The Gut Microbiome Looks Different for People With Treatment-Resistant Schizophrenia


Investigators suggested that this difference is caused by a common medication for treatment-resistant schizophrenia.

Investigators suggest that clozapine could change the composition of the gut microbiome in patients with treatment-resistant schizophrenia, according to new findings from a study published in JAMA Psychiatry. Patients with treatment-resistant schizophrenia had a significantly different gut microbiome than people without a psychiatric diagnosis or those who responded to treatment with nonclozapine antipsychotic medication.

A recent case-control study evaluated the possible link between gut microbiome composition and schizophrenia diagnosis, adjusting for demographic and lifestyle factors. They also evaluated if the gut microbiome impacts treatment resistance, clozapine response, and treatment-related adverse effects (AEs).

Credit: nobeastsofierce -

Credit: nobeastsofierce -

During the study, investigators measured the gut microbiome composition of 97 adults aged 20 to 63 years, and then collected stool samples and data pertaining to patient demographic, lifestyle, and medication use (ie, clozapine antipsychotic medication).

Patients were then divided into 4 groups: the control (no past or present psychiatric diagnosis); individuals with treatment-responsive schizophrenia who do not take clozapine; individuals with treatment-resistant schizophrenia who respond to clozapine; and individuals with treatment-resistant schizophrenia who do not respond to clozapine.

Generally, patients who have schizophrenia have significantly less microbial richness compared to control individuals (t95 = 4.25; P < .001; mean [SD] for control individuals, 151.8 [32.31]; mean [SD] for individuals with schizophrenia, 117.00 [36.2]; 95% CI, 18.6-51.0). However, there is not a significant difference in β microbial diversity between individuals with schizophrenia who respond to clozapine vs those who did not.

In addition, people with schizophrenia had different types of abundant bacterial species and metabolic pathways compared to people in the control group. These differences may be largely attributed to the clozapine treatment and/or treatment resistance, which reflect findings from previous studies which show that clozapine can alter the gut microbiome composition, according to the study authors.

Schizophrenia is a serious and debilitating mental condition that can be characterized by hallucinations, delusions, and disordered speech, thinking, and behavior. The condition can require lifelong treatment, but early-life treatment can reduce burden and disease progression in later life. Risk factors may include family history, pregnancy, and birth complications, and taking psychoactive or psychotropic drugs during developmental years.2

Clozapine is an antipsychotic drug indicated for patients with treatment-resistant schizophrenia—those with treatment-resistant disease experience persistent delusions or hallucinations after taking at least 2 lines of antipsychotic treatments. Clozapine is effective at reducing severe symptoms and risks (commonly suicide), but it is associated with significant AEs.3

It is possible that patients with treatment-resistant schizophrenia already have a different microbiome that precedes treatment-resistance, however, “these findings suggest that prior reports of microbiome alterations in individuals with chronic schizophrenia may be due to medication or lifestyle factors and that future studies should incorporate these variables in their design and interpretation,” study authors wrote.1


1. Vasileva SS, Yang Y, Baker A, et al. Associations of the Gut Microbiome With Treatment Resistance in Schizophrenia. JAMA Psychiatry. Published online January 31, 2024. doi:10.1001/jamapsychiatry.2023.5371

2. Schizophrenia. Mayo Clinic. Article. Accessed on February 15, 2024.,with%20schizophrenia%20require%20lifelong%20treatment.

3. Haidary HA, Padhy RK. Clozapine. StatPearls. Treasure Island (FL): StatPearlsPublishing; 2024 Jan.

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