Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment

  • Elsa Gilbert
  • Chantal Mérette
  • Valérie Jomphe
  • Claudia Émond
  • Nancie Rouleau
  • Roch-Hugo Bouchard
  • Marc-André Roy
  • Thomas Paccalet
  • Michel Maziade
Original Paper

Abstract

Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response.

Keywords

Schizophrenia Heterogeneity Cognitive profiles Functioning Response to treatment 

Supplementary material

406_2013_463_MOESM1_ESM.doc (118 kb)
Supplementary material 1 (DOC 118 kb)

References

  1. 1.
    Perlis RH (2011) Translating biomarkers to clinical practice. Mol Psychiatry 16:1076–1087PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Keshavan MS, Nasrallah HA, Tandon R (2011) Schizophrenia, “just the facts” 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse. Schizophr Res 127:3–13PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Levine SZ, Leucht S (2010) Elaboration on the early-onset hypothesis of antipsychotic drug action: treatment response trajectories. Biol Psychiatry 68:86–92PubMedCrossRefGoogle Scholar
  4. 4.
    Levine SZ, Rabinowitz J (2010) Trajectories and antecedents of treatment response over time in early-episode psychosis. Schizophr Bull 36:624–632PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Levine SZ, Rabinowitz J, Faries D, Lawson AH, Ascher-Svanum H (2012) Treatment response trajectories and antipsychotic medications: examination of up to 18 months of treatment in the CATIE chronic schizophrenia trial. Schizophr Res 137(1–3):141–146PubMedCrossRefGoogle Scholar
  6. 6.
    Perkins DO, Gu H, Boteva K, Lieberman JA (2005) Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 162:1785–1804PubMedCrossRefGoogle Scholar
  7. 7.
    Dickinson D, Gold JM (2008) Less unique variance than meets the eye: overlap among traditional neuropsychological dimensions in schizophrenia. Schizophr Bull 34:423–434PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Green MF, Kern RS, Braff DL, Mintz J (2000) Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 26:119–136PubMedCrossRefGoogle Scholar
  9. 9.
    Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321–330PubMedGoogle Scholar
  10. 10.
    Fett AK, Viechtbauer W, Dominguez MD, Penn DL, van Os J, Krabbendam L (2011) The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neurosci Biobehav Rev 35:573–588PubMedCrossRefGoogle Scholar
  11. 11.
    Nuechterlein KH, Subotnik KL, Green MF, Ventura J, Asarnow RF, Gitlin MJ, Yee CM, Gretchen-Doorly D, Mintz J (2011) Neurocognitive predictors of work outcome in recent-onset schizophrenia. Schizophr Bull 37(Suppl 2):S33–S40PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Milev P, Ho BC, Arndt S, Andreasen NC (2005) Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry 162:495–506PubMedCrossRefGoogle Scholar
  13. 13.
    Bell MD, Johannesen JK, Greig TC, Wexler BE (2010) Memory profiles in schizophrenia: categorization validity and stability. Schizophr Res 118:26–33PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Potter AI, Nestor PG (2010) Iq subtypes in schizophrenia: distinct symptom and neuropsychological profiles. J Nerv Ment Dis 198:580–585PubMedCrossRefGoogle Scholar
  15. 15.
    Carrion RE, Goldberg TE, McLaughlin D, Auther AM, Correll CU, Cornblatt BA (2011) Impact of neurocognition on social and role functioning in individuals at clinical high risk for psychosis. Am J Psychiatry 168:806–813PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Knowles EE, David AS, Reichenberg A (2010) Processing speed deficits in schizophrenia: reexamining the evidence. Am J Psychiatry 167:828–835PubMedCrossRefGoogle Scholar
  17. 17.
    Allott K, Liu P, Proffitt TM, Killackey E (2011) Cognition at illness onset as a predictor of later functional outcome in early psychosis: systematic review and methodological critique. Schizophr Res 125:221–235PubMedCrossRefGoogle Scholar
  18. 18.
    Wittorf A, Wiedemann G, Buchkremer G, Klingberg S (2008) Prediction of community outcome in schizophrenia 1 year after discharge from inpatient treatment. Eur Arch Psychiatry Clin Neurosci 258:48–58PubMedCrossRefGoogle Scholar
