What is the definition of treatment-resistant schizophrenia (TRS)?

From the Guidelines

Treatment-resistant schizophrenia (TRS) is defined as a condition where patients with schizophrenia fail to respond adequately to at least two different antipsychotic medications, given at appropriate doses for sufficient duration (typically 6-8 weeks each), as recommended by the American Psychiatric Association 1. These prior antipsychotic trials should include at least one second-generation (atypical) antipsychotic. Adequate response is typically considered a reduction of less than 20-30% in psychotic symptoms or failure to achieve remission despite proper treatment adherence. Approximately 30% of individuals with schizophrenia meet criteria for treatment resistance. For patients with TRS, clozapine is considered the gold standard treatment, typically started at 12.5-25mg daily and gradually titrated to an effective dose range of 300-900mg daily, with blood level monitoring recommended (target levels of 350-500 ng/mL) 1. Due to the risk of agranulocytosis, regular white blood cell monitoring is mandatory when using clozapine. If clozapine is ineffective or not tolerated, augmentation strategies may include adding another antipsychotic, mood stabilizer, or electroconvulsive therapy. The biological basis for treatment resistance may involve different dopamine system dysfunction, glutamate abnormalities, or inflammatory processes compared to treatment-responsive schizophrenia, which explains why standard dopamine-blocking antipsychotics are often ineffective in this population.

Some key points to consider in the diagnosis and treatment of TRS include:

• The use of a validated rating scale to determine symptom severity
• A specification of minimum symptom duration
• A definition of adequate treatment that specified minimum dose, duration, and number of previous antipsychotics
• The importance of operationalized criteria for treatment resistance, as recommended by the Treatment Response and Resistance in Psychosis working group 1
• The need for a comprehensive and person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments, as recommended by the American Psychiatric Association 1

Overall, the diagnosis and treatment of TRS require a comprehensive and individualized approach, taking into account the patient's specific symptoms, treatment history, and preferences. By following the guidelines and recommendations outlined above, clinicians can provide effective and evidence-based care for patients with TRS, and improve their chances of achieving remission and improving their quality of life. It is also important to note that the treatment of TRS is a complex and ongoing process, and may require ongoing monitoring and adjustment of treatment plans to ensure optimal outcomes. Regular follow-up and collaboration with other healthcare professionals, such as psychiatrists and social workers, can help to ensure that patients with TRS receive the comprehensive and supportive care they need to manage their symptoms and improve their overall well-being.

From the FDA Drug Label

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 The 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. There must have been no period of good functioning within the preceding 5 years Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61 In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill)

Definition of Treatment-Resistant Schizophrenia:

• Inadequate response to at least 3 different antipsychotics from at least 2 different chemical classes in the preceding 5 years
• Antipsychotic trials must have been judged adequate, with dosages equivalent to or greater than 1000 mg per day of chlorpromazine for at least 6 weeks
• No period of good functioning within the preceding 5 years
• Baseline BPRS score of at least 45
• Score of at least 4 on at least two of the following BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content
• Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill) 2

From the Research

Definition of Treatment-Resistant Schizophrenia

• Treatment-resistant schizophrenia (TRS) is defined mainly by the severity of positive symptoms and response to antipsychotics, with a proposed definition requiring at least two failed adequate trials with different antipsychotics 3.
• The definition also requires 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.
• TRS can be classified into primary (or early) TRS, which is present from the beginning of therapy, and secondary (or later-onset) TRS, which develops over time, often after relapses 4.

Diagnostic Criteria

• The diagnostic criteria for TRS include failure to respond to at least two sequential antipsychotic trials of sufficient dose, duration, and adherence 4, 5.
• The response to antipsychotics is typically measured using scales such as the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS) 3, 6.

Clinical Characteristics

• 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 5.
• The clinical, neuroimaging, and neurobiological characteristics of TRS are complex and not fully understood, with ongoing research aimed at advancing the field of TRS research 5, 6.