Free Radical Scavenging Enzyme Activity and Related Trace Metals in Clozapine-Induced Agranulocytosis

Abstract

We hypothesized that patients who had experienced clozapine-induced agranulocytosis would have abnormalities in their free radical scavenging enzyme activity (FRESA) and levels of related trace metals. We therefore measured FRESA profiles and related trace metals in four groups: post-clozapine agranulocytosis (POST CLOZ AGRAN) (N = 9); clozapine no agranulocytosis (CLOZ NO AGRAN) (N = 12); West Coast controls (WC CONTROLS) (N = 14); and Long Island Jewish Medical Center controls (LIJ CONTROLS) (N = 12). Glutathione peroxidase (GSH-Px, P1) levels in plasma were slowest in the POST CLOZ AGRAN group (34.3 +/- 6.9 IU/dl [standard deviation; SD]; p < 0.002); red blood cell glutathione peroxidase (GSH-Px, RBC) was highest in the WC CONTROLS (38.7 +/- 4.7 IU/g hemoglobin [Hgb]; p < 0.008); and selenium (SE) levels in plasma were lower in both the POST CLOZ AGRAN group (111.6 +/- 14.7 ng/ml) and the CLOZ NO AGRAN group(115.0 +/- 17.8) than in the WC CONTROLS (142.5 +/- 18.3; p < 0.0006). SE was also lower in the POST CLOZ AGRAN group than in the LIJ CONTROLS (129.1 +/- 21.6; p < 0.04). The presence of at least one of the following: (1) GSH-Px, P1 < 37.6 IU/dl; (2) GSH-Px, RBC < 31.0 IU/g Hgb; or (3) SE < 112.4 ng/ml, distinguished POST CLOZ AGRAN subjects from the WC CONTROLS, but not from the LIJ CONTROLS. Data from this cross-sectional pilot study suggest that abnormalities in the body's antioxidant defense system may be involved in the pathogenesis of clozapine-associated agranulocytosis. If confirmed in large-scale, prospective studies, these preliminary findings have potential clinical application in the screening and prophylaxis of clozapine agranulocytosis.

Low blood selenium concentrations in schizophrenic patients on clozapine

“…Unfortunately it also has severe side‐effects, notably agranulocytosis, myocarditis and cardiomyopathy, which can cause death and sometimes sudden death in otherwise stable patients [6, 7]. In a small study of clozapine‐treated patients, the group that developed agranulocytosis and the group that did not had lower plasma selenium concentrations than normal controls [8]; however, the authors did not measure red‐cell selenium concentrations, and no comparisons were made with schizophrenic patients not treated with clozapine or with other psychiatric patients.…”

Racial Differences in Free Radical Scavenging Enzyme Activity in Children

“…[11][12][13] Both extracellular and intracellular defenses protect the host from free radical-mediated injury. [18][19][20][21][22][23] Preexisting genetically determined variations in baseline free radical scavenging enzyme activities or trace element concentrations could play an important role in explaining these clinically observable differences. [18][19][20][21][22][23] Preexisting genetically determined variations in baseline free radical scavenging enzyme activities or trace element concentrations could play an important role in explaining these clinically observable differences.…”

“…Extracellar defenses include a variety of proteins (eg, albumin, transferrin, and ceruloplasmin).14,15 Five intracellular free radical scavenging enzymes provide the major antioxidant defense: glutathione peroxidase, glutathione reductase, glutathione-Stransferase, catalase, and superoxide dismutase.l6 The trace elements selenium (Se), copper (Cu), and zinc (Zn) are essential for the proper functioning of these enzymes Clinically, some of these free radical-mediated illnesses demonstrate differences in their prevalence and outcome based on age, sex, ethnicity, and race. [18][19][20][21][22][23] Preexisting genetically determined variations in baseline free radical scavenging enzyme activities or trace element concentrations could play an important role in explaining these clinically observable differences. Erythrocyte glutathione peroxidase and superoxide dismutase are the most important enzymes involved in the pathophysiology of free radical-mediated neurologic diseases .…”

Sodium valproate and clozapine induced neutropenia: A case control study using register data

“…Further, sodium valproate has been shown to decrease the synthesis of glutathione peroxidase, thus inhibiting the production of the antioxidant glutathione (Pippenger et al 1992). The rapid reduction of nitrenium ions may be limited by valproates inhibition of glutathione production, which may contribute to or trigger the generation of excess free ions, leading to neutropenia (Linday et al 1995). This suggests that the combined effect on cell activation by clozapine and sodium valproate, combined with reduced glutathione production induced by valproate, may lead to increased reactive metabolites, leading to neutrophil toxicity and apoptosis.…”

“…Another potential mechanism for the increased risk for neutropenia relates to shared actions on cytokines. Both clozapine (Sperner-Unterweger et al 1993) and sodium valproate (Linday et al 1995) have been shown to inhibit the production of granulocyte-macrophage colony stimulating factor (GM-CSF) in vitro, thus reducing granulopoiesis and thus limiting the compensatory mechanisms against the increased rate of neutrophil destruction.…”