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Antipsychotic Interventions in Prodromal Psychosis

Safety Issues

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Abstract

In recent years, psychopharmacological intervention in prodromal psychosis, also known as the ultra-high risk (UHR) mental state for psychosis, has attracted much attention. Whilst it has been shown that antipsychotic use in UHR individuals may be effective in potentially delaying or even averting progression to frank psychosis, their use in subjects that do not necessarily convert to psychosis has raised considerable ethical concerns because of their adverse effects. Recent treatment guidelines for patients at UHR for psychosis recommend the use of antipsychotics only in exceptional conditions and with great precautions. To date only a few studies have investigated the use of antipsychotic medications in UHR patients and the potential benefits and risks related to their use in prodromal psychosis remain unclear. We review here all published studies that included UHR patients treated with antipsychotics, regardless of study design. These studies were all of second-generation antipsychotics, given that first-generation antipsychotics cannot be recommended because of their adverse drug reactions. We specifically examine the available descriptions of adverse reactions of the individual antipsychotic medication in each study and discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in UHR patients. Clinical trials to date investigating potential benefits of antipsychotic treatments in preventing transition to psychosis were of relatively short duration and have involved a small number of patients. Whilst it appears that pharmacological intervention at this stage may be effective in both reducing the psychopathology and decreasing transition rates, and is potentially safe, in the absence of sufficient evidence-based knowledge to guide treatment, definitive clinical recommendations and guidelines cannot be derived. Certain adverse events take time to develop, such as metabolic syndrome and endocrine-related effects, thus longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events. This can inform the development of timely strategies to prevent serious negative impacts and thus maximize the benefits of antipsychotic intervention in UHR patients that outweigh the risks associated with their use.

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References

  1. Falloon IR. Early intervention for first episodes of schizophrenia: a preliminary exploration. Psychiatry. 1992;55(1):4–15.

    PubMed  CAS  Google Scholar 

  2. McGlashan TH, Zipursky RB, Perkins D, et al. The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis: I. Study rationale and design. Schizophr Res. 2003;61(1):7–18.

    Article  PubMed  CAS  Google Scholar 

  3. McGorry PD, Yung AR, Phillips LJ. The “close-in” or ultra high-risk model: a safe and effective strategy for research and clinical intervention in prepsychotic mental disorder. Schizophr Bull. 2003;29(4):771–90.

    Article  PubMed  Google Scholar 

  4. Tsuang MT, Stone WS, Faraone SV. Towards the prevention of schizophrenia. Biol Psychiatry. 2000;48(5):349–56.

    Article  PubMed  CAS  Google Scholar 

  5. Fusar-Poli P, Borgwardt S, Bechdolf A, et al. The psychosis high risk state: a comprehensive state-of-the-art review. JAMA Psychiatry. 2013;70:107–20.

    PubMed  Google Scholar 

  6. Fusar-Poli P, Yung A. Should attenuated psychosis syndrome be included in the DSM5? The debate. Lancet. 2012;379(9816):591–2.

    Article  PubMed  Google Scholar 

  7. Kelly DL, Conley RR, Carpenter WT. First-episode schizophrenia: a focus on pharmacological treatment and safety considerations. Drugs. 2005;65(8):1113–38.

    Article  PubMed  CAS  Google Scholar 

  8. McGorry PD, Yung AR, Phillips LJ, 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.

    Article  PubMed  Google Scholar 

  9. Ruhrmann S, Bechdolf A, Kuhn KU, et al. Acute effects of treatment for prodromal symptoms for people putatively in a late initial prodromal state of psychosis. Br J Psychiatry Suppl. 2007;51:s88–95.

    Article  PubMed  CAS  Google Scholar 

  10. Woods SW, Breier A, Zipursky RB, et al. Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome. Biol Psychiatry. 2003;54(4):453–64.

    Article  PubMed  CAS  Google Scholar 

  11. Kruszewski SP, Paczynski RP. Atypical antipsychotic agents for the schizophrenia prodrome: not a clear first choice. Int J Risk Saf Med. 2008;20:37–44.

