Introduction: An increased risk for metabolic syndrome has been described for patients with psychotic disorders. Antipsychotic drugs possibly contribute to metabolic changes. Methods: Haloperidol or clozapine was orally fed to male and female Sprague Dawley rats for 12 weeks, and body weight gain, food and water intake were measured. The serum levels of fasting glucose, HbA1c, triglycerides, cholesterol, HDL and LDL, insulin, leptin, adiponectin and ghrelin were determined. Gonadal and perirenal fat pads were removed and weighed. Results: We found increased body weight in the male clozapine group, but decreased ones in the male haloperidol group. Clozapine-treated male and female animals had higher fasting glucose, adiponectin, leptin, ghrelin, cholesterol, HDL and LDL levels, whereas haloperidol caused increased levels of insulin and decreased values of HbA1c, cholesterol, HDL and LDL. Conclusion: Both antipsychotic drugs cause sex-dependent metabolic changes, which are risk factors for the metabolic syndrome, be it hyperinsulinemia under haloperidol treatment or hyperglycemia, hyperleptinemia and hyperlipidemia under clozapine.

OBJECTIVES:The aim of our study was to investigate the impact of typical and atypical antipsychotic drugs on leptin concentration in blood and changes in the receptor expression in the hypothalamus of male Wistar rats.METHODS:From the age of 13 to 18 weeks, three groups of 20 animals were fed an average dose of 3.5 ± 0.03 mg/ kg body weight (BW) haloperidol; 30.6 ± 0.22 mg/kg BW clozapine; or 14.9 ± 0.13 mg/kg BW ziprasidone in ground food pellets containing 15% fat. Twenty control animals received no drugs. Blood samples were taken at week 14, 16, and 19. Locomotor activity and exploratory behavior were measured using the alcove test at weeks 15 and 17. The expression of the hypothalamic leptin receptor in rat brains was determined by using a Western blot.RESULTS:Rats medicated with haloperidol and ziprasidone showed a significantly decreased percentage weight gain and food consumption. We observed no differences in the alcove test, but locomotor activity was significantly reduced in the haloperidol group. Except for rats in the clozapine and ziprasidone groups, after 2 weeks of drug application, we found no changes in the leptin blood concentrations among the four groups or animals within each group. Moreover, we did not find specific differences in hypothalamic leptin receptor expression among the groups.CONCLUSION:We concluded that in male Wistar rats during this treatment period, the tested drugs did not act directly on the leptin regulatory system. We recommend further studies using long-term treatment of different rat strains.

Antipsychotic drugs are known to have sex-dependent effects on metabolic homeostasis. Liver plays a crucial role in drug degradation as well as in glucose and lipid metabolism. The present study examines the influence of clozapine and haloperidol on metabolic liver parameters. Over 12 weeks, male and female Sprague-Dawley rats were fed ground pellets containing clozapine or haloperidol. Liver mass was weighed and liver index calculated. Liver transaminases (ALAT, ALP), malondialdehyde, glucose, triglycerides, total cholesterol, HDL-cholesterol, and glycogen were determined. Finally, SREBP-1 and SREBP-2 as well as neutral fat deposits were examined. In male rats fed with clozapine, we found increased liver mass correlated with an increased liver index, high triglyceride levels, a high ratio of SREBP-1, and an elevated neutral fat distribution. Male and female haloperidol treated rats showed decreased liver mass and increased neutral fat deposition. Malondialdehyde was increased in all rats receiving antipsychotic medication indicating elevated oxidative stress. In both male and female clozapine treated rats, we found glycogen depletion related to decreased glucose levels in females. While liver transaminases were unchanged in the clozapine group, ALAT was elevated after haloperidol treatment in both sexes. Chronic clozapine intake exerts sex-dependent effects on hepatic metabolism. Although haloperidol has been shown to change fewer metabolic parameters, it causes oxidative stress and neutral fat deposits in liver tissue in both sexes.

Objective Sex‐dependent disturbances of peripheral glucose metabolism are known complications of antipsychotic drug treatment. The influence of long‐term clozapine and haloperidol medication on hypothalamus, maintaining aspects of internal body homeostasis, has not yet been completely clarified. Methods After puberty, male and female Sprague Dawley rats were fed orally with ground pellets containing haloperidol (1 mg/kgBW/day) or clozapine (20 mg/kgBW/day) for 12 weeks. The hypothalamic protein expression of dopamine receptors D2R and D4R, melanocortin receptor MC4R, and glucose transporters Glut1 and Glut3 was examined. Glucose, glycogen, lactate, and pyruvate levels were determined, also malondialdehyde equivalents as markers of oxidative stress. Results D2R expression was increased in the male haloperidol and clozapine group but decreased in females medicated with clozapine. D4R expression was upregulated under clozapine medication. While females showed increased Glut1, Glut3 was elevated in both male and female clozapine‐medicated animals. We found no changes of hypothalamic malondialdehyde, glycogen, and MC4R. Hypothalamic lactate was elevated in the female clozapine group. Conclusion Clozapine sex‐dependently affects the expression of D2R, Glut1, and Glut3. The upregulation of the glucose transporters indicates glucose deprivation in the endothelial cells and consequently in astrocytes and neurons. Increased hypothalamic lactate in females under clozapine points to enhanced glycolysis with a higher glucose demand to produce the required energy. Haloperidol did not change the expression of the glucose transporters and upregulated D2R only in males.

We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded.

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OBJECTIVESAlthough schizophrenia affects both human genders, there are gender-dependent differences with respect to age of onset, clinical characteristics, course and prognosis of the disease.METHODSTo investigate sex-dependent differences in motor coordination and activity as well as in cognitive and social behavior, we repeatedly tested female (n = 14) and male (n = 12) Fisher rats (postnatal days, PD 56–174) that had received intracerebroventricular injections of kainic acid as well as female (n = 15) and male (n = 16) control animals. The hippocampus was examined histologically.RESULTSCompared to male controls, in the alcove test both female controls and female animals with prenatal intervention spent less time in a dark box before entering an unknown illuminated area. Again, animals that received prenatal injection (particularly females) made more perseveration errors in the T-maze alternation task compared to controls. Female rats exhibited a higher degree of activity than males, suggesting these effects to be sex-dependent. Finally, animals that received prenatal intervention maintained longer lasting social contacts. Histological analyses showed pyramidal cells in the hippocampal area CA3 (in both hemispheres) of control animals to be longer than those found in treated animals. Sex-dependent differences were found in the left hippocampi of control animals and animals after prenatal intervention.CONCLUSIONThese results demonstrate important differences between males and females in terms of weight gain, response to fear, working memory and social behavior. We also found sex-dependent differences in the lengths of hippocampal neurons. Further studies on larger sample sets with more detailed analyses of morphological changes are required to confirm our data.

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.