Treatment-Resistant Schizophrenia

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


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.


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


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Additional Resources


    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


    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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