Abstract
BackgroundPersons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, particularly hypertriglyceridemia and low high-density lipoprotein. More detailed molecular information on the metabolic abnormalities may reveal clues about the pathophysiology of these changes, as well as about disease specificity.MethodsWe applied comprehensive metabolomics in serum samples from a general population-based study in Finland. The study included all persons with DSM-IV primary psychotic disorder (schizophrenia, n = 45; other non-affective psychosis (ONAP), n = 57; affective psychosis, n = 37) and controls matched by age, sex, and region of residence. Two analytical platforms for metabolomics were applied to all serum samples: a global lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry, which covers molecular lipids such as phospholipids and neutral lipids; and a platform for small polar metabolites based on two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC-TOFMS).ResultsCompared with their matched controls, persons with schizophrenia had significantly higher metabolite levels in six lipid clusters containing mainly saturated triglycerides, and in two small-molecule clusters containing, among other metabolites, (1) branched chain amino acids, phenylalanine and tyrosine, and (2) proline, glutamic, lactic and pyruvic acids. Among these, serum glutamic acid was elevated in all psychoses (P = 0.0020) compared to controls, while proline upregulation (P = 0.000023) was specific to schizophrenia. After adjusting for medication and metabolic comorbidity in linear mixed models, schizophrenia remained independently associated with higher levels in seven of these eight clusters (P < 0.05 in each cluster). The metabolic abnormalities were less pronounced in persons with ONAP or affective psychosis.ConclusionsOur findings suggest that specific metabolic abnormalities related to glucoregulatory processes and proline metabolism are specifically associated with schizophrenia and reflect two different disease-related pathways. Metabolomics, which is sensitive to both genetic and environmental variation, may become a powerful tool in psychiatric research to investigate disease susceptibility, clinical course, and treatment response.
Highlights
Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, hypertriglyceridemia and low high-density lipoprotein
Previous metabolomic studies in schizophrenia and related psychoses have highlighted the importance of glucoregulatory processes [15,16] and tryptophan metabolism [17] in psychosis, and lipidomics approaches have identified specific drug-response profiles for three commonly used atypical antipsychotics [18]
Metabolomic analysis Two analytical platforms for metabolomics were applied to all serum samples: a global lipidomics platform based on UltraPerformance LCTM system (UPLC)-mass spectrometry (MS), which covers molecular lipids such as phospholipids, sphingolipids, and neutral lipids; and a platform for small polar metabolites based on GC × GC-TOFMS covers small molecules such as amino acids, free fatty acids, keto-acids, various other organic acids, sterols, and sugars
Summary
Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, hypertriglyceridemia and low high-density lipoprotein. The current view is that schizophrenia is a developmental disorder caused by a combination of genetic vulnerability, early environmental insults, subtle developmental and cognitive impairments, and later pathogenic factors of specific diseases would be of high relevance, to assist in their early detection and diagnosis, and to subsequently facilitate disease monitoring and treatment responses. Concentration changes of specific groups of circulating metabolites may be sensitive to pathogenically relevant factors, such as genetic variation, diet, age, or gut microbiota [8,9,10,11,12]. No metabolomics studies have so far been conducted to discriminate between different groups of psychotic disorders
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