Natural History of Schizophrenia

  • Oliver Freudenreich
Part of the Current Clinical Psychiatry book series (CCPSY)


Having a good understanding of the natural history of schizophrenia, admittedly an abstraction, allows clinicians to make a correct diagnosis based on the longitudinal history. In this chapter, I describe the clinical phases of schizophrenia that need to be recognized, particularly the prodromal phase of schizophrenia that often begins with non-specific symptoms several years before schizophrenia declares itself with the onset of frank psychosis. A corresponding phase exists in chronic patients, where an impending relapse is heralded by non-specific early warning sign. This chapter also discussing the problem of prognostication as schizophrenia has many possible outcomes, ranging from a restitutio ad integrum in about 20–30% of cases to severe, unremitting illness in 10% of cases. For most patients treated schizophrenia is a manageable illness, particularly if help is provided when needed.


Natural history Course Onset Childhood-onset schizophrenia (COS) Late-onset schizophrenia (LOS) Very late-onset schizophrenia-like psychosis Postpartum psychosis Premorbid phase Prodrome First episode of psychosis Conrad stages of beginning psychosis Chronic schizophrenia Psychotic relapse Long-term outcome Prognosis Culture 


  1. 1.
    Wikipedia. Yogi Berra. Available from: Accessed on 7/1/2019.
  2. 2.
    Shorter E. The history of nosology and the rise of the diagnostic and statistical manual of mental disorders. Dialogues Clin Neurosci. 2015;17:59–67.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Lieberman JA. Neurobiology and the natural history of schizophrenia. J Clin Psychiatry. 2006;67:e14.PubMedCrossRefGoogle Scholar
  4. 4.
    Aleman A, Kahn RS, Selten JP. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry. 2003;60:565–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Zipursky RB, Reilly TJ, Murray RM. The myth of schizophrenia as a progressive brain disease. Schizophr Bull. 2013;39:1363–72.CrossRefGoogle Scholar
  6. 6.
    Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50:884–97.PubMedCrossRefGoogle Scholar
  7. 7.
    Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Farmer PE, Nizeye B, Stulac S, Keshavjee S. Structural violence and clinical medicine. PLoS Med. 2006;3:e449.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Nicolson R, Rapoport JL. Childhood-onset schizophrenia: rare but worth studying. Biol Psychiatry. 1999;46:1418–28.PubMedCrossRefGoogle Scholar
  10. 10.
    Girard C, Simard M. Clinical characterization of late- and very late-onset first psychotic episode in psychiatric inpatients. Am J Geriatr Psychiatry. 2008;16:478–87.PubMedCrossRefGoogle Scholar
  11. 11.
    Maglione JE, Thomas SE, Jeste DV. Late-onset schizophrenia: do recent studies support categorizing LOS as a subtype of schizophrenia? Curr Opin Psychiatry. 2014;27:173–8.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Howard R, Rabins PV, Seeman MV, Jeste DV. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am J Psychiatry. 2000;157:172–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Riecher-Rossler A, Rossler W, Forstl H, Meise U. Late-onset schizophrenia and late paraphrenia. Schizophr Bull. 1995;21:345–54.PubMedCrossRefGoogle Scholar
  14. 14.
    Brodaty H, Sachdev P, Koschera A, Monk D, Cullen B. Long-term outcome of late-onset schizophrenia: 5-year follow-up study. Br J Psychiatry. 2003;183:213–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Almeida OP, Howard RJ, Levy R, David AS. Psychotic states arising in late life (late paraphrenia). The role of risk factors. Br J Psychiatry. 1995;166:215–28.PubMedCrossRefGoogle Scholar
  16. 16.
    Jones I, Chandra PS, Dazzan P, Howard LM. Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period. Lancet. 2014;384:1789–99.PubMedCrossRefGoogle Scholar
  17. 17.
    Sit D, Rothschild AJ, Wisner KL. A review of postpartum psychosis. J Women’s Health. 2006;15:352–68.CrossRefGoogle Scholar
  18. 18.
    Chaudron LH, Pies RW. The relationship between postpartum psychosis and bipolar disorder: a review. J Clin Psychiatry. 2003;64:1284–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Bergink V, Rasgon N, Wisner KL. Postpartum psychosis: madness, mania, and melancholia in motherhood. Am J Psychiatry. 2016;173:1179–88.PubMedCrossRefGoogle Scholar
  20. 20.
    Spinelli M. Infanticide and American criminal justice (1980–2018). Arch Womens Ment Health. 2019;22:173–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Welham J, Isohanni M, Jones P, McGrath J. The antecedents of schizophrenia: a review of birth cohort studies. Schizophr Bull. 2009;35:603–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Tempelaar WM, Termorshuizen F, MacCabe JH, Boks MP, Kahn RS. Educational achievement in psychiatric patients and their siblings: a register-based study in 30 000 individuals in the Netherlands. Psychol Med. 2017;47:776–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Reichenberg A, Harvey PD. Neuropsychological impairments in schizophrenia: integration of performance-based and brain imaging findings. Psychol Bull. 2007;133:833–58.PubMedCrossRefGoogle Scholar
