Anti-inflammatory treatment of depression: study protocol for a randomised controlled trial of vortioxetine augmented with celecoxib or placebo

Abstract

BackgroundIn patients with major depressive disorder (MDD), antidepressant response and remission rates are low, highlighting the need for new treatment approaches. Recently, the abundant literature linking inflammatory processes and depressive symptoms have led to the hypothesis that selecting treatment for MDD based on the patient’s inflammatory status could be a promising strategy to improve outcomes in patients suffering from MDD. The aim of the randomised control trial we propose is to investigate the antidepressant efficacy of the combined treatment of MDD with antidepressant medication plus anti-inflammatory medication in individuals with raised inflammation levels. For the first time, this study will prospectively test the efficacy of an antidepressant plus anti-inflammatory augmentation based on baseline inflammatory maker levels in MDD using a randomised controlled trial design.MethodsThis study proposes to measure blood C-reactive protein (CRP) levels before the initiation of treatment in 200 participants with MDD. Study participants are then assigned into one of two study strata: either into the ‘Depression with inflammation’ stratum (CRP levels > 3 mg/L); or into the ‘Depression without inflammation’ stratum (CRP levels ≤ 3 mg/L). Within each of the two study strata, participants randomly receive either antidepressant medication alone (vortioxetine) plus anti-inflammatory medication (celecoxib) or vortioxetine plus placebo for six weeks. At the end of the treatment period, participants have the opportunity to continue vortioxetine alone for a six-month post-trial period. Clinical outcomes are measured at baseline, fortnightly during the treatment period and at the three-month and six-month post-trial visits. The primary outcome is change in MADRS score, with a primary endpoint of a score reduction by 50% from baseline to six weeks (end of augmentation treatment with celecoxib). Secondary clinical outcomes are changes in the cognitive dimensions of depression (cognitive function, emotion processing and social cognition). Biological outcome measures (levels of CRP and other inflammatory markers) are measured at baseline, after six weeks of treatment and at the six-month post-trial visit.DiscussionThe current study will generate novel evidence for biomarker-based personalised antidepressant treatment selection based on patient inflammatory status before treatment.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2829-7) contains supplementary material, which is available to authorized users.

Cognitive dysfunction in major depression: From assessment to novel therapies

“…Building on the evidence base for vortioxetine, an RCT conducted by Fourrier et al, 2018 is trialing vortioxetine as an add-on therapy alongside celecoxib 400mg, an antiinflammatory COX-2 inhibitor, or placebo in 200 MDD patients (Fourrier et al, 2018).…”

“…Since only 33-47% of depressed patients may have high peripheral inflammation, it follows that it is these patients who are most likely to benefit from anti-inflammatory therapies (Dooley et al, 2018). Additionally, if genotype can increase depression risk through altered immune response and increased levels of inflammatory mediators, this could further determine how patients respond to treatments such as omega-3 supplementation, or COX-2 inhibitors such as celecoxib, for which inflamed individuals might be more suitable than others (Fourrier et al, 2018). Stratifying subsets of patients and targeting agents according to biological marker concentrations may be a more successful application of novel treatments and will be more likely to lead to more definitive results.…”

“…Patient stratification should be improved, i.e. by using 'cognitively preserved' and 'cognitively impaired', or 'depression with inflammation' and 'depression without inflammation', and biomarkers incorporated into study designs (Fourrier et al, 2018;Vicent-Gil et al, 2018). Evidence has underscored that executive function, attention, and memory impairments are most significantly associated with poorer outcomes in MDD patients.…”

Diet-induced hypothalamic dysfunction and metabolic disease, and the therapeutic potential of polyphenols

“…Inflammation is not limited to the hypothalamus, affects other brain regions, and is believed to be linked to the increased prevalence of neuropsychiatric symptoms [88]. The interplay between obesity and mood disorders facilitate the development of both these conditions, and increase the risk of additional metabolic and cardiovascular complications [89].…”

Commentary: Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

“…Sethi and colleagues provide an important and timely review of pre-clinical and clinical studies investigating the use of COX-2 inhibitors across multiple psychiatric disorders including major depressive disorder, schizophrenia, bipolar affective disorder, autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). Other than a clinical trial protocol for celecoxib as an adjunct to vortioxetine in depression published in 2018 (13), their review of randomized controlled trials (RCT's) through November 2017 remains up to date 2 years later. In this commentary, we highlight three factors arising from their results that are essential to advancing this research agenda.…”