Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options


Two experts offer a refresher on predictors and identification of treatment-resistant schizophrenia. Drs Correll and Howes also review therapeutic strategies.

Target Audience


Learning Objective

Provide evidence-based therapy for resistant schizophrenia, with appropriate monitoring


Treatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18–26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.

From the Series: Managing Treatment-Resistant Schizophrenia: From Recognition to Gold Standard Treatment
To cite: Correll CU, Howes OD. Treatment-resistant schizophrenia: definitions, predictors, and therapy options. J Clin Psychiatry. 2021;82(5):MY20096AH1C.
To share:
© Copyright 2021 Physicians Postgraduate Press, Inc.

Activity summary
Available credit: 
  • 1.00 AMA PRA Category 1 Credit™
  • 1.00 Participation
Activity opens: 
Activity expires: 

Support Statement

Supported by an educational grant from Viatris, Inc.

Learning Objective

After completing this educational activity, you should be able to:

  • Provide evidence-based therapy for resistant schizophrenia, with appropriate monitoring

Release, Review, and Expiration Dates

This Academic Highlights activity was published in August 2021 and is eligible for AMA PRA Category 1 Credit™ through August 31, 2023. The latest review of this material was August 2021.

Statement of Need and Purpose

Psychiatrists have reported uncertainty on how to identify refractory illness among patients with schizophrenia. These clinicians need education about current criteria and practical assessment tools for recognizing treatment-resistant schizophrenia (TRS). Additionally, because gold standard medication for TRS is underused, clinicians need education about strategies to improve the management of refractory schizophrenia, including dose optimization and monitoring according to guidelines.

Disclosure of Off-Label Usage

Dr Correll has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents or device therapies that is outside US Food and Drug Administration–approved
labeling has been presented in this activity.

Review Process

The faculty members agreed to provide a balanced and evidence-based presentation and discussed the topics and CME objectives during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by the Chair and a peer reviewer who is without conflict of interest.


This activity is derived from the teleconference series “Managing Treatment-Resistant Schizophrenia: From Recognition to Gold Standard Treatment,” which was held in March and April 2021 and supported by an educational grant from Viatris, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

Faculty Affiliation

Christoph U. Correll, MD
Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York

Oliver D. Howes, MD, PhD
Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK


Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The Accreditation Council for Continuing Medical Education (ACCME) defines a commercial interest as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Correll is a consultant for AbbVie, Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan (Viatris), Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva; has received grant/research support for Janssen, and Takeda; has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan (Viatris), Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva; is a member of the speakers/advisory boards for Acadia, Alkermes, Allergan, Angelini, Gedeon Richter, ITCI, Janssen, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Mylan (Viatris), Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Supernus, Takeda, Teva; is a stock shareholder of LB Pharma; and has given expert
testimony for Janssen and Otsuka. Dr Howes has received grant/research support from and is a member of the speakers/advisory boards for Angelini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, InviCRO, Janssen, Lundbeck, Mylan (Viatris), Neurocrine, Otsuka, Sunovion, Rand, Recordati, and Roche.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

Non-US clinicians may be eligible to receive credit for this educational activity. After completing the posttest and evaluation, download the Participant certificate to submit to your credit organization.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.


Available Credit

  • 1.00 AMA PRA Category 1 Credit™
  • 1.00 Participation


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