PARIS – Researchers have identified a series of metabolites strongly involved with neurodevelopment and memory that are unique to patients with schizophrenia.
Among 265 patients with schizophrenia and 216 healthy controls, 22 metabolites differed significantly between the schizophrenia and control groups (P value less than 3.8 x 10-4), Dr. Dan Rujescu said at the annual congress of the European College of Neuropsychopharmacology. Of the 163 possible metabolites initially evaluated, 92 involved glycerophospholipids.
Stepwise regression analysis that included age, sex, and body mass index (BMI) further whittled the field down to a panel of seven candidate metabolites: ornithine, arginine, glutamine, histidine, phosphatidylcholine acyl-alkyl C38:2, dodecenoyl carnitine, and octenoyl carnitine. Only ornithine was downregulated in patients with schizophrenia, with the remaining upregulated.
"The panel had fairly high discriminatory power," said Dr. Rujescu, with the University of Munich.
The researchers then constructed a schizophrenia gene-metabolite network consisting of 13 schizophrenia genes associated with five metabolites. In all, 52% of the networks were related to neurodevelopment and learning or memory, he said. Impaired memory and cognitive function are increasingly being recognized as hallmarks of schizophrenia.
The use of metabolomics is new in schizophrenia, and its application to pharmacology even newer. Pharmacometabolomics measures both the disease and the environmental effects, so is highly dynamic, compared with genetics, Dr. Rujescu said. Moreover, not all patients correct their aberrant metabolic profiles upon treatment. Thus, metabolic profiling could be used as an additional tool to complement clinical evaluation in defining drug response phenotypes, he said.
An analysis in 117 patients on monotherapy, however, was unable to distinguish between treatment arms, although the patient numbers were small, Dr. Rujescu said. Clozapine, quetiapine, and risperidone were the most frequently used drugs, followed by olanzapine, amisulpride, and haloperidol. The patients were not on any other drugs whatsoever, including aspirin. They also were not smokers.
Four of the seven identified metabolites – histidine, arginine, ornithine and glutamine – are related to genes involved in arginine-glutamine metabolism and nitrogen compound biosynthesis. One of the involved genes, TCF4, is involved in arginine metabolism and is essential for normal brain development, Dr. Rujescu said.
A marker in intron four of transcription factor 4 (TCF4) on chromosome 18q21.2 was among seven markers previously identified through genomics, by a team of researchers including Dr. Rujescu, as being significantly associated with schizophrenia (Nature 2009; 460:744-7). Another marker located upstream of the neurogranin gene on chromosome 11q24.2 also pointed to disturbances in pathways involved in brain development, memory, and cognition. The remaining markers spanned the major histocompatibility complex region on chromosome 6p21.3-22.1, supporting the potential role for an autoimmune component in schizophrenia.
The next step for the researchers is to identifiy pharmacometabolomic signatures for response and side effects among 350 medication-naïve patients with schizophrenia whose first episode of psychosis was treated with amisulpride in the ongoing OPTIMISE (Optimization of Treatment and Management of Schizophrenia in Europe) trial. The trial (www.optimisetrial.eu) is being conducted by a consortium of 18 European psychiatric institutes, including the Helmholtz Center Munich, and has enrolled 350 patients to date.
The authors report no disclosures.