The role of the gut microbiome in treatment-resistant schizophrenia

There is growing interest in the role of the gut microbiome in mental health disorders (Nikolova et al, 2021; Clarke, 2023). Recent evidence suggests that the composition and function of the microbiome differs in those with a schizophrenia diagnosis compared to those without (Szeligowski et al, 2020).

Individuals diagnosed with schizophrenia have a reduced life expectancy compared to the general population, partially attributable to the high incidence of physical health comorbidities in patients, including metabolic and cardiovascular disease (Hjorthøj et al, 2017). Such comorbidities have also been associated with antipsychotic medication use and lifestyle differences (Firth et al, 2019).

Atypical antipsychotics are currently the mainstay of treatment for schizophrenia. Up to 30% of people diagnosed with schizophrenia are considered to be ‘treatment resistant’, defined as the persistence of symptoms despite two or more trials of an adequate antipsychotic treatment (Siskind et al, 2022). Clozapine, a second-generation antipsychotic, is typically a clinician’s medication of choice for patients with treatment resistance to other antipsychotics. Previous studies have shown that clozapine is effective at reducing severe symptoms and risks such as suicidality, but it is also associated with significant side effects (Xu et al, 2022). Moreover, up to 60% of individuals prescribed clozapine, report persistent symptoms and are subsequently classified as ‘clozapine nonresponsive’ (Siskind et al, 2017).

The gut microbiome has been implicated in schizophrenia symptom severity and treatment response (Zhu et al, 2020; Schwarz et al, 2018). Animal and human studies have also associated the use of atypical antipsychotics, such as olanzapine (Morgan et al, 2014) and risperidone (Yuan et al, 2018), with gut microbiome alterations. However, findings to date have been inconsistent and the role of the gut microbiome in schizophrenia, including in relation to treatment response and treatment-related adverse effects, remains unclear.

Here, Vasileva et al. (2024) set out to explore associations between the gut microbiome and schizophrenia diagnosis, treatment resistance, clozapine response, and treatment-related adverse effects. They investigate associations not only at a microbial compositional level, but also explore downstream functional consequences.

The gut microbiome differs in those with schizophrenia compared to those without and seems to impact symptom severity.

Methods

This case-control study involved 97 participants aged 20 to 63 years from Brisbane, Australia. Data was compared for four distinct groups:

• Control individuals without a psychiatric diagnosis (matched for sex, age, and body mass index/BMI).
• Individuals with treatment-responsive schizophrenia who were taking non-clozapine antipsychotic medications.
• Clozapine-responsive individuals with treatment-resistant schizophrenia.
• Clozapine-nonresponsive individuals with treatment-resistant schizophrenia.

The primary trait investigated was diagnosis of schizophrenia and treatment resistance. Data on demographic characteristics, lifestyle, and medication use were collected. Stool samples were also collected and gut microbiome measures were obtained using shotgun metagenomics. This approach allows researchers to read all genomic DNA in a stool sample.

Microbial associations were explored at compositional levels (e.g., diversity and common species) and functional levels (e.g., metabolic pathways). Omics-Databased Complex Trait Analysis software was used for variance analysis whereby variance of certain microbiome features was compared between paired individuals.

Alpha and Beta Diversity were calculated. These are commonly used measures of microbiome diversity:

• Alpha diversity provides a summary of the microbial community in individual samples. It can then be compared across groups to evaluate the role that symptomatology or functional consequence may play in the number (richness) and distribution (evenness) of bacterial species within samples.
• Beta diversity is a measure of between-group diversity. It allows us to assess the similarity of microbiome communities between patient samples, e.g., those with psychosis compared with those without (Bastiaanssen et al, 2019).

Results

This study explored associations between changes in microbiota and schizophrenia diagnosis, treatment resistance, and clozapine response. It is worth noting that causal effects were not established. Data were collected for 97 individuals (74% male; average age of 40 years). Mean BMI in the sample was high (32.8). This sample included 25 control individuals and 24 individuals with treatment-responsive schizophrenia who were taking atypical antipsychotics at the time of recruitment. The study also identified 48 individuals with treatment-resistant schizophrenia, 26 of whom were considered to be responsive to clozapine.

In terms of alpha diversity, individuals with schizophrenia were found to have decreased microbial richness compared to control individuals. Differences in beta diversity were also found between control individuals and those with schizophrenia. However, whilst no differences were found between clozapine groups, consistent differences in beta diversity were found between those taking atypical antipsychotics and those taking clozapine.

Schizophrenia and, in particular, treatment resistance were found to be associated with common microbial species (defined by the researchers as species with median count >0). In contrast, there was little association with clozapine response, constipation, or metabolic syndrome and common microbial species.

Interestingly, this study also explored microbial associations at a functional level. Multiple differentially abundant bacterial species (19) and metabolic pathways (162) were found in individuals with schizophrenia and were primarily associated with treatment resistance and clozapine exposure.

The overall pattern of results suggests that the microbiome composition of participants with treatment-responsive schizophrenia (atypical antipsychotics) was more similar to that of the control individuals without psychiatric diagnoses than to that of participants with treatment-resistant schizophrenia who were taking clozapine. Some changes in gut microbiota might, in fact, be driven by clozapine exposure.

