Neurotoxicity Research

, Volume 18, Issue 3–4, pp 272–286 | Cite as

Neurocognitive Indicators of Clinical High-Risk States for Psychosis: A Critical Review of the Evidence



The present review investigates the empirical evidence from cross-sectional and long-term follow-up studies on neurocognitive indicators of an increased risk for developing schizophrenia spectrum psychoses in clinically defined high-risk samples. First, the investigations at the Cologne center for early recognition and intervention are briefly summarized and then integrated within the available literature. Thirty-two studies with original data could be identified by extensive literature search. Cross-sectional investigations of neurocognitive baseline assessments in high-risk samples with unknown conversion status have produced rather inconsistent results. Nevertheless, most convincing evidence could be collected for abnormal functioning in processing speed measures (digit symbol coding, Trailmaking Test-B, Stroop Color Naming), the Continuous Performance Test, verbal working memory measures, verbal memory and learning, and verbal fluency, though negative findings have also been reported in every instance. Moreover, high-risk subjects were found to perform both at the schizophrenia performance level and at a close to normal level. Longitudinal follow-up assessments provided predictive evidence with regard to psychosis conversion for measures of processing speed and of verbal memory and learning. However, a substantial number of negative findings does not allow for straight-forward conclusions. Finally, some reasons for inconsistent findings are discussed critically speculating on demographic differences, reliability and sample sizes, and conceptual imprecision in communicating results.


