Current Treatment Options in Psychiatry

, Volume 5, Issue 1, pp 113–128 | Cite as

Identifying and Treating the Prodromal Phases of Bipolar Disorder and Schizophrenia

  • Susan K. Conroy
  • Michael M. Francis
  • Leslie A. Hulvershorn
Child and Adolescent Psychiatry (M Brotman, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Child and Adolescent Psychiatry

Opinion statement

Purpose of review

The goal of this paper is to review recent research on the identification and treatment of prodromal periods that precede bipolar and psychotic disorders. We also sought to provide information about current best clinical practices for prodromal youth.

Recent findings

Research in the areas of identifying prodromal periods has rapidly advanced. Calculators that can predict risk are now available for use during both bipolar and psychotic disorder prodromes. Cognitive behavior therapies have emerged as the gold standard psychosocial interventions for the psychosis prodrome, while several other types of therapies hold promise for treatment during the bipolar prodrome. Due to safety and efficacy concerns, pharmacologic treatments are not currently recommended during either prodromal periods.


While additional research is needed to develop useful clinical tools to screen and diagnose during prodromal phases, existing literature has identified constellations of symptoms that can be reliably identified in research settings. Specialized psychotherapies are currently recommended to treat prodromal symptoms in clinical settings. They may also be useful to curtail future episodes, although further research is needed.


