Associations of the Gut Microbiome and Treatment Resistance in Schizophrenia


More than a gut feeling? Researchers investigated associations between the gut microbiome and treatment resistance in schizophrenia.




“Mr Paul” is a 55-year-old Caucasian male with a 20-plus-year history of schizophrenia, including multiple psychiatric hospitalizations. He has a chronic delusion that his mental illness is secondary to a chronic Candidia infection in his gut.

As a result, he purchases many different probiotic supplements on the internet. He maintains a blog about research on Candida and mental health. He is intermittently adherent with outpatient appointments and psychotropic medications, often changing dose and switching medications on his own.

Routine laboratory studies, including a CBC and C-reactive protein level, have always been unremarkable. A stool sample was negative for Candida. On examination, there was no evidence of oral candidiasis. Four months after his last outpatient visit, Mr Paul became depressed in response to a severe psychosocial stressor and died by suicide.

Almost 1 in 3 patients with schizophrenia have treatment-resistant illness, defined as persistent symptoms despite 2 or more adequate antipsychotic trials.1 Clozapine, the gold standard antipsychotic for treatment-resistant schizophrenia, is associated with adverse gastrointestinal effects.2 Abnormalities of the gut microbiome has been implicated in schizophrenia.3,4 However, its role in both treatment response and treatment-related adverse effects remains unclear.5

The Current Study

Vasileva and colleagues6 performed shotgun metagenomics on 97 stool samples to investigate correlates of gut microbiome composition and function in schizophrenia. This case-control study was reported according to the Strengthening the Organization and Reporting of Microbiome Studies (STORMS) checklist.

Participants aged 18 to 64 years from Brisbane, Australia, were recruited between November 2020 and November 2021. Patients with schizophrenia (n=72) were recruited from community clinics and inpatient units. Controls (n=25) were recruited through posters and advertisements.

Patients with schizophrenia were divided into 3 groups: (1) treatment-responsive, non-clozapine antipsychotic, and PANSS total score ≤ 60 (n=24); (2) treatment-resistant, clozapine responders with PANSS total score ≤ 60 (n=26); and (3) treatment-resistant, clozapine non-responders with PANSS total score > 60 (n=22). Patients and controls were matched for age, sex, and body mass index (BMI).

Exclusion criteria were antibiotics in the past 2 months; pregnant or planning to become pregnant; or any concomitant disease or condition deemed unsuitable by study investigators. Data were obtained on antipsychotic dose, clozapine level, metabolic syndrome, constipation, medications, illness duration, diet, and exercise.

Stool samples were collected by participants at home, immediately frozen at -20C, and then transported within 24 hours for storage at -80C. DNA extraction, shotgun metagenomic sequencing, and bioinformatics were performed by Microba Life Sciences. Variance components analyses were performed using the Omics-Databased Complex Trait Analysis software.

Alpha diversity was quantified using species richness and Shannon and Simpson indices. Beta diversity was calculated using a weighted UniFrac distance matrix. An analysis of the composition of microbiomes with bias correction (ANCOM-BC), which controls for false discovery rate (FDR), was conducted to test for differential abundance of bacterial species and metabolic pathways.

The mean participant age was 20 years, the mean BMI was 33, and 74% of participants were male, with no significant between-group differences. There were FDR-significant associations between schizophrenia diagnosis and all taxonomic and functional microbiome measures, after adjusting for age, sex, BMI, diet, physical activity, stool type, and principal components.

There was significantly decreased microbial richness in schizophrenia compared with controls, after adjusting for covariates. Limited evidence was found for microbiome associations with clozapine response, constipation, or metabolic syndrome. Schizophrenia was associated with multiple differentially abundant bacterial species (n=19) and metabolic pathways (n=162), which were primarily driven by treatment resistance and clozapine exposure.

Study Conclusions

The investigators found that schizophrenia was associated with robust taxonomic and functional microbiome alternations after adjusting for multiple covariates. Findings were further supported by differential abundance of individual bacterial species and metabolic pathways. These associations were largely a signature of treatment resistance.

Study strengths included the consideration of multiple potential confounding factors and consideration of treatment resistance and effects of clozapine. Study limitations included the modest sample size, and the fact that stool samples were collected once, after treatment initiation—this delimits causal inferences regarding effects of medication exposure.

The Bottom Line

Gut microbiome associations with schizophrenia may be largely driven by medications. Future longitudinal studies, with stool samples before and after treatment, are needed. Findings may have implications for adjunctive strategies in treatment-resistant schizophrenia, including diet, physical activity, and probiotics.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Siskind D, Orr S, Sinha S, et al. Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysisBr J Psychiatry. 2022;220(3):115-120.

2. De Hert M, Dockx L, Bernagie C, et al. Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive studyBMC Gastroenterol. 2011;11:17.

3. Zhu F, Ju Y, Wang W, et al. Metagenome-wide association of gut microbiome features for schizophreniaNat Commun. 2020;11(1):1612.

4. Schwarz E, Maukonen J, Hyytiäinen T, et al. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment responseSchizophr Res. 2018;192:398-403.

5. Vasileva SS, Tucker J, Siskind D, Eyles D. Does the gut microbiome mediate antipsychotic-induced metabolic side effects in schizophrenia? Expert Opin Drug Saf. 2022;21(5):625-639.

6. Vasileva SS, Yang Y, Baker A, et al. Associations of the gut microbiome with treatment resistance in schizophreniaJAMA Psychiatry. 2024;81(3):292-302.

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