A RETROSPECTIVE COMPARATIVE STUDY OF CLINICAL RESPONSE TO CLOZAPINE BETWEEN PATIENTS WITH EARLY TREATMENT-RESISTANT SCHIZOPHRENIA (TRS) AND LATE TRS
Authors: Kanahara *Nobuhisa , Okada Kazuki , Otsuka Yuji , Kobayashi Remiko , Kimura Hiroshi , Yamanaka Hiroshi , Takaoki Yuri , Yoshida Taisuke , Oiwa Takahiro , Ito Fumiaki , Komatsu Hiroshi , Ono Takashi , Kikuchi Yuki , Saiga Takahisa , Noda Shingo , Iyo Masaomi 
Published: February 2025

Abstract

Background
Clozapine is the only antipsychotic with established efficacy for patients with treatment- resistant schizophrenia (TRS) and this medication serves as the last resort for applicable patients. However, clozapine has been underused worldwide, which is presumed to be related to both serious side effects such as agranulocytosis and the lack of a promising indicator predictive of response to this agent. Recent longitudinal observational studies report that TRS can be classified into at least two subtypes, early TRS and late TRS, based on clinical courses. It has been suggested that early TRS might be etiologically related to non-enhanced dopamine synthesis, whereas late TRS might be related to enhanced dopamine synthesis and the subsequent development of dopamine supersensitivity. We hypothesize that these TRS subtypes may differ in their response to clozapine and in the factors predictive of response.

Methods
The present study had a retrospective design and was conducted at 12 hospitals in Chiba, Miyagi and Iwate Prefectures in Japan. We identified patients who (1) were treated with clozapine, and (2) had confirmed medical records from the commencement of treatment to 1 year following the introduction of clozapine. We examined age at illness onset, response to initial antipsychotic regimens at first-episode psychosis, medication history, the duration of delaying clozapine introduction, and dopamine supersensitivity. Response to clozapine was evaluated by Global Assessment of Functioning (GAF), Social and Occupational Functioning Assessment Scale (SOFAS) and Clinical Global Impression-Change (CGI-C). This study was approved by the Ethics Committee of Chiba University Hospital, and was conducted with an opt-out approach under which patients were notified the study through their respective hospitals.

Results
To date, we have collected the data of a total 132 TRS patients (early TRS: n=31, 36.46 years; late TRS: n=101, 37.82 years). The majority of late TRS patients were deemed to have a history of dopamine supersensitivity psychosis. Upon clozapine commencement, there were significant differences between the subgroups in terms of number of admission (2.61 in early TRS vs. 4.62 in late TRS), treatment duration (8.98 vs. 15.32 years) and age at clozapine introduction (29.68 vs. 37.82 years). No significant differences were observed in psychopathology or functioning. At 1 year following clozapine commencement, the average CGI-C score in late TRS patients (5.75) was significantly greater than that in early TRS patients (5.39), indicating that the late TRS group exhibited greater improvement with clozapine.

Discussion
The present study remains in progress, however, our outcomes to date suggest that clozapine response may differ according to TRS subtype. We plan to identify potential predictive factor(s) of clozapine response for each subtype by analyzing the relationships of various clinical measures with clozapine response.