Funded by: 2021 MSH Research Support Scheme
Approximately 3% of the population are affected by psychoses, characterised by disturbance in cognition, affect, perception and behaviour. Whilst antipsychotic drugs and supportive therapies reduce symptom burden and relapse rate to certain extent, many will have persistent symptoms and concomitant cognitive and social disabilities, poor physical health and curtailed life expectancy . Up to one third of people with schizophrenia will have treatment refractory schizophrenia (TRS), defined as being refractory to first- and second-line treatments.
For people with TRS, clozapine is the most effective antipsychotic for reducing psychotic symptoms and reducing psychiatric hospital bed days. However, because of cardiac and haematological adverse effects, clozapine is reserved solely for people with TRS. The pipeline for new drug development for schizophrenia has been limited in the past decade. Understanding the mediators of schizophrenia treatment response or non-response is essential for the development of novel therapeutic strategies.
There is growing evidence implicating the microbiome in a variety of neuropsychiatric disorders, notably schizophrenia. Schizophrenia is associated with reduced microbial diversity, and specific microbial community differences compared to the general population, with higher relative proportions of Firmicutes, and lower Bacteroidetes and Actinobacteria. The microbiome has been shown to have predictive ability in schizophrenia. A recent study was able to discriminate between patients with schizophrenia and healthy controls using a microbial panel analysis. When germ-free mice are gavaged with patient microbiome, mice exposed to biomes from schizophrenia patients had lower glutamate and higher glutamine and GABA in the hippocampus and displayed schizophrenia-relevant behaviours similar to other mouse models of schizophrenia involving glutamatergic hypofunction.
There is increasing suggestion that an abnormal microbiota composition may predict course of schizophrenia. Patients with first-episode psychosis with the greatest abnormalities in microbiota composition had the lowest rates of disease remission after one year. First episode patients who developed treatment refractory schizophrenia had elevated levels of Lactobacillus. Lactobacillus is a major component of probiotics treatments which have been proposed as adjunct interventions in schizophrenia, particularly for weight gain. There is a risk that inadequate understanding of microbiome may lead to inappropriate treatment approaches. As such, we need to identify and characterise the species associated with treatment refractory schizophrenia to avoid inadvertent use of interventions which may be deleterious for the disease course.
Antipsychotic medications, notably clozapine, are associated with increased risk of constipation. Studies have shown that slow intestinal transit may facilitate growth of methanogenic bacteria which impacts results of methane breath testing. Significantly decreased abundance in Prevotella and Bifidobacteria and increased representation in several genera of Firmicutes were observed in constipated patients compared with controls. Any study of microbiome among people with schizophrenia must allow for the effects of constipation.
Moreover, there is increasing evidence of a bidirectional interaction between antipsychotic medications and the gut microbiome. Olanzapine, an antipsychotic with a similar metabolic profile to clozapine, has been shown to have antimicrobial properties in mouse microbiome, potentiating weight gain. Microbiome alterations secondary to antipsychotics potentially result in body weight gain and metabolic disturbances.
This study aims to compare anaerobically collected faecal samples from healthy controls, people with schizophrenia responsive to first-line treatments, and people with treatment-refractory schizophrenia to:
1. sequence and compare cross-sectional microbiome flora for the major commensal bacterial species between samples and attempt to fit a predictive diagnostic and treatment responsive model
2. transplant purified representative commensal biomes from the three groups into germ-free mice and examine weight gain, gut integrity and inflammatory markers
We hypothesise that we will identify significant differences in commensal bacterial flora in the microbiome of healthy controls, and of people with treatment responsive and treatment refractory schizophrenia. Additionally, when the purified representative commensal biomes from both responsive and resistant patients are transplanted into germ-free mice we predict they will
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