Paliperidone for schizophrenia
ABSTRACT The efficacy, safety, pharmacology, pharmacokinetics, drug-drug interactions, and administration of paliperidone for schizophrenia are reviewed.
Paliperidone is a benzisoxazole derivative and the principal active metabolite of risperidone. Representative of most oxidative metabolites, paliperidone is less lipophilic than risperidone. Like other atypical antipsychotics, paliperidone has a greater affinity for serotonin type 2A- receptor blockade relative to dopamine type 2-receptor blockade. Paliperidone's advanced-generation osmotic release delivery system allows for the avoidance of dosage adjustment when initiating therapy and may decrease the frequency of antido-paminergic effects that would occur with an immediate-release formulation. The pharmacologic actions of paliperidone are similar to other high potency atypical antipsychotics. The receptor-binding profile of paliperidone most closely resembles that of risperidone and ziprasidone. Paliperidone differs from risperidone and most other antipsychotics by its relatively low extent of enzymatic metabolism. A limited number of investigations have demonstrated the ability of paliperidone to produce significant improvements in psychopathology, functioning, and relapse in patients with schizophrenia when compared with placebo. Paliperidone appears to have a similar adverse-effect profile compared to risperidone, except for an increased rate of hyperprolactinemia. The recommended dose of paliperidone for the treatment of adults with schizophrenia is 6 mg every morning.
Paliperidone does not offer any clear advantage over other atypical antipsychotics with a similar receptor-binding profile, such as risperidone and ziprasidone. Nevertheless, a few investigations have demonstrated the ability of paliperidone to produce significant improvements in psychopathology, functioning, and relapse when compared with placebo. Based on limited studies, the frequency of adverse effects, except for hyperprolactinemia, appears to favor paliperidone over risperidone.
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ABSTRACT: "All-causes discontinuation" refers to discontinuation of treatment for any reason, and adherence to medication is an important component of this measure. Two recent landmark studies suggest that adherence is a major issue in patients with first-episode psychosis (FEP) right from the onset of treatment. In this review, the incidence, reasons for, and clinical outcomes of medication discontinuation in FEP are considered. More than 40% of patients with FEP discontinue medication during the first 9 months of treatment, at which point the chances of relapse increase dramatically. Findings concerning predictors of medication discontinuation in this patient population that have been replicated in more than one study include severity of psychopathology, lack of insight into illness, negative attitudes towards medications, comorbid substance use, and medication side effects. Interventions that have the potential to decrease discontinuation rates in patients with psychotic disorders include orally disintegrating tablets, long-acting injectable drugs, cognitive-behavioral therapy, compliance therapy, family support/intervention, and peer support, although these strategies have largely been unexplored in FEP. In addition to the question of medication discontinuation in the acute treatment of FEP, another important issue is how long patients with FEP should be treated with antipsychotics once they have achieved remission; unfortunately, little evidence is available to guide the decision as to whether medication should be discontinued or maintenance treatment provided in this situation. Studies are therefore needed to identify predictors of patients with remitted FEP who are less likely to relapse when medication is discontinued. Taken together, the findings presented in this article underscore the importance of addressing issues related to medication discontinuation as a means of preventing long-term morbidity and enhancing remission and functional recovery in FEP.01/2008; 14(5):289-300. DOI:10.1097/01.pra.0000336756.65308.83
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ABSTRACT: Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the "prototypical" or "gold standard" atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years. Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed. Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine's cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine's cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs. There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While low-dose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine's discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.Psychopharmacology 10/2008; 203(2):279-94. DOI:10.1007/s00213-008-1308-3 · 3.99 Impact Factor
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ABSTRACT: Atypical antipsychotics are commonly prescribed to clinically referred youngsters for treatment of heightened aggressive behavior associated with various psychiatric disorders. Previously, we demonstrated risperidone's anti-aggressive effects using a well-validated animal model of offensive aggression. Paliperidone, the main active metabolite of risperidone, is a potent serotonin-2A and dopamine-2 receptor antagonist with slightly different pharmacodynamic properties compared to risperidone. Given that much of risperidone's therapeutic efficacy is due to its active metabolite, paliperidone may effectively suppress aggression with fewer adverse side effects. Investigate whether paliperidone administration would reduce heightened aggressive behavior induced by low-dose cocaine exposure in a developmentally sensitive model of offensive aggression. Male Syrian hamsters (n = 12/group) were administered an acute dose of paliperidone (0.05, 0.1, 0.2, and 0.3 mg/kg) and then tested for aggressive behavior using the resident-intruder paradigm. To investigate the effects of chronic paliperidone administration, a separate set of animals (n = 12/group) was exposed to repeated paliperidone administration (0.1 mg kg(-1) day(-1)) during different developmental periods and varying lengths of time (1-4 weeks). Experiment 1 results revealed a dose-dependent decrease in bite and attack behaviors with an effective dose observed at 0.1 mg/kg. In Experiment 2, the maximal reduction in aggressive behavior in response to chronic paliperidone treatment was observed in animals treated during the third week of adolescence, and this reduction occurred without concomitant alterations in non-aggressive behaviors. These results support the specific aggression-suppressing properties of paliperidone and the potential use of this compound in the treatment of maladaptive aggression in clinical settings.Psychopharmacology 01/2009; 203(4):653-63. DOI:10.1007/s00213-008-1412-4 · 3.99 Impact Factor