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Evaluation and management of treatment-resistant schizophrenia

John Kane, MD
Taishiro Kishimoto, MD
Christoph U Correll, MD
Section Editor
Stephen Marder, MD
Deputy Editor
Richard Hermann, MD


Antipsychotic medication is first-line treatment for schizophrenia. Most patients show substantial improvement in psychotic symptoms in response to antipsychotics; however, for many, improvement is insufficient to meet stringent criteria for remission, and a substantial proportion experience residual treatment-resistant symptoms.

Patients who do not respond adequately to antipsychotics should be reevaluated to rule out or address causes other than nonresponsiveness to medication. Current medication and psychosocial interventions should be optimized. Treatment strategies for patients who remain incompletely responsive include changes to antipsychotic doses and drugs, use of clozapine, and drug augmentation.

This topic addresses the evaluation and management of treatment-resistant schizophrenia. Topics discussed separately include: the epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis of schizophrenia; comorbid anxiety; comorbid depression; acute, maintenance, and long-acting pharmacotherapy; guidelines for prescribing clozapine; and psychosocial interventions for schizophrenia. (See "Schizophrenia: Epidemiology and pathogenesis" and "Schizophrenia: Clinical manifestations, course, assessment, and diagnosis" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side effect management" and "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis" and "Anxiety in schizophrenia" and "Depression in schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)


Clinical trials and practice guidelines have employed various definitions of treatment resistance in schizophrenia. No clear consensus exists for a single definition for use across populations and settings [1]. Existing definitions do not clearly distinguish treatment resistance from terms indicating other levels of response, such as partial response, lack of remission, or failure to prevent relapse [2,3].

For the purpose of determining a patient’s eligibility for a trial of clozapine, we define treatment resistance as an inadequate response to at least two antipsychotic drugs at the maximally tolerated dose within the recommended therapeutic range (table 1) in trials lasting six weeks or more. Termination of a medication due to adverse events before reaching the appropriate dose and duration should not be regarded as a failed trial due to nonresponse to the medication.


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Literature review current through: Sep 2016. | This topic last updated: Jun 7, 2016.
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