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Treatment-Resistant Schizophrenia

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

Abstract

A significant minority of patients (about one quarter to one third) will have a poor response to first-line antipsychotics and be considered treatment-resistant. In this chapter, I outline a sequential approach to treatment-resistant schizophrenia. An important first step is to rule out “pseudo-refractoriness,” most commonly due to insufficient adherence. Therapeutic drug monitoring and a long-acting injectable trial are key tools to correctly establishing treatment resistance. The gold standard for treatment resistance is clozapine, and every treatment-resistant patient deserves a time-limited trial of clozapine in order to determine if he or she is a good clozapine responder. The chapter concludes with a discussion of clozapine augmentation and non-pharmacological interventions for patients who remain ill despite clozapine.

Keywords

Treatment-resistant schizophrenia Pseudo-refractoriness Therapeutic drug monitoring Long-acting injectable antipsychotic trial Clozapine trial Electroconvulsive therapy (ECT) Clozapine augmentation Asylum 

References

  1. 1.
    Cousins ND. Schweitzer of Lambaréné. New York: Harper & Brothers; 1960.Google Scholar
  2. 2.
    Meltzer HY. Treatment-resistant schizophrenia–the role of clozapine. Curr Med Res Opin. 1997;14:1–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Kane JM, Agid O, Baldwin ML, Howes O, Lindenmayer JP, Marder S, et al. Clinical guidance on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry. 2019;80:pii: 18com12123.Google Scholar
  4. 4.
    Mouaffak F, Tranulis C, Gourevitch R, Poirier MF, Douki S, Olie JP, et al. Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia. Clin Neuropharmacol. 2006;29:28–33.PubMedCrossRefGoogle Scholar
  5. 5.
    Lally J, Ajnakina O, Di Forti M, Trotta A, Demjaha A, Kolliakou A, et al. Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med. 2016;46:3231–40.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174:216–29.CrossRefPubMedGoogle Scholar
  7. 7.
    Penttila M, Jaaskelainen E, Hirvonen N, Isohanni M, Miettunen J. Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2014;205:88–94.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    England ML, Ongur D, Konopaske GT, Karmacharya R. Catatonia in psychotic patients: clinical features and treatment response. J Neuropsychiatry Clin Neurosci. 2011;23:223–6.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Schoeler T, Petros N, Di Forti M, Klamerus E, Foglia E, Murray R, et al. Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: a prospective analysis. Lancet Psychiatry. 2017;4:627–33.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Emsley R, Rabinowitz J, Medori R. Time course for antipsychotic treatment response in first-episode schizophrenia. Am J Psychiatry. 2006;163:743–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Gallego JA, Robinson DG, Sevy SM, Napolitano B, McCormack J, Lesser ML, et al. Time to treatment response in first-episode schizophrenia: should acute treatment trials last several months? J Clin Psychiatry. 2011;72:1691–6.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Agid O, Seeman P, Kapur S. The “delayed onset” of antipsychotic action–an idea whose time has come and gone. J Psychiatry Neurosci. 2006;31:93–100.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Horvitz-Lennon M, Mattke S, Predmore Z, Howes OD. The role of antipsychotic plasma levels in the treatment of schizophrenia. Am J Psychiatry. 2017;174:421–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Lindenmayer JP, Czobor P, Volavka J, Lieberman JA, Citrome L, Sheitman B, et al. Olanzapine in refractory schizophrenia after failure of typical or atypical antipsychotic treatment: an open-label switch study. J Clin Psychiatry. 2002;63:931–5.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Goff DC, McEvoy JP, Citrome L, Mech AW, Bustillo JR, Gil R, et al. High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study. J Clin Psychopharmacol. 2013;33:485–90.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012;73:13–20.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Lindenmayer JP, Citrome L, Khan A, Kaushik S. A randomized, double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective disorder. J Clin Psychopharmacol. 2011;31:160–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Lieberman JA, Tollefson G, Tohen M, Green AI, Gur RE, Kahn R, et al. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry. 2003;160:1396–404.PubMedCrossRefGoogle Scholar
  20. 20.
    Leucht S, Winter-van Rossum I, Heres S, Arango C, Fleischhacker WW, Glenthoj B, et al. The optimization of treatment and management of schizophrenia in Europe (OPTiMiSE) trial: rationale for its methodology and a review of the effectiveness of switching antipsychotics. Schizophr Bull. 2015;41:549–58.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Kahn RS, Winter van Rossum I, Leucht S, McGuire P, Lewis SW, Leboyer M, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry. 2018;5:797–807.CrossRefPubMedGoogle Scholar
  22. 22.
    Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry. 2011;72:1439–44.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Porcelli S, Balzarro B, Serretti A. Clozapine resistance: augmentation strategies. Eur Neuropsychopharmacol. 2012;22:165–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Kelly DL, Freudenreich O, Sayer MA, Love RC. Addressing barriers to clozapine underutilization: a national effort. Psychiatr Serv. 2018;69:224–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Takeuchi H, Lee J, Fervaha G, Foussias G, Agid O, Remington G. Switching to clozapine using immediate versus gradual antipsychotic discontinuation: a pilot, double-blind, randomized controlled trial. J Clin Psychiatry. 2017;78:223–8.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology. 2003;28:995–1003.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Girgis RR, Phillips MR, Li X, Li K, Jiang H, Wu C, et al. Clozapine v. chlorpromazine in treatment-naive, first-episode schizophrenia: 9-year outcomes of a randomised clinical trial. Br J Psychiatry. 2011;199:281–8.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Tharyan P, Adams CE. Electroconvulsive therapy for schizophrenia. Cochrane Database Syst Rev. 2005;2:CD000076.Google Scholar
  29. 29.
    Lally J, Tully J, Robertson D, Stubbs B, Gaughran F, MacCabe JH. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2016;171:215–24.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry. 2015;172:52–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Sinclair DJ, Zhao S, Qi F, Nyakyoma K, Kwong JS, Adams CE. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2019;3:CD011847.PubMedGoogle Scholar
  32. 32.
    Ward HB, Szabo ST, Rakesh G. Maintenance ECT in schizophrenia: a systematic review. Psychiatry Res. 2018;264:131–42.PubMedCrossRefGoogle Scholar
  33. 33.
    Wagner E, Wobrock T, Kunze B, Langguth B, Landgrebe M, Eichhammer P, et al. Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine. Schizophr Res. 2019;208:370–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Ortiz-Orendain J, Castiello-de Obeso S, Colunga-Lozano LE, Hu Y, Maayan N, Adams CE. Antipsychotic combinations for schizophrenia. Cochrane Database Syst Rev. 2017;6:CD009005.PubMedGoogle Scholar
  35. 35.
    Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res. 2019;208:217–20.PubMedCrossRefGoogle Scholar
  36. 36.
    Lin CH, Lin CH, Chang YC, Huang YJ, Chen PW, Yang HT, et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2018;84:422–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Fogel BS, Duffy J, McNamara ME, Salloway S. Skeptics and enthusiasts in neuropsychiatry. J Neuropsychiatry Clin Neurosci. 1992;4:458–62.PubMedCrossRefGoogle Scholar
  38. 38.
    Tracy DK, Joyce DW, Sarkar SN, Mateos Fernandez MJ, Shergill SS. Skating on thin ice: pragmatic prescribing for medication refractory schizophrenia. BMC Psychiatry. 2015;15:174.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Berlant JL. Neuroleptics and reserpine in refractory psychoses. J Clin Psychopharmacol. 1986;6:180–4.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Leff J, Williams G, Huckvale MA, Arbuthnot M, Leff AP. Computer-assisted therapy for medication-resistant auditory hallucinations: proof-of-concept study. Br J Psychiatry. 2013;202:428–33.PubMedCrossRefGoogle Scholar
  41. 41.
    Craig TK, Rus-Calafell M, Ward T, Leff JP, Huckvale M, Howarth E, et al. AVATAR therapy for auditory verbal hallucinations in people with psychosis: a single-blind, randomised controlled trial. Lancet Psychiatry. 2018;5:31–40.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Killaspy H, Marston L, Green N, Harrison I, Lean M, Cook S, et al. Clinical effectiveness of a staff training intervention in mental health inpatient rehabilitation units designed to increase patients’ engagement in activities (the Rehabilitation Effectiveness for Activities for Life [REAL] study): single-blind, cluster-randomised controlled trial. Lancet Psychiatry. 2015;2:38–48.PubMedCrossRefGoogle Scholar
  43. 43.
    Sisti DA, Segal AG, Emanuel EJ. Improving long-term psychiatric care: bring back the asylum. JAMA. 2015;313:243–4.PubMedCrossRefGoogle Scholar

