Biomarkers for Psychosis and Schizophrenia Risk

by William Yates, M.D. in Brain Posts

Prefrontal Cortex Highlighted in RedIdentifying valid biomarkers for psychosis and schizophrenia is an active focus in brain research.Tyronne Cannon, Ph.D. from Yale University recently presented a summary of research on this topic at the William K. Warren Neuroscience Symposium in Tulsa, Oklahoma. Here are my notes from his presentation along with related free full-text research references.Biomarker research in psychosis is important because current treatment for psychosis with the antipsychotic drugs is limited by:discovery by serendipity without a specific molecular mechanismabsence of effect on psychosis negative symptoms (anergia, anhedonia and amotivation)poor tolerability of antipsychotic drugs with significant compliance issuesno evidence that antipsychotic drugs modify the progression of the diseaseBiomarker research in psychosis is promising because an extended prodrome period is present in childhood and adolescence.  Biomarker research can be divided into markers with a progressively deviant pattern and those with a stable deviant pattern.Two studies are available to summarize current findings: The North American Prodrome Longitudinal Study, parts I and II (NAPLS I and NAPLS II).  These studies have identified three biomarker candidate categories:Hormonal disruption involving the hypothalamic-pituitary-adrenal (HPA) axisEvent related potential abnormalities including the p300 marker and an NMDA synapse-related marker identified in a negativity mismatch taskBrain magnetic resonance imaging (MRI) showing a greater cortical gray matter volume decline (primarily in bilateral frontal cortex regions) in high-risk individuals who later convert to psychosisThe first two biomarkers appear to be of the stable deviant type while the gray matter deficit biomarker appears to be a progressive deviant markerAn important potential confounding issue in gray matter deficits is the role of antipsychotic drug exposure in producing gray matter changes.  Research to date supports an independent contribution of psychosis progression risk with frontal gray matter reductionProgress in understanding the MRI biomarker changes in psychosis/schizophrenia require a better understanding of the mechanism of this change.  At least three avenues of research for a mechanism are promising:Disruption of neuroplasticity: fetal hypoxia environments produce impairment in brain neuroplasticity possibly through disruption of the BDNF systemDisruption of brain inflammation: risk for progression to psychosis is linked to increase blood inflammation using a multiplex composite variable.  This variable is associated with 35% of the variance in brain gray matter volumesHPA-Glutamate pathways: The glutamate pathway is known to be involved in psychosis with the psychotic effect produce by PCP and ketamine.  It is possible glutamate disruption effects gray matter reduction through effects on the microgliaAlthough not discussed in this lecture, other promising targets for understanding psychosis mechanism and risk include: neuropsychologic deficits, brain white matter abnormalities and fMRI activation abnormalities and resting connectivity deficits.Further identification of biomarkers in psychosis will be key in designing prevention strategies and in smart drug development through understanding the mechanism of risk and progression of the disease.Readers with more interest in this topic are directed to the free full-text citations below.Image of the frontal cortex noted to be a biomarker of psychosis risk above is from a iPad screen shot from the Sun D, van Erp TG, Thompson PM, Bearden CE, Daley M, Kushan L, Hardt ME, Nuechterlein KH, Toga AW, & Cannon TD (2009). Elucidating a magnetic resonance imaging-based neuroanatomic biomarker for psychosis: classification analysis using probabilistic brain atlas and machine learning algorithms. Biological psychiatry, 66 (11), 1055-60 PMID: 19729150... Read more »