Bipolar disorder Schizophrenia Psychosis prodrome 


Compliance with Ethical Standards

Conflict of interest

Susan Conroy declares that she has no conflicts of interest. Michael Francis declares that he has no conflicts of interest. Leslie Hulvershorn declares that she has no conflicts of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rössler A, Schultze-Lutter F, et al. The psychosis high-risk state a comprehensive state-of-the-art review. Jama Psychiatry. 2013;70(1):107–20. Scholar
  2. 2.
    Faedda GL, Marangoni C, Serra G, Salvatore P, Sani G, Vázquez GH, et al. Precursors of bipolar disorders: a systematic literature review of prospective studies. J Clin Psychiatry. 2015;76(5):614–24. Scholar
  3. 3.
    Mayer-Gross, W., Die Klinik der Schizophrenie, ed. H.d. Geisteskrankheiten. 1932, Berlin, Germany: Springer.Google Scholar
  4. 4.
    Hafner H, Maurer K, Loffler W, et al. The ABC Schizophrenia Study: a preliminary overview of the results. Soc Psychiatry Psychiatr Epidemiol. 1998;33(8):380–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Hafner H, Maurer K, Loffler W, et al. The influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry. 1993;162(01):80–6. Scholar
  6. 6.
    Hafner H, Riecher-Rossler A, Hambrecht M, et al. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophr Res. 1992;6(3):209–23. Scholar
  7. 7.
    Hafner H, Riecher-Rossler A, Maurer K, et al. First onset and early symptomatology of schizophrenia. A chapter of epidemiological and neurobiological research into age and sex differences. Eur Arch Psychiatry Clin Neurosci. 1992;242(2–3):109–18. Scholar
  8. 8.
    Dominguez-Martinez T, Cristobal-Narvaez P, Kwapil TR, et al. Clinical and psychosocial characterization of at-risk mental state and recent onset psychosis patients from an early psychosis program in Barcelona (Spain). Actas Esp Psiquiatr. 2017;45(4):145–56.PubMedGoogle Scholar
  9. 9.
    Yung AR, McGorry PD. The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N Z J Psychiatry. 1996;30(5):587–99. Scholar
  10. 10.
    Woodberry KA, Shapiro DI, Bryant C, Seidman LJ. Progress and future directions in research on the psychosis prodrome: a review for clinicians. Harv Rev Psychiatry. 2016;24(2):87–103. Scholar
  11. 11.
    Dominguez MD, Saka MC, Lieb R, et al. Early expression of negative/disorganized symptoms predicting psychotic experiences and subsequent clinical psychosis: a 10-year study. Am J Psychiatry. 2010;167(9):1075–82. Scholar
  12. 12.
    Gourzis P, Katrivanou A, Beratis S. Symptomatology of the initial prodromal phase in schizophrenia. Schizophr Bull. 2002;28(3):415–29. Scholar
  13. 13.
    Hafner H, Maurer K, Loffler W, der Heiden W, Hambrecht M, Schultze-Lutter F. Modeling the early course of schizophrenia. Schizophr Bull. 2003;29(2):325–40. Scholar
  14. 14.
    Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull. 1996;22(2):353–70. Scholar
  15. 15.
    Giuliano AJ, Li H, Mesholam-Gately RI, et al. Neurocognition in the psychosis risk syndrome: a quantitative and qualitative review. Curr Pharm Des. 2012;18(4):399–415. Scholar
  16. 16.
    Woodberry KA, Giuliano AJ, Seidman LJ. Premorbid IQ in schizophrenia: a meta-analytic review. Am J Psychiatry. 2008;165(5):579–87. Scholar
  17. 17.
    Woods SW, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, et al. Validity of the prodromal risk syndrome for first psychosis: findings from the North American Prodrome Longitudinal Study. Schizophr Bull. 2009;35(5):894–908. Scholar
  18. 18.
    Yung AR, Nelson B, Stanford C, Simmons MB, Cosgrave EM, Killackey E, et al. Validation of “prodromal” criteria to detect individuals at ultra high risk of psychosis: 2 year follow-up. Schizophr Res. 2008;105(1–3):10–7. Scholar
  19. 19.
    Hutton P, Bowe S, Parker S, Ford S. Prevalence of suicide risk factors in people at ultra-high risk of developing psychosis: a service audit. Early Interv Psychiatry. 2011;5(4):375–80. Scholar
  20. 20.
    Fusar-Poli P, Bonoldi I, Yung AR, Borgwardt S, Kempton MJ, Valmaggia L, et al. Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk. Arch Gen Psychiatry. 2012;69(3):220–9. Scholar
  21. 21.
    Yung AR, Yuen HP, McGorry PD, et al. Mapping the onset of psychosis: the comprehensive assessment of at-risk mental states. Aust N Z J Psychiatry. 2005;39(11–12):964–71. Scholar
  22. 22.
    McGlashan T, Walsh BC, Woods SW. The psychosis risk syndrome: handbook for diagnosis and follow up. New York: Oxford University Press; 2010.Google Scholar
  23. 23.
