LAUSR

Abstract Background None of the currently available treatments are effective for negative symptoms of schizophrenia, which represent a long-lasting burden on sufferers, their families and on wider society. The gut-microbiota has been emerging as a putative novel target of intervention for negative symptoms of schizophrenia. This hypothesis has been welcomed with enthusiasm by the scientific community as showed by the growing number of commentaries and not-systematised reviews on the topic. To date, only few clinical trials tested the efficacy of interventions with the a-priori rationale of targeting the gut-microbiome in schizophrenia, with contrasting results. However, there is a number of trials that used compounds, such as antibiotics, antimicrobials, pre- and pro-biotics with a clear potential of modifying the gut-microbiome in patients. Interpreting and analysing data from these studies will help to shed light on the potential of the gut-microbiome as a therapeutic target in schizophrenia. Here we provide the first systematic review and meta-analysis on augmentation strategies targeting the gut-microbiome in schizophrenia. Methods Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobics, pre/probiotics, and fecal transplant in schizophrenia. Primary outcomes were negative symptoms at end of follow-up and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Results We identified 28 placebo-controlled trials: 21 investigated antibiotics, 4 antimicrobials, 3 pre/probiotics, none faecal transplant. None of the investigated compounds were effective for treating negative symptoms of schizophrenia, with the exception of the antimicrobial Sodium benzoate. It was possible to perform individual meta-analyses on three compounds for the outcome negative symptoms: (i) D-Cycloserine vs placebo (10 studies, N=389; SMD, -0.15; 95% CI -0.39, 0.10; P=0.24; I2: 26.4%); (ii) Minocycline vs placebo (7 studies, N=713, SMD: -0.35; 95% CI -0.70, 0.00; P=0.05, I2:77.7%) (iii) Sodium benzoate vs placebo (2 studies, N=107, SMD, -0.83; 95%CI -1.12, -0.42; P<0.001; I2:0%) Acceptability of interventions was similar to placebo. Qualitative and quantitative subgroup analyses suggested that baseline severity of negative symptoms and stage of illness have the potential to influence treatment outcomes. Discussion None of the available treatment with a putative action on the gut-microbiome are effective for the treatment of negative symptoms of schizophrenia, with limited evidence supporting the use of the antimicrobial Sodium benzoate. However, this latter finding is likely to be related to the central effect of the compound. The effect of some compounds might be beneficial if timing of intervention and clinical heterogeneity are taken into account. A more detailed characterisation of the gut microbiome and the pathophysiological path linking it with schizophrenia is needed before engaging in further trials