  19. 19.
    Wolwer W, Brinkmeyer J, Riesbeck M, Freimuller L, Klimke A, Wagner M, Moller HJ, Klingberg S, Gaebel W (2008) Neuropsychological impairments predict the clinical course in schizophrenia. Eur Arch Psychiatry Clin Neurosci 258(Suppl 5):28–34PubMedCrossRefGoogle Scholar
  20. 20.
    Bell MD, Tsang HW, Greig T, Bryson G (2007) Cognitive predictors of symptom change for participants in vocational rehabilitation. Schizophr Res 96(1–3):162–168PubMedCrossRefGoogle Scholar
  21. 21.
    Seaton BE, Goldstein G, Allen DN (2001) Sources of heterogeneity in schizophrenia: the role of neuropsychological functioning. Neuropsychol Rev 11:45–67PubMedCrossRefGoogle Scholar
  22. 22.
    Basso MR, Nasrallah HA, Olson SC, Bornstein RA (1998) Neuropsychological correlates of negative, disorganized and psychotic symptoms in schizophrenia. Schizophr Res 31:99–111PubMedCrossRefGoogle Scholar
  23. 23.
    Rethelyi JM, Czobor P, Polgar P, Mersich B, Balint S, Jekkel E, Magyar K, Meszaros A, Fabian A, Bitter I (2012) General and domain-specific neurocognitive impairments in deficit and non-deficit schizophrenia. Eur Arch Psychiatry Clin Neurosci 262:107–115PubMedCrossRefGoogle Scholar
  24. 24.
    Weickert TW, Goldberg TE, Gold JM, Bigelow LB, Egan MF, Weinberger DR (2000) Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 57:907–913PubMedCrossRefGoogle Scholar
  25. 25.
    Kremen WS, Seidman LJ, Faraone SV, Toomey R, Tsuang MT (2000) The paradox of normal neuropsychological function in schizophrenia. J Abnorm Psychol 109:743–752PubMedCrossRefGoogle Scholar
  26. 26.
    Ilonen T, Taiminen T, Karlsson H, Lauerma H, Leinonen KM, Wallenius E, Salokangas RK (2004) Neuropsychological subtyping of schizophrenia. Psychiatry Res 129:191–199PubMedCrossRefGoogle Scholar
  27. 27.
    Hill SK, Ragland JD, Gur RC, Gur RE (2002) Neuropsychological profiles delineate distinct profiles of schizophrenia, an interaction between memory and executive function, and uneven distribution of clinical subtypes. J Clin Exp Neuropsychol 24:765–780PubMedCrossRefGoogle Scholar
  28. 28.
    Kremen WS, Seidman LJ, Faraone SV, Toomey R, Tsuang MT (2004) Heterogeneity of schizophrenia: a study of individual neuropsychological profiles. Schizophr Res 71:307–321PubMedCrossRefGoogle Scholar
  29. 29.
    Ammari N, Heinrichs RW, Miles AA (2010) An investigation of 3 neurocognitive subtypes in schizophrenia. Schizophr Res 121:32–38PubMedCrossRefGoogle Scholar
  30. 30.
    Raffard S, Bayard S (2012) Understanding the executive functioning heterogeneity in schizophrenia. Brain Cogn 79:60–69PubMedCrossRefGoogle Scholar
  31. 31.
    Fioravanti M, Bianchi V, Cinti ME (2012) Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence. BMC Psychiatry 12:64PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Mesholam-Gately RI, Giuliano AJ, Goff KP, Faraone SV, Seidman LJ (2009) Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology 23:315–336PubMedCrossRefGoogle Scholar
  33. 33.
    Maziade M, Rouleau N, Merette C, Cellard C, Battaglia M, Marino C, Jomphe V, Gilbert E, Achim A, Bouchard RH, Paccalet T, Paradis ME, Roy MA (2011) Verbal and visual memory impairments among young offspring and healthy adult relatives of patients with schizophrenia and bipolar disorder: selective generational patterns indicate different developmental trajectories. Schizophr Bull 37:1218–1228PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Maziade M, Rouleau N, Gingras N, Boutin P, Paradis ME, Jomphe V, Boutin J, Letourneau K, Gilbert E, Lefebvre AA, Dore MC, Marino C, Battaglia M, Merette C, Roy MA (2009) Shared neurocognitive dysfunctions in young offspring at extreme risk for schizophrenia or bipolar disorder in eastern Quebec multigenerational families. Schizophr Bull 35:919–930PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, Poulton R (2002) Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry 59:449–456PubMedCrossRefGoogle Scholar
  36. 36.
