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

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.

Systematic Review on Loxapine: A Typical Antipsychotic Drug Used to Treat Agitation in Schizophrenic Patients

Loxapine is an antipsychotic drug used in neuroleptic disorders since 1980 with an entrenched drug profile. Drug possesses dibenzoxazepine tricyclic 7-membered heterocyclic ring available commercially as oral, intramuscular and inhalation dosage forms. This review comprises the various study designs of loxapine irrespective of its dose formulations. A comprehensive and systematic search was conducted on “Scopus”, “Web of science” and “Pub-med” data base and findings were critically analyzed. The data suggests that there is no significant difference in efficacy between typical and atypical antipsychotics. Till now, oral and intramuscular route is widely in use. Oral dosage forms are available in the market for the treatment of agitation related to schizophrenia but it has limitation of delayed onset of action that results in increased risk. Intramuscular formulations reveal a significant difference compared to placebo with respect to agitation but time range could be in range of 15 to 60 minutes. Therefore, there is a need for a novel drug delivery system with rapid action, increased half life, better tolerance by the patient and sustained release to get enhanced patient compliance.