Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia

Shimeng Jiao; Nana Li; Ting Cao; Liwei Wang; Hui Chen; Chenquan Lin; Hualin Cai

doi:10.1016/j.pnpbp.2024.111011

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Apr 18:133:111011. doi: 10.1016/j.pnpbp.2024.111011. Online ahead of print.

Authors

Shimeng Jiao¹, Nana Li¹, Ting Cao¹, Liwei Wang¹, Hui Chen¹, Chenquan Lin¹, Hualin Cai²

Affiliations

¹ Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.
² Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China; National Clinical Research Center on Mental Disorders, Changsha, China. Electronic address: hualincai@csu.edu.cn.

PMID: 38642730
DOI: 10.1016/j.pnpbp.2024.111011

Abstract

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

Keywords: Clozapine; Fatty acid; Intermittent treatment; Prefrontal cortex; Schizophrenia.