Author Response for "plasmatic Endocannabinoids Are Decreased in Subjects with Ultra‐high Risk of Psychosis"

The onset of frank psychosis is usually preceded by a prodromal phase characterized by attenuated psychotic symptoms. Currently, research on schizophrenia prodromal phase (ultra-high risk for psychosis [UHR]) has focused on the risk of developing psychosis, on the transition to full blown psychosis and on its prediction. Neurobiological differences between UHR individuals who fully recover (remitters) versus those who show persistent/progressive prodromal symptoms (nonremitters) have been little explored. The endocannabinoid system constitutes a neuromodulatory system that plays a major role in brain development, synaptic plasticity, emotional behaviours and cognition. It comprises two cannabinoid receptors (CB1/CB2), two endocannabinoid ligands, arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) along with their inactivation enzymes. Despite much evidence that the endocannabinoid system is imbalanced during psychosis, very little is known about it in UHR. Therefore, we aimed to quantify the plasma endocannabinoid levels in UHR and healthy controls (HC) and verify if these metabolites could differentiate between remitters and nonremitters. Circulating concentrations of AEA (p = .003) and 2AG (p < .001) were lower in UHR when compared with HC, with no difference between remitters and nonremitters. Regarding clinical evolution, it was observed that out of 91 UHRs initially considered, 16 had psychiatric complaints (3 years of follow-up). Considering those subjects, there were weak correlations between clinical parameters and plasma concentrations of endocannabinoids. Our results suggest that the endocannabinoids are imbalanced before frank psychosis and that changes can be seen in plasma of UHR individuals. These molecules proved to be potential biomarkers to identify individuals in the prodromal phase of psychosis.