Common microbial species found in the gut were associated with treatment resistance and clozapine exposure in patients with a diagnosis of schizophrenia, but causality remains unclear.

Conclusions

This study identified compositional and functional microbiome associations with schizophrenia after adjusting for age, sex, BMI, stool consistency, diet and physical activity. The associations were supported by analyses of individual bacterial species and metabolic pathways. Compositionally, consistent differences in beta diversity were found between those taking atypical antipsychotics and those taking clozapine. Functionally, multiple common bacterial species and metabolic pathways were found in individuals with schizophrenia and were primarily associated with treatment resistance and clozapine exposure. The microbiome of those taking atypical antipsychotics was more similar to that of control individuals than to that of participants taking clozapine.

It is helpful to understand factors contributing to treatment response and treatment-related adverse effects, particularly for clozapine. However, the study does not address the question of whether alterations in gut microbiome are associated with treatment resistance, as opposed to exposure to clozapine. The findings in this study suggest that gut microbiome associations in schizophrenia may be largely driven by medications.

The gut microbiome of individuals with schizophrenia not exposed to clozapine was more similar to controls than patients exposed to clozapine. This suggests that the differences in microbiome may be largely driven by medications.

Strengths and limitations

This is a robust and reliable study, which was reported according to the Strengthening the Organization and Reporting of Microbiome Studies (STORMS) checklist. Inclusion and exclusion criteria for participants were well defined and the preparation and processing of samples was robust.

The metabolic analysis here has led to interesting findings – 162 differential metabolic pathways associated with schizophrenia were identified. Many previous studies have relied on compositional assessments of the gut microbiota, and thus functional outcomes are a helpful addition. The integration of gut microbiome and metabolic signatures increases our insight into the role of biological factors in schizophrenia.

Unfortunately, the sample size here was modest and therefore, the study lacked statistical power for some analyses. Additionally, it may have been prudent to include a fifth comparison group here: Individuals with treatment-resistant schizophrenia taking a-typical (non-clozapine) antipsychotics. Samples were collected once (after treatment commencement) and this means the study was unable to establish causal relationships between microbiome differences and medication exposure, in particular for clozapine. The authors also note that whilst all participants with treatment-resistant schizophrenia were taking clozapine, one-third of participants were also taking other antipsychotics. This was an uncontrolled confounding factor in the study that may have significant impact on the results obtained.

Implications for practice

This study has produced interesting findings: It identified both compositional and functional microbiome associations with schizophrenia after adjusting for several lifestyle factors.

Associations between select gut microbes and total antipsychotic dosage were also identified. Interestingly, unlike previous studies, no associations with metabolic syndrome or constipation were found. Awareness of these associations increases our insight into the biological factors at play in schizophrenia, but causal links for alterations in the gut microbiome (e.g., with treatment resistance versus clozapine exposure) have not been established, and so discerning direct implications for clinical practice is difficult at this stage.

Overall, the results suggest that despite exposure to antipsychotics and other lifestyle differences, the microbiome composition of participants with treatment-responsive schizophrenia (atypical antipsychotics) was more similar to that of the control individuals without psychiatric diagnoses than to that of participants with treatment-resistant schizophrenia who were taking clozapine. This raises the question of whether clozapine use alters the gut microbiome or if the bacteria present prior to clozapine exposure mediate the effects of frontline antipsychotics and thus the emergence of treatment resistance.

The findings in this study also suggest that alterations in the gut microbiome in schizophrenia may be largely driven by antipsychotic medications. This in and of itself has implications for clinical practice. It might be reasonable to assume that those exposed to clozapine are also treatment resistant, so alterations in gut microbiome may be present. This study highlights the importance of considering medication intake in microbiome studies, but also for clinicians to consider the impact of medications on the gut.

Future large-scale longitudinal studies that collect microbiome data before and after antipsychotic commencement to investigate whether the observed alterations are associated with treatment resistance in schizophrenia alone, rather than clozapine exposure, are needed. These are key outstanding, clinically-relevant questions. It is all too often that patients forgo effective antipsychotic treatment due to adverse side effects and tolerability. Understanding the biological factors that mediate these effects – such as alterations in the gut microbiome – so that we can take pre-emptive steps to ameliorate them, may have major implications for clinical practice.

This study highlights the importance of considering medication intake in microbiome studies, but also for clinicians to consider the impact of medications on the gut.

Statement of interests

Nuala Murray has recently completed a systematic review and meta-analysis looking at compositional and functional alterations in the intestinal microbiota of patients with schizophrenia.

Links

Primary Paper

Vasileva SS, Yang Y, Baker A, Siskind D, Gratten J, Eyles D. (2024) Associations of the Gut Microbiome With Treatment Resistance in Schizophrenia. JAMA Psychiatry. 2024;81(3):292–302. doi:10.1001/jamapsychiatry.2023.5371

Other references

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Clarke, G. (2023). Gut microbiome disruptions in depression: shifting the focus to metabolic signatures in blood. The Mental Elf, 27^th September 2023. Available at: https://www.nationalelfservice.net/publication-types/mendelian-randomisation/gut-microbiome-disruptions-in-depression-shifting-the-focus-to-metabolic-signatures-in-blood/ (Accessed 30^th October 2024)

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