Increased apoptosis of neutrophils in a case of clozapine-induced agranulocytosis - a case report.
A 45-year-old female suffering from severe chronic schizophrenia of the paranoid type did not respond to typical antipsychotics. Five weeks after starting therapy with clozapine, she developed a clozapine-induced agranulocytosis (CA). Discontinuation of clozapine and treatment with granulocyte colony-stimulating factor (G-CSF) led to normalization of blood neutrophil counts within three weeks. This report suggests enhanced apoptosis of blood neutrophils during the acute phase of CA resulting from enhanced expression of the pro-apoptotic proteins Bax and Bik and from a decrease of the anti-apoptotic BCl-X(L) mRNA. The time course of decline and recovery of neutrophilic cells, as well as the release pattern of endogenous G-CSF, resembles those of chemotherapy-induced neutropenia. The kinetics of CD 34-positive cells mimics that of cytotoxic progenitor cell mobilization, e. g., after cytostatic drug administration. Our findings argue against the hypothesis that clozapine-mediated inhibition of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) release is involved in CA development. Because clozapine-induced cell death mainly affects the neutrophil lineage, the elucidation of the exact mechanism of CA may open new perspectives for the treatment of psychiatric and possibly hematological disorders.
Loeffler
S
S
Fehsel
K
K
Henning
U
U
Fischer
J
J
Agelink
M
M
Kolb-Bachofen
V
V
Klimke
A
A
D000380:Agranulocytosis / Q000139:chemically induced*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D003024:Clozapine / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D012563:Schizophrenia, Paranoid / Q000188:drug therapy*
D014150:Antipsychotic Agents; D003024:Clozapine