  24. 24.
    Hafner H, Loffler W, Maurer K, Hambrecht M, an der Heiden W. Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatr Scand. 1999;100:105–18.PubMedCrossRefGoogle Scholar
  25. 25.
    Hafner H, Maurer K, an der Heiden W. ABC schizophrenia study: an overview of results since 1996. Soc Psychiatry Psychiatr Epidemiol. 2013;48:1021–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Yung AR, McGorry PD. The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N Z J Psychiatry. 1996;30:587–99.CrossRefGoogle Scholar
  27. 27.
    Klosterkotter J. Indicated prevention of schizophrenia. Dtsch Arztebl Int. 2008;105:532–9.PubMedPubMedCentralGoogle Scholar
  28. 28.
    McGorry PD, McFarlane C, Patton GC, Bell R, Hibbert ME, Jackson HJ, et al. The prevalence of prodromal features of schizophrenia in adolescence: a preliminary survey. Acta Psychiatr Scand. 1995;92:241–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Mishara AL. Klaus Conrad (1905–1961): delusional mood, psychosis, and beginning schizophrenia. Schizophr Bull. 2010;36:9–13.CrossRefGoogle Scholar
  30. 30.
    Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160:13–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Tranulis C, Park L, Delano L, Good B. Early intervention in psychosis: a case study on normal and pathological. Cult Med Psychiatry. 2009;33:608–22.PubMedCrossRefGoogle Scholar
  32. 32.
    Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry. 2005;62:975–83.CrossRefGoogle Scholar
  33. 33.
    Addington J, Heinssen RK, Robinson DG, Schooler NR, Marcy P, Brunette MF, et al. Duration of untreated psychosis in community treatment settings in the United States. Psychiatr Serv. 2015;66:753–6.CrossRefGoogle Scholar
  34. 34.
    Koreen AR, Siris SG, Chakos M, Alvir J, Mayerhoff D, Lieberman J. Depression in first-episode schizophrenia. Am J Psychiatry. 1993;150:1643–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Gleeson JF, Rawlings D, Jackson HJ, McGorry PD. Early warning signs of relapse following a first episode of psychosis. Schizophr Res. 2005;80:107–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Spaniel F, Bakstein E, Anyz J, Hlinka J, Sieger T, Hrdlicka J, et al. Relapse in schizophrenia: definitively not a bolt from the blue. Neurosci Lett. 2018;669:68–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Remington G, Foussias G, Agid O, Fervaha G, Takeuchi H, Hahn M. The neurobiology of relapse in schizophrenia. Schizophr Res. 2014;152:381–90.PubMedCrossRefGoogle Scholar
  38. 38.
    Wiedemann G, Hahlweg K, Hank G, Feinstein E, Muller U, Dose M. Detection of early warning signs in schizophrenic patients. Possible applications in prevention of recurrence. Nervenarzt. 1994;65:438–43.PubMedGoogle Scholar
  39. 39.
    Bleuler M, Huber G, Gross G, Schuttler R. Long-term course of schizophrenic psychoses. Joint results of two studies. Nervenarzt. 1976;47:477–81.PubMedGoogle Scholar
  40. 40.
    Harding CM, Zubin J, Strauss JS. Chronicity in schizophrenia: revisited. Br J Psychiatry Suppl. 1992;161:27–37.CrossRefGoogle Scholar
  41. 41.
    Volavka J, Vevera J. Very long-term outcome of schizophrenia. Int J Clin Pract. 2018;72:e13094.PubMedCrossRefGoogle Scholar
  42. 42.
    Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) advisory committee on clinical trials of new agents in multiple sclerosis. Neurology. 1996;46:907–11.PubMedCrossRefGoogle Scholar
  43. 43.
    Torrey EF. Onset, course, and prognosis. In: Surviving schizophrenia : a family manual. 7th ed. New York: Harper Perennial; 2019. p. 85–114.Google Scholar
  44. 44.
    Lally J, Maloudi S, Krivoy A, Murphy KC. Simple schizophrenia: a forgotten diagnosis in psychiatry. J Nerv Ment Dis. 2019;207(9):721–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Edgerton RB, Cohen A. Culture and schizophrenia: the DOSMD challenge. Br J Psychiatry. 1994;164:222–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Cohen A, Patel V, Thara R, Gureje O. Questioning an axiom: better prognosis for schizophrenia in the developing world? Schizophr Bull. 2008;34:229–44.PubMedCrossRefGoogle Scholar
  47. 47.
    Ran M, Xiang M, Huang M, Shan Y. Natural course of schizophrenia: 2-year follow-up study in a rural Chinese community. Br J Psychiatry. 2001;178:154–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Alem A, Kebede D, Fekadu A, Shibre T, Fekadu D, Beyero T, et al. Clinical course and outcome of schizophrenia in a predominantly treatment-naive cohort in rural Ethiopia. Schizophr Bull. 2009;35:646–54.PubMedCrossRefGoogle Scholar
  49. 49.
    Taipale H, Mittendorfer-Rutz E, Alexanderson K, Majak M, Mehtala J, Hoti F, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274–80.PubMedCrossRefGoogle Scholar
  50. 50.
    Hopper K, Wanderling J. Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative follow-up project. International Study of Schizophrenia. Schizophr Bull. 2000;26:835–46.PubMedCrossRefGoogle Scholar
  51. 51.
    Karp DA. The burden of sympathy : how families cope with mental illness. Oxford: Oxford University Press; 2001.Google Scholar

