Paliperidone Treatment Research Articles

Genome-wide association study of paliperidone efficacy.

Clinical response to the atypical antipsychotic paliperidone is known to vary among schizophrenic patients. We carried out a genome-wide association study to identify common genetic variants predictive of paliperidone efficacy. We leveraged a collection of 1390 samples from individuals of European ancestry enrolled in 12 clinical studies investigating the efficacy of the extended-release tablet paliperidone ER (n1=490) and the once-monthly injection paliperidone palmitate (n2=550 and n3=350). We carried out a genome-wide association study using a general linear model (GLM) analysis on three separate cohorts, followed by meta-analysis and using a mixed linear model analysis on all samples. The variations in response explained by each single nucleotide polymorphism (hSNP) were estimated. No SNP passed genome-wide significance in the GLM-based analyses with suggestive signals from rs56240334 [P=7.97×10 for change in the Clinical Global Impression Scale-Severity (CGI-S); P=8.72×10 for change in the total Positive and Negative Syndrome Scale (PANSS)] in the intron of ADCK1. The mixed linear model-based association P-values for rs56240334 were consistent with the results from GLM-based analyses and the association with change in CGI-S (P=4.26×10) reached genome-wide significance (i.e. P<5×10). We also found suggestive evidence for a polygenic contribution toward paliperidone treatment response with estimates of heritability, hSNP, ranging from 0.31 to 0.43 for change in the total PANSS score, the PANSS positive Marder factor score, and CGI-S. Genetic variations in the ADCK1 gene may differentially predict paliperidone efficacy in schizophrenic patients. However, this finding should be replicated in additional samples.

Disruptive behaviour's treatment with paliperidone in autistic disorder: Review and case report

IntroductionAutistic disorder (AD) is a neuropsychiatric disorder that often presents significant disruptive symptoms such as irritability, aggression and self-injury in addition to impairment of social skills and communication. These symptoms interfere both individuals with AD and their families and social environment.ObjectiveShow paliperidone effect in behavioural symptoms in AD.MethodsLiterature review about behavioural symptoms in AD and paliperidone effect in its treatment, followed by a case report of clinical improvement after treatment with paliperidone in a patient with autism. Agitation subscale Aberrant Behavior Checklist (ABC-I) scores was compared prior and 4 weeks after paliperidone treatment, and clinical improvement was assessed with Clinical Global Impression-Improvement Scale (CGI-I).ResultsAlthough risperidone has been one of the most studied atypical antipsychotic to treat this symptoms, its use should be limited in order to avoid extrapyramidal and metabolic symptoms. Paliperidone – the major metabolite of risperidone – has shown effectiveness in the treatment of behavioral symptoms in patients with autism, even in subjects with a prior ineffective trial of risperidone. Our patient, 21-years-old male with AD and significant disruptive symptoms was treated with paliperidone 9 mg/day. We observed a 20-points reduction in ABC-I scores 4 weeks later, with most significant improvement in items like auto-agression, heteroaggressivity, irritability and slams. CGI-I scores showed a much better improvement, and no significant adverse effects appeared.ConclusionsPaliperidone is an effective and safe treatment in behavioral symptoms associated to AD, with reduction in ABC-I subscale scores. More studies are needed to confirm our data.Disclosure of interestThe authors have not supplied their declaration of competing interest.

White-matter connectivity related to paliperidone treatment response in patients with schizophrenia.

The objective of this study was to examine whether white-matter (WM) connectivity of patients with schizophrenia at early stage of treatment is related to treatment response after paliperidone extended-release (ER) treatment. Forty-one patients with schizophrenia and 17 age- and sex-matched healthy control subjects were included in this study. Brain magnetic resonance scans at 3 Tesla were conducted at early stage of treatment. Voxel-wise statistical analysis of the fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics. At baseline and eight weeks after paliperidone treatment, patients were assessed using the Positive and Negative Syndrome Scale, the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Among the patients with schizophrenia, the FA values of the corpus callosum, corona radiata, internal capsule, external capsule, superior longitudinal fasciculus and fronto-temporal WM regions showed significant negative correlations with scores of the treatment response. The current study suggests that the treatment response after paliperidone ER treatment may be associated with the fronto-temporo-limbic WM connectivity at early stage of treatment in patients with schizophrenia, and it could be used as a predictor of treatment response to paliperidone ER treatment after studies with large samples verify these results.

