Advertisement

A Multivariate Electrophysiological Endophenotype, from a Unitary Cohort, Shows Greater Research Utility than Any Single Feature in the Western Australian Family Study of Schizophrenia

  • Gregory W. Price
    Correspondence
    Address reprint requests to Gregory W. Price, Electrophysiology, Centre for Clinical Research in Neuropsychiatry, Private Mail Bag No. 1, Claremont 6010, Western Australia
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital
    Search for articles by this author
  • Patricia T. Michie
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital

    School of Psychology, University of Western Australia, Perth, Australia

    School of Behavioural Sciences, The University of Newcastle, Callaghan, Australia.
    Search for articles by this author
  • Julie Johnston
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital
    Search for articles by this author
  • Hamish Innes-Brown
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital
    Search for articles by this author
  • Aaron Kent
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital
    Search for articles by this author
  • Peter Clissa
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital
    Search for articles by this author
  • Assen V. Jablensky
    Affiliations
    School of Psychiatry and Clinical Neuroscience and Centre for Clinical Research in Neuropsychiatry, University of Western Australia and Graylands Hospital
    Search for articles by this author
Published:December 19, 2005DOI:https://doi.org/10.1016/j.biopsych.2005.09.010

      Background

      Previous studies have found several electrophysiological endophenotypes that each co-varies individually with schizophrenia. This study extends these investigations to compare and contrast four electrophysiological endophenotype, mismatch negativity, P50, P300, and antisaccades, and analyze their covariance on the basis of a single cohort tested with all paradigms. We report a multivariate endophenotype that is maximally associated with diagnosis and evaluate this new endophenotype with respect to its application to genetic analysis.

      Methods

      Group differences and covariance were analyzed for probands (n = 60), family members (n = 53), and control subjects (n = 44). Associations between individual endophenotypes and diagnostic groups, as well as between the multivariate endophenotype and diagnostic groups, were investigated with logistic regression.

      Results

      Results from all four individual endophenotypes replicated previous findings of deficits in the proband group. The P50 and P300 endophenotypes similarly replicated significant deficits in the family member group, whereas mismatch negativity and antisaccade measures showed a trend. There was minimal correlation between the different endophenotypes. A logistic regression model based on all four features significantly represented the diagnostic grouping (χ2 = 32.7; p < .001), with 80% accuracy in predicting group membership.

