title: Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia.
abstract: OBJECTIVE
  Neurophysiologic 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 associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene.
  
  
  OBJECTIVE
  To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia.
  
  
  METHODS
  Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment.
  
  
  METHODS
  Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. 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
  Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean [SD] age, 46 [11] years; 979 males [69.2%] and 619 white [43.7%]). Early auditory information processing 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. The indirect effect of EAP on functional outcome was significant as well (β = 0.14, P < .001). Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that involved or bypassed negative symptoms.
  
  
  CONCLUSIONS
  The data support a model in which 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 end points in early-stage procognitive intervention studies.
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla2VISN-22 Mental Illness Research, Education, and Clinical Center, Veterans Affairs (VA) San Diego Healthcare System, San Diego, California.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, UCLA (University of California Los Angeles)4VISN-22 Mental Illness Research, Education, and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, UCLA (University of California Los Angeles)4VISN-22 Mental Illness Research, Education, and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hellemann
authors.affiliation: Department of Biostatistics, University of California, Los Angeles, School of Public Health, Los Angeles.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla2VISN-22 Mental Illness Research, Education, and Clinical Center, Veterans Affairs (VA) San Diego Healthcare System, San Diego, California.
authors.forename: Melissa
authors.initials: M
authors.lastname: Tarasenko
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, UCLA (University of California Los Angeles).
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle9VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts11Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Shiluk
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, New York13VISN-3 Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, New York, New York.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, New York13VISN-3 Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, New York, New York.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts11Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston.
authors.forename: William S
authors.initials: WS
authors.lastname: Stone
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle9VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla14Center for Behavioral Genomics, and Institute for Genomic Medicine, University of California, San Diego, La Jolla15Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, Massachusetts16VISN-20 Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia.
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla2VISN-22 Mental Illness Research, Education, and Clinical Center, Veterans Affairs (VA) San Diego Healthcare System, San Diego, California.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
mesh_terms: D000328:Adult; D001308:Auditory Perceptual Disorders / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology*; D003072:Cognition Disorders / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology*; D003265:Contingent Negative Variation / Q000502:physiology; D003430:Cross-Sectional Studies; D004185:Disability Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008960:Models, Psychological; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology*; D012559:Schizophrenia / Q000175:diagnosis*; D012565:Schizophrenic Psychology; D012920:Social Behavior Disorders / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology*