Add-on probiotics for inflammatory depression – A double-blind randomized placebo-controlled trial

• This is one of the largest MDD RCTs to investigate the antidepressant effects of a probiotic. • The study sample was enriched for low-grade inflammation using mild elevations of hs-CRP and BMI as inclusion criteria. • We found no significant differences between probiotics and placebo on any of the primary or secondary outcomes. • Lower baseline levels, and and a greater treatment-associated increase, of fecal formic acid was signficantly associated with clinical improvement. Previous treatment studies have suggested an antidepressant effect of adjunctive probiotics, but more high-quality Randomized Controlled Trials (RCTs) are needed before clinical implementation. The mechanisms underlying putative antidepressant effects of probiotics are not understood, but one possibility is that they are mediated via short-chain fatty acids (SCFAs) − neuroactive bacterial metabolites with anti-inflammatory properties. The main aim of this study was to test the adjunctive antidepressant efficacy of a Lactobacillus probiotic in depressed patients with concomitant systemic low-grade inflammation, and to test the relationship between treatment response and short-chain fatty acids (SCFAs) in blood and feces. In this 8-week double-blind RCT, patients with major depressive disorder (MDD), BMI ≥ 25 kg/m 2 and high-sensitivity C-reactive protein (hs-CRP) ≥ 1 mg/L were randomized to receive either a Limosilactobacillus reuteri (L. reuteri) probiotic supplement or placebo added to their regular and stable treatment. Primary outcomes were change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and “inflammatory depressive symptoms” defined as a composite score of Patient Health Questionnaire-9 items related to sleep disturbance, energy levels, and appetite disturbance. Secondary outcomes included anxiety symptoms, anhedonia, insomnia, fatigue and gastrointestinal symptoms. SCFAs were analyzed in blood and feces pre- and post-intervention. In a modified intention-to-treat analysis including all patients with at least one post-baseline visit (n = 75), there were no significant effects of probiotics relative to placebo on any of the primary or secondary outcomes (all p > 0.25). Lower baseline levels, and a greater treatment-associated increase, of fecal formic acid was significantly associated with a decrease in MADRS score in the probiotics group (p < 0.01). While we did not observe an overall antidepressant effect of add-on L. reuteri probiotic for overweight depressed patients with systemic low-grade inflammation, we found preliminary evidence for anti-inflammatory formic acid as a biomarker, and possibly a mediator, of treatment response.