Clinical high risk Prodromal schizophrenia Cognition Neuropsychology Review 


Numbers in brackets after a reference refer to Tables 14

  1. Bilder RM, Goldman RS, Robinson D, Reiter G, Bell L, Bates JA, Pappadopulos E, Willson DF, Alvir JMJ, Woerner MG, Geisler S, Kane JM, Lieberman JA (2000) Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 157:549–559CrossRefPubMedGoogle Scholar
  2. Brewer WJ, Wood SJ, McGorry PD, Francey SM, Phillips LJ, Yung AR, Anderson V (2003) Impairment of olfactory identification ability in individuals at ultra-high risk for psychosis who later develop schizophrenia. Am J Psychiatry 160:1790–1794 (1)CrossRefPubMedGoogle Scholar
  3. Brewer WJ, Francey SM, Wood SJ, Jackson HJ, Pantelis C, Phillips LJ, Yung AR, Anderson VA, McGorry PD (2005) Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry 162:71–78 (2)CrossRefPubMedGoogle Scholar
  4. Cannon TD, Bearden CE, Hollister JM (2000) Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophr Bull 26:379–393PubMedGoogle Scholar
  5. Carr V, Halpin S, Lau N, O’Brien S, Beckmann J, Lewin T (2000) A risk factor screening and assessment protocol for schizophrenia and related psychosis. Aust N Z J Psychiatry 34(Supp):170–180 (3)CrossRefGoogle Scholar
  6. Chung YS, Kang DH, Shin NY, Yoo SY, Kwon JS (2008) Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia. Schizophr Res 99:111–118 (4)CrossRefPubMedGoogle Scholar
  7. Cornblatt BA (1996) Continuous performance test—identical pairs version computer software. Author, New YorkGoogle Scholar
  8. Cornblatt B, Obuchowski M, Roberts S, Pollack S, Erlenmeyer-Kimling L (1999) Cognitive and behavioral precursors of schizophrenia. Dev Psychopathol 11:487–508CrossRefPubMedGoogle Scholar
  9. Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mark M (1999) Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry 156:1328–1335PubMedGoogle Scholar
  10. Dickinson D, Ramsey EM, Gold JM (2007) Overlooking the obvious. A meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry 64:532–542CrossRefPubMedGoogle Scholar
  11. Eastvold AD, Heaton RK, Cadenhead KS (2007) Neurocognitive deficits in the (putative) prodrome and first episode of psychosis. Schizophr Res 93:266–277 (5)CrossRefPubMedGoogle Scholar
  12. Francey SM, Jackson HJ, Phillips LJ, Wood SJ, Yung AR, McGorry PD (2005) Sustained attention in young people at high risk of psychosis does not predict transition to psychosis. Schizophr Res 79:127–136 (6)CrossRefPubMedGoogle Scholar
  13. Frommann I, Pukrop R, J Brinkmeyer, Bechdolf A, Ruhrmann S, J Berning, Decker P, Möller HJ, Wölwer W, Gaebel W, Klosterkötter J, Maier W, Wagner M (in press) Cognitive decline in the psychosis prodrome: specific executive impairment in the early—and additional memory dysfunction in the late prodromal state. Schizophr Bull (7)Google Scholar
  14. Gediga G, Schöttke H (1994) Turm von Hanoi. In: Hänsgen KD (ed) Hogrefe Testsystem. Hogrefe, GöttingenGoogle Scholar
  15. Gold J, Carpenter C, Randolph C, Goldberg T, Weinberger D (1997) Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry 54:159–165PubMedGoogle Scholar
  16. Gschwandtner U, Aston J, Borgwardt S, Drewe M, Feinendegen C, Lacher D, Lanzarone A, Stieglitz RD, Riecher-Rössler A (2003) Neuropsychological and neurophysiological findings in individuals suspected to be at risk for schizophrenia: preliminary results from the Basel early detection of psychosis study—Früherkennung von Psychosen (FEPSY). Acta Psychiatr Scand 108:152–155 (8)CrossRefPubMedGoogle Scholar
  17. Gschwandtner U, Pflüger M, Aston J, Borgwardt S, Drewe M, Stieglitz R-D, Riecher-Rössler A (2006) Fine motor function and neuropsychological deficits in individuals at risk for schizophrenia. Eur Arch Psychiatry Clin Neurosci 256:201–206 (9)CrossRefPubMedGoogle Scholar
  18. Hambrecht M, Lammertink M, Klosterkötter J, Matuschek E, Pukrop R (2002) Subjective and objective neuropsychological abnormalities in a psychosis prodrome clinic. Br J Psychiatry 181:30–37 (10)CrossRefGoogle Scholar
  19. Hawkins KA, Addington J, Keefe RSE, Christensen B, Perkins DO, Zipursky R, Woods SW, Miller TJ, Marquez E, Breier A, McGlashan TH (2004) Neuropsychological status of subjects at high risk for a first episode of psychosis. Schizophr Res 67:115–122 (11)CrossRefPubMedGoogle Scholar
  20. Hawkins KA, Keefe RSE, Christensen BK, Addington J, Woods SW, Callahan J, Zipursky RB, Perkins D, Tohen M, Breier A, McGlashan TH (2008) Neuropsychological course in the prodrome and first episode of psychosis: findings from the PRIME North America Double Blind Treatment Study. Schizophr Res 105:1–9 (12)CrossRefPubMedGoogle Scholar
