Neurophysiological Studies in Schizophrenia and Psychiatric Disorders

The overall goal of this project is to identify intermediate phenotypes for psychosis across
the schizophrenia and bipolar disorders boundary with implications for future genetic
studies. Recent studies provide considerable evidence that schizophrenia and psychotic
bipolar disorder may share overlapping etiologic determinants. Identifying disease-related
genetic effects is a major focus in schizophrenia and bipolar research, with enormous
implications for diagnosis and treatment for these two disorders. Efforts have been
multifaceted, with the ultimate goal of describing causal paths from specific genetic
variants, to changes in neuronal functioning, to altered brain anatomy, to behavioral and
functional impairments. Parallel efforts have identified and refined several alternative
endophenotypes that are stable, heritable, have (partly) known biological substrates, and are
associated with psychosis liability. Although many such endophenotypes have been individually
studied in schizophrenia, and to a lesser extent in bipolar disorder, no study has
comprehensively assessed a broad panel of these markers in the two disorders with parallel
recruitment, and the extent to which they mark independent aspects of psychosis risk, or
their overlap in the two disorders. In this research project, we will examine a broad panel
of putative endophenotypes in affected individuals and their first degree, biological
relatives in order to: 1) characterize the degree of familial phenotypic overlap between
schizophrenia and psychotic bipolar disorders; 2) identify patterns of endophenotypes unique
to the two disorders; and, 3) contrast the heritability of endophenotypes across the
disorders. We will obtain measures of neurophysiology (e.g., eye tracking, P50 gating, PPI,
and P300), neurocognition (e.g., attention/vigilance, episodic and working memory), and brain
structure (e.g., volumes of gray and white matter in specified brain regions). Blood samples
will also be collected and stored for formal DNA linkage analyses using the independent
phenotypes identified above. All volunteers will also be given the option to donate dermal
biopsies for future research studies.

Establishing similarities and differences in the endophenotypic signatures within
schizophrenia and bipolar families will provide important insights for future genetic
studies, and clarify concepts about common and distinct aspects of pathophysiology,
potentially meaningful heterogeneity with disorders, and the clinical boundaries of the two
most common psychotic disorders in adult psychiatry. This line of investigation will
potentially impact our conceptualization of psychotic disorders, help us make critical
strides to identify the pathophysiology of psychosis, and guide development of new specific
treatments targeting particular deficits.