Sex-dependent effects of long-term clozapine or haloperidol medication on red blood cells and liver iron metabolism in Sprague Dawley rats as a model of metabolic syndrome

Abstract

Background Patients with liver diseases often have some form of anemia. Hematological dyscrasias are known side effects of antipsychotic drug medication and the occurrence of agranulocytosis under clozapine is well described. However, the sex-dependent impact of clozapine and haloperidol on erythrocytes and symptoms like anemia, and its association with hepatic iron metabolism has not yet been completely clarified. Therefore, in the present study, we investigated the effect of both antipsychotic drugs on blood parameters and iron metabolism in the liver of male and female Sprague Dawley rats. Methods After puberty, rats were treated orally with haloperidol or clozapine for 12 weeks. Blood count parameters, serum ferritin, and liver transferrin bound iron were determined by automated counter. Hemosiderin (Fe3+) was detected in liver sections by Perl’s Prussian blue staining. Liver hemoxygenase (HO-1), 5’aminolevulinate synthase (ALAS1), hepcidin, heme-regulated inhibitor (HRI), cytochrome P4501A1 (CYP1A1) and 1A2 (CYP1A2) were determined by Western blotting. Results We found anemia with decreased erythrocyte counts, associated with lower hemoglobin and hematocrit, in females with haloperidol treatment. Males with clozapine medication showed reduced hemoglobin and increased red cell distribution width (RDW) without changes in erythrocyte numbers. High levels of hepatic hemosiderin were found in the female clozapine and haloperidol medicated groups. Liver HRI was significantly elevated in male clozapine medicated rats. CYP1A2 was significantly reduced in clozapine medicated females. Conclusions The characteristics of anemia under haloperidol and clozapine medication depend on the administered antipsychotic drug and on sex. We suggest that anemia in rats under antipsychotic drug medication is a sign of an underlying liver injury induced by the drugs. Changing hepatic iron metabolism under clozapine and haloperidol may help to reduce these effects of liver diseases.

Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats

“…In short, male and female rats received daily treatment of clozapine or haloperidol by oral feeding in ground pellets over 12 weeks. Serum levels of haloperidol, clozapine, and its metabolite N-desmethylclozapine, body weight, motor activity, food and water intake (raw data and calculated on 1 kg body weight), and metabolic parameters were reported previously [23][24][25][26]. Male and female rats with haloperidol gained less weight than the control groups, associated with reduced food and water intake.…”

“…Hepcidin is considered the key regulator of iron metabolism. Haloperidol or clozapine-medicated female rats have higher serum ferritin levels and higher hepcidin levels in liver [26] and adipose tissue (Figure 3C). In mouse models of obesity, increased adiposity leads to iron deposits only in the epididymal adipose tissue (eAT) of male mice.…”

“…In contrast to VAT, the liver shows high oxidative stress for both sexes. In females, hemosiderin is deposited in the liver, while males show an iron deficiency, which is reflected in a low hemoglobin content and a reduced cytochrome level [26]. Males have extremely high hepatic triglyceride levels and increased lipid droplets.…”

“…Previously, we have examined the effects of clozapine and haloperidol on weight, food and water intake, and serum parameters [23], hepatic [24], hypothalamic [25] blood and iron parameters [26] in a rat model of metabolic syndrome. Finally, in this study, we examine the effects of the two antipsychotic drugs on basal metabolism of perirenal adipocytes.…”

Mechanisms Underlying Antipsychotic-Induced NAFLD and Iron Dysregulation: A Multi-Omic Approach

“…Hypoferritinemia and/or iron-deficiency anemia has also been reported for patients treated with risperidone [ 21 , 26 , 39 , 40 ]. Additionally, chronic treatment (12 weeks) of rats with the AA medication clozapine or the first generation (typical) antipsychotic medication haloperdol resulted in sex-dependent effects on hepatic iron metabolism and anemia [ 53 ]. Sudden-onset anemia associated with clozapine and lurasidone that resolves upon cessation of treatment has also been described in case reports [ 41 , 42 ].…”