Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study.

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest There are no funding, employment or personal financial interests of any kind that would undermine the objectivity, integrity or perceived value of the submitted publication. In order of authorship listing: Edgardo Torres Carmona declaration of interest: none. Shinichiro Nakajima declaration of interest: none. Yusuke Iwata declaration of interest: none. Fumihiko Ueno declaration of interest: none. Cristiana Stefan declaration of interest: none. Jianmeng Song declaration of interest: none. Ali Abdolizadeh declaration of interest: none. Michel Teruki Koizumi declaration of interest: none. Yasman Kambari declaration of interest: none. Aron Amaev declaration of interest: none. Sri Mahavir Agarwal declaration of interest: none. Wanna Mar declaration of interest: none. Vincenzo de Luca declaration of interest: none. Gary Remington has received advisory board support from HLS Therapeutics and consultant fees from Mitsubishi Tanabe Pharma Corporation. Philip Gerretsen declaration of interest: none. Ariel Graff-Guerrero declaration of interest: none.