  21. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtiss G (1993) Wisconsin Card Sorting Test manual. Psychological Assessment Resources, Odessa, FLGoogle Scholar
  22. Heaton RK, Gladsjo JA, Palmer BW, Kuck J, Marcotte TD, Jeste DV (2001) Stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry 58:24–32CrossRefPubMedGoogle Scholar
  23. Heinrichs RW (2005) The primacy of cognition in schizophrenia. Am Psychol 60:229–242CrossRefPubMedGoogle Scholar
  24. Hoffman RE, Woods SW, Hawkins KA, Pittman B, Tohen M, Preda A, Breier A, Glist J, Addington J, Perkins DO, McGlashan TH (2007) Extracting spurious messages from noise and risk of schizophrenia-spectrum disorders in a prodromal population. Br J Psychiatry 191:355–356 (13)CrossRefPubMedGoogle Scholar
  25. Kaplan E, Fein D, Morris R, Delis DC (1991) WAIS-R NI Manual. Psychological Corporation, San AntonioGoogle Scholar
  26. Keefe RSE, Perkins DO, Gu H, Zipursky RB, Christensen BK, Liebermann JA (2006) A longitudinal study of neurocognitive function in individuals at-risk for psychosis. Schizophr Res 88:26–35 (14)CrossRefPubMedGoogle Scholar
  27. Keri S, Benedek G (2007) Visual contrast sensitivity alterations in inferred magnocellular pathways anomalous perceptual experiences in people at high-risk for psychosis. Vis Neurosci 24:183–189 (15)CrossRefPubMedGoogle Scholar
  28. Klosterkötter J, Hellmich M, Steinmeyer EM, Schultze-Lutter F (2001) Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry 58:158–164CrossRefPubMedGoogle Scholar
  29. Koethe D, Kranaster L, Hoyer C, Gross S, Neatby MA, Schultze-Lutter F, Ruhrmann S, Klosterkötter J, Hellmich M, Leweke FM (2009) Binocular depth inversion as a paradigm of reduced visual information processing in prodromal state, anti-psychotic naïve and treated schizophrenia. Eur Arch Psychiatry Clin Neurosci 259:195–202 (16)CrossRefPubMedGoogle Scholar
  30. Lehrl S (1995) Mehrfachwahl-Wortschatz-Intelligenztest: MWT-B [Multiple Choice Vocabulary Test]. Perimed-spitta, BalingenGoogle Scholar
  31. Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA (2006) Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry 59:863–871 (17)CrossRefPubMedGoogle Scholar
  32. Lezak MD (1995) Neuropsychological assessment, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  33. McGorry PD, Yung AR, Bechdolf A, Amminger GP (2008) Back to the future: predicting and reshaping the course of psychotic disorder. Arch Gen Psychiatry 65:25–27CrossRefPubMedGoogle Scholar
  34. Nelson HE, O’Connell A (1978) Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex 14:234–244PubMedGoogle Scholar
  35. Niendam TA, Bearden CE, Rosso IM, Sanchez LE, Hadley T, Nuechterlein KH, Cannon TD (2003) A prospective study of childhood neurocognitive functioning in schizophrenic patients and their siblings. Am J Psychiatry 160:2060–2062CrossRefPubMedGoogle Scholar
  36. Niendam TA, Bearden CE, Johnson JK, McKinley M, Loewy R, O’Brien M, Nuechterlein KH, Green FM, Cannon TD (2006) Neurocognitive performance and functional disability in the psychosis prodrome. Schizophr Res 84:100–111 (18)CrossRefPubMedGoogle Scholar
  37. Niendam TA, Bearden CE, Zinberg J, Johnson JK, O’Brian M, Cannon TD (2007) The course of neurocognition and social functioning in individuals at ultra high risk for psychosis. Schizophr Bull 33:772–781 (19)CrossRefPubMedGoogle Scholar
  38. Olsen KA, Rosenbaum B (2005) Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatr Scand 113:247–272CrossRefGoogle Scholar
  39. Özgürdal S, Littmann E, Hauser M, von Reventlow H, Gudlowski Y, Witthaus H, Heinz A, Juckel G (2009) Neurocognitive performances in participants of at-risk mental state for schizophrenia and in first-episode patients. J Clin Exp Neuropsychol 31:392–401 (20)CrossRefPubMedGoogle Scholar
  40. Parnas J, Vianin P, Saebye D, Jansson L, Volmer-Larsen A, Bovet P (2001) Visual binding abilities in the initial and advanced stages of schizophrenia. Acta Psychiatr Scand 103:171–180 (21)CrossRefPubMedGoogle Scholar
  41. Petrides M (1995) Impairments on nonspatial self-ordered and externally ordered working memory tasks after lesions of the mid-dorsal part of the lateral cortex in the monkey. J Neurosci 15:359–375PubMedGoogle Scholar
  42. Pflueger MO, Gschwandtner U, Stieglitz R-D, Riecher-Rössler A (2007) Neuropsychological deficits in individuals with an at risk mental state for psychosis—working memory as a potential trait marker. Schizophr Res 97:14–24 (22)CrossRefPubMedGoogle Scholar
  43. Phillips LJ, McGorry PD, Yung AR, McGlashan TH, Cornblatt B, Klosterkötter J (2005) Prepsychotic phase of schizophrenia and related disorders: recent progress and future opportunities. Br J Psychiatry 187:33–44CrossRefGoogle Scholar
