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

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.