¹Songde Branch, Taipei City Hospital, Department of Addiction Sciences, Taipei City, Taiwan, ²MacKay Medical University, Institute of Biomedical Sciences, New Taipei City, Taiwan

Background: Clozapine, an antipsychotic for treatment-resistant schizophrenia, is associated with increased cardiovascular risk. Endothelial progenitor cells support vascular repair, and their dysfunction may promote atherosclerosis. How clozapine and its metabolites affect endothelial progenitor cell survival and angiogenic activity is not well defined.

Aims & Objectives: To examine the effects of clozapine and its major metabolites on human endothelial progenitor cell growth and angiogenic function, and to explore whether these effects involve aryl hydrocarbon receptor–dependent pathways.

Method: Circulating endothelial progenitor cells from healthy adults were cultured with clozapine, N-desmethylclozapine, or clozapine N-oxide at 1 to 30 micromolar. Cell growth was quantified as a percentage of vehicle control, and cytotoxicity was assessed by lactate dehydrogenase release. Capillary tube formation on growth factor–reduced Matrigel was measured after exposure to clozapine or the multi-kinase inhibitor sorafenib. The selective aryl hydrocarbon receptor antagonist CH-223191 was used to test pathway involvement.

Results: Clozapine and N-desmethylclozapine reduced endothelial progenitor cell growth in a dose-dependent manner without causing overt lactate dehydrogenase release, indicating growth suppression without necrosis. Clozapine significantly impaired capillary tube formation, with high-dose clozapine producing suppression. Co-treatment with CH-223191 significantly restored tube formation in clozapine-treated cells, whereas CH-223191 alone had minimal effect.

Discussion & Conclusions: These data show that clozapine and its active metabolite suppress the angiogenic capacity of human endothelial progenitor cells at clinically relevant concentrations in the absence of overt cytotoxicity. Partial rescue by aryl hydrocarbon receptor antagonism suggests that receptor signaling contributes to clozapine-induced endothelial progenitor cell dysfunction. Targeting this pathway may help protect vascular repair mechanisms in people receiving clozapine.