Gut Microbiome’s Impact on Treatment-Resistant Schizophrenia

There is an increasing body of research highlighting the significant connection between the gut microbiome and mental health disorders, particularly in cases of schizophrenia (Nikolova et al, 2021; Clarke, 2023). Recent findings indicate that individuals diagnosed with schizophrenia exhibit distinct differences in the composition and functionality of their microbiome compared to those without such a diagnosis (Szeligowski et al, 2020). Understanding these differences is crucial for developing targeted interventions aimed at improving mental health outcomes.

People diagnosed with schizophrenia face a concerning reality of reduced life expectancy in comparison to the general population, with this disparity being partly linked to a high prevalence of physical health comorbidities such as metabolic and cardiovascular diseases (Hjorthøj et al, 2017). These comorbidities often correlate with both lifestyle factors and the utilization of antipsychotic medications (Firth et al, 2019). Addressing these health issues is vital for enhancing the overall well-being and longevity of individuals living with schizophrenia.

The primary treatment for schizophrenia currently revolves around the use of atypical antipsychotics. However, around 30% of individuals with schizophrenia are classified as ‘treatment resistant,’ meaning they continue to experience symptoms despite undergoing two or more adequate trials with antipsychotic medications (Siskind et al, 2022). For these patients, clozapine—a second-generation antipsychotic—is often the preferred option. While clozapine has demonstrated effectiveness in alleviating severe symptoms and mitigating risks such as suicidality, it is also associated with notable side effects (Xu et al, 2022). Alarmingly, up to 60% of those prescribed clozapine report ongoing symptoms, categorizing them as ‘clozapine nonresponsive’ (Siskind et al, 2017).

The gut microbiome has emerged as a significant factor influencing both the severity of schizophrenia symptoms and the effectiveness of treatment (Zhu et al, 2020; Schwarz et al, 2018). Research involving both animal and human subjects has linked the use of atypical antipsychotics, including olanzapine (Morgan et al, 2014) and risperidone (Yuan et al, 2018), to alterations in the gut microbiome. Nonetheless, current findings remain inconsistent, leaving the precise role of the gut microbiome in schizophrenia—especially regarding treatment response and medication-related side effects—still largely undefined.

In this context, Vasileva et al. (2024) aimed to examine the associations between the gut microbiome and various factors including schizophrenia diagnosis, treatment resistance, clozapine response, and the adverse effects linked to treatment. Their investigation delves into not only the microbial composition but also the downstream functional implications stemming from these associations.

Research Methodology for Analyzing Gut Microbiome in Schizophrenia

This case-control study engaged 97 participants aged between 20 to 63 years from Brisbane, Australia. The data gathered involved a comparison among four distinct groups:

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

The primary focus of the research was to investigate the diagnosis of schizophrenia and the factors contributing to treatment resistance. Data were meticulously collected regarding demographic characteristics, lifestyle choices, and medication usage. Additionally, stool samples were obtained, and gut microbiome metrics were analyzed using shotgun metagenomics—a method that enables researchers to access and analyze all genomic DNA present in a stool sample.

Microbial associations were evaluated at both compositional and functional levels, examining aspects such as diversity and the presence of common species, as well as specific metabolic pathways. The Omics-Databased Complex Trait Analysis software was utilized for variance analysis, which compared the variance of specific microbiome features between paired individuals.

To assess microbiome diversity, Alpha and Beta Diversity metrics were calculated, which are standard measures used in microbiome research:

• Alpha diversity summarizes the microbial community within individual samples, allowing for comparisons across groups to determine the impact of symptomatology or functional consequences on the richness and distribution of bacterial species within those samples.
• Beta diversity quantifies the diversity between groups, facilitating an analysis of the similarities in microbiome communities between patient samples, such as comparing those with psychosis against those without (Bastiaanssen et al, 2019).

