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European Biopharmaceutical Review

Diagnosing Schizophrenia


Psychiatric disorders pose unique challenges to biomarker development. Regulatory authorities are wising up to their benefits, however, and a shift to more reproducible and sensitive methods is in sight.


The development of biomarkers for psychiatric disorders has been faced with many challenges. These relate to the lack of a standardised pipeline for connecting biomarker discovery with validation and translation to platforms suitable for use in a clinical setting. As a consequence, the regulatory agencies have now stipulated that biomarkers are important for future drug development, and have initiated efforts to modernise methods and techniques to support these efforts. This report describes these developments and discusses the production of a novel molecular blood-test for schizophrenia as a promising first step towards achieving this goal.

The search for biomarkers for psychiatric disorders such as schizophrenia has been ongoing for many years. It is hoped that such biomarkers can be used in standardised tests to improve the diagnosis and clinical management of patients. Currently, psychiatric disorders are diagnosed by clinicians and psychiatrists based on subjective interviews using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or International Classification of Diseases (ICD-10) criteria, which have many shortcomings. There are now concerted efforts to identify biomarkers that are refl ective of the underlying pathologies or the mechanism of currently used medications. This may require deconstruction of the longstanding DSMIV or ICD-10 procedures in favour of using biomarkers to define disease subtypes. Ultimately, the results of these efforts may lead to personalised medicine approaches for more effective treatment of patients with these devastating conditions (see Figure 1).



The development of biomarkers for use in diagnostics and clinical trials has progressed at an unsteady pace. Consequently, there are now efforts to establish standard operating procedures to navigate through these problems and, at the same time, meet regulatory demands. The regulatory health authorities now consider that incorporation of biomarkers into the drug discovery pipeline is an essential next stage in the pharmaceutical industry. The Food and Drug Administration (FDA) has called for efforts to modernise and standardise technologies and methods for the delivery of safer, more effective drugs (1). This requires that biomarkers designated for use in clinical trials are validated prior to regulatory decision making. To help achieve this, the FDA has set guidelines based on three classes of biomarkers: exploratory biomarkers; probable valid biomarkers; and known valid biomarkers (2). For the exploratory biomarkers class, there must be scientific proof of concept. The probable valid biomarker class requires that biomarkers can be measured with strict performance characteristics and that the scientific findings can explain the relevance and significance of the results. The known valid biomarker class requires that all results must be replicated in different laboratories and sites.

For studies of psychiatric disorders, it has been anticipated that it will be difficult to meet these requirements. This is due to the fact that psychiatric conditions are poorly understood, there is an overlap of symptoms across different disorders and there is considerable heterogeneity in how these illnesses are manifested in different individuals. However, the application of emerging multiplexed molecular profiling platforms has facilitated identification of biomarkers through the simultaneous measurement of hundreds and even thousands of molecules. The multiplexing feature has also served to increase accuracy, minimise the amount of sample required and reduce running costs. For example, applying a multiplexed immunoassay profiling platform for analysis of serum from schizophrenia patients has recently resulted in the identification of a molecular fingerprint that could be used to classify schizophrenia subjects compared to controls, with an accuracy of greater than 80 per cent (3).



This report describes the challenges of developing and implementing molecular biomarker tests for psychiatric disorders. We will focus on the general problem of introducing molecular biomarkers into the field of psychiatry, which has traditionally relied on non-molecular approaches. We will also discuss the potential applications in this area, particularly for improved clinical classification and patient care, and as a means of revitalising drug discovery efforts for psychiatric disorders within the pharmaceutical industry.

The Importance of Using Biomarkers for Early Diagnosis

Most psychiatrists acknowledge that schizophrenia is an umbrella term for a mixture of conditions that present with similar symptoms and, therefore, misdiagnosis is a common problem. The DSM-IV and ICD-10 systems conceptualise that mental disorders are distinct disease entities with common pathologies and can be defined by operational sets of criteria based on signs and symptoms. However, it is unlikely that specific symptoms are linked to defined disease pathways (4). For example, patients with neurological, traumatic, infectious and metabolic disorders can present with symptoms similar to those in schizophrenia. A further complication is that most clinicians do not even use a classification system to establish a diagnosis. Instead, they reach a diagnosis based on experience and personal views, rather than by adhering to guidelines or criteria of a diagnostic system. A study from 1970 showed that time-dependent changes in diagnosis resulted often in misjudgement of prognosis and suboptimal treatment of patients (5). Also, prospective studies of patients who presented with psychosis found that the initial diagnosis of schizophrenia was mostly stable over five years, although this required frequent revision over time (6).

A number of studies have suggested that prevention or minimisation of schizophrenia might be possible if environmental risk-factors can be determined and avoided. Researchers have found that metabolic abnormalities such as insulin resistance and hyperinsulinaemia occur in 20-50 per cent of first onset subjects with schizophrenia (7). Other studies have found alterations in circulating inflammatory and immune response factors in first onset schizophrenia patients (8). Interestingly, various markers relating to these subgroups can be identified in patients even prior to disease onset, suggesting that effects on these pathways may be involved in the disease aetiology (9).

