Adults with resistant schizophrenia have significant gut microbiome differences compared with their counterparts who respond to treatment, a new finding that researchers speculate may be driven by treatment with clozapine.
Darryl Eyles, PhD, and colleagues with University of Queensland in Brisbane, Australia, believed this difference may be driven by clozapine-induced alterations in the gut, although the possibility that preexisting microbiome differences contribute to treatment resistance can’t be ruled out.
“Studies are needed to understand the clinical implications of our finding of an altered microbiome among people with treatment-resistant schizophrenia taking clozapine, specifically whether therapeutic strategies for treatment-resistant schizophrenia should consider microbiome adjuvants, including diet, physical activity, and probiotics,” they wrote.
The study was published online on January 31, 2024, in JAMA Psychiatry.
Signature of Treatment Resistance?
Up to 30% of people with schizophrenia are treatment-resistant and experience persistent symptoms despite two or more antipsychotic treatment trials. The role of the gut microbiome in schizophrenia, including in relation to treatment response, remains unclear.
To investigate, the researchers performed metagenomics on stool samples from 97 individuals from four distinct groups: 25 controls without a psychiatric diagnosis (past or present), 24 individuals with treatment-responsive schizophrenia taking nonclozapine antipsychotic medications, 26 clozapine-responsive individuals with treatment-resistant schizophrenia, and 22 clozapine-nonresponsive individuals with treatment-resistant schizophrenia.
After adjusting for age, sex, body mass index, stool consistency, diet, and physical activity, the investigators observed “robust” taxonomic and functional microbiome associations with schizophrenia and treatment resistance.
Associations between the gut microbiome and schizophrenia were a “signature” of treatment resistance and clozapine exposure and were not associated with demographic characteristics, lifestyle factors, or medication-related adverse effects, including constipation and metabolic syndrome, they reported.
Despite exposure to antipsychotics and other lifestyle differences, the microbiome composition of individuals with treatment-responsive schizophrenia was more similar to that of controls without psychiatric diagnoses than to that of individuals with treatment-resistant schizophrenia who were taking clozapine, they noted.
“This observation raises the question of whether clozapine use alters the gut microbiome or the bacteria present prior to clozapine exposure mediate the effects of frontline antipsychotics and thus the emergence of treatment resistance,” they pointed out.
It also highlights the importance of considering medication intake in microbiome studies in psychiatry, they added.
Experts Weigh In
Reached for comment, Xiaoduo Fan, MD, MPH, professor of psychiatry and director, UMass Mind, UMass Chan Medical School, Worcester, Massachusetts, said the study provides more evidence that the gut microbiome is implicated in treatment-resistant schizophrenia.
“The findings are complementary to what we reported based on our work in drug-naive, first-episode schizophrenia,” Fan told Medscape Medical News.
“This line of research is exciting because it has implications for both mechanistic understanding and therapeutics,” he noted.
However, Fan noted that “most findings from published studies are association rather than causal in nature regarding the relationships between alterations to gut microbiome and psychiatric or metabolic outcomes; the use of currently available antipsychotics including clozapine may further complicate these relationships.”
“Even with a better understanding about the causal relationships, it does not necessarily mean that a clinically useful diagnostic test or treatment targeting the gut microbiome can be developed any time soon,” Fan cautioned.
Also weighing in, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, Toronto, Ontario, Canada, said the study is “interesting and rigorous” and provides “preliminary evidence to support a different gut diversity signature in treatment-resistant populations, which may be a function of medication exposure.”
He cautioned, however, that more research is needed.
“I think this study is in the hypothesis-generating rather than hypothesis-confirming category” and the “mechanistic category rather than the clinically translatable and implementation category,” McIntyre told Medscape Medical News.
Ann Shinn, MD, MPH, director of clinical research, Schizophrenia and Bipolar Disorder Research Program, McLean Hospital, Belmont, and assistant professor of psychiatry, Harvard Medical School, Boston, Massachusetts, agreed.
This is a “complex study with interesting results, but I think the takeaways are a little bit limited. The main takeaway is that there are significant microbiome associations with treatment-resistant schizophrenia,” she told Medscape Medical News.
“The study provides insights into what the differences may be between treatment-responsive vs treatment-resistant schizophrenia, as well between schizophrenia vs people without schizophrenia, in terms of the gut microbiome. But I don’t think that this is information that can be applied for clinical use at the moment,” Shinn added.
Support for the study was provided in part by Metro South Health Research, Princess Alexandra Hospital, and the National Health and Medical Research Council. The authors had no relevant disclosures. Fan received research support from Intra-Cellular Therapies, Otsuka, Roche, and Avanir and is a contributor for BMJ Best Practice: Schizophrenia. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp. Shinn had no relevant disclosures.
Source link : https://www.medscape.com/viewarticle/gut-signature-treatment-resistant-schizophrenia-2024a10002op?src=rss
Publish date : 2024-02-07 13:26:20
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