By Matej Oresic, Jing Tang, Tuulikki Seppanen-Laakso, Ismo Mattila, Suoma E Saarni, Samuli I Saarni, Jouko Lonnqvist, Marko Sysi-Aho, Tuulia Hyotylainen, Jonna Perala and Jaana Suvisaari
Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, particularly hypertriglyceridemia and low HDL. More detailed molecular information on the metabolic abnormalities may reveal clues about the pathophysiology of these changes, as well as about disease specificity.
We 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 nonaffective 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: (1) global lipidomics platform based on Ultra Performance Liquid Chromatography coupled to mass spectrometry, which covers molecular lipids such as phospholipids and neutral lipids and (2) platform for small polar metabolites based on two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-TOFMS).
Compared 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) as compared to controls, while proline [moleculecular structure illustrated] 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. Conclusions
Our 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 may become a powerful tool in psychiatric research to investigate disease susceptibility, clinical course, and treatment response, sensitive to both genetic and environmental variation.
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