    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 160:2060–2062PubMedCrossRefGoogle Scholar
  37. 37.
    Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RS, Murray RM, Poulton R, Moffitt TE (2010) Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study. Am J Psychiatry 167:160–169PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Jones P, Rodgers B, Murray R, Marmot M (1994) Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 344:1398–1402PubMedCrossRefGoogle Scholar
  39. 39.
    Osler M, Lawlor DA, Nordentoft M (2007) Cognitive function in childhood and early adulthood and hospital admission for schizophrenia and bipolar disorders in Danish men born in 1953. Schizophr Res 92:132–141PubMedCrossRefGoogle Scholar
  40. 40.
    Cannon TD, Bearden CE, Hollister JM, Rosso IM, Sanchez LE, Hadley T (2000) Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophr Bull 26:379–393PubMedCrossRefGoogle Scholar
  41. 41.
    Dickinson D, Goldberg TE, Gold JM, Elvevag B, Weinberger DR (2011) Cognitive factor structure and invariance in people with schizophrenia, their unaffected siblings, and controls. Schizophr Bull 37:1157–1167PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK (2004) Identification of separable cognitive factors in schizophrenia. Schizophr Res 72:29–39PubMedCrossRefGoogle Scholar
  43. 43.
    Genderson MR, Dickinson D, Diaz-Asper CM, Egan MF, Weinberger DR, Goldberg TE (2007) Factor analysis of neurocognitive tests in a large sample of schizophrenic probands, their siblings, and healthy controls. Schizophr Res 94:231–239PubMedCrossRefGoogle Scholar
  44. 44.
    Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ 3rd, Gold JM, Goldberg T, Heaton RK, Keefe RS, Kraemer H, Mesholam-Gately R, Seidman LJ, Stover E, Weinberger DR, Young AS, Zalcman S, Marder SR (2008) The matrics consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry 165:203–213PubMedCrossRefGoogle Scholar
  45. 45.
    Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N, Dion C, Lavallee JC, Garneau Y, Gingras N, Nicole L, Pires A, Ponton AM, Potvin A, Wallot H, Merette C (2005) Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in eastern Quebec families. Mol Psychiatry 10:486–499PubMedCrossRefGoogle Scholar
  46. 46.
    Maziade M, Roy MA, Fournier JP, Cliche D, Merette C, Caron C, Garneau Y, Montgrain N, Shriqui C, Dion C et al (1992) Reliability of best-estimate diagnosis in genetic linkage studies of major psychoses: results from the Quebec pedigree studies. Am J Psychiatry 149:1674–1686PubMedGoogle Scholar
  47. 47.
    Maziade M, Roy MA, Martinez M, Cliche D, Fournier JP, Garneau Y, Nicole L, Montgrain N, Dion C, Ponton AM (1995) Negative, psychoticism, and disorganized dimensions in patients with familial schizophrenia or bipolar disorder: continuity and discontinuity between the major psychoses. Am J Psychiatry 152:1458–1463PubMedGoogle Scholar
  48. 48.
    Roy MA, Lanctôt G, Mérette C, Cliche D, Fournier JP, Boutin P, Rodrigue C, Charron L, Turgeon M, Hamel M, Montgrain N, Nicole L, Pires A, Wallot H, Ponton AM, Garneau Y, Dion C, Lavallée JC, Potvin A, Szatmari P, Maziade M (1997) Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure. Am J Psychiatry 154:1726–1733PubMedGoogle Scholar
  49. 49.
    Maziade M, Rouleau N, Cellard C, Battaglia M, Paccalet T, Moreau I, Gagnon V, Gingras N, Marino C, Gilbert E, Roy MA, Merette C (2011) Young offspring at genetic risk of adult psychoses: the form of the trajectory of IQ or memory may orient to the right dysfunction at the right time. PLoS ONE 6:e19153PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Slick DJ (2006) Psychometric in neuropsychological assessment. In: Strauss E, Sherman EMS, Spreen O (eds) A compendium of neuropsychological tests: Administration, norms, and commentary. Oxford University Press, USAGoogle Scholar
  51. 51.
    Endicott J, Spitzer RL, Fleiss JL, Cohen J (1976) The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 33:766–771PubMedCrossRefGoogle Scholar
  52. 52.
    Aas IH (2010) Global assessment of functioning (GAF): properties and frontier of current knowledge. Ann Gen Psychiatry 9:20PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Pedersen G, Hagtvet KA, Karterud S (2007) Generalizability studies of the global assessment of functioning-split version. Compr Psychiatry 48:88–94PubMedCrossRefGoogle Scholar
  54. 54.
    Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276PubMedCrossRefGoogle Scholar
  55. 55.
    Post RM, Roy-Byrne PP, Uhde TW (1988) Graphic representation of the life course of illness in patients with affective disorder. Am J Psychiatry 145:844–848PubMedGoogle Scholar
  56. 56.
    Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ (2010) International consensus study of antipsychotic dosing. Am J Psychiatry 167:686–693PubMedCrossRefGoogle Scholar
  57. 57.
    Marques TR, Arenovich T, Agid O, Sajeev G, Muthen B, Chen L, Kinon BJ, Kapur S (2011) The different trajectories of antipsychotic response: antipsychotics versus placebo. Psychol Med 41:1481–1488PubMedCrossRefGoogle Scholar
  58. 58.
    Levine SZ, Lurie I, Kohn R, Levav I (2011) Trajectories of the course of schizophrenia: from progressive deterioration to amelioration over three decades. Schizophr Res 126:184–191PubMedCrossRefGoogle Scholar
  59. 59.
    Butlen-Ducuing F, Haas M, Pani L, van Zwieten-Boot B, Broich K (2012) DSM-5 and clinical trials in psychiatry: challenges to come? Nat Rev Drug Discovery 11:583–584CrossRefGoogle Scholar
  60. 60.
    Braff DL, Freedman R, Schork NJ, Gottesman I (2007) Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull 33:21–32PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Levine SZ, Rabinowitz J, Case M, Ascher-Svanum H (2010) Treatment response trajectories and their antecedents in recent-onset psychosis: a 2-year prospective study. J Clin Psychopharmacol 30:446–449PubMedCrossRefGoogle Scholar
  62. 62.
    Stauffer V, Case M, Kollack-Walker S, Ascher-Svanum H, Ball T, Kapur S, Kinon BJ (2011) Trajectories of response to treatment with atypical antipsychotic medication in patients with schizophrenia pooled from 6 double-blind, randomized clinical trials. Schizophr Res 130:11–19PubMedCrossRefGoogle Scholar
  63. 63.
    Derntl B, Habel U (2011) Deficits in social cognition: a marker for psychiatric disorders? Eur Arch Psychiatry Clin Neurosci 261(Suppl 2):S145–S149PubMedCrossRefGoogle Scholar
  64. 64.
    Heaton RK, Gladsjo JA, Palmer BW, Kuck J, Marcotte TD, Jeste DV (2001) Stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry 58:24–32PubMedCrossRefGoogle Scholar
  65. 65.
    Holthausen EA, Wiersma D, Sitskoorn MM, Hijman R, Dingemans PM, Schene AH, van den Bosch RJ (2002) Schizophrenic patients without neuropsychological deficits: subgroup, disease severity or cognitive compensation? Psychiatry Res 112:1–11PubMedCrossRefGoogle Scholar
  66. 66.
    Cobia DJ, Csernansky JG, Wang L (2011) Cortical thickness in neuropsychologically near-normal schizophrenia. Schizophr Res 133:68–76PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Albus M, Hubmann W, Mohr F, Hecht S, Hinterberger-Weber P, Seitz NN, Kuchenhoff H (2006) Neurocognitive functioning in patients with first-episode schizophrenia : results of a prospective 5-year follow-up study. Eur Arch Psychiatry Clin Neurosci 256:442–451PubMedCrossRefGoogle Scholar
  68. 68.
    Blishen BR, Carroll WK, Moore C (1987) The 1981 socioeconomic index for occupations in Canada. Can Rev Soc Anthrop 24:465–488CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elsa Gilbert
    • 1
  • Chantal Mérette
    • 1
    • 2
  • Valérie Jomphe
    • 1
  • Claudia Émond
    • 1
  • Nancie Rouleau
    • 1
    • 3
  • Roch-Hugo Bouchard
    • 1
  • Marc-André Roy
    • 1
    • 2
  • Thomas Paccalet
    • 1
  • Michel Maziade
    • 1
    • 2
  1. 1.Centre de rechercheInstitut universitaire en santé mentale de QuébecQuebecCanada
  2. 2.Faculté de MédecineLaval UniversityQuebecCanada
  3. 3.École de psychologieUniversité LavalQuebecCanada

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