Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.02.28.582623

The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine

Kamath, S.·Hunter, A.·Collins, K.·Wignall, A.·Joyce, P.
View original source ↗Export metadata ↓

Abstract

Background and PurposeAntipsychotics like olanzapine are associated with significant metabolic dysfunction, attributable to gut microbiota dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiota has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting, with most reports observing weight loss rather than gain. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiota to explore the hypothesis of "gut neutrality" for lurasidone exposure. Experimental ApproachUsing a Sprague-Dawley rat model, the impact of olanzapine and lurasidone administration on the gut microbiota was explored. Faecal and blood samples were collected weekly over a 21-day period to analyse changes to the gut microbiota and related metabolic markers. Key ResultsLurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating gut microbiota through increases in mean OTUs (+50 OTUs) and alpha diversity (+0.5 increase in Shannons index). This novel finding suggests an underlying mechanism for lurasidones metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs (-75 OTUs) and substantial compositional variation, suggesting a decrease in microbial richness. Microbiota alterations correlated with metabolic dysfunction, evidenced through a statistically significant 30% increase in weight gain, increase in pro-inflammatory cytokine expression, and increase in blood triglycerides and glycaemic levels. Conclusion and ImplicationsThe study challenges the notion that all antipsychotics disrupt the gut microbiota similarly and highlights the potential benefits of gut positive or neutral antipsychotics like lurasidone in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia. Bullet point summary- What is already known: O_LIOlanzapine induces weight gain by disrupting the gut microbiome. C_LIO_LIThe impact of lurasidone on the gut microbiome is unknown and weight gaining propensities unclear. C_LI - What this study adds: O_LILurasidone positively modulates gut microbiota through enhancement of microbial diversity and richness. C_LIO_LIPotential mechanisms underlying lurasidones weight and metabolic neutrality are elucidated. C_LI - Clinical significance: O_LIGut neutral antipsychotics like lurasidone could be favourable alternatives for patients unable to tolerate olanzapine. C_LIO_LIPersonalised treatment for schizophrenia considering individual sensitivities to metabolic effects is emphasised. C_LI

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kamath, S., Hunter, A., Collins, K., Wignall, A., Joyce, P.. 2024-03-03. The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine. https://doi.org/10.1101/2024.02.28.582623

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

PCB-Exposed Gut Microbiota Recapitulate Neurobehavioral Deficits and Reprogram Hippocampal Transcriptomic Signatures

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants associated with developmental neurotoxicity and autism spectrum disorder (ASD). However, whether PCB-induced alterations in gut microbiota contribute to neurodevelopmental toxicity independently of direct chemical exposure remains unclear. Here, we investigated whether transplantation of PCB-associated gut microbiota produces early neurobehavioral alterations and disrupts brain molecular pathways in offspring. Gut microbiota from conventional dams exposed to the Fox River PCB mixture (FRM; 6.0 mg/kg/day) or vehicle were transplanted into germ-free recipient females without direct PCB administration. At postnatal day 7 (P7), offspring underwent ultrasonic vocalization (USV) testing, whole-brain RNA sequencing (n = 4/sex/group), and untargeted serum metabolomics. Untargeted serum metabolomics were also performed in donor dams. PCB-associated fecal microbiota transplantation (FMT) significantly reduced offspring USVs, reproducing effects observed following direct maternal PCB exposure. Brain transcriptomics in offspring identified substantially more differentially expressed genes in males (9,339) than females (1,082), including 512 shared genes. Concordantly regulated genes revealed downregulation of neurotransmitter signaling and ion channel pathways alongside upregulation of RNA processing pathways. Male-associated responses involved altered protein synthesis and neuronal signaling, whereas female-associated responses involved DNA repair and extracellular matrix remodeling. Despite these molecular differences, behavioral responses showed no significant sex-dependent effect. Maternal metabolomics revealed increased bile acids and decreased indole-3-propionic acid, highlighting potential AhR-NF{kappa}B and bile acid-associated signaling mechanisms. Offspring metabolomics further identified alterations in lipid-associated metabolites and metabolic profiles. Collectively, these findings show that transferring PCB-exposed microbiota reproduces early neurobehavioral alterations and induces shared and sex-biased molecular responses, identifying the maternal gut microbiome as a candidate mediator linking PCB exposure to developmental neurotoxicity.