  44. Pukrop R, Schultze-Lutter F, Ruhrmann S, Brockhaus-Dumke A, Tendolkar I, Bechdolf A, Matuschek E, Klosterkötter J (2006) Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first and multiple episode schizophrenia. J Clin Exp Neuropsychol 28:1388–1407 (23)CrossRefPubMedGoogle Scholar
  45. Pukrop R, Ruhrmann S, Schultze-Lutter F, Bechdolf A, Brockhaus-Dumke A, Klosterkötter J (2007) Neurocognitive indicators for a conversion to psychosis: Comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophr Res 92:116–125 (24)CrossRefPubMedGoogle Scholar
  46. Quine WVO (1961) From a logical point of view, 2nd edn. Harvard University Press, CambridgeGoogle Scholar
  47. Reitan RM, Wolfson D (1985) The Halstead-Reitan neuropsychological test battery. Neuropsychology Press, TucsonGoogle Scholar
  48. Rey A (1941) L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 28:286–340Google Scholar
  49. Riecher-Rössler A, Pflüger M, Aston J, Borgwardt S, Brewer WJ, Gschwandtner U, Stieglitz RD (2009) Efficacy of using cognitive status in predicting psychosis: a 7-year follow-up. Biol Psychiatry 66(11):1023–1030 (25)CrossRefPubMedGoogle Scholar
  50. Salthouse TA (1996) The processing-speed theory of adult age-differences in cognition. Psychol Rev 103:403–428CrossRefPubMedGoogle Scholar
  51. Seidman LJ, Buka SL, Goldstein JM, Tsuang MT (2006) Intellectual decline in schizophrenia: evidence from a prospective birth cohort 28 year follow-up study. J Clin Exp Neuropsychol 28:225–242CrossRefPubMedGoogle Scholar
  52. Silverstein S, Uhlhaas PJ, Essex B, Halpin S, Schall U, Carr V (2006) Perceptual organization in first episode schizophrenia and ultra-high-risk states. Schizophr Res 83:41–52 (26)CrossRefPubMedGoogle Scholar
  53. Simon AE, Dvorsky DN, Boesch J, Roth B, Isler E, Schueler P, Petralli C, Umbricht D (2006) Defining subjects at risk for psychosis: a comparison of two approaches. Schizophr Res 81:83–90 (27)CrossRefPubMedGoogle Scholar
  54. Simon AE, Cattapan-Ludewig K, Zmilacher S, Arbach D, Gruber K, Dvorsky DN, Roth B, Isler E, Zimmer A, Umbricht D (2007) Cognitive functioning in the schizophrenia prodrome. Schizophr Bull 33:761–771 (28)CrossRefPubMedGoogle Scholar
  55. Smith CW, Park S, Cornblatt B (2006) Spatial working memory deficits in adolescents at clinical high risk for schizophrenia. Schizophr Res 81:211–215 (29)CrossRefPubMedGoogle Scholar
  56. Trotman H, McMillan A, Walker E (2006) Cognitive function and symptoms in adolescents with schizotypal personality disorder. Schizophr Bull 32:489–497 (30)CrossRefPubMedGoogle Scholar
  57. Walder DJ, Mittal V, Trotman HD, McMillan AL, Walker EF (2008) Neurocognition and conversion to psychosis in adolescents at high-risk. Schizophr Res 101:161–168 (31)CrossRefPubMedGoogle Scholar
  58. Walker EF, Walder D, Reynolds F (2001) Developmental changes in cortisol secretion in normal and at-risk youth. Dev Psychopathol 13:721–732CrossRefPubMedGoogle Scholar
  59. Wechsler D (1997a) Wechsler memory scale III. Administration and scoring manual. Psychological Corporation, New YorkGoogle Scholar
  60. Wechsler D (1997b) Wechsler adult intelligence scale III. Administration and scoring manual. Psychological Corporation, San AntonioGoogle Scholar
  61. Whyte MC, Brett C, Harrison LK, Byrne M, Miller P, Lawrie SM, Johnstone EC (2006) Neuropsychological performance over time in people at high risk of developing schizophrenia and controls. Biol Psychiatry 59:730–739CrossRefPubMedGoogle Scholar
  62. Wood SJ, Pantelis C, Proffitt T, Phillips LJ, Stuart GW, Buchanan JA, Mahony K, Brewer W, Smith DJ, McGorry PD (2003) Spatial working memory ability is a marker of risk-for-psychosis. Psychol Med 33:1239–1247 (32)CrossRefPubMedGoogle Scholar
  63. Woods BT (1998) Is schizophrenia a progressive neurodevelopmental disorder ? Toward a unitary pathogenic mechanism. Am J Psychiatry 155:1661–1670PubMedGoogle Scholar
  64. Yung AR, Phillips LJ, Yuen HP, Francey SM, McFarlane CA, Hallgren M, McGorry PD (2003) Psychosis prediction: 12-month follow-up of a high risk (‘prodromal’) group. Schizophr Res 60:21–32CrossRefPubMedGoogle Scholar
  65. Yung AR, Phillips LJ, Yuen HP, McGorry PD (2004) Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophr Res 67:131–142CrossRefPubMedGoogle Scholar
  66. Yung AR, Yuen HP, Berger G, Francey S, Hung TC, Nelson B, Phillips L, McGorry P (2007) Declining transition rate in ultra high risk (prodromal) services: dilution or reduction of risk? Schizophr Bull 33:673–681CrossRefPubMedGoogle Scholar
  67. Zimmermann P, Fimm B (2000) Testbatterie zur Aufmerksamkeitsprüfung. Psytest, Herzogenrath, GermanyGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Psychiatry and PsychotherapyUniversity of CologneCologneGermany

Personalised recommendations