Metabolic map is made

HELSINKI, Finland—Scientists in Finland have taken a smallbut significant step toward developing a clinical test for diagnosingschizophrenia—and a giant leap for schizophrenics forced to live with the delusions,hallucinations and behavior that mark the chronic and severe brain disorder.

The key to this diagnostic breakthrough has come in a studyperformed by a team led by Matej Orešič, chief research scientist at the VTTTechnical Research Centre of Finland near Helsinki, in collaboration with JaanaSuvisaari from the Finnish National Institute for Health and Welfare.

These findings, published online March 23 in thepeer-reviewed journal Genome Medicine,may prove an important step towards the development of a clinical diagnostictest for schizophrenia.

Researchers found that rather than waiting for symptoms toappear, schizophrenia can be diagnosed by identifying specific metabolicabnormalities found in people with the disease.

This new knowledge is expected to help researchers learnabout the susceptibility, progression and treatment of schizophrenia, whichaffects 1 percent of the global population, including an estimated 2.7 millionAmericans.

Notably, the researchers also revealed that schizophreniacould be differentiated from other psychotic disorders just by looking atcertain metabolic abnormalities, Orešič says. The team used metabolomics, ahigh-throughput method for detecting small metabolites, to produce profiles ofthe serum metabolites associated with schizophrenia, other non-affectivepsychosis (ONAP) or affective psychosis. This analysis indicated thatschizophrenia is associated with elevated serum levels of specifictriglycerides, indicative of hyperinsulinemia and upregulation of the serumamino acid proline. Orešič and his colleagues then combined these metabolicprofiles to create a diagnostic model with the potential to discriminateschizophrenia from other psychoses.

This study demonstrates how metabolomics can be a powerful toolfor dissecting disease-related metabolic pathways and for identifying candidatediagnostic and prognostic markers in psychiatric research, he says.

"Schizophrenia is diagnosed according to the Diagnostic andStatistical Manual for Mental Disorders (DSM-IV)," Orešič explains. "Diagnosticclassification is based on symptoms, course and outcome—but not on etiology andpathophysiology."

The criteria, Orešič explains, include: characteristicsymptoms for at least one month of two of the following—delusions,hallucinations, grossly disorganized speech, catatonia or grossly disorganizedbehavior; continuous signs of the disturbance for at least six months; andsocial or occupational dysfunction.

The exclusion criteria include direct physiological effectsof a substance (for example, a drug that has been abused), general medicalcondition, schizoaffective and mood disorder. If there is a history of autisticdisorder or another pervasive developmental disorder, the additional diagnosisof schizophrenia is made only if prominent delusions or hallucinations are alsopresent.

"We found (in the study) that persons with schizophrenia hadsignificantly higher saturated triglycerides, branched chain amino acids,phenylalanine, tyrosine, proline, glutamic, lactic and pyruvic acids," Orešičsays. "Among these, serum glutamic acid was elevated in all psychoses ascompared to controls, while proline upregulation was specific to schizophrenia.Most of these associations remained significant after adjusting for medicationand metabolic comorbidity (type 2 diabetes, BMI, metabolic syndrome)."

The VTT investigators concluded: "Our findings suggest thatspecific metabolic abnormalities related to glucoregulatory processes andproline metabolism are specifically associated with schizophrenia and reflecttwo different disease-related pathways. Metabolomics, which is sensitive toboth genetic and environmental variation, may become a powerful tool inpsychiatric research to investigate disease susceptibility, clinical course andtreatment response."

Getting the scientific and psychiatric communities on boardto formally accept these metabolic abnormalities as diagnostic criteria isanother matter, but Orešič is cautiously optimistic.

"The diagnostic landscape of psychotic disorders isevolving, and it is expected that the future diagnostic criteria will startincorporating etiologically or pathophysiologically relevant markers such asthe metabolic marker," he says. "Further validations will need to be conductedin prospective studies including the drug naïve first-episode patients.However, such molecular markers will not replace the psychiatric evaluation,but they may facilitate the diagnosis. This may be particularly helpful incases when trying to discriminate between different psychotic disorders, andthus, also may help in selecting the best therapeutic options."

This study, "as well as still unpublished data from anotherstudy we have (in twins), suggests a great potential of metabolomics in thediagnoses of mental illnesses in general," Orešič says. "The brain is a majormetabolic organ, and small molecules which are measured by metabolomics may betransported across the blood brain barrier."

Additionally, schizophrenia is a complex disorder withstrong genetic and environmental components (and the interaction of the two),he notes, adding that this may provide a suitable tool to detectpathophysiologically relevant changes.

"Given the metabolites associated with schizophrenia in ourstudy do appear to have the pathophysiological basis, metabolomics may behelpful for example to follow the clinical course as well as to predict as wellas characterize the treatment response," Orešič says. "The treatment responsemarkers could be useful when evaluating the treatment options."

Orešič also sees the research going beyond schizophrenia.

"Our study may help to establish the 'metabolic map' ofmental illnesses, which is likely going to contribute to better understandingof these diseases," Orešič says. "For example, our findings related to prolinemetabolism may share a pathophysiological basis with autism, another braindevelopmental disorder, as also discussed in our paper."

Could schizophrenia be one day cured or controlled?

"This is a realistic possibility if the biology behind thedisease and related to this markers such as ours are better understood, leadingto new kinds of treatments targeting the disease pathophysiology, not just thesymptoms," Orešič says. "In fact, for some individuals, the currentsecond-generation antipsychotics do help to control the disease."

Orešič and his team plan to take their research on the road.

"We are also involved in the new longitudinal study inFinland on first episode psychosis, where first-episode (and mostly drug naïve)patients will be followed-up in order to validate current and develop novelmarkers for diagnosis and in particular for predicting the patient outcomes(treatment response, brain structural changes)," Orešič says. "The lattermarkers could be used, for example, to help define the optimal patient therapy.We also have plans to perform similar studies in a few other Europeanfirst-episode cohorts.