Key Findings on Microbiome Associations in Schizophrenia

This study provided insights into the associations between changes in microbiota, schizophrenia diagnosis, treatment resistance, and clozapine response. It is essential to note that causal relationships were not established. Data were collected from 97 individuals (74% male; average age of 40 years), with a mean BMI of 32.8. The sample consisted of 25 control individuals and 24 individuals diagnosed with treatment-responsive schizophrenia who were on atypical antipsychotics at the time of recruitment. Additionally, the study included 48 individuals with treatment-resistant schizophrenia, with 26 classified as responsive to clozapine.

Regarding alpha diversity, individuals with schizophrenia exhibited reduced microbial richness when compared to control individuals. Differences in beta diversity were also evident between the control group and those diagnosed with schizophrenia. However, while no significant differences were found between the clozapine groups, consistent variations in beta diversity were observed between individuals taking atypical antipsychotics and those on clozapine.

Moreover, schizophrenia and particularly treatment resistance were correlated with specific common microbial species (identified by the researchers as species with a median count greater than zero). Conversely, there was minimal association with clozapine response, constipation, or metabolic syndrome concerning these common microbial species.

Interestingly, the investigation also delved into microbial associations at a functional level. A total of 19 differentially abundant bacterial species and 162 metabolic pathways were identified in individuals with schizophrenia, primarily linked to treatment resistance and clozapine exposure.

The overall findings suggest that the microbiome composition of participants responding to treatment with atypical antipsychotics bore a closer resemblance to that of control individuals without psychiatric diagnoses, compared to those with treatment-resistant schizophrenia undergoing clozapine therapy. It is possible that some alterations in gut microbiota may indeed be influenced by exposure to clozapine.

Implications of Microbiome Research for Schizophrenia Treatment

This study successfully identified both compositional and functional microbiome associations with schizophrenia following adjustments for variables such as age, sex, BMI, stool consistency, diet, and physical activity. These associations were corroborated through analyses of individual bacterial species and metabolic pathways. Compositionally, consistent differences in beta diversity were noted between individuals taking atypical antipsychotics and those on clozapine. Functionally, various common bacterial species and metabolic pathways were identified in individuals with schizophrenia, primarily linked to treatment resistance and clozapine exposure. Notably, the gut microbiome of those treated with atypical antipsychotics closely resembled that of control individuals rather than participants receiving clozapine.

Understanding the factors that contribute to treatment response and the adverse effects related to treatment is crucial, particularly concerning clozapine usage. However, this study does not clarify whether the alterations in the gut microbiome are directly associated with treatment resistance or primarily due to clozapine exposure. The findings suggest that associations between the gut microbiome and schizophrenia may largely be influenced by medication effects.

Strengths and Limitations of the Microbiome Study

This research presents as a robust and reliable study, adhering to the guidelines outlined in the Strengthening the Organization and Reporting of Microbiome Studies (STORMS) checklist. The criteria for participant inclusion and exclusion were clearly defined, ensuring a solid foundation for the integrity of the study. Furthermore, the preparation and processing of samples were conducted meticulously.

The metabolic analysis yielded intriguing results, revealing 162 differential metabolic pathways linked to schizophrenia. While many prior studies have focused primarily on compositional assessments of the gut microbiota, the inclusion of functional outcomes adds a valuable dimension. The integration of gut microbiome and metabolic profiles enhances our understanding of the biological factors involved in schizophrenia.

Nonetheless, the sample size was relatively modest, which limited the statistical power for certain analyses. Additionally, it may have been advantageous to incorporate a fifth comparison group: individuals with treatment-resistant schizophrenia undergoing atypical (non-clozapine) antipsychotic treatment. The fact that samples were collected only once (post-treatment commencement) restricted the study’s ability to establish causal relationships between microbiome variations and medication exposure, particularly concerning clozapine. The authors acknowledge that while all participants with treatment-resistant schizophrenia were receiving clozapine, one-third were also on other antipsychotics, presenting an uncontrolled confounding variable that could significantly affect the results.

