HIGHER OREXIN-A LEVELS ARE ASSOCIATED WITH BETTER TREATMENT RESPONSE TO CLOZAPINE IN PATIENTS WITH TREATMENT RESISTANT SCHIZOPHRENIA

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 CHEN, P. Y., CHANG, C. K., CHEN, C. H., FANG, S. C., MONDELLI, V., CHIU, C. C., LU, M. L., HWANG, L. L. &HUANG, M. C. 2022. Orexin-a elevation in antipsychotic-treated compared to drug-free patients with schizophrenia: A medication effect independent of metabolic syndrome. J Formos Med Assoc, 121,2172- 2181. CHIEN, Y. L., LIU, C. M., SHAN, J. C., LEE, H. J., HSIEH, M. H., HWU, H. G. &CHIOU, L. C. 2015. Elevated plasma orexin A levels in a subgroup of patients with schizophrenia associated with fewer negative and disorganized symptoms. Psychoneuroendocrinology, 53, 1-9. GRACE, A. A. &GOMES, F. V. 2019. The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention. Schizophr Bull, 45, 148-157. USUI, M., KANEKO, K., OI, Y. &KOBAYASHI, M. 2019. Orexin facilitates GABAergic IPSCs via postsynaptic OX1 receptors coupling to the intracellular PKC signalling cascade in the rat cerebral cortex. Neuropharmacology, 149, 97-112.