Add-on effects of a low-dose aripiprazole in resolving hyperprolactinemia induced by risperidone or paliperidone

This study investigated the effects of a low-dose aripiprazole adjunctive treatment for risperidone- or paliperidone-induced hyperprolactinemia in Han Chinese women with schizophrenia. After 4 weeks of risperidone or paliperidone treatment, 60 out of 66 patients improved significantly and experienced hyperprolactinemia. They were randomly assigned to the treatment group (aripiprazole adjunctive treatment) (n=30) or control group (non-adjunctive treatment) (n=30). The dosage of risperidone and paliperidone were maintained; and aripiprazole was maintained at 5mg/day during the 8-week study period. The prolactin levels at the end of the 8th week were significantly lower in the treatment group than in the control group. The estradiol level correlated negatively with serum prolactin level both in the treatment group and the control group at the end of the 8th week and the 4th week respectively. The Positive and Negative Syndrome Scale score improved significantly during the 8-week study period in both groups. The incidence of treatment-emergent adverse event was similar in two groups. Low-dose aripiprazole adjunctive treatment is effective in relieving risperidone- and paliperidone-induced hyperprolactinemia in female schizophrenic patients without increasing adverse event.

Mania associated with paliperidone treatment in schizophrenia: A case report

Paliperidone is an atypical antipsychotic drug used to treat schizophrenia. Paliperidone can cause some rare side effects during treatment. Despite many publications of mania and hypomania induced by antipsychotics, mania cases induced by paliperidone are few in the literature. In this case a schizophrenia patient showing symptoms of mania during usage of paliperidone with a dose of 9 mg/day in which the symptoms rapidly disappeared after discontinuation of paliperidone and initiation of aripiprazole was reported. Clinicians should be aware of that Paliperidone treatment may trigger mania symptoms. J Clin Exp Invest 2015; 6 (3): 321-323

Large-scale candidate gene study to identify genetic risk factors predictive of paliperidone treatment response in patients with schizophrenia.

Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy. A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856). We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy. These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)-ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts.

Paliperidone Use in Behavioural Symptoms in Patients with Intellectual Disabilities

Introduction Behavioural symptoms are the first reason of psychiatric assessment in patients with intellectual disabilities (ID), and also the most frequent cause of psychopharmacological treatment. Different rates of prevalence of these symptoms appear in literature data (10-60%). Paliperidone has shown effectiveness in the treatment of behavioural symptoms in patients with autism and asperger syndrome, with significant reduction in ABC-I subscale scores. Conclusions Objectives: Study paliperidone effect in behavioural symptoms' improvement in patients with intellectual disabilities of diverse etiology. Methods 10 outpatients with intellectual disabilities and behavioral symptoms were selected and treated with paliperidone. Sociodemographic and clinical data (type of intellectual disability, previous antipsychotic and paliperidone dose) were registered. Agitation subscale Aberrant Behavior Checklist (ABC-I) scores were compared prior and 4 weeks after psychopharmacological treatment change. Otherwise we assessed clinical improvement with Clinical Global Impression-Improvement (CGI-I). Results All patients were similar in clinical and sociodemographic characteristics. Paliperidone mean dose was 8,4 mg/day (3-18 mg/day), changing from risperidone (44,4%), olanzapine (44,4%) and levomepromacine (11,1%). Mean reduction in ABC-I scores with paliperidone treatment was 6,2 points [with most significant improvement in items like irritability (1,2 points), aggressions (1,1 points) and slams (0,9 points)]. CGI-I scores showed a much better improvement in 60% patients, mildly betterin 30% patients and slightly better in 10% patients. No significant adverse effects leaded to treatment discontinuation. Conclusions 1. Paliperidone is an effective and safe treatment in behavioral symptoms associated to intellectual disabilities. 2. Paliperidone treatment reduces ABC-I subscale scores, with most significant improvement in irritability and aggressions.

Use of high-conductivity sample solution with sweeping-micellar electrokinetic capillary chromatography for trace-level quantification of paliperidone in human plasma.