Additional Resources

    Book

    1. Buckley PF, Gaughran F, editors. Treatment-refractory schizophrenia : a clinical conundrum. Heidelberg: Springer; 2014. – A whole book about TRS, with international authors from Australia, Europe, and the Americas.Google Scholar

    Articles

    1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–96. – Read this one, as it is one of only a handful of truly seminal articles on the treatment of schizophrenia. Note the excellent clinical trials methodology, with a prospective treatment period to establish non-response.CrossRefPubMedGoogle Scholar
    2. Kane JM, Agid O, Baldwin ML, Howes O, Lindenmayer JP, Marder S, et al. Clinical guidance on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry. 2019;80:pii: 18com12123. – Excellent review of treatment-resistant schizophrenia by John Kane who conducted the Kane trial over 20 years ago (see above).Google Scholar
    3. Sisti DA, Segal AG, Emanuel EJ. Improving long-term psychiatric care: bring back the asylum. JAMA. 2015;313:243–4. – An important viewpoint that argues for the ethical imperative to provide the whole continuum of psychiatric care, including caring for those with serious illness that have been hurt the most from deinstitutionalization (or rather, transinstitutionalization). While the title is provocative, the authors do not argue for a return to the state of hospitals of late but simply to provide humane and safe spaces for those who cannot help themselves.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

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

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