paliperidone-palmitate and Insulin-Resistance

To compare matched paliperidone-ER- and olanzapine-treated schizophrenic patients on measures of glucose and lipid metabolism.. Eighty hospitalized patients with schizophrenia (DSM-IV) were randomly assigned to treatment with paliperidone ER or olanzapine for a period of 12 weeks. At baseline and every 4 weeks, we assessed weight, subcutaneous fat, waist and hip circumferences, fasting glucose, insulin, glycohemoglobin A1, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and prolactin. We also assessed at every time point body mass index (BMI), homeostasis insulin resistance (HOMA-IR), and homeostasis β-cell function (HOMA-B).. Thirty-three patients randomly assigned to paliperidone ER and 23 patients randomly assigned to olanzapine groups completed the entire 12-week treatment. Within-group analyses showed that fasting measures in both groups increased for weight, BMI, waist circumferences, hip circumference, subcutaneous fat, cholesterol, triglycerides, and prolactin. In contrast, fasting glucose, LDL, and HOMA-B increased during treatment only in the olanzapine group. We also detected significantly different serum prolactin levels at all time point between the paliperidone ER- and olanzapine-treated groups, as well as a statistical trend for HOMA-B to increase more in the olanzapine compared to paliperidone-ER group over the 12 weeks of the trial. We did not detect, however, differential drug effects over the 12 weeks of the trial on fasting measures of BMI, glucose, glycohemoglobin A1, insulin, HDL, LDL, cholesterol, triglyceride, or HOMA-IR.. This study reinforces the necessity of regularly monitoring metabolic parameters in patients with schizophrenia taking atypical antipsychotics, including paliperidone ER.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Delayed-Action Preparations; Female; Follow-Up Studies; Humans; Insulin Resistance; Insulin-Secreting Cells; Isoxazoles; Lipid Metabolism; Male; Olanzapine; Paliperidone Palmitate; Prospective Studies; Pyrimidines; Schizophrenia; Time Factors; Young Adult

The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals.. Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp.. Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance.. In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.

Topics: Animals; Antipsychotic Agents; Female; Glucose Clamp Technique; Glucose Tolerance Test; Insulin Resistance; Metabolic Diseases; Models, Animal; Paliperidone Palmitate; Rats; Rats, Sprague-Dawley; Risperidone

Schizophrenia doubles the odds of diabetes, and atypical antipsychotics (AAPs) also increase risk of diabetes. Indeed, little is known about the effects of AAPs on vascular dysfunctions associated with diabetes. This study aimed to determine the effects of risperidone (RISP) and paliperidone (PALI) on the vascular function of diabetic rats. Diabetes was induced by feeding with a high-fat diet followed by the administration of streptozotocin (35 mg·(kg body mass)(-1), by intraperitoneal injection). Rats received RISP or PALI (1.25 mg·kg(-1)·d(-1), per os) for 3 weeks. Endothelium-dependent relaxation, systolic blood pressure, lipid profile, insulin resistance, and adhesion molecules, vascular cell-adhesion-molecule-1 (VCAM-1), intracellular-adhesion-molecule-1 (ICAM-1), and E-selectin were investigated. RISP significantly worsened the impaired endothelium-dependent relaxation of diabetic aortic rings with upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin, and proinflammatory cytokines MPC-1 and TNF-α. RISP augmented the metabolic dysfunctions and reduced insulin sensitivity in the insulin tolerance test as well as HOMA-IR. PALI produced insignificant effects on vascular and metabolic aberrations. Our results suggest that RISP, but not PALI, aggravates the metabolic abnormalities and vascular dysfunction associated with diabetes, which may be mediated by upregulation of VCAM-1, ICAM-1, and E-selectin. Nevertheless, future investigation for the possible mechanisms underlying the difference noticed between the 2 AAPs is warranted.

Topics: Animals; Antipsychotic Agents; Aorta; Blood Pressure; Cell Adhesion Molecules; Chemokine CCL2; Cytokines; Diabetes Mellitus, Experimental; Diet, High-Fat; E-Selectin; Endothelium, Vascular; Glucose; Insulin Resistance; Isoxazoles; Lipids; Male; Paliperidone Palmitate; Pyrimidines; Rats; Rats, Wistar; Risperidone; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Cell Adhesion Molecule-1