Although they’re not supposed to be fatal, psychotic disorders such as schizophrenia can be very difficult to cope with. So difficult in fact that some patients will fail in their efforts to keep a healthy lifestyle and manage the side-effects of medication. So far, this struggle has been thought to cause the high prevalence of cardiovascular disease, type 2 diabetes and metabolic syndrome amongst patients with psychotic disorders, and, ultimately, a life expectancy that’s 15 to 20 years shorter than that of the average person. But what if there was more to it? As Dr Matej Oresic points out, abnormal glucose homeostasis, hyperinsulinemia and accumulation of visceral fat can actually be detected in drug-naïve first episode psychosis (FEP) patients, independent of obesity. Hence the need to better understand the link between lipid metabolism and the metabolic co-morbidities of psychotic disorders. “We considered that primary obesity and psychotic disorders are similar with respect to the associated changes in energy balance and co-morbidities, including metabolic syndrome. But the mechanisms linking the expansion of adipose tissue to these co-morbidities are unknown. Rather than demonstrating causal links, these similarities suggest that specific causes of – and metabolic disturbances associated with – obesity play a role in the development of psychotic disorders, potentially even before obesity develops,” he says. In other words, lipid metabolism may be the link between psychosis and its associated metabolic co-morbidities. This existence of such a link may offer new opportunities for the development of novel diagnostic tools, which was one of the purposes of the METSY (Neuroimaging platform for characterisation of metabolic co-morbidities in psychotic disorders) project. Using a multi-modal approach including a hybrid PET/MR system for brain imaging, mass spectrometry for the determination of circulating levels of endocannabinoids and other lipids, and integrative analysis of the acquired data using bioinformatics tools specifically developed by project partners, the team notably found a close association between endocannabinoid levels in the blood and CB1R availability in the brains of healthy individuals. This association happens to break down in patients with psychosis. “Besides, our research suggests that FEP patients who gain most weight in the follow-up phase have a specific circulating lipid signature which is indicative of elevated liver fat, independent of obesity. From a clinical standpoint, this is significant because it may help identify patients at highest risk of developing metabolic co-morbidities associated with psychosis, and it may guide the choice of therapy,” Dr Oresic enthuses. Besides helping to identify psychotic patients who are at the highest risk of developing metabolic co-morbidities and potentially leading to their prevention, METSY’s findings offer new opportunities to the diagnostic and pharmaceutical sectors. “The former can benefit from the identified biomarkers, while the latter can explore the possibility of combining antipsychotic and antidiabetic/antiobesity treatments in order to tackle psychosis as well as prevent metabolic complications,” Dr Oresic explains. Follow-up research is already underway. This includes: additional studies to examine the role of fatty liver, and gut-liver-brain axis in general, in psychosis and associated metabolic co-morbidities; studies of the endocannabinoid system in psychotic disorders; and the further development of tools and methods to analyse and interpret multi-modal data in psychosis studies. “We intend to develop these approaches further, particularly those focusing on the integration of neuroimage and ‘multi-omics’ data, which in the future will also include gut microbiome (shotgun sequencing) data. Additionally, it is our intention to help bring the decision support tool developed within METSY towards clinical practice, as it has already been achieved in the domain of neurodegenerative diseases,” Dr Oresic concludes.
METSY, psychosis, obesity, lipids, schizophrenia, co-morbidities