Neurophysiological biomarkers for schizophrenia therapeutics

Chronic psychotic disorders, including schizophrenia (SZ), are highly heterogeneous at many levels of analysis, from genetics to clinical presentation and treatment sensitivity. This heterogeneity reflects both a divergence of shared biological pathways moving from over a hundred “risk genes” to many different clinical phenotypes, and the convergence of distinct biological pathways to a shared “phenocopies” of chronic psychosis. Successful strategies for developing “next generation” interventions in SZ – including “pro-cognitive” medications, cognitive remediation, neurostimulation and combinations thereof – will address these pathways to clinical heterogeneity by using biological signals, or “biomarkers” that characterize treatment-sensitive subpopulations. Identifying and detecting these meaningful signals in the complex biology of SZ is a vexing scientific challenge. We propose that rational starting points are neurophysiological measures of early auditory information processing (EAIP), based on their functional importance as strong mediators of both cognition and function in SZ, their plasticity in response to both pharmacologic and non-pharmacologic therapeutic “challenge”, and their experimental characteristics as highly quantitative, robust and reliable measures of brain activity. Here we describe some of our current approaches to developing neurophysiological biomarkers for “next generation” therapeutic sensitivity in SZ, and some potentially novel experimental strategies that we envision on the near horizon.