    Google Scholar 

  12. Corcoran CM, First MB, Cornblatt B. The psychosis risk syndrome and its proposed inclusion in the DSM-V: a risk-benefit analysis. Schizophr Res. 2010;120(1–3):16–22.

    Article  PubMed  Google Scholar 

  13. Yung AR, Yuen HP, Berger G, et al. Declining transition rate in ultra high risk (prodromal) services: dilution or reduction of risk? Schizophr Bull. 2007;33(3):673–81.

    Article  PubMed  Google Scholar 

  14. Simon AE, Umbricht D. High remission rates from an initial ultra-high risk state for psychosis. Schizophr Res. 2010;116(2–3):168–72.

    Article  PubMed  Google Scholar 

  15. Ziermans TB, Schothorst PF, Sprong M, et al. Transition and remission in adolescents at ultra-high risk for psychosis. Schizophr Res. 2011;126(1–3):58–64.

    Article  PubMed  Google Scholar 

  16. Corcoran C, Malaspina D, Hercher L. Prodromal interventions for schizophrenia vulnerability: the risks of being “at risk”. Schizophr Res. 2005;73(2–3):173–84.

    Article  PubMed  Google Scholar 

  17. Haroun N, Dunn L, Haroun A, et al. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophr Bull. 2006;32(1):166–78.

    Article  PubMed  Google Scholar 

  18. Yang LH, Wonpat-Borja AJ, Opler MG, et al. Potential stigma associated with inclusion of the psychosis risk syndrome in the DSM-V: an empirical question. Schizophr Res. 2010;120(1–3):42–8.

    Article  PubMed  CAS  Google Scholar 

  19. Early Psychosis Guidelines Writing Group. Australian clinical guidelines for early psychosis. 2nd ed. Melbourne (VIC): Orygen Youth Health; 2010.

    Google Scholar 

  20. Barnes TR. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2011;25(5):567–620.

    Article  PubMed  CAS  Google Scholar 

  21. Marshall M, Rathbone J. Early intervention for psychosis. Cochrane Database Syst Rev. 2011;(6):CD004718.

  22. Lin HY, Chiu YN, Liu CC. Is symptomatic treatment an option for a boy with clinically significant psychotic-like experiences and depressed mood? Comment on Ruhrmann et al., “intervention in at-risk states for developing psychosis.” (Eur Arch Psychiatry Clin Neurosci 260 Suppl 2:S90–S94). Eur Arch Psychiatry Clin Neurosci. 2012;262(2):179–80.

    Article  PubMed  Google Scholar 

  23. Ruhrmann S, Schultze-Lutter F, Klosterkotter J. Probably at-risk, but certainly ill: advocating the introduction of a psychosis spectrum disorder in DSM-V. Schizophr Res. 2010;120(1–3):23–37.

    Article  PubMed  Google Scholar 

  24. Woods SW, Addington J, Cadenhead KS, 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.

    Article  PubMed  Google Scholar 

  25. Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65(1):28–37.

    Article  PubMed  Google Scholar 

  26. Ruhrmann S, Schultze-Lutter F, Salokangas RK, et al. Prediction of psychosis in adolescents and young adults at high risk: results from the prospective European prediction of psychosis study. Arch Gen Psychiatry. 2010;67(3):241–51.

    Article  PubMed  Google Scholar 

  27. Fusar-Poli P, Bonoldi I, Yung AR, et al. Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk. Arch Gen Psychiatry. 2012;69(3):220–9.

    Article  PubMed  Google Scholar 

  28. Fusar-Poli P, Bechdolf A, Taylor M, et al. At risk for schizophrenic or affective psychosis? A meta-analysis of ICD/DSM diagnostic outcomes in individuals at high clinical risk. Schizophr Bull. [Epub 2012 May 15].

  29. Kapur S, Mizrahi R, Li M. From dopamine to salience to psychosis: linking biology, pharmacology and phenomenology of psychosis. Schizophr Res. 2005;79(1):59–68.

    Article  PubMed  Google Scholar 

  30. Fusar-Poli P, Broome MR, Matthiasson P, et al. Prefrontal function at presentation directly related to clinical outcome in people at ultrahigh risk of psychosis. Schizophr Bull. 2011;37(1):189–98.