Practical Implications of Microbiome Research in Mental Health

The findings of this study are significant, revealing both compositional and functional microbiome associations with schizophrenia after controlling for various lifestyle factors. Associations between specific gut microbes and overall antipsychotic dosage were also observed. Notably, contrary to previous research, no associations with metabolic syndrome or constipation were identified. This heightened awareness of the biological factors influencing schizophrenia enhances our understanding; however, establishing causal links regarding alterations in the gut microbiome—especially in relation to treatment resistance versus clozapine exposure—remains challenging at this stage.

Overall, the results suggest that despite the influence of antipsychotics and other lifestyle differences, the microbiome composition of participants treated with atypical antipsychotics closely resembled that of control individuals without psychiatric conditions, as opposed to those with treatment-resistant schizophrenia undergoing clozapine therapy. This raises critical questions about whether clozapine usage alters the gut microbiome or if pre-existing bacterial profiles mediate the effects of first-line antipsychotics, contributing to the emergence of treatment resistance.

The implications of this research also indicate that alterations in the gut microbiome among individuals with schizophrenia may be significantly driven by antipsychotic medications. This consideration is essential for clinical practice, as it can be inferred that individuals prescribed clozapine are likely to be treatment resistant, potentially leading to microbiome alterations. This study underscores the necessity for clinicians to consider the impact of medications on gut health during treatment planning and microbiome research.

Future large-scale longitudinal studies are essential, particularly those that gather microbiome data before and after the initiation of antipsychotic treatment, to determine whether the observed changes are associated with treatment resistance in schizophrenia itself, as opposed to solely clozapine exposure. Addressing these clinically relevant questions is imperative, especially as patients often avoid effective antipsychotic treatments due to adverse side effects and issues with tolerability. Gaining insights into the biological factors that mediate these effects—such as modifications in the gut microbiome—could lead to significant advancements in clinical practice.

Disclosures and Author Contributions

Nuala Murray recently completed a systematic review and meta-analysis focused on compositional and functional changes in the intestinal microbiota of patients diagnosed with schizophrenia.

Access to the Primary Research 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

Additional References for Further Reading

Bastiaanssen, T. F., Cowan, C. S., Claesson, M. J., Dinan, T. G., & Cryan, J. F. (2019). Making sense of… the microbiome in psychiatry. International Journal of Neuropsychopharmacology, 22(1), 37-52.

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)

Firth, J., Siddiqi, N., Koyanagi, A. I., Siskind, D., Rosenbaum, S., Galletly, C., … & Stubbs, B. (2019). The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness. The Lancet Psychiatry, 6(8), 675-712.

Hjorthøj, C., Stürup, A. E., McGrath, J. J., & Nordentoft, M. (2017). Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. The Lancet Psychiatry, 4(4), 295-301.

Morgan, A. P., Crowley, J. J., Nonneman, R. J., Quackenbush, C. R., Miller, C. N., Ryan, A. K., … & Sullivan, P. F. (2014). The antipsychotic olanzapine interacts with the gut microbiome to cause weight gain in mice. PloS one, 9(12), e115225.

Nikolova, V. L., Smith, M. R., Hall, L. J., Cleare, A. J., Stone, J. M., & Young, A. H. (2021). Perturbations in gut microbiota composition in psychiatric disorders: a review and meta-analysis. JAMA psychiatry, 78(12), 1343-1354.

Siskind, D., Orr, S., Sinha, S., Yu, O., Brijball, B., Warren, N., … & Kisely, S. (2022). Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis. The British Journal of Psychiatry, 220(3), 115-120.

Siskind, D., Siskind, V., & Kisely, S. (2017). Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. The Canadian Journal of Psychiatry, 62(11), 772-777.

Schwarz, E., Maukonen, J., Hyytiäinen, T., Kieseppä, T., Orešič, M., Sabunciyan, S., … & Suvisaari, J. (2018). Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophrenia research, 192, 398-403.

Szeligowski, T., Yun, A. L., Lennox, B. R., & Burnet, P. W. (2020). The gut microbiome and schizophrenia: the current state of the field and clinical applications. Frontiers in psychiatry, 11, 156.

Xu, Y., Shao, M., Fang, X., Tang, W