depression. This way the generic concept of MDD used in these studies is not helpful. Depression has more than 8 clinical types of various presentations. As a psychiatrist, I think to use NSAIDS when seeing inflammatory markers or pain in my patients, but not in all patients.

Dr. Paul Waraich (11/10/2019 11:32 AM)

The response and remission rates actually *favored* placebo, not anti-inflammatories. Only symptom severity was reduced (slighty). This implies that the effects are quite small and not clinically significant for most.