Does isovaleric acid play a key role in the interaction between probiotics and antidepressants? A secondary analysis of a randomized clinical trial.

Background: Dysbiosis appears to be a significant contributor to the complex pathophysiology of mood disorders, and short-chain fatty acids (SCFAs), the main metabolites produced in the colon by bacterial fermentation, have been found to play a role in gut-brain communication. Probiotics were shown to be effective in managing and alleviating depressive symptoms, especially as an add-on protocol. This study aimed to assess the change in fecal SCFAs levels after supplementation with probiotics in patients with depression, depending on baseline antidepressant treatment.

Methods: This was a secondary analysis of a two-arm, parallel-group, randomized, double-blind, controlled trial. Data from 65 participants were analyzed. The intervention included probiotic formulation (Lactobacillus helveticus Rosell®-52 and Bifidobacterium longum Rosell®-175; R0052/R0175) or placebo over a 60-day period. Then, stratification was performed by the type of antidepressant medications. Fecal SCFAs were measured by the gas chromatography method. Pre-intervention socio-demographic, clinical, and laboratory data were assessed.

Results: Probiotics used decreased the levels of isovaleric acid compared with placebo when administered with non-selective serotonin reuptake inhibitors antidepressants (non-SSRIs) with large effect size (p = .019, |r|=.653), but not when used with SSRIs (p = .572, |r|=.109) or applied alone (p = .404, |r|=.182). Isovalerate levels decreased as depression improved in the probiotic plus non-SSRIs group. Conclusions: R0052/R0175 as an add-on to non-SSRI antidepressants may offer antidepressant action partly through the decrease in isovaleric acid levels. More research with a larger sample size is needed to study SCFAs' role as a mediator of antidepressant action of both probiotics and medications. ClinicalTrials.gov identifier: NCT04756544.