No abstract

Accumulating evidence supports an association between depression and inflammatory processes, a connection that seems to be bidirectional. Clinical trials have indicated antidepressant treatment effects for anti-inflammatory agents, both as add-on treatment and as monotherapy. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity of the inflammatory cascade, limited clinical evidence, and the risk for side effects stress cautiousness before clinical application. Thus, despite proof-of-concept studies of anti-inflammatory treatment effects in depression, important challenges remain to be investigated. Within this paper, we review the association between inflammation and depression together with the current evidence on use of anti-inflammatory treatment in depression. Based on this, we address the questions and challenges that seem most important and relevant to future studies, such as timing, most effective treatment lengths and identification of subgroups of patients potentially responding better to different anti-inflammatory treatment regimens.

Studies have indicated antidepressant effects of anti-inflammatory treatment; however, results have been conflicting and side effects may contraindicate anti-inflammatory treatment. Objectives: To systematically review the antidepressant and possible side effects of anti-inflammatory interventions. Aims: To include trials published prior to December, 31 st 2013, and evaluate depression scores after treatment and side effects. Methods: We identified randomized, placebo-controlled trials assessing efficacy and side effects of pharmacological anti-inflammatory treatment in adults with depressive symptoms including adults fulfilling depressioncriteria. We calculated standard mean difference (SMD) and Odds ratios (OR). Results: 10 publications covering 14 trials (n=6,262) were included: 10 on non-steroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and four on cytokine-inhibitors (n=2,004). Anti-inflammatory treatment reduced depression (SMD=-0.54; 95%-CI:-1.08 to-0.01; I 2 =68%) and depressive symptoms (SMD=-0.27; 95%-CI:-0.53 to-0.01; I 2 =93%). Sub-analyses particularly emphasized antidepressant properties for the selective cyclooxygenase-2 inhibitor celecoxib in general (SMD=-0.29; 95%-CI:-0.49 to-0.08; I 2 =73%), on remission (OR=7.89; 95%-CI: 2.94 to 21.17; I 2 =0%) and response (OR=6.59; 95%-CI: 2.24 to 19.42; I 2 =0%). Among 6 studies (n=2,523), we found no evidence of an increased number of gastrointestinalor cardiovascular events after 6 weeks nor infections after 12 weeks of anti-inflammatory treatment. All trials were associated with high risk of bias. Conclusions: Anti-inflammatory treatment, in particular celecoxib, decreased depressive symptoms without increased risks of side effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit hereof might be warranted.

Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors.