From Molecules to the Clinic: Linking Schizophrenia and Metabolic Syndrome through Sphingolipids Metabolism

Abstract

Metabolic syndrome (MS) is a prevalent and severe comorbidity observed in schizophrenia (SZ). The exact nature of this association is controversial and very often accredited to the effects of psychotropic medications and disease-induced life-style modifications, such as inactive lifestyle, poor dietary choices, and smoking. However, drug therapy and disease-induced lifestyle factors are likely not the only factors contributing to the observed converging nature of these conditions, since an increased prevalence of MS is also observed in first episode and drug-naïve psychosis populations. MS and SZ share common intrinsic susceptibility factors and etiopathogenic mechanisms, which may change the way we approach clinical management of SZ patients. Among the most relevant common pathogenic pathways of SZ and MS are alterations in the sphingolipids (SLs) metabolism and SLs homeostasis. SLs have important structural functions as they participate in the formation of membrane “lipid rafts.” SLs also play physiological roles in cell differentiation, proliferation, and inflammatory processes, which might be part of MS/SZ common pathophysiological processes. In this article we review a plausible mechanism to explain the link between MS and SZ through a disruption in SL homeostasis. Additionally, we provide insights on how this hypothesis can lead to the developing of new diagnostic/therapeutic technologies for SZ patients.

Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration

“…In addition, analysis of prefrontal cortical and hippocampal samples from Df(16)A+/− mice, a model of 22q11.2 chromosome deletion (a major genetic risk factor of schizophrenia), identified alterations in ceramide phosphoethanolamines and sphingomyelin levels [ 49 ]. Overall, our findings combined with the literature demonstrate alterations in central and peripheral sphingolipids in first episode and recently diagnosed schizophrenia, preclinical schizophrenia modelling, and as a result of acute antipsychotic drug treatment (also see [ 29 ]).…”

“…Ceramide inhibits glycogen synthesis and insulin-stimulated glucose uptake, blockade of ceramide synthesis improves insulin sensitivity and glucose homeostasis, and levels of ceramide species are higher in skeletal muscle of obese insulin-resistant subjects compared to lean controls [ 27 ]. Interestingly, sphingolipids are also altered in schizophrenia, for example increased ceramide levels have been reported in the white matter of the pre-frontal cortex [ 28 ] (also see review by Castillo et al [ 29 ]), and in response to chronic haloperidol treatment, a first generation antipsychotic drug [ 30 ]. Altered sphingolipids in key glucometabolic tissues, such as the liver and skeletal muscle, may contribute to the disruption in glucose homeostasis that leads to hyperglycemia and insulin-resistance side-effects; however, this has not previously been examined.…”

Enrichment of gene variants associated with treatable genetic disorders in psychiatric populations

“…Individuals with NPC exhibit cholesterol disturbances that can negatively affect the homeostasis of myelinated axons, which are lipidrich and highly lipid-dependent brain structures, suggesting a possible mechanism by which NPC1 and NPC2 mutations could be contributing to mental illnesses. 25 Controlled studies of heterozygous NPC1(+/-1 0 ) mice show motor dysfunction, anxiety-like behaviour, and neurodegeneration, possibly through tau protein mechanisms, supporting the hypothesis that heterozygous NPC carrier states increase the risk for neuropsychiatric phenotypes. 26,27 Miglustat, the only approved treatment for NPC, has been shown to lower total tau levels in the cerebrospinal fluid of NPC patients, suggesting the possibility that treatment of heterozygous NPC carriers with miglustat could improve neuropsychiatric symptoms and prevent further neurodegeneration.…”

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“…Προκειμένου να εκτιμήσουμε αν επηρεάστηκε η ροή νέων περιστατικών από τις δυνατότητες του ΚΚΨΥ για έναρξη θεραπείας σε νέα περιστατικά, καταγράφηκε παράλληλα ο αριθμός συνεδριών κατ' έτος -συνολικών και κατά κλάδο-τα αντίστοιχα έτη. Αυτά τα δεδομένα παρουσιάζονται στο διάγραμμα 100 Κ. ΠΙΚΟΥΛΗ και συν ΨΥΧΙΑΤΡΙΚΗ 30 (2), 2019 της εικόνας 1. Όπως προκύπτει από το διάγραμμα αυτό, στα έτη μετά την έναρξη της κρίσης -και ιδιαίτερα στα έτη 2008-2011-εμφανίζεται μεγάλη αύξηση των συνεδριών που πραγματοποιούνται στο ΚΚΨΥ από όλες τις ειδικότητες της θεραπευτικής ομάδας.…”

“…Ο ίδιος μηχανισμός μπορεί να συνδέει αιτιοπαθογενετικά τη σχιζοφρένεια με το μεταβολικό σύνδρομο, η ύπαρξη του οποίου διαπιστώνεται σε εξαιρετικά υψηλό ποσοστό (60% στους ασθενείς με σχιζοφρένεια έναντι 30% στον γενικό πληθυσμό). 100…”