What is the definition of treatment-resistant schizophrenia?

From the Guidelines

Treatment-resistant schizophrenia (TRS) is defined as a condition where a person with schizophrenia fails to respond adequately to at least two different antipsychotic medications, each given at appropriate doses for 6-8 weeks, as per the consensus guidelines developed by the Treatment Response and Resistance in Psychosis (TRRIP) working group 1. This definition is based on the most recent and highest quality studies, which emphasize the need for operationalized criteria to determine treatment resistance in schizophrenia. The key elements of this definition include:

• A confirmed diagnosis of schizophrenia based on validated criteria
• Adequate pharmacological treatment, which is typically defined as at least two different antipsychotic medications given at appropriate doses for 6-8 weeks
• Persistence of significant symptoms despite this treatment, which can include hallucinations, delusions, disorganized thinking, or negative symptoms that substantially impact functioning
• Adherence to the medication regimen must be confirmed, and the medications must have been taken at doses equivalent to at least 600mg of chlorpromazine daily. The TRRIP working group consensus guidelines provide a benchmark for research and clinical translation, and are intended to improve the design of studies and facilitate literature searches and meta-analyses. Some of the key points from the guidelines include:
• The use of standardized rating scales, such as the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale, to assess symptom severity
• The importance of assessing past adherence to medication regimens
• The need for clear criteria for determining treatment resistance, including the use of operationalized criteria and the specification of minimum symptom duration and adequate treatment duration. Overall, the definition of treatment-resistant schizophrenia is complex and multifaceted, and requires careful consideration of a range of factors, including symptom severity, treatment history, and adherence to medication regimens. By using the TRRIP working group consensus guidelines, clinicians and researchers can improve the accuracy and consistency of diagnoses, and develop more effective treatment strategies for individuals with treatment-resistant schizophrenia. It is worth noting that, clozapine is considered the gold standard treatment for TRS, typically started at 12.5-25mg daily and gradually increased to an effective dose, usually between 300-450mg daily, with blood monitoring required due to the risk of agranulocytosis 1.

From the FDA Drug Label

Clozapine tablets are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years

Definition of Treatment-Resistant Schizophrenia:

• Patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment
• Inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years
• Antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms 2 2

From the Research

Definition of Treatment-Resistant Schizophrenia

• Treatment-resistant schizophrenia (TRS) is defined mainly by the severity of symptoms and response to antipsychotics, with various definitions proposed in the literature 3, 4, 5, 6.
• A commonly used definition includes failure of at least two adequate trials with different antipsychotics, with a relative change in representative scales such as a ≥ 20% decrease in the Positive and Negative Syndrome Scale (PANSS) 3, 6.
• Other proposed criteria for defining TRS include a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales 3.
• The definition of TRS may also involve prospective failure to respond to one or more antipsychotic trials, with a minimum criterion of two failed adequate antipsychotic trials 4, 5.

Characteristics of Treatment-Resistant Schizophrenia

• TRS is characterized by significant symptoms and poor outcomes despite treatment, with a wide variability in inclusion criteria challenging the consistency and reproducibility of results from studies 4.
• Treatment-resistant patients may show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients 7.
• TRS may be categorized as primary (or early) or secondary (or later-onset), with primary TRS present from the beginning of therapy and secondary TRS developing over time after relapses 5.

Treatment Options for Treatment-Resistant Schizophrenia

• Clozapine is recognized as the most effective treatment option for TRS, but its use is often limited due to various barriers 7, 5.
• Response rates to clozapine are higher when initiated earlier in the treatment course, and therapeutic drug monitoring of clozapine trough plasma levels can guide dosing 5.
• Other treatment options for TRS include pharmacological and non-pharmacological augmentation of clozapine, such as medication combinations, electroconvulsive therapy, repetitive transcranial magnetic stimulation, deep brain stimulation, and psychotherapies 4.