It will be important to determine whether or not disease conversion can be prevented or minimised in at-risk individuals. A delayed or incorrect diagnosis can have deleterious effects on patient lives, including increased substance abuse, social alienation from family and friends, increased accidents, self harm and harm to others (10). For example, a misdiagnosis of bipolar disorder as schizophrenia has been associated with increased risk of suicide attempts, longer hospitalisation and worsened psychological problems (11). Also, misdiagnosis has socioeconomic consequences including high medical costs, absence from work and negative effects on family and relationships.

The FDA, pharmaceutical and biotechnology companies now accept that the use of biomarker-based platforms will be of benefit in the development of improved diagnostics and surrogate biomarkers for drug discovery. In the case of psychiatric conditions, there are many anticipated benefits (see Table 1). Currently, only a few biomarker tests have been used in the study or diagnosis of subjects with psychiatric disorders. For example, the niacin skin fl ush response test was in sporadic use over several years for diagnosis of schizophrenia (12). More recently, genomic biomarkers have been used for prediction of toxicities in distinct populations of schizophrenia patients in response to antipsychotic treatments (13). Also, polymorphisms in serotonergic neurotransmitter pathway genes have been associated with the response to antidepressants (14).



The Need for Biomarker Standardisation

The field of clinical proteomics raised high hopes through several early reports on potential biomarkers. However, in most cases these could not be validated or translated into clinical use. Potential reasons for the failure to incorporate biomarkers into clinical projects include problems in design, enrolling patients at different stages of the disease process and the possibility that biomarkers may not be causal but rather a result of the disease process.

The Human Proteome Organisation (HUPO), which emerged from the Human Genome Project, has developed several initiatives aimed at overcoming the issues of irreproducibility including projects on disease biomarkers, the Human Antibody Initiative and the Proteomics Standards Initiative. Each programme is based in one country and includes subprojects based in other countries. Early results have indicated that the irreproducibility problem results from variability at the level of the sample, sample handling, study design, technical issues and user-related differences.

The movement towards biomarkers has triggered the need to establish standard operating procedures to meet regulatory demands. In its Critical Path Initiative, the FDA produced a white paper for modernising methods and tools to facilitate development of more efficient and safer drugs (2). The regulatory aspects were described in a guidance associated with the Pharmacogenomic Data Submission by the FDA. This stipulated that molecules must achieve the status of validated biomarkers (described above) before they can be considered in regulatory decision-making. The rat kidney safety biomarker panel is an example of a test which was developed in accordance with the biomarker qualification process. This panel became part of a cross-validation study and achieved the status of known valid biomarkers as part of the Predictive Safety Testing Consortium (PSTC). The PSTC was founded by the FDA to act as a liaison between the FDA, pharmaceutical companies and academia in biomarker qualification for preclinical and clinical use. The nephrotoxicity subgroup of the PSTC identified seven kidney safety biomarkers for limited use in preclinical and clinical drug development (15).

The FDA has advised that the most useful strategy for biomarker qualification is via co-development with drugs. The rationale is that an increased understanding of the biology associated with a particular biomarker and strong association between the biomarker and clinical outcome, will lead to a more efficient development process with fewer risks. Also, early interaction with the relevant regulatory agencies is essential so that studies and biomarker tests are carried out correctly. The European health authorities have also supported the implementation of biomarkers for more efficient identification and development of medicines through agencies such as the Innovative Medicines Initiative. One of their main objectives is the discovery of translational biomarkers, including those for psychiatric conditions like schizophrenia and autism spectrum disorders. The European Commission has contributed 1 billion to this programme and this has been matched by in-kind contributions from member companies of the European Federation of Pharmaceutical Industries and Associations. Diagnostic assays in the US are regulated by the Clinical Laboratory Improved Amendments (CLIA). These regulations govern tests performed in clinical laboratories on human samples for diagnosis, disease prevention, treatment or assessment of health.

Commercially available tests marketed under CLIA are categorised by the FDA into three groups depending on potential risks for health. This categorisation considers the necessary knowledge, training, materials and judgement to carry out the tests, as well as other factors including operational and quality control procedures. The development of diagnostic assays for all diseases, including psychiatric disorders, requires the repeated demonstration of accuracy, precision, sensitivity and specificity. These are absolute requirements since variability in biomarker measurements can be affected by biological, environmental, sample collection and analytical factors. Development of multiplexed immunoassays, for example, requires validation of the assay structure and analytical performance including factors such as selection and immobilisation of capture ligands, calibration, reagentantibody compatibility, dynamic range and limits of detection (16).

