Paliperidone extended-release: does it have a place in antipsychotic therapy?

Abstract

Paliperidone (9-hydroxy-risperidone), the active metabolite of risperidone, was approved for treating schizophrenia worldwide in 2006 as paliperidone extended-release (PER), and became the first second-generation antipsychotic specifically licensed for treating schizoaffective disorder in 2009. However, at the same time, its comparatively high cost gave rise to concerns about the cost-effectiveness of PER as compared with its precursor, risperidone. This paper reviews the existing knowledge of the pharmacology, kinetics, efficacy, tolerability, and fields of application of PER, and compares PER with risperidone in order to determine whether it has a place in antipsychotic therapy. An independent assessment of all relevant publications on PER published until July 2010 was undertaken. PER has a unique pharmacological profile, including single dosing, predominantly renal excretion, low drug–drug interaction risk, and differs from risperidone in terms of mode of action and pharmacokinetics. High-level evidence suggests that PER is efficacious and safe in schizophrenia, schizoaffective disorder, and acute manic episodes. There is a striking lack of published head-to-head comparisons between PER and risperidone, irrespective of indication. Low-level evidence shows a lower risk for hyperprolactinemia and higher patient satisfaction with PER than with risperidone. PER adds to the still limited arsenal of second-generation antipsychotics. In the absence of direct comparisons with risperidone, it remains difficult to come to a final verdict on the potential additional therapeutic benefits of PER which would justify its substantially higher costs as compared with risperidone. However, in terms of pharmacology, the available evidence cautiously suggests a place for PER in modern antipsychotic therapy.

Paliperidone ER versus risperidone for neurocognitive function in patients with schizophrenia

“…This delayed release minimizes side effects related to high serum levels that occur with immediate-release formulations (Canuso et al, 2008). Furthermore, in the absence of direct comparisons with risperidone, it remains difficult to come to a final verdict on the potential additional therapeutic benefits of paliperidone ER that would justify its substantially higher cost as compared with risperidone (Gahr et al, 2011). These clinical and pharmacological profiles suggest that paliperidone ER may also contribute to improving cognitive function.…”

Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort

“…C min of 9-hydroxyrisperidone was not found to be associated with any neurologic side effects, which could be tentatively explained by a lower affinity to D 2 receptor and a higher affinity to 5-HT2A receptor compared to risperidone [65] . This is also in agreement with prospective studies reporting a decrease of neurologic symptoms after switching from risperidone to 9-hydroxyrisperidone (paliperidone) [66,67] , although more studies are needed to validate the strategy of switching from risperidone to paliperidone in case of poor tolerability.…”

The Pharmacological Role and Clinical Applications of Antipsychotics’ Active Metabolites: Paliperidone versus Risperidone

“…Recovery of serotonin release inhibited by risperidone can be achieved by jointly administering a 5-HT 1A (WAY 100635) receptor blockade and a norepinephrine reuptake inhibitor (desipramine). Hence, we can conclude that risperidone inhibits the release of 5-HT neurons by activating autoreceptors 5-HT 1A and blocking α 1 receptors, leading us to believe paliperidone is less active at these two receptors than risperidone [110].…”

“…Data collected in rats by Schotte et al [70] are on the order of 0.15 nM for risperidone and 0.82 nM for paliperidone. In both cases, paliperidone's affinity for 5-HT 2A receptors The fact that paliperidone ER exhibits receptor occupancy such that 5-HT 2A >D 2 with little plasma fluctuation, the ability to gradually occupy D 2 receptors, and quick dissociation from said receptors, are all grounds to consider it an atypical antipsychotic with a lower risk of extrapyramidal side effects than risperidone has [76,110].…”

“…Similarly, paliperidone can be considered different from other atypical antipsychotics. It does not inhibit neuronal release of serotonin like olanzapine and clozapine by inhibiting α 1 receptors, and unlike ziprasidone and aripiprazole, it is not a 5-HT 1A receptor agonist [110]. The differences between paliperidone and risperidone, as far as norepinephrine release in vivo, may be due to its low capacity to bind at 5-HT 2A and α 1 -receptors, observed in vitro [71].…”