The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study

Abstract

Alterations in the expanded endocannabinoid system (eECS) and cell membrane composition have been implicated in the pathophysiology of schizophrenia spectrum disorders. We enrolled 54 antipsychotic (AP)-naïve first-episode psychosis (FEP) patients and 58 controls and applied a targeted metabolomics approach followed by multivariate data analysis to investigate the profile changes in the serum levels of endocannabinoids: 2-arachidonoylglycerol (2-AG) and anandamide, endocannabinoids-like N-acylethanolamines (NAEs: linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide), and their dominating lipid precursor’s phosphatidylcholines. Biomolecule profiles were measured at the onset of first-episode psychosis (FEP) and 0.6 years and 5.1 years after the initiation of AP treatment. The results indicated that FEP might be characterized by elevated concentrations of NAEs and by decreased 2-AG levels. At this stage of the disease, the NAE-mediated upregulation of peroxisome proliferator-activated receptors (PPARs) manifested themselves in energy expenditure. A 5-year disease progression and AP treatment adverse effects led to a robust increase in 2-AG levels, which contributed to strengthened cannabinoid (CB1) receptor-mediated effects, which manifested in obesity. Dynamic 2-AG, NAEs, and their precursors in terms of phosphatidylcholines are relevant to the description of the metabolic shifts resulting from the altered eECS function during and after FEP.

A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study

“…These alterations appeared against the background of persistent BMI and waist circumference increases in the sample of patients. Meta-analyses [ 1 , 43 ] and our previous studies [ 31 , 32 ] have convincingly shown that patients with a chronic psychotic disorder have an increased risk of abdominal obesity, diabetes and MetS when compared with cohort-matched general population controls. It has been suggested that waist circumference appears to capture a major part of the health risks related to the amount of body fat [ 44 ].…”

“…The same FEP and CSs groups were partially characterized in our previous studies [ 7 , 8 , 30 ], wherein we focused on describing the inflammatory biomarkers and metabolomic profiles in AP-naïve FEPs ( n = 38) compared to controls ( n = 37) and demonstrated changes in biomolecule profiles over 0.6 years. To describe even longer-term changes due to disease and treatment, we then increased the total number of subjects in the study, also collected patient data at 5.1 years after initiation of AP therapy, and described changes in amino acid, biogenic amine profiles and endocannabinoids in the FEP group, before initiating AP therapy, as well as over 0.6- and 5.1-year periods [ 31 , 32 ]. At present, 5.1-year longitudinal data from 54 patients and data from 58 controls (partially the same cohort as described previously) were included in this study.…”

Current State of Fluid Lipid Biomarkers for Personalized Diagnostics and Therapeutics in Schizophrenia Spectrum Disorders and Related Psychoses: A Narrative Review

“…Unbiased lipidomic profiling with LC-MS/MS is conventionally measured using data-dependent acquisition, a lipid screening format that biases abundant lipids. Targeted screening methods, such as MRM, aid the identification of lipids of interest, down to picomolar concentrations, and were employed to identify eCBs and eicosanoid disruptions in SSD etiology ( 51 , 52 , 62 , 69 , 74 , 75 ). Data-independent acquisition is an alternative global lipidomic approach, providing a more diverse lipidomics profile.…”

“…Most recently, Parksepp et al . ( 75 ) conveyed a direct and dynamic influence of membrane phospholipids on ECS regulation in SSD. In their 5-year investigation, levels of peripheral ECS regulators and NAEs were examined along with their phospholipid precursors.…”

“…Although underlying mechanisms remain still conjectural, growing evidence suggests CBD may exert its antipsychotic properties, at least in part, via lipid signaling in the ECS ( 93 – 96 ). A systematic examination of lipids in response to CBD might shed light on their physiological relevance to CBD efficacy, particularly given recent dynamics investigating the consequence of phospholipidomic shifts on altered ECS function ( 75 ). To the best of our knowledge, so far, no clinical investigations have explored peripheral lipid profiles in response to CBD, either as a stand-alone or adjunct therapy with antipsychotics.…”