Additional Resources


    1. Watters E. The shifting mask of schizophrenia in Zanzibar. Crazy like us: the globalization of the American psyche. New York: Free Press; 2011. – Read this book! It makes you question the wisdom of imposing our Western ideas about psychiatric illnesses (what counts as disease, how to you best treat it) on other, non-Western societies. Some societies may offer a more hopeful conceptual framework that allows for inclusion and healing and prevents psychological damage to patients. The book contains a chapter on schizophrenia.Google Scholar


    1. Farmer PE, Nizeye B, Stulac S, Keshavjee S. Structural violence and clinical medicine. PLoS Med. 2006;3:e449. – A manuscript worth reading if you are interested in a critique of the idea of a “natural history” of any disease. Paul Farmer is an ID doctor from Boston who has brought first-rate health care to Haiti, proving that the outcome of disease is fundamentally a function of the society you live in – that social interventions are at least as important as any molecular advance.PubMedPubMedCentralCrossRefGoogle Scholar
    2. Mishara AL. Klaus Conrad (1905–1961): delusional mood, psychosis, and beginning schizophrenia. Schizophr Bull. 2010;36:9–13. – An excellent summary in English if you are interested in learning more about Conrad’s descriptions of beginning psychosis.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Oliver Freudenreich
    • 1
  1. 1.Department of PsychiatryMassachusetts General HospitalBostonUSA

Personalised recommendations