title: Clozapine-induced agranulocytosis: Evidence for an immune-mediated mechanism from a patient-specific in-vitro approach.
abstract: Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing.
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Regen
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Irmelin
authors.initials: I
authors.lastname: Herzog
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Hahn
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruehl
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Le Bret
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dettling
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Heuser
authors.affiliation: Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address: julian.hellmann@charite.de.
authors.forename: Julian
authors.initials: J
authors.lastname: Hellmann-Regen
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced* / Q000276:immunology*; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D012559:Schizophrenia / Q000188:drug therapy / Q000276:immunology
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: Antigen-specific lymphocytes; Clozapine; Clozapine-induced agranulocytosis; PBMC in vitro immune assay; Personalized Medicine; Side effects