    Riecher-Rössler A, Aston J, Ventura J, Merlo M, Borgwardt S, Gschwandtner U, et al. The Basel Screening Instrument for Psychosis (BSIP): development, structure, reliability and validity. Fortschr Neurol Psychiatr. 2008;76(4):207–16. Scholar
  24. 24.
    Schultze-Lutter, F., & Klosterkötter, J. Bonn Scale for the Assessment of Basic Symptoms-Prediction list (BSABS-P). 2002, University of Cologne, Cologne.Google Scholar
  25. 25.
    Fusar-Poli P, Deste G, Smieskova R, Barlati S, Yung AR, Howes O, et al. Cognitive functioning in prodromal psychosis: a meta-analysis. Arch Gen Psychiatry. 2012;69(6):562–71. Scholar
  26. 26.
    •• Cannon TD, Yu C, Addington J, Bearden CE, Cadenhead KS, Cornblatt BA, et al. An individualized risk calculator for research in prodromal psychosis. Am J Psychiatry. 2016;173(10):980–988. Risk caluclator for prodromal psychosis. Scholar
  27. 27.
    Addington J, Stowkowy J, Weiser M. Screening tools for clinical high risk for psychosis. Early Interv Psychiatry. 2015;9(5):345–56. Scholar
  28. 28.
    Addington J, Penn D, Woods SW, Addington D, Perkins DO. Social functioning in individuals at clinical high risk for psychosis. Schizophr Res. 2008;99(1–3):119–24. Scholar
  29. 29.
    Mason O, Startup M, Halpin S, Schall U, Conrad A, Carr V. Risk factors for transition to first episode psychosis among individuals with ‘at-risk mental states’. Schizophr Res. 2004;71(2–3):227–37. Scholar
  30. 30.
    Schmidt SJ, Schultze-Lutter F, Schimmelmann BG, Maric NP, Salokangas RKR, Riecher-Rössler A, et al. EPA guidance on the early intervention in clinical high risk states of psychoses. Eur Psychiatry. 2015;30(3):388–404. Scholar
  31. 31.
    Stafford MR, Jackson H, Mayo-Wilson E, Morrison AP, Kendall T. Early interventions to prevent psychosis: systematic review and meta-analysis. BMJ. 2013;346(jan18 1):f185. Scholar
  32. 32.
    van der Gaag M, Smit F, Bechdolf A, French P, Linszen DH, Yung AR, et al. Preventing a first episode of psychosis: meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups. Schizophr Res. 2013;149(1–3):56–62. Scholar
  33. 33.
    Addington J, Epstein I, Liu L, French P, Boydell KM, Zipursky RB. A randomized controlled trial of cognitive behavioral therapy for individuals at clinical high risk of psychosis. Schizophr Res. 2011;125(1):54–61. Scholar
  34. 34.
    Morrison AP, French P, Stewart SL, et al. Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial. BMJ. 2012;344(apr05 1):e2233. Scholar
  35. 35.
    Morrison AP, French P, Walford L, Lewis SW, Kilcommons A, Green J, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185(04):291–7. Scholar
  36. 36.
    •• van der Gaag M, Nieman DH, Rietdijk J, Dragt S, Ising HK, Klaassen RMC, et al. Cognitive behavioral therapy for subjects at ultrahigh risk for developing psychosis: a randomized controlled clinical trial. Schizophr Bull. 2012;38(6):1180–1188. Recently published national treatment guidelines for the prodromal period preceding psychosis. Scholar
  37. 37.
    Addington J, Addington D, Abidi S, Raedler T, Remington G. Canadian treatment guidelines for individuals at clinical high risk of psychosis. Can J Psychiatr. 2017;62(9):656–61. Scholar
  38. 38.
    Ising HK, Kraan TC, Rietdijk J, Dragt S, Klaassen RMC, Boonstra N, et al. Four-year follow-up of cognitive behavioral therapy in persons at ultra-high risk for developing psychosis: the Dutch Early Detection Intervention Evaluation (EDIE-NL) trial. Schizophr Bull. 2016;42(5):1243–52. Scholar
  39. 39.
    McGorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry. 2002;59(10):921–8. Scholar
  40. 40.
    Hastrup LH, Kronborg C, Bertelsen M, Jeppesen P, Jorgensen P, Petersen L, et al. Cost-effectiveness of early intervention in first-episode psychosis: economic evaluation of a randomised controlled trial (the OPUS study). Br J Psychiatry. 2013;202(1):35–41. Scholar
  41. 41.
    McFarlane WR, Levin B, Travis L, Lucas FL, Lynch S, Verdi M, et al. Clinical and functional outcomes after 2 years in the early detection and intervention for the prevention of psychosis multisite effectiveness trial. Schizophr Bull. 2015;41(1):30–43. Scholar
  42. 42.
    Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123(2–3):225–33. Scholar
  43. 43.
    Sullivan G, Lukoff D. Sexual side effects of antipsychotic medication: evaluation and interventions. Hosp Community Psychiatry. 1990;41(11):1238–41.PubMedGoogle Scholar
  44. 44.
    Tschoner A, Engl J, Laimer M, Kaser S, Rettenbacher M, Fleischhacker WW, et al. Metabolic side effects of antipsychotic medication. Int J Clin Pract. 2007;61(8):1356–70. Scholar
  45. 45.
