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Schizophrenia's Metabolome

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Clinicians and researchers have long noticed that people with schizophrenia show high rates of obesity, as well as glucose intolerance or diabetes. The prevalence of type 2 diabetes in people with schizophrenia is anywhere from two to 10 times that of the general population, according to multiple reports.

One question, however, is whether this increased rate of metabolic disorders is due to the disease or to the drugs that treat the disease. "One interesting thing about schizophrenia is that it has a very major metabolic co-morbidity. People who have schizophrenia — and it's not the same for other psychotic disorders — have much more diabetes and metabolic syndrome," says Matej Orešic, a research professor at VTT Technical Research Centre in Espoo, Finland.

Orešic and his team set out to examine the metabolic profiles of people with schizophrenia and other psychotic disorders, along with matched controls. "We had decided to look at this metabolic profile using metabolomics because we have done a lot of studies before in obesity and diabetes using metabolomics. So we were basically interested to see if it is similar in psychotic disorders," he says.

Orešic and his colleagues turned to participants from Finland's Health 2000 survey — a general population study of more than 8,000 people — and its sub-study, Psychoses in Finland, which focuses on those diagnosed with a psychotic disorder. They then characterized those participants' metabolomes using UPLC-MS and 2-D GC-MS. UPLC-MS gave the group a sense of the lipids present while 2-D GC-MS analyzed small metabolites like amino acids. "We basically tried to cover the metabolome very broadly," he says.

In addition, the team took standard biochemical measurements of metabolism, assessing high-density lipoprotein, low-density lipoprotein, and glucose levels, while noting which antipsychotic medications the participants were on.

As the researchers recently reported in Genome Medicine, people with schizophrenia had higher levels of certain metabolites, including saturated triglycerides, branched chain amino acids, and other amino acids, as compared to people with other psychotic disorders or controls — all independent of antipsychotic medication. "The schizophrenia was having a major effect on metabolomic profiles, but not other psychoses," Orešic says. Furthermore, he notes that a recent study from the Broad Institute, published in Nature Medicine, found a link between branched-chain amino acids, aromatic amino acids, and diabetes risk.

One hypothesis as to how schizophrenia and diabetes could be linked may be at the blood-brain barrier, Orešic says. High levels of branched amino acids could be competing with aromatic amino acids for entry to the brain. Aromatic amino acids are the building blocks of catecholamines like dopamine, which is known to be involved in schizophrenia. "But that of course doesn't mean that there is one single mechanism that will lead to schizophrenia, because this could be quite misleading," he adds. "It doesn't mean that somebody who is obese or has diabetes will develop schizophrenia; there are many other environmental factors, of course, and genetics, that all together contribute."

Knowing which metabolites are involved in a disease, however, could aid in diagnosis and in choosing the best treatment for a given patient. Although the diagnostic criteria in The Diagnostic and Statistical Manual of Mental Disorders-IV are well established, Orešic says they are not etiologically based. "It's not so much about differentiating a normal person from a psychotic person — because psychiatrists can do that — but more within the psychotic group, try to discriminate between different disorders on a biological basis," he says. "I think that's something that's really helpful in the treatment."

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