pharmacology and toxicology↗
bioRxiv2026

Cisplatin-triggered sensory dysfunction in NER-defective C. elegans involves GABAergic and cholinergic signaling

Cisplatin (CisPt) is a widely used anticancer drug that causes neurotoxicity as a dose-limiting adverse effect. DNA damage contributes to CisPt-induced neurotoxicity, yet the molecular mechanisms involved remain unclear. Here, we aim to identify pathophysiological mechanisms contributing to DNA damage-driven development of sensory neuronal dysfunction using the 3R-compliant model organism Caenorhabditis elegans. To this end, we employed the nucleotide excision repair (NER)-deficient ercc-1 mutant, which shows enhanced CisPt-induced sensory dysfunction as monitored by the chemotaxis assay, to elucidate drug-induced alterations in neurotransmission and transcriptome. We found that CisPt reduces gamma-aminobutyric acid (GABA) levels in the nematode and that GABA supplementation rescues ercc-1 mutants from CisPt-evoked sensory neurotoxicity, pointing to a neuroprotective function of GABA in the context of our study. Moreover, CisPt impairs the morphological integrity of GABAergic neurons particularly in ercc-1 mutants, which again is rescued by GABA substitution. Conversely, the cholinergic agonist carbachol impairs sensory function and exacerbates the neurotoxic effects of CisPt in ercc-1 mutants, indicating detrimental effects resulting from cholinergic excitation. Transcriptome analysis revealed that CisPt treatment stimulates a broard transcriptional response, including pathways involved in the regulation of neuronal communication, including acetylcholine-mediated neurotransmission, with pronounced effects occurring in the absence of ERCC-1. Based on these finding we suggest impaired GABAergic signaling and the loss of neuronal integrity GABAergic neurons as well as excessive cholinergic excitation as key mechanisms linking CisPt-induced DNA damage in NER defective nematodes to sensory dysfunction. Hence, targeting the balance between GABAergic inhibition and cholinergic excitation is suggested to counteract sensory neurotoxicity triggered by CisPt.

pharmacology and toxicology↗
bioRxiv2026

Mathematical model of phenotypic plasticity predicts interconversion is a drug target for neuroblastoma.

Neuroblastoma is a paediatric cancer arising from the sympathetic nervous system as neural crest cells, made up of noradrenergic (NOR/ADRN/N), mesenchymal like (MES/S), and intermediate (I-type/I) cell types. These cells can interconvert between types, contributing to treatment resistance and relapse. We developed a mathematical model to investigate how interconversion patterns affect the efficacy of phenotype-specific inhibitors. We used three ordinary differential equations to describe the dynamics of the three populations, including logistic growth, interconversion, and drug-induced death. Of the 64 possible interconversion patterns, five reduced the target population: two for N cells and three for S cells. N targeting patterns were more effective with higher interconversion rates, while mesenchymal targeting patterns were more effective with lower interconversion rates. Stability analysis revealed that natural tumour growth was always unstable, but during treatment, N-suppressing patterns combined with an S inhibitor gave the most consistently stable origin. Testing multi-stage and cyclic treatment schedules revealed that N-suppressing patterns with an S inhibitor, followed by an S-suppressing pattern with an N inhibitor, achieved more reliable remission. Three of the five patterns of interest correspond to reported biological plausibility, and known compounds exist to induce most of the required transitions, supporting the clinical relevance of these strategies for improving neuroblastoma treatment outcomes.

pharmacology and toxicology↗