Unravelling the mechanisms of clozapine-induced neutropenia in treatment-resistant schizophrenia using cellular genomics

In treatment-resistant schizophrenia, CIN-linked single-nucleus RNA-seq in peripheral blood mononuclear cells identified a SREBF1-driven co-expression module in naive CD4 T cells.

• Why it matters: Clozapine’s superior efficacy for TRS is limited by a 1% risk of potentially fatal CIN, yet the underlying biology is poorly defined.
• What they did: Six TRS participants were profiled after in vitro exposure to untreated, clozapine alone, or clozapine plus two major metabolites, yielding 59,313 cells across 26 clusters.
• The result: Multiple cell type-specific gene expression differences and altered cell-cell communication across seven ligand-receptor pairs were linked to CIN status and/or clozapine exposure in donors with CIN, with limited metabolite contribution.

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