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BackgroundEndophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.MethodsParticipants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.ResultsMost neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.ConclusionsThe majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research.

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Importance Neurophysiological measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these relationships by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. Objective We sought to characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve both cognition and psychosocial functioning in schizophrenia. Design Cross-sectional data were analyzed using structural equation modeling to examine the associations between EAP, cognition, negative symptoms, and functional outcome. Setting Participants were recruited from the community at five geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia-2 (COGS-2). Participants This well-characterized cohort of schizophrenia patients (N = 1,415) underwent EAP and cognitive testing as well as thorough clinical and functional assessment. Main Outcome and Measures EAP was measured by mismatch negativity, P3a, and reorienting negativity. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test - Second Edition, the Wechsler Memory Scale Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. Results EAP had a direct effect on cognition (β = 0.37, p < .001), cognition had a direct effect on negative symptoms (β = −0.16, p < .001), and both cognition (β = 0.26, p < .001) and experiential negative symptoms (β = −0.75, p < .001) had direct effects on functional outcome. Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that either involved or bypassed negative symptoms. Conclusions and Relevance The data support a model where EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments, and support the strategy of using EAP measures as surrogate endpoints in early stage pro-cognitive intervention studies.