Difference between treatment-resistant schizophrenia and clozapine-resistant schizophrenia

Abstract

We read the impressive review article “Clozapine resistant schizophrenia: Newer avenues of management” with great enthusiasm and appreciation. The author believes that preventing clozapine resistance from developing may be the most effective treatment strategy for patients with clozapine-resistant schizophrenia (CRS), and optimizing clozapine treatment is a key component. Disentangling the differences between treatment-resistant schizophrenia and CRS is important for studies addressing treatment strategies for these difficult-to-treat populations.

Key Words: Treatment-resistant schizophrenia; Clozapine; Clozapine-resistant schizo-phrenia; Ultra-resistant schizophrenia; Ultra-treatment-resistant schizophrenia; Super-refractory schizophrenia

Core Tip: A diagnosis of clozapine-resistant schizophrenia (CRS) is made after administering an adequate trial of clozapine and excluding “pseudo-resistance” in patients who have been diagnosed with treatment-resistant schizophrenia (TRS). Disentangling the differences between TRS and CRS is important point for studies addressing treatment strategies for patients with CRS.

TO THE EDITOR

We read the impressive review article by Chakrabarti[1] with great enthusiasm and appreciation. The author suggests that clinicians need newer treatment approaches that go beyond the evidence for patients with clozapine-resistant schizophrenia (CRS). The author believes that preventing clozapine resistance from developing may be the most effective treatment strategy for patients with CRS, and optimizing clozapine treatment is a key component. Although this suggestion is new and insightful, we would like to discuss the differences between treatment-resistant schizophrenia (TRS) and CRS.

Treatment Response and Resistance in Psychosis (TRRIP) Working Group has suggested that CRS is a subspecifier of TRS[2]. A valid diagnosis of CRS needs to be based on: (1) Administering an adequate trial of clozapine; (2) Excluding the possibility of nonadherence to clozapine (i.e., pseudo-resistance); and (3) Blood levels of clozapine ≥ 350 ng/mL. The TRRIP Work Group also recommend a minimum dose of 500 mg/d for patients who cannot undergo the blood test for clozapine concentration[2]. In the review article[1], the recommended adequate dose of clozapine is 200 to 500 mg/d, which may be low for patients with CRS.

Besides, when pooling available evidence for the management of CRS, we need to include studies that specifically addressing patients with a valid diagnosis of CRS. For example, Chakrabarti[1] cited a study by Masoudzadeh and Khalillian[3] who compared three interventions for patients with TRS, namely, clozapine, electroconvulsive therapy (ECT), and combined clozapine and ECT. In this study, a 40% reduction in the Positive and Negative Syndrome Scale scores was observed in patients who were treated with only clozapine[3]. It is clear that the study by Masoudzadeh and Khalillian[3] had included patients with TRS not CRS. Therefore, this study could not be considered as a CRS study.