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Endophenotypes may hold clues to schizophrenia diagnosis
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A select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable indicators of schizophrenia, even when other symptoms may not be apparent, according to the results of a study published online.
Gregory A. Light, PhD, associate professor of psychiatry at the University of California, San Diego School of Medicine, and colleagues, measured biomarkers in 550 patients with schizophrenia, and then re-tested 200 of the patients 1 year later.
The researchers noted “six neurophysiological and neurocognitive endophenotypes with both prior heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes.”
The researchers noted that most of the markers were significantly abnormal in patients with schizophrenia, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient.
Light said further research is required, including whether endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions, or even be used to predict which subjects are at high risk of developing a psychotic illness.
However, in a press release about the study, Light concluded, “We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia.”
Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient’s ability to describe what's happening inside their mind, but many of these patients have cognitive and functional impairments, which hinders their ability to explain what they are thinking, according to the researchers.
Disclosure: Dr. Light reported no relevant disclosures. Funding for this research came, in part, from National Institute of Mental Health grants MH042228, MH079777 and MH065571 and the Department of Veterans Affairs.
Perspective
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Robert Paul Liberman, MD
While there is undoubtedly a genetic contribution to the development of schizophrenia, just as with any disease, longevity and personal characteristics such as intelligence, social competence, hair color, height and athletic ability, the vast array of genes that may at some future time be implicated in these traits are multiple and are better understood as "vulnerability factors.” Genetic vulnerability very likely varies from person to person and is influenced by the environment and gene-environment-behavioral interactions. Thus, to claim that one trait — such as abnormalities in neurocognition among persons with schizophrenia — reflects an "endophenotype" or "marker" for the gene or genes that influence vulnerability is flawed.
Identifying endophenotypes is made further challenging by the use of current diagnostic criteria to identify a sample of persons with schizophrenia. There are so many variations in the presenting symptoms, differences in severity, response to treatment, change over time as affected by social and environmental supports and services and relationship of the broad category of persons with schizophrenia with putative endophenotypes, that claims of identifying endophenotypes such as neurocognitive performance or abnormalities in brain function and structure are premature. We simply don't know whether schizophrenia as it is currently diagnosed reflects a singular disorder, multiple disorders or a blend with other disorders such as bipolar disorder.
The fact that individuals who are reliably diagnosed as having the strict criteria used in defining schizophrenia can recover (even without medication in some cases), regain normal psychosocial functioning and display normal brain structure and function as well as normal neurocognition (Kopelowicz et al., 2005) limits the significance of so-called endophenotypes. Moreover, the finding that a sample of individuals diagnosed with the criteria of schizophrenia have on average significantly greater impairments in neurocognitive and neurophysiological parameters than a sample of normal individuals is a statistical inference with a wide variance in the factors being measured. Some of the individuals in almost every large sample of persons diagnosed as having schizophrenia overlap with the normal range to some degree when putative neurocognitive or neurophysiological endophenotypes are reported (Egan et al., 2003). With the etiology of schizophrenia still unclear, deciphering the genetic contributions to this disorder remains a challenge for psychiatric geneticists.
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