paliperidone-palmitate and Metabolic-Diseases

Paliperidone, which is available in extended-release (ER) tablets, was approved by the US Food and Drug Administration in 2007 for the acute and maintenance treatment of schizophrenia. It is the seventh second-generation antipsychotic (SGA) to be introduced to the US market. Paliperidone is the major active metabolite of risperidone, an established anti-psychotic agent.. This article reviews the available literature on the pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability of paliperidone.. A comprehensive search of MEDLINE using the terms paliperidone, 9-hydroxy-risperidone, and Invega was performed for the years 1950 through December 2007. Articles that discussed the efficacy and tolerability of 9-hydroxy-risperidone formed as a metabolite of risperidone were excluded; all others were included. Abstracts and posters presented at recent national and international scientific meetings were also included in the review.. At therapeutic doses (3-12 mg), paliperidone ER follows linear pharmacokinetics. Like that of its parent drug, paliperidone's mechanism of action is thought to be through antagonistic actions at dopamine D(2) and serotonin-2A receptors. In vivo studies suggest that the cytochrome P450 enzyme system plays a minimal role in paliperidone metabolism, with none of the metabolites accounting for >10% of a dose. The majority (59%) of paliperidone is eliminated through the kidneys as unchanged drug. The results of three 6-week, randomized, double-blind, parallel-group trials indicated the efficacy of paliperidone ER compared with placebo in the treatment of acute exacerbations of schizophrenia, with response rates ranging from 39.8% to 61.0% for paliperidone ER, compared with 18.3% to 34.0% for placebo. During a 52-week, double-blind, relapse-prevention trial, the time to 25% of patients experiencing a recurrence was 83 days for paliperidone ER, compared with 23 days for placebo. The proportions of patients in the 6-week trials who reported at least 1 extrapyramidal symptom-related adverse event were 13%, 10%, 25%, 26%, and 24% for paliperidone ER 3, 6, 9, 12, and 15 mg/d, respectively; the pooled incidence rate was not statistically different from that with placebo (11%). Headache and insomnia were the most common adverse events in patients treated with paliperidone ER in the 6-week trials (pooled data: 11%-18% and 4%-14%, respectively). In the relapse-prevention trial, the incidence of prolactin-related adverse events was 4% for paliperidone ER and 0% for placebo.. Current evidence supports the efficacy and tolerability of paliperidone ER in the acute and long-term treatment of schizophrenia. Randomized, head-to-head comparisons with other SGAs, particularly risperidone, are needed to define the role of paliperidone ER in the treatment of schizophrenia.

Topics: Antipsychotic Agents; Delayed-Action Preparations; Dopamine Antagonists; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Humans; Isoxazoles; Metabolic Diseases; Paliperidone Palmitate; Pyrimidines; Randomized Controlled Trials as Topic; Schizophrenia; Secondary Prevention; Serotonin Antagonists; Tablets; Treatment Outcome

There are no direct comparisons of paliperidone extended-release (ER), aripiprazole and ziprasidone in efficacy and metabolic influence in patients with first-episode schizophrenia.. The present study examined the efficacy and metabolic influence of paliperidone ER, aripiprazole and ziprasidone in patients with first-episode schizophrenia in China.. Subjects were recruited from outpatient and 254 patients entered the trial. These patients received treatment randomly with paliperidone ER, aripiprazole and ziprasidone and were assessed at baseline, 13, 26 and 52 weeks, respectively with Positive and Negative Syndrome Scale (PANSS), 7-item Clinical Global Impressions-Severity (CGI-S), anthropometric (weight, body mass index and waist circumference) and metabolic (fasting blood glucose, HbA1c, cholesterol, high density lipoproteins (HDL), low density lipoproteins and triglycerides) measures.. A total of 203 patients completed the trial. Paliperidone group had significant greater reduction in PANSS than aripiprazole group and ziprasidone group from 13 weeks, although the a reduction in PANSS of each group was more than 20%. There was no difference in CGI-S among the three groups, and all three groups had a significant reduction from baseline in CGI-S. Aripiprazole group increased in weight and body mass index despite no statistical change in waist circumference. Other two groups showed no changes in anthropometric measure. At the end of the study, two glucose metabolic indices (fasting blood glucose and HbA1c) of aripiprazole group were significantly higher than that of baseline. In lipid metabolism, aripiprazole group reduced triglycerides significantly and had no changes in other indices. Paliperidone group reduced HDL and increased triglycerides despite no changes in glucose metabolism. Ziprasidone group also had no significant changes in glucose metabolism, but reduced cholesterol, low density lipoproteins and increased HDL. Furthermore, 22 subjects in three groups reached the diagnostic criteria of metabolic syndrome.. Paliperidone ER, aripiprazole and ziprasidone are effective in treating first-episode schizophrenia, and the ranking of efficacy from high to low is paliperidone ER > aripiprazole > ziprasidone. Paliperidone ER can impair lipid metabolism potentially but had no influence on glucose metabolism. Aripiprazole can damage glucose metabolism and has little influence on lipid metabolism. Ziprasidone is considered an atypical antipsychotic with no evidence of harm to glucose and lipid metabolism.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Body Mass Index; China; Delayed-Action Preparations; Diagnostic and Statistical Manual of Mental Disorders; Female; Follow-Up Studies; Humans; Hyperglycemia; Hyperlipidemias; Isoxazoles; Male; Metabolic Diseases; Paliperidone Palmitate; Piperazines; Psychiatric Status Rating Scales; Pyrimidines; Quinolones; Schizophrenia; Thiazoles; Weight Gain; 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