It is now accepted that single biomarkers are unlikely to be effective given the complexity of diseases such as psychiatric disorders. Therefore, a panel of biomarkers must be employed to address this complexity and increase specificity. Such biomarker panels must be rigorously validated in multiple centres and across different time points to produce reproducible and accurate tests. Biomarker panels must also be disease-specific, at least relative to other diseases which have similar symptoms. Again, this is particularly difficult for psychiatric disorders as these can have multiple overlapping symptoms. Also, biomarker tests must be delivered in a format that is high throughput and user friendly to allow use by clinicians, hospital staff and scientists alike. Mass spectrometry and two-dimensional gel electrophoresis platforms would be too cumbersome and necessitate too much expertise to be considered as realistic possibilities. Instead, automated platforms such as the multiplexed immunoassay system and multiple reaction monitoring are more likely candidates as clinically-friendly platforms which have already shown promise (16,17). Also, holographic sensors have already been employed for detection of biomarkers and could easily be adapted as robust and user friendly tests in clinical applications (18).

Conclusion

This article has described the challenges and recent successes associated with the production of blood-based biomarker tests for psychiatric disorders. The current diagnostic process and strategies for developing novel medicines are in need of a paradigm change. The regulatory health authorities now consider the incorporation of biomarkers into clinical platforms to be of critical importance for future drug discovery. As a result, they have now called for efforts to modernise methods, tools and techniques to achieve this goal. Given the complex nature and low abundance of many proteomic biomarkers, this will most likely require the development of more reproducible and sensitive methods and a massive integration of technologies. However, there is now reason to be optimistic that technological and interdisciplinary advancements in this area will help to usher the study of psychiatric disorders fully into the 21st century.



References

  1. Ovens J, Funding for accelerating drug development initiative critical, Nature Reviews Drug Discovery 5: p271, 2006
  2. Goodsaid F and Frueh FW, Implementing the US FDA guidance on pharmacogenomic data submissions, Enviromental and Molecular Mutagenesis 48: pp354- 358, 2007
  3. Schwarz et al, Identification of a biological signature for schizophrenia in serum, Molecular Psychiatry, 2011 [Epub ahead of print]
  4. Follette WC and Houts AC, Models of scientific progress and the role of theory in taxonomy development: a case study of the DSM, Journal of Consulting and Clinical Psychology 64: pp1,120-1,132, 1996
  5. Robins E and Guze SB, Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia, American Journal of Psychiatry 126: pp983-987, 1970
  6. Schwartz et al, Congruence of diagnoses 2 years after a firstadmission diagnosis of psychosis, Archives of General Psychiatry 57: pp593-600, 2000
  7. Guest et al, Increased levels of circulating insulin-related peptides in first-onset, antipsychotic naive schizophrenia patients, Molecular Psychiatry 15: pp118-119, 2010
  8. Szulc A, Galinska B, Konarzewska B, Gudel-Trochimowicz I and Popławska R, Immunological marker activity in first episode schizophrenic patients, Pol Merkur Lekarski 10: pp450-452, 2001
  9. Schwarz et al, Identification of a blood-based biological signature in subjects with psychiatric disorders prior to clinical manifestation, World Journal of Biological Psychiatry, 2011
  10. Yap HL, Early psychosis intervention, Singapore Medical Journal 51; pp689-693, 2010
  11. Post RM, The impact of bipolar depression, Journal of Clinical Psychiatry 66 Suppl 5: pp5-10, 2005
  12. Wilson DW and Douglass AB, Niacin skin flush is not diagnostic of schizophrenia, Biological Psychiatry 21: pp974-977, 1986
  13. Fleeman et al, Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses, The Pharmacogenomics Journal 11: pp1-14, 2010
  14. Kato M and Serretti A, Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder, Molecular Psychiatry 15: pp473-500, 2010 
  15. Dieterle et al, Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium, Nature Biotechnology 28: pp455-462, 2010 
  16. Ellington AA, Kullo IJ, Bailey KR and Klee GG, Antibody-based protein multiplex platforms: technical and operational challenges, Clinical Chemistry 56: pp186-93, 2010 
  17. Gallien S, Duriez E and Domon B, Selected reaction monitoring applied to proteomics, Journal of Mass Spectrometry 46: pp298-312, 2011
  18. Tan EV and Lowe CR, Holographic enzyme inhibition assays for drug discovery, Analytic Chemistry 81: pp7,579-89, 2009 
  19. Schwarz et al, Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia, Biomarker Insights 5: pp39-47, 2010


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Sabine Bahn is a practising psychiatrist, leading research scientist, Director of the Cambridge Centre for Neuropsychiatric Research at Cambridge University and Chair in Translational Neuropsychiatry at the Erasmus Medical Centre in Rotterdam, Netherlands. Her main research interests are to understand the molecular basis of neuropsychiatric disorders, with a focus on schizophrenia and mood disorders. Sabine has published numerous articles in high impact journals over the past years. In 2005 she co-founded Psynova Neurotech Ltd, which, together with Rules Based Medicine has launched the first blood test aiding in the early diagnosis of Schizophrenia. Email: sb209@cam.ac.uk

Paul C Guest is Head of Proteomics at the Cambridge Centre for Neuropsychiatric Research at Cambridge University. He also has 10 years of experience in heading the biomarker facility at the Merck Sharp & Dohme Neuroscience Research Centre and eight years of experience working in the field of metabolic disorders. He has published numerous articles in the fields of neuroscience, stem cells, metabolic diseases and biomarkers. Email: pg110@cam.ac.uk
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