Abstract
BackgroundThe presentation of schizophrenia (SCH) symptoms differs between the sexes. Long-term treatment with antipsychotics is frequently associated with decreased bone mineral density, increased fracture risk and metabolic side effects. Perinatal phencyclidine (PCP) administration to rodents represents an animal model of SCH. The aim of this study was to assess the effects of chronic haloperidol and clozapine treatment on bone mass, body composition, corticosterone, IL-6 and TNF-α concentrations and metabolic parameters in male and female rats perinatally treated with PCP.MethodsSix groups of male and six groups of female rats (n = 6-12 per group) were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal day (PN), with either PCP (10 mg/kg) or saline. At PN35, one NaCl and PCP group (NaCl-H and PCP-H) started receiving haloperidol (1 mg/kg/day) and one NaCl and PCP group (NaCl-C and PCP-C) started receiving clozapine (20 mg/kg/day) dissolved in drinking water. The remaining NaCl and PCP groups received water. Dual X-ray absorptiometry measurements were performed on PN60 and PN98. Animals were sacrificed on PN100. Femur was analysed by light microscopy. Concentrations of corticosterone, TNF-α and IL-6 were measured in serum samples using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Glucose, cholesterol and triacylglycerol concentrations were measured in serum spectrophotometrically.ResultsOur results showed that perinatal PCP administration causes a significant decrease in bone mass and deterioration in bone quality in male and female rats. Haloperidol had deleterious, while clozapine had protective effect on bones. The effects of haloperidol on bones were more pronounced in male rats. It seems that the observed changes are not the consequence of the alterations of corticosterone, IL-6 and TNF-α concentration since no change of these factors was observed. Clozapine induced increase of body weight and retroperitoneal fat in male rats regardless of perinatal treatment. Furthermore, clozapine treatment caused sex specific increase in pro-inflammatory cytokines.ConclusionTaken together our findings confirm that antipsychotics have complex influence on bone and metabolism. Evaluation of potential markers for individual risk of antipsychotics induced adverse effects could be valuable for improvement of therapy of this life-long lasting disease.
Highlights
The presentation of schizophrenia (SCH) symptoms differs between the sexes
Spine bone mineral density (BMD) was significantly lower in NaCl-H and PCP-C group (p < 0.05), as well as, in PCP-H (p < 0.01) group while total BMD was reduced in NaCl-H and PCP-C group (p < 0.01) and PCPH group (p < 0.001) compared to controls
Among these animals decrease of total BMD and bone mineral content (BMC) was only seen in male haloperidol treated rats. It seems that observed changes are not the consequence of the alterations of corticosterone, IL-6 and Tumor necrosis factor alpha (TNF-α) concentration since no change of these factors was observed
Summary
Long-term treatment with antipsychotics is frequently associated with decreased bone mineral density, increased fracture risk and metabolic side effects. The aim of this study was to assess the effects of chronic haloperidol and clozapine treatment on bone mass, body composition, corticosterone, IL-6 and TNF-α concentrations and metabolic parameters in male and female rats perinatally treated with PCP. “Atypical” antipsychotics have both anti-dopaminergic and anti-serotonergic activity These drugs have greater anti-psychotic efficiency and fewer extrapyramidal side effects [4]. Decreased bone mineral density (BMD) and increased fracture risk are noticed in SCH patients, who receive long-term antipsychotic therapy [7]. Changes of bone mass [8] and metabolic parameters [9] are found in drug naive or SCH patients minimally exposed to antipsychotics. It is not clear whether the disease per se or a life style (smoking, sedentary, nutrition, vitamin D deficiency, etc) together with antipsychotics is the cause of observed bone and metabolic changes
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