Endocannabinoids and polyunsaturated fatty acids in early schizophrenia: Changes under antipsychotics and association...

Evidence supports polyunsaturated fatty acid (PUFA) and endocannabinoid (eCB) metabolism dysregulation in schizophrenia. However, data on the topic are inconsistent, and the precise role of these mediators remains unclear. The study aimed to analyze free plasma PUFAs, endocannabinoids, and endocannabinoid-like compounds in first-episode schizophrenia (FES) and examine their association with psychopathology and changes under antipsychotic therapy. Seventy-nine antipsychotic-naïve/free FES patients and 78 healthy controls underwent clinical, psychometric, and laboratory evaluations. Thirty-six patients were reassessed after three months of antipsychotic therapy. Selected PUFAs and endocannabinoids were quantified using targeted LC-MS/MS. During the acute stage, arachidonic, docosapentaenoic, and docosahexaenoic acids were lower, whereas anandamide, 2-arachidonoyl glycerol, oleylethanolamide, alpha-linolenylethanolamide, and docosahexaenoylethanolamide) were higher in FES patients than in controls. The alpha-linolenylethanolamide to docosahexaenoic acid ratio exhibits good discriminant power for FES [AUC: 0.79 (0.71-0.86)]. Anandamide levels were inversely correlated with psychotic and negative symptoms. Three-month antipsychotic therapy increased PUFA but did not change eCB levels, which remained increased in treated patients than in controls. Higher baseline AA, DPA, and DHA are predictive of a better response to antipsychotics. The study provided evidence for PUFA and endocannabinoid system dysregulations in FES. The cause and meaning of PUFA deficit and increased eCB tone are poorly understood. However, the dysregulations should have implications for neurotransmission, mood modulation, and cognitive functions. Further research is needed to understand the role of PUFAs and the endocannabinoid system in the pathophysiology and management of schizophrenia.