Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients.
The present study examined cellular effects of the atypical antipsychotic drug clozapine on blood cells of treated patients with and without clozapine-induced agranulocytosis (CA). Blood from one patient who commenced clozapine treatment was examined at weekly intervals for 128 days. Olanzapine-treated (n = 5) and polymedicated (n = 14) schizophrenic patients, as well as healthy subjects (n = 19) and septic shock patients (n = 8), were studied for comparison. We observed dramatically increased numbers of native neutrophils stained for superoxide anion production (P < or = 0.005, n = 10) and significantly elevated expression levels of the proapoptotic genes p53 (P < or = 0.020), bax alpha (P < or = 0.001), and bik (P < or = 0.002) in all tested non-CA patients (n = 19) and CA patients (n = 4). In non-CA patients, the expression of these genes did not correlate to the percentage of apoptotic neutrophils (2.0% +/- 1.3%), but in CA patients about 37% of the neutrophils show morphologic signs of apoptosis (P < or = 0.001). Under G-CSF therapy of CA, the number of apoptotic neutrophils and the expression of the proapoptotic genes decreased significantly. In conclusion, high production of reactive oxygen species in neutrophils of clozapine-treated patients, together with increased expression of proapoptotic genes, suggests that neutrophils are predisposed to apoptosis in schizophrenic patients under clozapine therapy. The correlation between drug and proapoptotic markers was highest for clozapine and bax alpha as well as superoxide anion radicals. This indicates oxidative mitochondrial stress in neutrophils of clozapine-treated patients which probably contributes to the induction of apoptosis and sudden loss of neutrophils and their precursors in CA patients.
Fehsel
Karin
K
Neurobiochemical Research Unit, Psychiatric Department, Heinrich-Heine-University of Duesseldorf. Fehsel@uni-duesseldorf.de
Loeffler
Stefan
S
Krieger
Klaus
K
Henning
Uwe
U
Agelink
Markus
M
Kolb-Bachofen
Victoria
V
Klimke
Ansgar
A
D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D004247:DNA / Q000096:biosynthesis / Q000302:isolation & purification; D015870:Gene Expression / Q000187:drug effects*; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics; D008856:Microscopy, Fluorescence; D024101:Mitochondrial Proteins; D009504:Neutrophils / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D014150:Antipsychotic Agents; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013481:Superoxides; D004247:DNA; D003024:Clozapine