paliperidone-palmitate and Long-QT-Syndrome

Paliperidone is FDA-approved for schizophrenia aged 12-17. However, the pharmacologic portfolio, extrapolation from adult studies, and the long track record of the parent drug, risperidone in child/adolescent psychiatric (CAP) population might expand its therapeutic potential.. EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies of using paliperidone in child psychiatry up to date of February 2019.. Sound evidence base supports its use in early-onset schizophrenia, juvenile bipolar, and autism spectrum disorder. A modicum of evidence supports its use in Tourette syndrome and as adjuventia in attention-deficit/hyperactivity disorder (ADHD).. Paliperidone has some dynamic and kinetic superiority to the parent drug risperidone. Nonetheless, larger rigorous studies would define the real place of the atypical antipsychotic paliperidone in child and adolescent psychiatry. Until then, risperidone with its long track record in CAP population would remain a first option though.

Topics: Adolescent; Antipsychotic Agents; Attention Deficit and Disruptive Behavior Disorders; Autism Spectrum Disorder; Basal Ganglia Diseases; Bipolar Disorder; Child; Child Psychiatry; Humans; Long QT Syndrome; Off-Label Use; Paliperidone Palmitate; Schizophrenia; Tourette Syndrome; Treatment Outcome

A dose-dependent increase in risk of sudden cardiac death for the antipsychotic drug risperidone was reported. However, few reports have so far addressed QT prolongation associated with the use of risperidone or its major active metabolite, which is also used as a separate antipsychotic drug, paliperidone.. The present study evaluated associations between risperidone metabolism and QT interval in 61 psychiatric patients who had been receiving risperidone for ≥4 weeks at an average dosage of 4.7 mg/day. Plasma risperidone and paliperidone levels were measured and electrocardiographic measurements were also obtained.. There was no correlation between risperidone dosage and QTc or plasma risperidone levels and QTc. However, there was a significant positive correlation between plasma paliperidone levels and QTc (r = 0.361; p = 0.004). There was no correlation between age and dose-corrected plasma risperidone levels or between age and QTc. There was a significant positive correlation between age and dose-corrected plasma paliperidone levels (r = 0.290; p = 0.023).. Clinically, paliperidone is considered to play a more important role in QT prolongation than risperidone.

Topics: Adult; Age Factors; Antipsychotic Agents; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Isoxazoles; Long QT Syndrome; Male; Paliperidone Palmitate; Pyrimidines; Risperidone; Young Adult

The effect of two atypical antipsychotics on QTc intervals (heart rate-corrected QT interval) was evaluated. Patients (N=109) with schizophrenia (79%) or schizoaffective disorder (21%) were randomly assigned in 2 : 2 : 1 ratio to paliperidone extended release (ER), quetiapine, or placebo. Doses of 12 and 18 mg/day of paliperidone ER were compared with quetiapine 800 mg/day. Least-squares mean change from baseline in population-specific linear-derived correction method from baseline to days 6-7 at individual tmax was 5.1 ms less [90% confidence interval: -9.2 to -0.9] with paliperidone ER 12 mg/day than with quetiapine 800 mg/day. On the basis of a prespecified 10-ms noninferiority margin, paliperidone ER was thus declared noninferior to quetiapine (primary analysis). Mean change in population-specific linear-derived correction method from baseline to days 11-12 at individual tmax was 2.3 ms less (90% confidence interval: -6.8 to 2.3) with paliperidone ER 18 mg/day than with quetiapine 800 mg/day. Treatment-emergent adverse events occurred in 36 (82%) patients treated with paliperidone ER, 41 (95%) patients treated with quetiapine, and 14 (64%) patients treated with placebo. No adverse events of a proarrhythmic nature were noted. The effect on the QTc interval in patients with schizophrenia or schizoaffective disorder was comparable between paliperidone ER 12 mg/day (maximum recommended dose), paliperidone ER 18 mg/day (supratherapeutic dose), and quetiapine 800 mg/day.

Topics: Adult; Antipsychotic Agents; Delayed-Action Preparations; Dibenzothiazepines; Double-Blind Method; Electrocardiography; Female; Humans; Isoxazoles; Long QT Syndrome; Male; Middle Aged; Paliperidone Palmitate; Pyrimidines; Quetiapine Fumarate; Schizophrenia; Treatment Outcome

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Ether-A-Go-Go Potassium Channels; Humans; Isoxazoles; Long QT Syndrome; Paliperidone Palmitate; Pyrimidines; Risk Factors

The role of certain drug metabolizing enzymes in cardiotoxicity, such as CYP2D6 for thioridazine, has been suggested. Risperidone has been shown to inhibit the delayed rectifier leading to lengthening of cardiac repolarization. The heart-rate corrected QT (QTc) interval lengthening has been reported in psychiatric patients receiving risperidone under steady-state conditions. CYP2D6 is involved in the metabolism of risperidone to 9-hydroxy (OH)-risperidone. CYP2C9 enzyme is also involved in the metabolism of several psychotropic drugs, although there are no data about its implication in risperidone metabolism. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and plasma concentrations of risperidone and 9-OH-risperidone on the QTc interval in patients under steady-state conditions. The relevance of CYP2D6 and CYP2C9 genotypes on risperidone metabolism was also analysed. Thirty-five White European psychiatric patients receiving risperidone monotherapy were studied. QTc interval was longer (p < 0.05) in subjects with one active CYP2D6 gene compared to those with two. The number of CYP2D6 active genes was related to the dose-corrected plasma concentration of risperidone (p < 0.05), the active moiety (risperidone plus 9-OH-risperidone) (p < 0.05) and the risperidone/9-OH-risperidone ratio (p < 0.05). CYP2C9 genotypes were not related to plasma concentrations of risperidone or 9-OH-risperidone, nor QTc interval. The results suggest that CYP2D6, but not CYP2C9, may be related to QTc lengthening during treatment with risperidone. The effect of the CYP2D6 genotype in risperidone metabolism is also shown.

Topics: Administration, Oral; Adult; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Drug Administration Schedule; Electrocardiography; Genotype; Humans; Isoxazoles; Long QT Syndrome; Middle Aged; Paliperidone Palmitate; Pyrimidines; Risperidone