      Conclusions

      A multivariate endophenotype, based on a weighted combination of electrophysiological features, provides greater diagnostic classification power than any single endophenotype.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Adler L.E.
        • Freedman R.
        • Ross R.G.
        • Olincy A.
        • Waldo M.C.
        Elementary phenotypes in the neurobiological and genetic study of schizophrenia.
        Biol Psychiatry. 1999; 46: 8-18
        • Adler L.E.
        • Pachtman E.
        • Franks R.D.
        • Pecevich M.
        • Waldo M.C.
        • Freedman R.
        Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia.
        Biol Psychiatry. 1982; 17: 639-654
        • Baker N.
        • Adler L.E.
        • Franks R.D.
        • Waldo M.
        • Berry S.
        • Nagamoto H.
        • et al.
        Neurophysiological assessment of sensory gating in psychiatric inpatients.
        Biol Psychiatry. 1987; 22: 603-617
        • Blackwood D.
        P300, a state and a trait marker in schizophrenia.
        Lancet. 2000; 355: 771-772
        • Blackwood D.H.
        • St. Clair D.M.
        • Muir W.J.
        • Duffy J.C.
        Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees.
        Arch Gen Psychiatry. 1991; 48: 899-909
        • Boutros N.N.
        • Zouridakis G.
        • Overall J.
        Replication and extension of P50 findings in schizophrenia.
        Clin Electroencephalogr. 1991; 22: 40-45
        • Brownstein J.
        • Krastoshevsky O.
        • McCollum C.
        • Kundamal S.
        • Matthysse S.
        • Holzman P.S.
        • et al.
        Antisaccade performance is abnormal in schizophrenia patients but not in their biological relatives.
        Schizophr Res. 2003; 63: 13-25
        • Burke J.G.
        • Reveley M.A.
        Improved antisaccade performance with risperidone in schizophrenia.
        J Neurol Neurosurg Psychiatry. 2002; 72: 449-454
        • Cadenhead K.S.
        • Light G.A.
        • Geyer M.A.
        • McDowell J.E.
        • Braff D.L.
        Neurobiological measures of schizotypal personality disorder.
        Am J Psychiatry. 2002; 159: 869-871
        • Calkins M.E.
        • Iacono W.G.
        • Curtis C.E.
        Smooth pursuit and antisaccade performance evidence trait stability in schizophrenia patients and their relatives.
        Int J Psychophysiol. 2003; 49: 139-146
        • Catts S.V.
        • Shelley A.M.
        • Ward P.B.
        • Liebert B.
        • McConaghy N.
        • Andrews S.
        • et al.
        Brain potential evidence for an auditory sensory memory deficit in schizophrenia.
        Am J Psychiatry. 1995; 152: 213-219
        • Clementz B.A.
        • Geyer M.A.
        • Braff D.L.
        Poor P50 suppression among schizophrenia patients and their first-degree biological relatives.
        Am J Psychiatry. 1998; 155: 1691-1694
        • Clementz B.A.
        • McDowell J.E.
        • Zisook S.
        Saccadic system functioning among schizophrenia patients and their first-degree biological relatives.
        J Abnorm Psychol. 1994; 103: 277-287
        • Cohen J.
        Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Lawrence Earlbaum Associates, Hillsdale, New Jersey1988
        • Coon H.
        • Plaetke R.
        • Holik J.
        • Hoff M.
        • Myles-Worsley M.
        • Waldo M.
        • et al.
        Use of a neurophysiological trait in linkage analysis of schizophrenia.
        Biol Psychiatry. 1993; 34: 277-289
        • Crawford T.J.
        • Haeger B.
        • Kennard C.
        • Reveley M.A.
        • Henderson L.
        Saccadic abnormalities in psychotic patients. I. Neuroleptic-free psychotic patients.
        Psychol Med. 1995; 25: 461-471
        • Crawford T.J.
        • Sharma T.
        • Puri B.K.
        • Murray R.M.
        • Berridge D.M.
        • Lewis S.W.
        Saccadic eye movements in families multiply affected with schizophrenia.
        Am J Psychiatry. 1998; 155: 1703-1710
        • Curtis C.E.
        • Calkins M.E.
        • Grove W.M.
        • Feil K.J.
        • Iacono W.G.
        Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives.
        Am J Psychiatry. 2001; 158: 100-106
        • Dursun S.M.
        • Burke J.G.
        • Andrews H.
        • Mlynik-Szmid A.
        • Reveley M.A.