    Francey SM, Nelson B, Thompson A, Parker AG, Kerr M, Macneil C, et al. Who needs antipsychotic medication in the earliest stages of psychosis? A reconsideration of benefits, risks, neurobiology and ethics in the era of early intervention. Schizophr Res. 2010;119(1–3):1–10. Scholar
  46. 46.
    McGorry PD, Nelson B, Phillips LJ, Yuen HP, Francey SM, Thampi A, et al. Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: twelve-month outcome. J Clin Psychiatry. 2013;74(4):349–56. Scholar
  47. 47.
    McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790–9. Scholar
  48. 48.
    Woods S, Saksa J, Compton M, Daley M, Rajarethinam R, Grahm K, et al. Effects of ziprasidone versus placebo in patients at clinical high risk for psychosis. Schizophr Bull. 2017;43(suppl_1):S58. Scholar
  49. 49.
    McGorry PD. “A stitch in time” ... the scope for preventive strategies in early psychosis. Eur Arch Psychiatry Clin Neurosci. 1998;248(1):22–31. Scholar
  50. 50.
    Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146–54. Scholar
  51. 51.
    McGorry PD, Nelson B, Markulev C, Yuen HP, Schäfer MR, Mossaheb N, et al. Effect of omega-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders: the NEURAPRO randomized clinical trial. JAMA Psychiatry. 2017;74(1):19–27. Scholar
  52. 52.
    Deas G, Kelly C, Hadjinicolaou AV, Holt C, Agius M, Zaman R. An update on: meta-analysis of medical and non-medicaltreatments of the prodromal phase of psychotic illness in at risk mental states. Psychiatr Danub. 2016;28(Suppl-1):31–8.PubMedGoogle Scholar
  53. 53.
    McGorry PD, Nelson B, Amminger GP, Bechdolf A, Francey SM, Berger G, et al. Intervention in individuals at ultra-high risk for psychosis: a review and future directions. J Clin Psychiatry. 2009;70(9):1206–12. Scholar
  54. 54.
    • Faedda GL, Serra G, Marangoni C, Salvatore P, Sani G, Vázquez GH, et al. Clinical risk factors for bipolar disorders: a systematic review of prospective studies. J Affect Disord. 2014;168:314–321. Review article covering prospective studies that identified risk factors prediciting bipolar disorder. Scholar
  55. 55.
    Axelson D, Goldstein B, Goldstein T, Monk K, Yu H, Hickey MB, et al. Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: a longitudinal study. Am J Psychiatry. 2015;172(7):638–46. Scholar
  56. 56.
    Nurnberger JI Jr, McInnis M, Reich W, et al. A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursors of major mood disorders. Arch Gen Psychiatry. 2011;68(10):1012–20. Scholar
  57. 57.
    Sparks GM, Axelson DA, Yu H, Ha W, Ballester J, Diler RS, et al. Disruptive mood dysregulation disorder and chronic irritability in youth at familial risk for bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2014;53(4):408–16. Scholar
  58. 58.
    Hafeman DM, Merranko J, Axelson D, Goldstein BI, Goldstein T, Monk K, et al. Toward the definition of a bipolar prodrome: dimensional predictors of bipolar spectrum disorders in at-risk youths. Am J Psychiatry. 2016;173(7):695–704. Scholar
  59. 59.
    Correll CU, Hauser M, Penzner JB, Auther AM, Kafantaris V, Saito E, et al. Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode. Bipolar Disord. 2014;16(5):478–92. Scholar
  60. 60.
    Correll CU, Penzner JB, Frederickson AM, Richter JJ, Auther AM, Smith CW, et al. Differentiation in the preonset phases of schizophrenia and mood disorders: evidence in support of a bipolar mania prodrome. Schizophr Bull. 2007;33(3):703–14. Scholar
  61. 61.
    Van Meter AR, Burke C, Youngstrom EA, Faedda GL, Correll CU. The bipolar prodrome: meta-analysis of symptom prevalence prior to initial or recurrent mood episodes. J Am Acad Child Adolesc Psychiatry. 2016;55(7):543–55. Scholar
  62. 62.
    Leibenluft E. Severe mood dysregulation, irritability, and the diagnostic boundaries of bipolar disorder in youths. Am J Psychiatry. 2011;168(2):129–42. Scholar
  63. 63.
    Benarous X, Consoli A, Milhiet V, Cohen D. Early interventions for youths at high risk for bipolar disorder: a developmental approach. Eur Child Adolesc Psychiatry. 2016;25(3):217–33. Scholar
  64. 64.
    Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. 2014;16(5):493–504. Scholar
  65. 65.
    Scott J, Marwaha S, Ratheesh A, Macmillan I, Yung AR, Morriss R, et al. Bipolar at-risk criteria: an examination of which clinical features have optimal utility for identifying youth at risk of early transition from depression to bipolar disorders. Schizophr Bull. 2017;43(4):737–44. Scholar
  66. 66.