Paliperidone is a new antipsychotic drug with a relatively low therapeutic concentration of 20-60ng/mL. We established an accurate and sensitive CE method for the determination of paliperidone concentrations in human plasma in this study. To minimize matrix effect caused by quantification errors, paliperidone was extracted from human plasma using Oasis HLB SPE cartridges with three-step washing procedure. To achieve sensitive quantification of paliperidone in human plasma, a high-conductivity sample solution with sweeping-MEKC method was applied for analysis. The separation is performed in a BGE composed of 75 mM phosphoric acid, 100 mM SDS, 12% acetonitrile, and 15% tetrahydrofuran. Sample solution consisted of 10% methanol in 250mM phosphoric acid and the conductivity ratio between sample matrix and BGE was 2.0 (γ, sample/BGE). The results showed it able to detect paliperidone in plasma samples at concentration as low as 10ng/mL (S/N= 3) with a linear range between 20 and 200ng/mL. Compared to the conventional MEKC method, the sensitivity enhancement factor of the developed sweeping-MEKC method was 100. Intra- and interday precision of peak area ratios were less than 6.03%; the method accuracy was between 93.4 and 97.9%. This method was successfully applied to the analysis of plasma samples of patients undergoing paliperidone treatment.

Cost-Utility Analysis of Long-Acting Paliperidone in Comparison with Oral Risperidone, Oral Paliperidone and Long-Acting Risperidone in the Maintenance Treatment of Schizophrenia in the Czech Republic.

The number of patients with schizofrenia in the Czech Republic amounts annually to approximately 126,000. Schizophrenia causes significant increases in mortality, shortening life expectancy by 25 years compared to the general population which implies high disease burden. The aim was to estimate the cost-effectiveness of long-acting paliperidone in the treatment with schizofrenia compared to oral risperidone, oral paliperidone and long-acting risperidone. Cost-utility analysis was performed using a Markov model. The primary outcome was ICER/QALY. Oral risperidone, oral paliperidone and long-acting risperidone were selected as comparators. The basic components of the model include probabilities of relapse, individual hazard ratios for non-compliance by medication type and switch of treatment probabilities. Specific utilities for each health state were considered. Among relevant costs, reflecting payer's perspective, drug acquisition costs, monitoring costs, costs of relapses, follow-up care and adverse events were considered. Long-acting paliperidone reached ICER of EUR 16,233/QALY compared to oral risperidone, EUR 15,058/QALY to oral paliperidone and EUR 335/QALY to long-acting risperidone. The robustness of the model was supported by one-way deterministic analysis and probabilistic sensitivity analysis, which gave stable Results. Long-acting paliperidone was cost effective in 97% of the simulations compared to oral risperidone. Long-acting paliperidone treatment gained incremental 0.903 QALYs on average compared to oral risperidone. The treatment of schizophrenia using long-acting paliperidone is associated with increased QALYs. It reduces incidence of adverse events, Results in better prevention of relapses and can be considered a cost-effective treatment in the Czech Republic.

No change of the lipid profile under the control of ApoE gene polymorphism in schizophrenics under paliperidone treatment.

The present study tried to explore the effects of Paliperidone on the lipid profiles of schizophrenia patients. One hundred twenty-nine subjects diagnosed with schizophrenia were enrolled into this study and completed the lipid profile evaluation. Their blood samples were obtained on the morning following a 12-hours fast. Cholesterol and triglyceride (TG) levels in plasma were determined, and lipoproteins were determined by enzymatic methods. All participants provided written informed consent, and underwent additional venous blood withdrawal for DNA extraction for genetic study of the ApoE gene polymorphism. Under T test, TC, TG and HDL levels all declined after Paliperidone treatment although with no statistically significant difference. The ratios of TC/HDL declined after Paliperidone treatment, but without statistically significant difference. After GEE-I analysis, we found that ApoE4 genotype (β = 34.471; p < 0.001) had a positive effect on the total cholesterol (TC) level; female had positive effect on the high-density lipoprotein (HDL) level (β = 15.361; p = 0.003); and age had a positive effect on the TG level (β = 1.317; p = 0.030). Smoking (β = 0.961; p = 0.016) had a positive effect on the ratio of TC/HDL change. Lipid profiles were not increased after Paliperidone treatment under the control of ApoE gene polymorphism.

Improvement of mitochondrial function by paliperidone attenuates quinolinic acid-induced behavioural and neurochemical alterations in rats: implications in Huntington's disease.

Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopaminergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminergic system and efficient amelioration of chorea following a tetrabenazine administration in Huntington's disease patients. Therefore, the present study has been designed to explore the neuroprotective potential of paliperidone, an active metabolite of risperidone (a dopaminergic antagonist) against QA-induced neurotoxicity and related complications in rats. QA (200nmol) was administered bilaterally to the striatum over a period of 2min by means of a 28-gauge stainless steel needle attached to a Hamilton syringe. The study protocol involves seven treatment groups (n=12): naïve, sham, control (QA), paliperidone (0.5, 1 and 2mg/kg) and paliperidone (2) per se. Single bilateral intrastriatal injection of QA (200nmol/2μl saline) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-α, IL-6, PGE2, PGF2α, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treatment. Treatment with paliperidone (0.5, 1 and 2mg/kg) for 21days significantly attenuated the QA-induced behavioural (motor and memory function), neurochemical (antioxidant enzymes and biogenic amines) and cellular alterations, as well as striatal neurodegeneration. The study indicated that modulation of dopaminergic pathway by paliperidone treatment could be a useful approach in the management of motor and memory abnormality in HD patients.

Two Cases of Diabetic Ketoacidosis Associated with Paliperidone Treatment in Schizophrenia

Two Cases of Diabetic Ketoacidosis Associated with Paliperidone Treatment in Schizophrenia

An open-label, prospective study to evaluate social function and overall improvement of extended-release paliperidone treatment in Thai schizophrenia patients

Previous studies with extended-release (ER) paliperidone have reported an effective outcome in terms of personal and social functioning improvement and also reported schizophrenia symptom improvement. The main objectives of this study were to further investigate improvements in symptom control and social functioning of paliperidone ER and acknowledge the safety profile of paliperidone ER in Thai patients with schizophrenia. Patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders criteria were allowed flexible 3-12 mg/day dosing during the 10-week study duration. Patients were interviewed and assessed in social functioning using the Personal and Social Performance (PSP) scale. Patients were also rated on overall severity of illness using the Clinical and Global Impressions - Severity (CGI-S) scale. In total, 40 patients were enrolled, 80% of enrolled patients (n = 32) completed the 10-week study period. Thirty-eight eligible patients were included in the intention-to-treat analysis set (male 39.5%, female 60.5%). One patient was lost to follow-up without postbaseline-efficacy measurements. Another patient was terminated early due to a change in diagnosis during the trial. Statistically significant improvements from baseline in PSP total score were observed at all time points. Clinically relevant improvement in PSP (increase of at least one 10-point category) was observed in 47.40% of patients at end point. Improvement in CGI-S was observed at end point (P < 0.001). The mean reduction ± standard deviation at end point in CGI-S was 0.8 ± 1.04 (95% confidence interval 0.48-1.16). The most commonly reported adverse events (≥5% of patients) were daytime drowsiness (15%) and headache (15%). Three subjects (7.5%) discontinued due to adverse events. This study suggests that paliperidone ER is well tolerated in Thai patients with schizophrenia. Paliperidone ER showed improvement in schizophrenic symptom control and social functioning.

A prospective open-label trial of paliperidone monotherapy for the treatment of bipolar spectrum disorders in children and adolescents

Treatment studies for the management of pediatric bipolar disorder are limited. This study evaluates the safety and efficacy of paliperidone monotherapy as an acute treatment of mania and related symptoms in youth with bipolar spectrum disorders. An 8-week, prospective, open-label paliperidone monotherapy trial to assess effectiveness and tolerability in treating pediatric bipolar spectrum and related disorders (depression, psychosis, attention-deficit/hyperactivity disorder [ADHD]). Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impression scale (CGI), Children's Depression Rating Scale-Revised (CDRS-R), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis. Fifteen youth with bipolar spectrum disorders (YMRS at entry: 32.8 ± 6.1) were enrolled in the study and 11 (73 %) completed the 8-week trial. The total daily dose of paliperidone at study endpoint was 3 mg in 12 subjects and 6 mg in three subjects. Treatment with paliperidone was associated with statistically significant levels of improvement in mean YMRS scores (-18.7 ± 13.9, p < 0.001) at endpoint. Paliperidone treatment also resulted in significant improvement in the severity of ADHD and psychotic symptoms. Although treatment with paliperidone was generally well tolerated and was not associated with clinically significant change in cardiovascular or metabolic parameters, increases in body weight (4.1 ± 5.5 lb) were substantial. Open-label paliperidone treatment appears to be beneficial in the treatment of bipolar spectrum disorders and associated conditions in youth. Future placebo-controlled studies are warranted to confirm these findings.