        The effects of antipsychotic medication on saccadic eye movement abnormalities in Huntington’s disease.
        Prog Neuropsychopharmacol Biol Psychiatry. 2000; 24: 889-896
        • Ettinger U.
        • Kumari V.
        • Crawford T.J.
        • Corr P.J.
        • Das M.
        • Zachariah E.
        • et al.
        Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia.
        J Psychiatr Res. 2004; 38: 177-184
        • Fischer B.
        • Gezeck S.
        • Hartnegg K.
        On the production and correction of involuntary prosaccades in a gap antisaccade task.
        Vision Res. 2000; 40: 2211-2217
        • Ford J.M.
        • Mathalon D.H.
        • Marsh L.
        • Faustman W.O.
        • Harris D.
        • Hoff A.L.
        • et al.
        P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia.
        Biol Psychiatry. 1999; 46: 94-101
        • Frangou S.
        • Sharma T.
        • Alarcon G.
        • Sigmudsson T.
        • Takei N.
        • Binnie C.
        • et al.
        The Maudsley Family Study, II.
        Schizophr Res. 1997; 23: 45-53
        • Freedman R.
        Biological phenotypes in the genetics of schizophrenia.
        Biol Psychiatry. 1998; 44: 939-940
        • Freedman R.
        • Waldo M.
        • Bickford-Wimer P.
        • Nagamoto H.
        Elementary neuronal dysfunctions in schizophrenia.
        Schizophr Res. 1991; 4: 233-243
        • Freedman R.
        • Adler L.E.
        • Leonard S.
        Alternative phenotypes for the complex genetics of schizophrenia.
        Biol Psychiatry. 1999; 45: 551-558
        • Freedman R.
        • Adler L.E.
        • Myles-Worsley M.
        • Nagamoto H.T.
        • Miller C.
        • Kisley M.
        • et al.
        Inhibitory gating of an evoked response to repeated auditory stimuli in schizophrenic and normal subjects. Human recordings, computer simulation, and an animal model.
        Arch Gen Psychiatry. 1996; 53: 1114-1121
        • Freedman R.
        • Adler L.E.
        • Waldo M.C.
        • Pachtman E.
        • Franks R.D.
        Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia.
        Biol Psychiatry. 1983; 18: 537-551
        • Fukushima J.
        • Fukushima K.
        • Chiba T.
        • Tanaka S.
        • Yamashita I.
        • Kato M.
        Disturbances of voluntary control of saccadic eye movements in schizophrenic patients.
        Biol Psychiatry. 1988; 23: 670-677
        • Gottesman I.I.
        • Gould T.D.
        The endophenotype concept in psychiatry.
        Am J Psychiatry. 2003; 160: 636-645
        • Gottesman I.I.
        • Shields J.
        Genetic theorizing and schizophrenia.
        Br J Psychiatry. 1973; 122: 15-30
        • Hallett P.E.
        Primary and secondary saccades to goals defined by instructions.
        Vision Res. 1978; 18: 1279-1296
        • Hallmayer J.F.
        • Jablensky A.
        • Michie P.
        • Woodbury M.
        • Salmon B.
        • Combrinck J.
        • et al.
        Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia.
        Mol Psychiatry. 2003; 8: 511-523
        • Heinrichs R.W.
        Meta-analysis and the science of schizophrenia.
        Neurosci Biobehav Rev. 2004; 28: 379-394
        • Hutton S.B.
        • Crawford T.J.
        • Puri B.K.
        • Duncan L.J.
        • Chapman M.
        • Kennard C.
        • et al.
        Smooth pursuit and saccadic abnormalities in first-episode schizophrenia.
        Psychol Med. 1998; 28: 685-692
        • Iacono W.G.
        Identifying psychophysiological risk for psychopathology.
        Psychophysiology. 1998; 35: 621-637
        • Iacono W.G.
        • Carlson S.R.
        • Malone S.M.
        Identifying a multivariate endophenotype for substance use disorders using psychophysiological measures.
        Int J Psychophysiol. 2000; 38: 81-96
        • Jablensky A.
        Researching psychiatry in Western Australia.
        Aust N Z J Psychiatry. 2004; 38: 306-315
        • Javitt D.C.
        • Doneshka P.
        • Grochowski S.
        • Ritter W.
        Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia.
        Arch Gen Psychiatry. 1995; 52: 550-558
        • Javitt D.C.
        • Doneshka P.
        • Zylberman I.
        • Ritter W.
        • Vaughan Jr, H.G.
        Impairment of early cortical processing in schizophrenia.