    •• Correll CU, Olvet DM, Auther AM, Hauser M, Kishimoto T, Carrión RE, et al. The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. Bipolar Disord. 2014;16(5):505–522. Risk calculator for person-level prediction of bipolar disorder. Scholar
  67. 67.
    Hafeman DM, Merranko J, Goldstein TR, Axelson D, Goldstein BI, Monk K, et al. Assessment of a person-level risk calculator to predict new-onset bipolar spectrum disorder in youth at familial risk. JAMA Psychiatry. 2017;74(8):841–7. Scholar
  68. 68.
    McNamara RK, Strawn JR, Chang KD, DelBello MP. Interventions for youth at high risk for bipolar disorder and schizophrenia. Child Adolesc Psychiatr Clin N Am. 2012;21(4):739–51. Scholar
  69. 69.
    • Vallarino M, Henry C, Etain B, Gehue LJ, Macneil C, Scott EM, et al. An evidence map of psychosocial interventions for the earliest stages of bipolar disorder. Lancet Psychiatry. 2015;2(6):548–563. Important review article that covers psychosocial interventions for the early bipolar disorder and its associated prodrome. Scholar
  70. 70.
    Nadkarni RB, Fristad MA. Clinical course of children with a depressive spectrum disorder and transient manic symptoms. Bipolar Disord. 2010;12(5):494–503. Scholar
  71. 71.
    Miklowitz DJ, Chang KD, Taylor DO, George EL, Singh MK, Schneck CD, et al. Early psychosocial intervention for youth at risk for bipolar I or II disorder: a one-year treatment development trial. Bipolar Disord. 2011;13(1):67–75. Scholar
  72. 72.
    Miklowitz DJ, Schneck CD, Singh MK, Taylor DO, George EL, Cosgrove VE, et al. Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. J Am Acad Child Adolesc Psychiatry. 2013;52(2):121–31. Scholar
  73. 73.
    Miklowitz, D.J., C.D. Schneck, P.D. Walshaw, et al. Early intervention for youth at high risk for bipolar disorder: a multisite randomized trial of family-focused treatment. Early Interv Psychiatry 2017.Google Scholar
  74. 74.
    Goldstein TR, Fersch-Podrat R, Axelson DA, Gilbert A, Hlastala SA, Birmaher B, et al. Early intervention for adolescents at high risk for the development of bipolar disorder: pilot study of Interpersonal and Social Rhythm Therapy (IPSRT). Psychotherapy (Chic). 2014;51(1):180–9. Scholar
  75. 75.
    Fristad MA, Young AS, Vesco AT, Nader ES, Healy KZ, Gardner W, et al. A randomized controlled trial of individual family psychoeducational psychotherapy and omega-3 fatty acids in youth with subsyndromal bipolar disorder. J Child Adolesc Psychopharmacol. 2015;25(10):764–74. Scholar
  76. 76.
    Lambert M, Niehaus V, Correll C. Pharmacotherapy in children and adolescents at clinical-high risk for psychosis and bipolar disorder. Pharmacopsychiatry. 2016;49(6):229–44. Scholar
  77. 77.
    Schneck, C.D., K.D. Chang, M.K. Singh, et al., A pharmacologic algorithm for youth who are at high risk for bipolar disorder. J Child Adolesc Psychopharmacol 2017.Google Scholar
  78. 78.
    Geller B, Cooper TB, Zimerman B, Frazier J, Williams M, Heath J, et al. Lithium for prepubertal depressed children with family history predictors of future bipolarity: a double-blind, placebo-controlled study. J Affect Disord. 1998;51(2):165–75. Scholar
  79. 79.
    Chang KD, Dienes K, Blasey C, Adleman N, Ketter T, Steiner H. Divalproex monotherapy in the treatment of bipolar offspring with mood and behavioral disorders and at least mild affective symptoms. J Clin Psychiatry. 2003;64(8):936–42. Scholar
  80. 80.
    Findling RL, Frazier TW, Youngstrom EA, McNamara NK, Stansbrey RJ, Gracious BL, et al. Double-blind, placebo-controlled trial of divalproex monotherapy in the treatment of symptomatic youth at high risk for developing bipolar disorder. J Clin Psychiatry. 2007;68(5):781–8. Scholar
  81. 81.
    Findling RL, Lingler J, Rowles BM, McNamara NK, Calabrese JR. A pilot pharmacotherapy trial for depressed youths at high genetic risk for bipolarity. J Child Adolesc Psychopharmacol. 2008;18(6):615–21. Scholar
  82. 82.
    DelBello MP, Adler CM, Whitsel RM, Stanford KE, Strakowski SM. A 12-week single-blind trial of quetiapine for the treatment of mood symptoms in adolescents at high risk for developing bipolar I disorder. J Clin Psychiatry. 2007;68(5):789–95. Scholar
  83. 83.
    Verrotti A, D'Egidio C, Mohn A, Coppola G, Parisi P, Chiarelli F. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia. 2011;52(2):199–211. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Susan K. Conroy
    • 1
  • Michael M. Francis
    • 1
  • Leslie A. Hulvershorn
    • 1
    • 2
  1. 1.Department of PsychiatryIndiana University School of MedicineIndianapolisUSA
  2. 2.IndianapolisUSA

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