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News Brief—Metabolites in Blood and Urine: Future Laboratory Test for Schizophrenia?

11 November 2011. A laboratory test to diagnose schizophrenia has long been near the top of the clinical wish list, but to date, no widely accepted biomarkers have been identified (see SRF related news story). A report published online October 25 in Molecular Psychiatry pushes a new candidate into the ring: Researchers led by Chunling Wan and Wei Jia of Shanghai Jiao Tong University, China, performed a global metabolic profiling study of biomarkers in schizophrenia and, using a combined serum and urine metabolite panel, was able to distinguish schizophrenia subjects from controls with a high degree of accuracy.

By dividing the subject cohort (comprising 112 schizophrenia subjects and 110 healthy controls) into a training set and a test set, first authors Jinglei Yang and Tianlu Chen identified a panel of serum biomarkers that differed between the two diagnostic groups. Those that made the cut: glycerate, eicosenoic acid, β-hydroxybutyrate, pyruvate, and cysteine. The addition of urine β-hydroxybutyrate increased the accuracy of the panel, and resulted in a correct diagnosis for every subject. Importantly, approximately 60 percent of the schizophrenia subjects were first-episode patients who had never received antipsychotics, and the remainder had been off medication for at least four weeks, suggesting that the metabolite changes are unlikely to be due to an effect of neuroleptics.

In addition, Yang, Chen, and colleagues report increased levels of multiple fatty acids and ketone bodies in schizophrenia, which may reflect an upregulation of fatty acid catabolism that the authors attribute to deficient brain glucose supply.—Allison A. Curley.

Reference:
Yang J, Chen T, Sun L, Zhao Z, Qi X, Zhou K, Cao Y, Wang X, Qiu Y, Su M, Zhao A, Wang P, Yang P, Wu J, Feng G, He L, Jia W, Wan C. Potential metabolite markers of schizophrenia. Mol Psychiatry. 2011 Oct 25. Abstract

Comments on News and Primary Papers


Primary Papers: Potential metabolite markers of schizophrenia.

Comment by:  Michael O'Donovan, SRF Advisor
Submitted 1 November 2011
Posted 2 November 2011
  I recommend this paper

The authors suggest they have developed a biomarker test for schizophrenia based upon a handful of serum measures and one urine metabolite. The properties are said to be equivalent to a diagnostic interview. However, caution is required, and the history suggests so is a healthy dose of skepticism. But if the findings of a perfect test, or even a remotely near-perfect test, are confirmed, and particularly if they apply to very early disease, this will prove to be a landmark paper. Confirmatory studies are essential, which is why I have recommended this paper.

View all comments by Michael O'Donovan

Primary Papers: Potential metabolite markers of schizophrenia.

Comment by:  Sabine BahnPaul C. Guest
Submitted 14 November 2011
Posted 14 November 2011

The development of biomarkers and the implications of using these to improve diagnostics and clinical trials are becoming more apparent, even for cases of psychiatric disorders such as schizophrenia. The regulatory health authorities now consider biomarkers as important in the pharmaceutical industry, and the Food and Drug Administration (FDA) has called for modernization and standardization of methods, tools, and techniques for the purpose of delivering better and safer drugs (Owens, 2006; Marson, 2007). The FDA has stipulated that molecules must achieve the status of validated biomarkers before they can be used in the regulatory process for clinical trials. This means that biomarkers should be measured in a test system with strict performance characteristics, that there is an established scientific proof of concept to explain the results, and that the test can be replicated with similar results in different laboratories and at different sites.

In the latest Issue of Molecular Psychiatry, Yang and coworkers describe the identification of a composite panel of serum and urine biomarkers which they used to distinguish schizophrenia patients from controls with high accuracy. It should be noted that all of the subjects used in the study were recruited from the Anhui Province of China. This work should be acknowledged as an important early step in the development of biomarkers to help improve the lives of patients with schizophrenia.

However, considerable caution is required before even preliminary steps can be taken towards achieving this goal. First and foremost, the results require replication at multiple sites using different schizophrenia patient cohorts. In addition, the tests will require transfer to a platform which is suitable for use in a clinical environment.

We recently employed an approach based on multiplexed immunoassay profiling, which resulted in identification of a serum signature that could identify schizophrenia patients with an accuracy of 82 percent across five independent patient cohorts, with similar results in subsequent validation studies in different laboratories (Schwarz et al., 2011; Schwarz et al., 2010). This is an automated test that uses a single serum sample to measure approximately 50 molecules simultaneously. It was designed in its first form to help mental health professionals arrive at a diagnosis. This test has now been launched in the U.S. under the trade name VeriPsych as part of a collaboration between Psynova Neurotech in the U.K. and Myriad-RBM in the U.S. The next phase will be to develop a version of the test which can be used to distinguish schizophrenia from other psychiatric disorders with overlapping symptoms. There is now reason for optimism that, with concerted efforts in this field, the application of biomarkers in the field of psychiatric disorders will soon become a reality (Bahn et al., 2011).