    Article  PubMed  CAS  Google Scholar 

  31. Fusar-Poli P, Broome MR, Matthiasson P, et al. Spatial working memory in individuals at high risk for psychosis: longitudinal fMRI study. Schizophr Res. 2010;123(1):45–52.

    Article  PubMed  CAS  Google Scholar 

  32. Fusar-Poli P, Borgwardt S, Crescini A, et al. Neuroanatomy of vulnerability to psychosis: a voxel-based meta-analysis. Neurosci Biobehav Rev. 2011;35(5):1175–85.

    Article  PubMed  CAS  Google Scholar 

  33. Fusar-Poli P, Radua J, McGuire P, et al. Neuroanatomical maps of psychosis onset: voxel-wise meta-analysis of antipsychotic-naive VBM studies. Schizophr Bull. 2012;38(6):1297–307.

    Article  PubMed  Google Scholar 

  34. Fusar-Poli P, Meyer-Lindenberg A. Striatal presynaptic dopamine in schizophrenia, part I: meta-analysis of dopamine active transporter (DAT) density. Schizophr Bull. 2013;39(1):22–32.

    Article  PubMed  Google Scholar 

  35. Fusar-Poli P, Meyer-Lindenberg A. Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [18F]/[11C] DOPA PET studies. Schizophr Bull. 2013;39(1):33–42.

    Article  PubMed  Google Scholar 

  36. Fusar-Poli P, Howes OD, Allen P, et al. Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry. 2010;67(7):683–91.

    Article  PubMed  Google Scholar 

  37. Fusar-Poli P, Howes OD, Allen P, et al. Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Mol Psychiatry. 2011;16(1):67–75.

    Article  PubMed  CAS  Google Scholar 

  38. Fusar-Poli P, Stone J, Broome M, et al. Thalamic glutamate levels predicts cortical response during executive functioning in subjects at high risk for psychosis. Arch Gen Psychiatry. 2011;68(9):881–90.

    Article  PubMed  CAS  Google Scholar 

  39. Howes OD, Bose SK, Turkheimer F, et al. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am J Psychiatry. 2011;168(12):1311–7.

    PubMed  Google Scholar 

  40. Mechelli A, Riecher-Rossler A, Meisenzahl EM, et al. Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study. Arch Gen Psychiatry. 2011;68(5):489–95.

    Article  PubMed  Google Scholar 

  41. Stone JM, Day F, Tsagaraki H, et al. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry. 2009;66(6):533–9.

    Article  PubMed  CAS  Google Scholar 

  42. Fusar-Poli P, Deste G, Smieskova R, et al. Cognitive functioning in prodromal psychosis: a meta-analysis. Arch Gen Psychiatry. 2012;69(6):1–10.

    Google Scholar 

  43. Pantelis C, Velakoulis D, McGorry PD, et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003;361(9354):281–8.

    Article  PubMed  Google Scholar 

  44. Fusar-Poli P, Allen P, McGuire P. Neuroimaging studies of the early stages of psychosis: a critical review. Eur Psychiatry. 2008;23(4):237–44.

    Article  PubMed  Google Scholar 

  45. Howes O, Bose S, Turkheimer F, et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry. 2011;16(9):885–6.

    Article  PubMed  CAS  Google Scholar 

  46. Smieskova R, Fusar-Poli P, Allen P, et al. Neuroimaging predictors of transition to psychosis: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2010;34(8):1207–22.

    Article  PubMed  CAS  Google Scholar 

  47. Fusar-Poli P, Broome MR. Conceptual issues in psychiatric neuroimaging. Curr Opin Psychiatry. 2006;19(6):608–12.

    Article  PubMed  Google Scholar 

  48. Fusar-Poli P, Broome M, Barale F, et al. Why is psychiatric imaging clinically unreliable? Epistemological perspectives in clinical neuroscience. Psychother Psychosom. 2009;78(5):320–1.

    Article  PubMed  CAS  Google Scholar 

  49. Yung AR, Phillips LJ, Nelson B, et al. Randomized controlled trial of interventions for young people at ultra high risk for psychosis: 6-month analysis. J Clin Psychiatry. 2011;72(4):430–40.