Incidence and time course of extrapyramidal symptoms with oral and long-acting injectable paliperidone: a posthoc pooled analysis of seven randomized controlled studies

BackgroundThe purpose of this study was to compare incidence rates and time course of extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) between oral and long-acting injectable (LAI) paliperidone.MethodsThe analysis included pooled data (safety analysis set, 2,256 antipsychotic-treated and 865 placebo-treated patients with schizophrenia) from seven randomized, double-blind, placebo-controlled paliperidone studies (three oral [6 weeks each] and four LAI [9–13 weeks]) and assessed comparable doses (oral, 3–15 mg; LAI, 25–150 mg eq. [US doses 39–234 mg]). We summarized incidence rates and time of onset for EPS-related TEAE, categorized by EPS group terms, ie, tremor, dystonia, hyperkinesia, parkinsonism, and dyskinesia, and use of anti-EPS medication. Mean scores over time for the Abnormal Involuntary Movement Scale (AIMS, for dyskinesia), Barnes Akathisia Rating Scale (BARS, for akathisia), and Simpson Angus Rating Scale (SAS, for parkinsonism) were graphed.ResultsIncidence rates for all categories of spontaneously reported EPS-related TEAEs except for hyperkinesia, were numerically lower in pooled LAI studies than in pooled oral studies. Highest rates were observed in the first week of paliperidone-LAI (for all EPS symptoms except dyskinesia) and oral paliperidone treatment (except parkinsonism and tremor). Anti-EPS medication use was significantly lower in LAI (12%) versus oral studies (17%, P = 0.0035). Mean values for EPS scale scores were similar between LAI and oral treatment at endpoint, and no dose response was evident. Mean reductions (standard deviation) from baseline to endpoint in EPS scale scores were larger for LAI (AIMS, −0.10 [1.27]; BARS, −0.09 [1.06]; SAS, −0.04 [0.20]) versus oral studies (AIMS, −0.08 [1.32]; BARS, −0.03 [1.24]; SAS, 0.0 [0.23]). These changes favored LAI for BARS (P = 0.023) and SAS (P < 0.0001), but not for AIMS (P = 0.49), at endpoint for the studies.ConclusionIn this posthoc descriptive analysis, incidence rates of spontaneously reported EPS-related TEAEs were numerically lower following approximately 90 days of exposure with LAI and approximately 40 days with oral paliperidone at comparable doses.

Treatment With Paliperidone in Children With Behavior Disorders Previously Treated With Risperidone

Paliperidone is the main active metabolite of risperidone, with certain pharmacokinetic and tolerability characteristics that suggest it may be used in special groups, such as children. Our purpose is to document the clinical experience with the use of paliperidone in children with severe behavior problems that were partially refractory to treatment with risperidone and psychological treatment. This is a prospective 16-week open-label study of paliperidone in 18 patients (mean age, 13.4 years) with severe and excessive irritability in the context of generalized developmental disorders or attention-deficit/hyperactivity disorder. Patients who had exhibited an inadequate response to treatment with risperidone (1.5-2 mg/d) over a treatment period of 6 months were treated with paliperidone at 3 mg/d. Symptom severity at the beginning of the study and in response to paliperidone were rated with the Clinical Global Impression (CGI) scale and Overt Aggression Scale. A significant difference was documented between the mean score before treatment and the score after the drug intervention with paliperidone. There was a noticeable clinical improvement in 50% of the cases, as reflected in the CGI. Severity of aggressive behavior, as assessed by the Overt Aggression Scale, decreased significantly after paliperidone treatment: mean (SD), 2.7 (0.92) before treatment versus 1.5 (0.60) after treatment. This compound was safe and well tolerated. Half of the patients clearly responded to paliperidone extended release. Tolerance to this treatment was distinctly better than to risperidone. These preliminary results lay the foundation for further research into the use of paliperidone to treat pediatric disruptive behavior disorders within the context of randomized, double-blind, controlled clinical trials.

