Gastrointestinal treatment of severe mental disorders (GUTS) - Intestinal inflammation and permeability to predict treatment effect add-on

Bipolar disorder (BD) and schizophrenia (SCZ) are severe mental disorders, both placing significant burden on patients’ lives, societal costs and global health. Although the introduction of antipsychotic medications has substantially improved clinical symptoms of SCZ, the disease is still causing considerable morbidity and mortality. In BD, lithium is since many years the first-choice maintenance-treatment, with anticonvulsants and antipsychotics as major alternatives. However, up to 50% of patients with BD do not respond adequately to these treatments and still suffer from manic and/or depressive episodes, often severely affecting functioning. Therefore, currently available pharmacotherapy for SCZ and BD leaves ample room for improvement. Recent investigations have pointed to the gut-brain axis as a new venue for treatment, with increased inflammation stemming from leaky gut to further affect brain functioning in a significant subset of patients. Probiotics are promising candidates to improve patients’ symptomatology and functioning and there are rational methods to personalize its application with accessible and tolerable predictive biomarkers. Thus far the two clinical studies that have been performed in these disorders demonstrated inconsistent effects. In BD patients that were recently discharged after hospitalization for mania, treatment with probiotic was associated with a lower rate of rehospitalization compared to placebo. Another trial in SCZ demonstrated immune modulatory effects, but did not show significant differences in symptom severity between probiotic and placebo supplementation. Possible reasons for not finding an effect on symptom severity in this study could be the relatively short duration of the intervention, the daily dose of the probiotic product, or the selection of patients with long-term illness. Probiotics may be more effective in a subpopulation, emphasizing the need for early and personalized treatment. Indeed, evidence is accumulating that the immune system is more activated in patients with BD and SCZ, or at least in a subgroup of these patients. Intestinal microbiota of patients with major psychiatric disorders, including SCZ and BD, show subtle abnormalities, which can lead to increased intestinal permeability, causing increased activation of the immune system in the intestines and the rest of the body. Administration of probiotics may offer a non-invasive and relatively simple strategy to improve intestinal permeability and decrease peripheral immune activation, which can improve symptoms and functioning in patients with BD and SCZ. In a novel double blind randomized controlled trial, starting in 2019, we will trans-dimensionally examine the effect of the probiotic product Ecologic Barrier (Winclove Probiotics, Amsterdam, the Netherlands) on (BPRS) psychiatric symptom improvement in 120 patients with SCZ or BD (GUTS RCT). To maximize clinical and sociological impact we will focus on patients in the early stages of the illness (=5 years). In this prediction of treatment effect add-on I will extend the planned GUTS RCT with measures of intestinal inflammation and intestinal permeability to predict the clinical effect of the probiotic product: calprotectin in feces, lipopolysaccharides (LPS) binding protein (LBP), soluble CD14 (sCD14), zonuline and fatty acid binding proteins in serum. To further unravel the effects of probiotic treatment in these severe mental disorders, microbiota in fecal samples with metagenomic analysis; neurocognitive, immunological and metabolic functioning; and physical activity will be evaluated, next to symptom improvement.