    Article  PubMed  Google Scholar 

  50. 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.

    Article  PubMed  Google Scholar 

  51. Woods SW, Tully EM, Walsh BC, et al. Aripiprazole in the treatment of the psychosis prodrome: an open-label pilot study. Br J Psychiatry Suppl. 2007;51:s96–101.

    Article  PubMed  Google Scholar 

  52. Kobayashi H, Morita K, Takeshi K, et al. Effects of aripiprazole on insight and subjective experience in individuals with an at-risk mental state. J Clin Psychopharmacol. 2009;29(5):421–5.

    Article  PubMed  CAS  Google Scholar 

  53. Liu CC, Sheu YH, Wu SY, et al. Rapid response to antipsychotic treatment on psychotic prodrome: implications from a case series. Psychiatry Clin Neurosci. 2010;64(2):202–6.

    Article  PubMed  Google Scholar 

  54. Liu CC, Chien YL, Hsieh MH, et al. Aripiprazole for drug-naïve or antipsychotic-short-exposure subjects with ultra-high risk state and first episode psychosis: an open-label study. J Clin Psychopharmacol. 2013;33(1):18–23.

    Article  PubMed  CAS  Google Scholar 

  55. Woods SW, Martin A, Spector SG, et al. Effects of development on olanzapine-associated adverse events. J Am Acad Child Adolesc Psychiatry. 2002;41(12):1439–46.

    Article  PubMed  Google Scholar 

  56. Chiang CL, Liu CC. Micturition difficulty associated with aripiprazole: report of 2 cases. J Clin Psychopharmacol. 2011;31(1):128–9.

    Article  PubMed  Google Scholar 

  57. Takahashi H, Oshimo T, Ishigooka J. Efficacy and tolerability of aripiprazole in first-episode drug-naive patients with schizophrenia: an open-label trial. Clin Neuropharmacol. 2009;32(3):149–50.

    Article  PubMed  CAS  Google Scholar 

  58. Girgis RR, Merrill DB, Vorel SR, et al. Aripiprazole versus haloperidol treatment in early-stage schizophrenia. J Psychiatr Res. 2011;45(6):756–62.

    Article  PubMed  Google Scholar 

  59. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68(2):128–37.

    Article  PubMed  Google Scholar 

  60. Smieskova R, Fusar-Poli P, Allen P, et al. The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia? A systematic review. Curr Pharm Des. 2009;15(22):2535–49.

    Article  PubMed  CAS  Google Scholar 

  61. Carpenter WT, van Os J. Should attenuated psychosis syndrome be a DSM-5 diagnosis? Am J Psychiatry. 2011;168(5):460–3.

    Article  PubMed  Google Scholar 

  62. Addington J, Cornblatt BA, Cadenhead KS, et al. At clinical high risk for psychosis: outcome for nonconverters. Am J Psychiatry. 2011;168(8):800–5.

    Article  PubMed  Google Scholar 

  63. Tandon R, Carpenter WT Jr. DSM-5 status of psychotic disorders: 1 year prepublication. Schizophr Bull. 2012;38(3):369–70.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was proposed by Dr. Paolo Fusar-Poli and done by Dr. Chen-Chung Liu’s visit at the Orygen Youth Health (OYH) Research Center in Melbourne, Australia. The authors appreciate Dr. Fusar-Poli’s guidance and the critical and informative comments provided by the OYH researchers and psychiatrists. Dr. Chen-Chung Liu has received payments for lectures at company-sponsored symposia provided by Astra-Zeneca, Janssen-Cilag, Otsuka and Pfizer. These payments had no role in the preparation of this manuscript. Dr. Demjaha has no conflicts of interest to declare.

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  1. Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7 Chung Shan S. Rd, Taipei, 10002, Taiwan

    Chen-Chung Liu

  2. Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, UK

    Arsime Demjaha

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  1. Chen-Chung Liu
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  2. Arsime Demjaha
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Correspondence to Chen-Chung Liu.

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Liu, CC., Demjaha, A. Antipsychotic Interventions in Prodromal Psychosis. CNS Drugs 27, 197–205 (2013). https://doi.org/10.1007/s40263-013-0046-1

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