Paliperidone for irritability in adolescents and young adults with autistic disorder

Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies. The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism. This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months. Twenty-one (84 %) of 25 subjects ages 12-21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3-12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range -3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001). Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.

Paliperidone Palmitate in a Child with Autistic Disorder

To the Editor: Autistic disorder (autism) is a neuropsychiatric disorder characterized by impairments in social interaction, communication, and stereotyped behaviors and interests (American Psychiatric Association 2000). Individuals with this disorder often exhibit associated interfering symptoms including irritability, hyperactivity, and inattention. Irritability, defined as aggression, severe tantrums, and self-injury, is a particularly limiting symptom with the capacity to diminish the quality of life for both the affected individual and their caregivers. Historically, antipsychotics have been the pharmacologic treatment of choice for irritability in youth with autism. Early research focused on typical antipsychotics such as haloperidol (Cohen et al. 1980; Anderson et al. 1984). Atypical antipsychotics have a lower rate of side effects such as dyskinesias and are currently considered first-line choice for treatment of irritability associated with autistic disorder (Erickson et al. 2007; Blankenship et al. 2010). Both risperidone and aripiprazole were approved by the U.S. Food and Drug Administration (FDA) to treat irritability in youth with autism aged 5–16 and 6–17 years, respectively. Multiple double-blind, placebo-controlled studies have demonstrated the efficacy of risperidone (Research Units on Pediatric Psychopharmacology Autism 2002; Shea et al. 2004) and aripiprazole (Marcus et al. 2009; Owen et al. 2009) for the treatment of this symptom domain. Paliperidone is the active metabolite of risperidone and was approved by FDA to treat schizophrenia and schizoaffective disorder in adults. Stigler et al. (2010) recently described the effectiveness of paliperidone in treating irritability in two individuals with autism. A 16-year-old female patient and a 20-year-old male patient, both diagnosed with autism, were treated with paliperidone (3 and 12 mg/day, respectively) after they demonstrated a lack of adequate improvement on other medication regimens. Both were judged to have significant improvement in their symptoms, including aggression and tantrums, with paliperidone treatment. No adverse events were reported. Both individuals lost weight and experienced improvements in their fasting lipid profiles while taking paliperidone. In 2009, the FDA approved a sustained-release intramuscular (IM) formulation of paliperidone, paliperidone palmitate, for the treatment of adults with schizophrenia. In this report, we demonstrate the successful use of paliperidone palmitate for the treatment of irritability in a child with autism who was unable to tolerate oral medications.

Med Check

Med Check

The Pharmacokinetics of Paliperidone Versus Risperidone

Several new atypical antipsychotics have become available for use, but knowledge about their pharmacology may not be widespread. This review aims to increase awareness and knowledge about risperidone (R) and paliperidone (9-hydroxyrisperidone [9-OHR]), their pharmacokinetics, and pharmacodynamics. The authors present a review of the literature on R and 9-OHR. Oral R may be approximately twice as potent as oral 9-OHR. Levels of R and 9-OHR in R-treated patients may help clinicians prescribe 9-OHR. In R-treated patients, the R/9-OHR concentration ratio is an index of CYP2D6 activity; an inverted ratio (>1) indicates a CYP2D6 poor metabolizer (PM) or the presence of a powerful CYP2D6 inhibitor. The concentration-to-dose (C/D) ratio, where C includes R+9-OHR, is an index of total clearance from the body. A C/D ratio decreased by half is associated with CYP3A inducers or a lack of compliance, whereas an increased C/D ratio may indicate CYP2D6 PM phenotype, use of CYP2D6 and/or CYP3A4 inhibitors, or, possibly, renal insufficiency. In in-vitro studies, R and 9-OHR have similar receptor binding (except for blocking alpha(1)). 9-OHR may have less ability to enter the brain because of greater affinity for the transporter P-glycoprotein. The limited available paliperidone pharmacokinetic information suggests that there are four minor metabolic pathways. In contrast to R treatment, being a CYP2D6 PM may not be clinically relevant for paliperidone treatment. Information on paliperidone drug-drug interactions is limited. Renal excretion may be the major route of paliperidone elimination. Clinicians can use R/9-OHR and the C/D ratios to interpret plasma R levels and guide treatment.