        Biol Psychiatry. 1993; 33: 513-519
        • Javitt D.C.
        • Shelley A.
        • Ritter W.
        Associated deficits in mismatch negativity generation and tone matching in schizophrenia.
        Clin Neurophysiol. 2000; 111: 1733-1737
        • Jessen F.
        • Fries T.
        • Kucharski C.
        • Nishimura T.
        • Hoenig K.
        • Maier W.
        • et al.
        Amplitude reduction of the mismatch negativity in first-degree relatives of patients with schizophrenia.
        Neurosci Lett. 2001; 309: 185-188
        • Karoumi B.
        • Laurent A.
        • Rosenfeld F.
        • Rochet T.
        • Brunon A.M.
        • Dalery J.
        • et al.
        Alteration of event related potentials in siblings discordant for schizophrenia.
        Schizophr Res. 2000; 41: 325-334
        • Kendler K.S.
        • Karkowski-Shuman L.
        • Straub R.E.
        • MacLean C.J.
        • Walsh D.
        Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families.
        Am J Psychiatry. 1997; 154: 191-198
        • Liddle P.F.
        The symptoms of chronic schizophrenia. A re-examination of the positive-negative dichotomy.
        Br J Psychiatry. 1987; 151: 145-151
        • Light G.A.
        • Geyer M.A.
        • Clementz B.A.
        • Cadenhead K.S.
        • Braff D.L.
        Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications.
        Am J Psychiatry. 2000; 157: 767-771
        • Louchart-dela Chapelle S.
        • Nkam I.
        • Houy E.
        • Belmont A.
        • Menard J.F.
        • Roussignol A.C.
        • et al.
        A concordance study of three electrophysiological measures in schizophrenia.
        Am J Psychiatry. 2005; 162: 466-474
        • McCarley R.W.
        • Faux S.F.
        • Shenton M.E.
        • Nestor P.G.
        • Adams J.
        Event-related potentials in schizophrenia.
        Schizophr Res. 1991; 4: 209-231
        • Mathysse S.
        • Holzman P.S.
        Genetic latent structure models.
        Psychol Med. 1987; 17: 271-274
        • Michie P.T.
        What has MMN revealed about the auditory system in schizophrenia?.
        Int J Psychophysiol. 2001; 42: 177-194
        • Michie P.T.
        • Innes-Brown H.
        • Todd J.
        • Jablensky A.V.
        Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders.
        Biol Psychiatry. 2002; 52: 749-758
        • Näätanen R.
        Attention and Brain Function. Lawrence Erlbaum Associates, Hillsdale, New Jersey1992
        • Nagamoto H.T.
        • Adler L.E.
        • Waldo M.C.
        • Freedman R.
        Sensory gating in schizophrenics and normal controls.
        Biol Psychiatry. 1989; 25: 549-561
        • Pekkone E.
        • Hirvonen J.
        • Ahveninen J.
        • Kahkonen S.
        • Kaakkola S.
        • Huttunen J.
        • et al.
        Memory-based comparison process not attenuated by haloperidol.
        Neuroreport. 2002; 13: 177-181
        • Pfefferbaum A.
        • Ford J.M.
        • White P.M.
        • Roth W.T.
        P3 in schizophrenia is affected by stimulus modality, response requirements, medication status, and negative symptoms.
        Arch Gen Psychiatry. 1989; 46: 1035-1044
        • Pfefferbaum A.
        • Wenegrat B.G.
        • Ford J.M.
        • Roth W.T.
        • Kopell B.S.
        Clinical application of the P3 component of event-related potentials. II. Dementia, depression and schizophrenia.
        Electroencephalogr Clin Neurophysiol. 1984; 59: 104-124
        • Phillips W.A.
        • Silvestein S.M.
        Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia.
        Behav Brain Sci. 2003; 26: 65-82
        • Pulver A.E.
        Search for schizophrenia susceptibility genes.
        Biol Psychiatry. 2000; 47: 221-230
        • Risch N.
        Linkage strategies for genetically complex traits. II. The power of affected relative pairs.
        Am J Hum Genet. 1990; 46: 229-241
        • Ross R.G.
        • Harris J.G.
        • Olincy A.
        • Radant A.
        • Adler L.E.
        • Freedman R.
        Familial transmission of two independent saccadic abnormalities in schizophrenia.
        Schizophr Res. 1998; 30: 59-70
        • Roth W.T.
        • Cannon E.H.
        Some features of the auditory evoked response in schizophrenics.
        Arch Gen Psychiatry. 1972; 27: 466-471
