Clozapine Induces Oxidative Stress and Proapoptotic Gene Expression in Neutrophils of Schizophrenic Patients

Abstract

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.

Clozapine enhances differentiation of adipocyte progenitor cells

“…They reported that propofol, an anesthetic agent, that inhibits mitochondrial respiration and reduces oxidative stress, significantly increased preadipocyte differentiation by 125710%. Similar to propofol 6 and beside its receptor-mediated effects, clozapine is known to induce mitochondrial superoxide release, previously detected in neutrophils of patients under clozapine treatment, 8 and also seen in clozapinetreated preadipocytes. Additionally, the phenolic moiety of both molecules scavenges radicals.…”

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…[283][284][285] Alternatively, it has been suggested that defective oxidative mechanisms may be the cause of agranulocytosis, and that oxidative mitochondrial stress in Europhiles of clozapine-treated patients probably contributes to it. 302 Myeloperoxidases (MPOs) and NADPH oxidases participate in the oxidative mechanism of neutrophils, and polymorphisms in the genes coding for MPO and for a subunit of NADPH oxidase (CYPA) were found related to clozapineinduced agranulocytosis, 281 although a preliminary study failed to find association with MPO variants. 282 NOQ1 variants, the oxidative gene involved in the detoxification of drugs, were associated with clozapineinduced agranulocytosis.…”

Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens

“…22 We are aware that also non-immunological but genetically based hypotheses exist, but aberrations in enzymatic pathways, which result in toxic reactive metabolites and/or abnormal high concentrations of the main metabolites of clozapine or focusing on defective oxidative mechanisms of CA, have not been convincingly supported as yet. [28][29][30] Genetic background might play a crucial role in the induction of drug reactions such as CA. However, we are far from the purpose to appreciate the patients' genotype-based risk for this severe side effect as the complex nature of adverse drug reactions implies that many genes might play a role.…”