Review of: Köhler-Forsberg O et al, Acta Psych Scand 2019;139(5):404–419

Study Type: Meta-analysis of randomized controlled trials

Several lines of evidence suggest that chronic inflammation contributes to depression. For example, markers of inflammation tend to be elevated in depressed patients, and inflammatory syndromes elicit depressive symptoms. Many of the causes of inflammation also overlap with the causes of depression: stress, insomnia, poor diet, and chronic health problems. Medications with different anti-inflammatory properties have been noted to improve mood in some patients, but few have been adopted in clinical practice. This meta-analysis gives us a fuller account of the current research.

The Danish authors performed a systematic review and meta-analysis of randomized controlled trials that studied anti-inflammatory interventions in depression. Both monotherapy and augmentation trials were included in the analysis. Reduction in depressive symptoms was the primary outcome.

The authors identified 36 trials published between 1995 and 2017 with almost 10,000 participating patients. Nearly a third of these were large studies with over 100 subjects. The trials included the following anti-inflammatory agents: NSAIDs (13 studies), cytokine inhibitors (9), statins (7), minocycline (3), pioglitazone (2), and glucocorticoids (2). On average, the anti-inflammatory agents were superior to placebo as augmentation of antidepressants in major depression and as monotherapy in patients with medical disorders. With the exception of pioglitazone, all classes of anti-inflammatory agents were effective. The overall effect size was moderate (0.49). This is in the same range seen with atypical antipsychotics and lithium augmentation (0.5–0.6), but comparing effect sizes is an approximate art unless the treatments are compared in a head-to-head trial. Only 19 studies reported on side effects, which were generally minimal but showed a trend toward increased rates of infection. All studies showed a high risk of bias, as assessed by irregularities in study design and presence of commercial support.

Two classes of anti-inflammatories—cytokine inhibitors and glucocorticoids—carry significant long-term risks such as infections and diabetes, which would limit their use for most patients with depression. Others, like the statins, NSAIDs, and the COX-2 inhibitor celecoxib, are more straightforward for psychiatrists to implement. Although celecoxib is well tolerated in the short-term, long-term use can raise the risk of heart attacks, stroke, gastrointestinal bleeding, and possibly nephrotoxicity.

TCPR’S TAKE

Most anti-inflammatory agents are effective in depression, but only a few are ready for clinical use. Among them, celecoxib has the best evidence, with seven trials supporting a large effect size of 0.82 (dosed 200 mg BID). Why, then, is it not used more often? Celecoxib carries long-term medical risks, but so do most of the other options for antidepressant augmentation, as does untreated depression. It will take a cultural shift to see widespread adoption of these treatments. Short of that, it’s reasonable to try an anti-inflammatory in severe cases of depression that haven’t responded to traditional therapies. To minimize long-term risks, attempt to taper off after 6 months of recovery.