The role of anti-inflammatory agents in the treatment of mood disorders

Abstract

Background: Multiple reviews have demonstrated that mood disorders are associated with abnormal pro- and anti-inflammatory immunological markers and recent studies suggest that anti-inflammatory medication may play an important role in the treatment of mood disorders. Aims: 1. To evaluate current evidence on the efficacy and acceptability of anti-inflammatory drugs in patients with major depressive disorder (MDD) and bipolar disorder. 2. To determine whether the anti-inflammatory tetracycline antibiotic minocycline, added to treatment as usual (TAU) for 3 months in patients with treatment-resistant depression leads to an improvement in depressive symptoms and if so, to estimate effect sizes to inform the development of a larger, hypothesis-testing study. Methods: A systematic review and meta-analysis of published trials of anti-inflammatory agents in mood disorders was conducted. The Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO and Clinicaltrials.gov were searched from inception until April 15, 2017 for completed and on-going clinical trials of anti-inflammatory agents for MDD and bipolar disorder. Data from randomized controlled trials (RCTs) assessing the antidepressant and antimanic effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with placebo and/or treatment as usual. To address the second aim a multi-site, 12-week, double blind, placebo-controlled, pilot trial was conducted. The trial was of minocycline added to treatment as usual for patients suffering from DSM-5 major depressive disorder whose current episode has failed to respond to at least 2 antidepressants. The primary outcome measure was mean change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 12. Secondary measures were the Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder scale (GAD-7) and EuroQoL (EQ-5D). Side effects checklists were also used. Minocycline was started at 100 mg once daily (OD) and increased to 200 mg OD after two weeks. Results: The meta-analysis found that patients receiving anti-inflammatory agents showed lower post-treatment depressive symptom scores compared with those receiving placebo with a SMD of -0.71 (6 RCTs, n=214, 95% CI -1.24 to -0.17, p=0.009). Anti-inflammatory treatment was found to reduce post-treatment manic symptom scores with a SMD of -0.72 (3 RCTs, n=96, 95% CI -1.31 to -0.13, p=0.02). Anti-inflammatory treatment was found to yield an improvement in depressive symptom scores from baseline to outcome with a SMD of -0.52 (5 RCTs, n=194, 95% CI -1.01 to 0.05) but this was not statistically significant (p=0.07). In the pilot RCT, a total of 41 participants were randomised, with 21 in the minocycline group and 20 in the placebo group. A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group (Standardized effect size -1.21, p < 0.001). CGI scores in the minocycline group also showed a large improvement compared with placebo (OR: 17.6, p < 0.001). PHQ-9 (ES -0.43), GAD-7 (ES -0.46) and EQ-5D total (ES -0.48) showed more moderate improvements. Conclusions: Anti-inflammatory treatments may confer benefit for both depressive and manic symptoms however current studies are limited by small sample sizes, short durations, differing baseline symptomatology and poorly defined illness durations. The findings of the pilot RCT indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression. However, the findings require replication in a larger sample. Overall, further high-quality trials are needed before making recommendations for the routine clinical use of anti-inflammatory interventions including minocycline, in the treatment of mood disorders.

Date of Award	2018
Original language	English
Awarding Institution	King's College London
Supervisor	Allan Young (Supervisor)