        • Saitoh O.
        • Niwa S.
        • Hiramatsu K.
        • Kameyama T.
        • Rymar K.
        • Itoh K.
        Abnormalities in late positive components of event-related potentials may reflect a genetic predisposition to schizophrenia.
        Biol Psychiatry. 1984; 19: 293-303
        • Salisbury D.F.
        • Shenton M.E.
        • Griggs C.B.
        • Bonner-Jackson A.
        • McCarley R.W.
        Mismatch negativity in chronic schizophrenia and first-episode schizophrenia.
        Arch Gen Psychiatry. 2002; 59: 686-694
        • Salisbury D.F.
        • Shenton M.E.
        • Sherwood A.R.
        • Fischer I.A.
        • Yurgelun-Todd D.A.
        • Tohen M.
        • et al.
        First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe.
        Arch General Psychiatry. 1998; 55: 173-180
        • Schreiber H.
        • Stolz-Born G.
        • Kornhuber H.H.
        • Born J.
        Event-related potential correlates of impaired selective attention in children at high risk for schizophrenia.
        Biol Psychiatry. 1992; 32: 634-651
        • Semlitsch H.V.
        • Anderer P.
        • Schuster P.
        • Presslich O.
        A solution for reliable and valid reduction of ocular artifacts, applied to the P300 ERP.
        Psychophysiology. 1986; 23: 695-703
        • Sereno A.B.
        • Holzman P.S.
        Antisaccades and smooth pursuit eye movements in schizophrenia.
        Biol Psychiatry. 1995; 37: 394-401
        • Shelley A.M.
        • Ward P.B.
        • Catts S.V.
        • Michie P.T.
        • Andrews S.
        • McConaghy N.
        Mismatch negativity.
        Biol Psychiatry. 1991; 30: 1059-1062
        • Shinozaki N.
        • Yabe H.
        • Sato Y.
        • Hiruma T.
        • Sutoh T.
        • Nashida T.
        • et al.
        The difference in Mismatch negativity between the acute and post-acute phase of schizophrenia.
        Biol Psychology. 2002; 59: 105-119
        • Shutara Y.
        • Koga Y.
        • Fujita K.
        • Takeuchi H.
        • Mochida M.
        • Takemasa K.
        An event-related potential study on the impairment of automatic processing of auditory input in schizophrenia.
        Brain Topogr. 1996; 8: 285-289
        • SPSS
        SPSS Base 10.0 for Windows User’s Guide. SPSS, Chicago1999
        • Thaker G.K.
        • Ross D.E.
        • Cassady S.L.
        • Adami H.M.
        • Medoff D.R.
        • Sherr J.
        Saccadic eye movement abnormalities in relatives of patients with schizophrenia.
        Schizophr Res. 2000; 45: 235-244
        • Turetsky B.I.
        • Cannon T.D.
        • Gur R.E.
        P300 subcomponent abnormalities in schizophrenia: III. Deficits In unaffected siblings of schizophrenic probands.
        Biol Psychiatry. 2000; 47: 380-390
        • Umbricht D.
        • Javitt D.
        • Novak G.
        • Bates J.
        • Pollack S.
        • Lieberman J.
        • et al.
        Effects of clozapine on auditory event-related potentials in schizophrenia.
        Biol Psychiatry. 1998; 44: 716-725
        • Umbricht D.
        • Koller R.
        • Schmid L.
        • Skrabo A.
        • Grubel C.
        • Huber T.
        • et al.
        How specific are deficits in mismatch negativity generation to schizophrenia?.
        Biol Psychiatry. 2003; 53: 1120-1131
        • Waldo M.C.
        • Adler L.E.
        • Leonard S.
        • Olincy A.
        • Ross R.G.
        • Harris J.G.
        • et al.
        Familial transmission of risk factors in the first-degree relatives of schizophrenic people.
        Biol Psychiatry. 2000; 47: 231-239
        • Waldo M.C.
        • Carey G.
        • Myles-Worsley M.
        • Cawthra E.
        • Adler L.E.
        • Nagamoto H.T.
        • et al.
        Codistribution of a sensory gating deficit and schizophrenia in multi-affected families.
        Psychiatry Res. 1991; 39: 257-268
        • Winkler I.
        • Karmos G.
        • Näätanen R.
        Adaptive modeling of the unattended acoustic environment reflected in the mismatch negativity event-related potential.
        Brain Res. 1996; 742: 239-252
        • Winterer G.
        • Egan M.F.
        • Radler T.
        • Coppola R.
        • Weinberger D.R.
        Event-related potentials and genetic risk for schizophrenia.
        Biol Psychiatry. 2001; 50: 407-417