Gut-lung microbiome shifts may explain clozapine's severe bowel and lung side effects
Schizophrenia is a severe mental health disorder characterized by hallucinations, false and rigid beliefs (i.e., delusions), impaired mental functions, disorganized speech and, in some cases, repetitive body movements. This debilitating disorder is typically treated with antipsychotics, medications that alter the signaling between neurons.
An antipsychotic that is commonly prescribed to patients who are found to be resistant to other available medications is clozapine. While this drug can help to ease symptoms of schizophrenia in some patients that did not respond well to other treatments, it can also cause severe adverse effects, including chronic constipation or life-threatening intestinal blockage and lung infections.
Researchers at Chiba University in Japan recently carried out a mouse study aimed at better understanding what gives rise to the unwanted side effects of clozapine on the lungs and digestive system. Their findings, published in Translational Psychiatry, suggest that the antipsychotic medication causes significant changes in microbes residing in both the gut and lungs, which can lead to digestive issues and respiratory complications.
"Our study was prompted by the puzzling co-occurrence of severe constipation and pneumonia in patients with schizophrenia who are receiving clozapine," Kenji Hashimoto, a researcher at Chiba University and senior author of the paper, told Medical Xpress. "We hypothesized that these complications may share a microbiota-mediated mechanism along the gut–lung axis. Therefore, we investigated whether clozapine disrupts gut and lung microbial communities and metabolic profiles in mice, impairs gastrointestinal (GI) motility, and increases susceptibility to inflammatory lung injury."
How clozapine affects digestion and microbiota in mice
To explore the effects of clozapine on microbiota within the gut and lungs, the researchers carried out an experiment involving adult mice. Half of the mice received daily doses of clozapine that were proportional to their weight for a total of 14 days, while the other half received a non-active substance (i.e., placebo).
"The body weight and fecal output of the mice were measured, to assess gastrointestinal (GI) motility," explained Hashimoto. "We profiled gut and lung microbial communities using 16S rRNA sequencing, and circulating metabolites were analyzed by untargeted metabolomics. The mice were then challenged with lipopolysaccharide (LPS) to induce acute lung injury, allowing us to link clozapine-induced microbiota and metabolic alterations to reduced survival and increased respiratory vulnerability."
The researchers compared the microbiota and body weight of mice who had received clozapine to those who received the non-active substance. They found that clozapine significantly reduced the quantity of feces produced by the animals, suggesting that it slowed down their digestion. In addition, mice treated with clozapine lost significant weight over the course of the experiment.
Notably, Hashimoto and his colleagues also observed significant differences in the bacteria present in both the gut and lungs of mice that received clozapine. The extent of the drug's effects on microbial communities appeared to vary greatly depending on the sex of the animals and across different parts of the body.
"We also showed that clozapine induces coordinated gut–lung dysbiosis, GI hypomotility, and systemic metabolic stress, which together increase susceptibility to inflammatory lung injury," said Hashimoto. "This microbiota-centered mechanism reframes the GI and respiratory risks associated with clozapine and suggests testable adjunctive strategies, such as microbiota monitoring or modulation, to improve treatment safety in patients with treatment-resistant schizophrenia."
New insight that could guide clinical practice
The results gathered by this research team pinpoint biological processes that could be responsible for the severe constipation and respiratory issues experienced by many patients after they are treated with clozapine. Specifically, they suggest that changes in microbes residing in the gut and lungs might underpin the drug's adverse effects on digestion and breathing.
If they are validated in humans, the researchers' findings could guide future clinical and psychiatric practices. For instance, they could encourage psychiatrists to prescribe clozapine in combination with probiotics and carefully designed dietary plans, to reduce its adverse effects. In addition, they might lead to the development of new drugs that could improve the safety of clozapine.
"Our work provides a mechanistic framework for clozapine-associated adverse events and hints at the value of microbiota-targeted strategies to improve the safety of clozapine treatment," added Hashimoto. "We now plan to conduct longitudinal human studies to identify microbiome- and metabolite-based biomarkers of clozapine toxicity, integrate respiratory monitoring, and evaluate microbiota-targeted adjunctive strategies to reduce clozapine-associated adverse events."
This article was originally published on MedicalXpress Breaking News-and-Events.