HIGHER OREXIN-A LEVELS ARE ASSOCIATED WITH BETTER TREATMENT RESPONSE TO CLOZAPINE IN PATIENTS WITH TREATMENT RESISTANT SCHIZOPHRENIA
Authors: Chen *Po-Yu , Chiu Chih-Chiang , Chang Chin-Kuo , Lu Mong-Liang , Huang Cho-Yin , Chen Chun- Hsin , Huang Ming-Chyi 
Published: February 2025

Abstract

Background
Clozapine stands as the drug of choice for treating individuals with treatment-resistant schizophrenia (TRS). However, only 40% of patients with TRS respond to clozapine, forming a subgroup of clozapine- resistant patients. Recently, the neuropeptide orexin-A has emerged its relevance in the pathophysiology of schizophrenia (Chien et al., 2015) and higher orexin-A levels has been found in patients treated with clozapine compared with drug-free patients (Chen et al., 2022).

Aims & Objectives
This study aimed to evaluate the association between peripheral orexin-A levels and the clozapine response in patients with TRS.

Method
One hundred and sixty-two clozapine-treated patients were categorized into clozapine-responsive (n = 100) and clozapine-resistant (n = 62) groups based on whether they had achieved psychotic remission defined by the 18-item Brief Psychiatric Rating Scale (BPRS-18). We compared blood orexin-A levels between the two groups and performed regression analysis to determine the effects of orexin-A level on the treatment response and BPRS-18 scores. We also examined the correlation between orexin-A levels and cognitive function assessed by the CogState Schizophrenia Battery.

Results
Clozapine-responsive patients exhibited higher orexin-A levels compared to their clozapine-resistant counterparts as well as drug-free patients (n = 37) adopted from our previous study (Chen et al., 2022). Orexin-A level was the only factor significantly associated with clozapine treatment response in regression model after adjustment for age, sex, years of education, and clozapine dosage. Orexin-A levels were negatively correlated with BPRS-18 full scale, as well as positive, negative, and general symptoms subscale scores. Furthermore, there was also a positive correlation between orexin-A levels and cognitive function domains such as verbal memory, visual learning and memory, and working memory.

Discussion & Conclusion
This cross-sectional study showed that higher levels of orexin-A are associated with a more favorable clinical response to clozapine treatment in terms of psychopathology and cognitive function in patients with TRS. The hypofunction of N-methyl-D-aspartate receptors (NMDARs) on parvalbumin-labeled (PV+) GABAergic interneurons is considered to be a potential mechanism underlying TRS (Grace and Gomes, 2019). Our finding was relevant to orexin-A shown activating effect on PV+ GABAergic interneurons (Usui et al., 2019). Future prospective studies examining changes in orexin-A level following clozapine treatment and the potential benefit of augmenting orexin-A signaling are warranted.

References
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