References:

Owens J. Funding for accelerating drug development initiative critical. Nat Rev Drug Discov . 2006 Apr 1 ; 5(4):271. Abstract

Marson, B. (2007) ''Critical Path'' is on the road forward; FDA reports industry activity is high. The Pink Sheet. 69; 29.

Schwarz E, Guest PC, Rahmoune H, Harris LW, Wang L, Leweke FM, Rothermundt M, Bogerts B, Koethe D, Kranaster L, Ohrmann P, Suslow T, McAllister G, Spain M, Barnes A, van Beveren NJ, Baron-Cohen S, Steiner J, Torrey FE, Yolken RH, Bahn S. Identification of a biological signature for schizophrenia in serum. Mol Psychiatry . 2011 Apr 12. Abstract

Schwarz E, Izmailov R, Spain M, Barnes A, Mapes JP, Guest PC, Rahmoune H, Pietsch S, Leweke FM, Rothermundt M, Steiner J, Koethe D, Kranaster L, Ohrmann P, Suslow T, Levin Y, Bogerts B, van Beveren NJ, McAllister G, Weber N, Niebuhr D, Cowan D, Yolken RH, Bahn S. Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia. Biomark Insights . 2010 Jan 1 ; 5():39-47. Abstract

Bahn S, Noll R, Barnes A, Schwarz E, Guest PC. Challenges of introducing new biomarker products for neuropsychiatric disorders into the market. Int Rev Neurobiol . 2011 Jan 1 ; 101():299-327. Abstract

View all comments by Sabine Bahn
View all comments by Paul C. GuestComment by:  Stephen J. Glatt
Submitted 22 November 2011
Posted 23 November 2011
  I recommend the Primary Papers

This line of work is immensely important, as the lack of reliable biomarkers presents a major barrier to the receipt of a definitive diagnosis and the initiation of treatment; ultimately, the detection of biomarkers that are present at first episode may also signal biomarkers that may be present in the prodrome and even before symptoms emerge, which might provide a basis for earlier intervention and prevention. As elegantly summarized by Drs. Bahn, Guest, and O'Donovan, these results will need replication in diverse samples before they can be capitalized upon in the form of a clinically useful test; however, it does make sense that a biomarker profile derived from multiple sources (serum and urine) might have better explanatory power than a profile derived from just one source. Similarly, the next frontier in the development of biomarker panels may involve what I've called a polyomic approach, taking into account genetic and functional genomic variation as well as metabolite variability as demonstrated here.

View all comments by Stephen J. Glatt

Comments on Related News


Related News: Potential Biomarkers of First-onset Schizophrenia Found in Cerebrospinal Fluid

Comment by:  Stephen J. Glatt
Submitted 4 December 2006
Posted 4 December 2006
  I recommend the Primary Papers

This paper by Huang, Bahn, and colleagues makes for very interesting reading and provides an early glimpse into the future of proteomic studies of schizophrenia and other mental disorders. Although some interesting new leads have been provided regarding particular proteins and peptides, these will need replication, as the authors themselves acknowledge. Thus, we should not get caught up in those details at this time, but rather appreciate this work for its greater contribution, which is in the modern theoretical framework that drives the study.

First and foremost, it is refreshing to see a focus on a syndrome, such as psychosis, rather than traditional focus on DSM-based diagnostic boundaries. This approach is one that our group has also endorsed in recent years in light of overlapping linkage, association, and gene expression data in schizophrenia and bipolar disorder. It just makes sense that biomarkers will work best for symptoms or other lower-level traits or states rather than hierarchical diagnoses with questionable validity. In turn, biomarker work performed in this manner may subsequently inform the derivation of novel, biologically based, valid diagnostic categories.

The use of CSF samples is laudatory, since this provides a good balance between access to the central nervous system and ease of sample collection, whereas other modern biomarker studies of blood or postmortem brain tissue do not allow for such balance. The protein-chip technology itself is also impressive, although as with any cutting-edge technology in its infancy, major improvements in resolution and throughput will be needed to move this technique into the mainstream.

In summary, this manuscript should be read carefully by all those among us who are interested in the frontiers of biomarker research on mental disorders. However, in contrast to the authors' statement that "An alternative approach to genetic studies is to screen for disease markers (biomarkers)," we might be wise to treat biomarker research as a useful adjunct to—rather than replacement for—analyses of genetic polymorphisms.

View all comments by Stephen J. Glatt