Investigating the link between visceral obesity, clinical and cardio-metabolic outcomes in patients at their psychotic episode.

Visceral fat accumulation represents a pervasive problem in patients with psychotic spectrum disorders (PSDs) since the earliest stages of illness. Rates of comorbidity range from 40 to 60%. The complex interplay between unhealthy life-style, side effects of medications, and pathophysiological mechanisms innate to the psychiatric illness, has been so far the most cited explanation for this high prevalence. In addition to its well-known role in increasing risk for various cardio-metabolic conditions, visceral fat accumulation has been shown to be responsible for cognitive deficits and poor functional outcomes in otherwise healthy individuals. For this reason, it is possible to hypothesize that it may have a similar negative effect in patients with PSDs. Understanding factors that are associated with cognitive performances and real-word functioning in PSDs is important, because they often lead to increased healthcare costs, lower quality of life, and impaired recovery. In the general population, visceral obesity is associated with relevant biobehavioral systems dysregulations and, in particular, with a specific pattern of (i) hypothalamicpituitary-adrenal (HPA) axis, (ii) inflammatory, (iii) gut-microbiome; and (iv) serum metabolite profile abnormalities. Of interest, similar abnormalities have been consistently related to the extent of cognitive and functional impairments, as well as to poor treatment response in drug-naïve and minimally medicated first episode patients (FEP). These observations suggest that visceral obesity may have a negative synergistic influence on key pathophysiological mechanisms innate to PSDs and significantly contribute to poor outcomes since the earliest stages of the disorder. This hypothesis is indirectly supported by the growing body of evidence on the benefic effect of visceral fat loss through dietary intervention and physical exercise on cognitive and functional outcomes in PSDs. Weight gain is most rapid during the first months of treatment. However, there is a significant individual variation in the propensity to develop visceral fat deposits in FEP. Thus, identifying early predictors of future visceral fat accumulation and the development of the associated cardiovascular, and (potential) cognitive and functional disabilities would be highly useful in clinical practice.

Aims
FEP will be assessed at baseline and then for their treatment response at 12 weeks. The antipsychotic treatment will be clinician-led. The aims of our study will be: 1) to investigate whether visceral obesity at baseline is associated with more severe cognitive and functional outcomes in FEP, both at baseline and at follow-up; 2) to investigate whether this putative association is mediated by HPA axis, inflammatory, microbiome, and serum metabolites abnormalities; 3) to investigate whether visceral obesity as well as HPA axis, inflammatory, microbiome, and serum metabolite abnormalities at baseline predict treatment response and worst cardio-metabolic outcomes at 12 weeks of follow-up.