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Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia.

ABSTRACT: CONTEXT:Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations. OBJECTIVES:Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects. DESIGN:Two groups of SZ subjects (RLAI, N=9; and RisO, N=13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and 6 months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked. MAIN OUTCOME MEASURE:ICM volume change scores were adjusted for the change in the HCs. RESULTS:ICM volume increased significantly (p=.005) in RLAI and non-significantly (p=.39) in the RisO groups compared with that of the healthy controls. A differential between-group treatment effect was at a trend level (p=.093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p<.05). CONCLUSIONS:The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.

SUBMITTER: Bartzokis G

PROVIDER: S-EPMC3567927 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia.

Bartzokis George G Lu Po H PH Raven Erika P EP Amar Chetan P CP Detore Nicole R NR Couvrette Alexander J AJ Mintz Jim J Ventura Joseph J Casaus Laurie R LR Luo John S JS Subotnik Kenneth L KL Nuechterlein Keith H KH

Schizophrenia research 20120717 1-3

<h4>Context</h4>Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable ...[more]

PMID: 22809684

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Project description:ObjectiveFirst-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone.DesignDouble-blind, randomized study.SettingOutpatient or inpatient.ParticipantsAdults with established (≥1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l-6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days.MeasurementsPositive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ≥30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted.ResultsPositive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period.ConclusionDuring the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.

Project description:BackgroundThis post hoc subgroup analysis of a randomized, double-blind trial evaluated the response to treatment with two long-acting injectable atypical antipsychotics, ie, paliperidone palmitate and risperidone long-acting injectable (RLAI), in subjects with schizophrenia experiencing clinically significant symptoms despite recent treatment with oral risperidone only or other oral antipsychotics.MethodsAdult subjects were eligible for the 13-week, double-blind, double-dummy trial (NCT00589914) if they had an established diagnosis of schizophrenia for at least one year and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 inclusive at screening. Subjects received either paliperidone palmitate (234 mg, day 1; 156 mg, day 8; then once-monthly flexible dosing) or RLAI (25-50 mg biweekly, with oral risperidone supplementation on days 1-28), plus matched placebo injections/tablets.ResultsThis post hoc analysis reports data on 747 subjects who, within 2 weeks of starting double-blind study medication, had reportedly received oral risperidone only (paliperidone palmitate group, n = 126; RLAI group, n = 107), other oral antipsychotics (paliperidone palmitate group, n = 199; RLAI group, n = 203), or no antipsychotic (paliperidone palmitate group, n = 56; RLAI group, n = 56). Mean PANSS total scores improved significantly at end point across all subgroups (mean change from baseline ranged from -17.5 to -19.5, all P < 0.0001). Clinical Global Impression-Severity and Personal and Social Performance scale measures also significantly improved from baseline (all P < 0.0001).ConclusionTreatment with paliperidone palmitate or RLAI resulted in a significant reduction in the symptoms of schizophrenia irrespective of previous recent treatment with oral risperidone only or other oral antipsychotics. For subjects who had previously received oral risperidone only, the difference in formulation was the main change in the intervention because the molecule delivered remained the same or similar. These data support the contribution of a long-acting formulation to improving the treatment response and suggest that nonadherence may be a significant contributor to inadequate efficacy of oral formulations in subjects with schizophrenia.

Project description:ImportanceLong-acting, injectable, second-generation antipsychotic medication has tremendous potential to bring clinical stability to persons with schizophrenia. However, long-acting medications are rarely used following a first episode of schizophrenia.ObjectiveTo compare the clinical efficacy of the long-acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia.Design, setting, and participantsA randomized clinical trial performed at a university-based research clinic, between 2005 and 2012. Eighty-six patients with recent onset of schizophrenia were randomized to receive long-acting injectable risperidone or oral risperidone. Half of each group was simultaneously randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being. An intent-to-treat analysis was performed between October 4, 2012, and November 12, 2014.InterventionsA 12-month trial comparing the long-acting injectable vs oral risperidone and cognitive remediation vs healthy-behaviors training.Main outcomes and measuresPsychotic relapse and control of breakthrough psychotic symptoms.ResultsOf the 86 patients randomized, 3 refused treatment in the long-acting injectable risperidone group. The psychotic exacerbation and/or relapse rate was lower for the long-acting risperidone group compared with the oral group (5% vs 33%; χ21 = 11.1; P < .001; relative risk reduction, 84.7%). Long-acting injectable risperidone better controlled mean levels of hallucinations and delusions throughout follow-up (β = -0.30; t68 = -2.6, P = .01). The cognitive remediation and healthy-behaviors training groups did not differ significantly regarding psychotic relapse, psychotic symptom control, or hospitalization rates, and there were no significant interactions between the 2 medications and the 2 psychosocial treatments. Discontinuations owing to inadequate clinical response were more common in the oral group than in the long-acting risperidone group (χ21 = 6.1; P = .01). Adherence to oral risperidone did not appear to differ before randomization but was better for the long-acting risperidone group compared with the oral group (t80 = 5.3; P < .001). Medication adherence was associated with prevention of exacerbation and/or relapse (χ21 =11.1; P = .003) and control of breakthrough psychotic symptoms (β = 0.2; t79 = 2.1; P = .04).Conclusions and relevanceThe use of long-acting injectable risperidone after a first episode of schizophrenia has notable advantages for clinical outcomes. The key clinical advantages are apparently owing to the more consistent administration of the long-acting injectable. Such formulations should be offered earlier in the course of illness.Trial registrationclinicaltrials.gov Identifier: NCT00333177.

Project description:Little is known about the comparative effectiveness of atypical antipsychotics in long-acting injection formulation. Due to the absence of head-to-head studies comparing olanzapine long-acting injection and risperidone long-acting injection, this study was intended to make exploratory, indirect, cross-study comparisons between the long-acting formulations of these two atypical antipsychotics in their effectiveness in treating patients with schizophrenia.Indirect, cross-study comparisons between olanzapine long-acting injection and risperidone long-acting injection used 12-month treatment-completion rates, because discontinuation of an antipsychotic for any cause is a recognized proxy measure of the medication's effectiveness in treating schizophrenia. Following a systematic review of the literature, two indirect comparisons were conducted using open-label, single-cohort studies in which subjects were stabilized on an antipsychotic medication before depot initiation. The first analysis compared olanzapine long-acting injection (one study) with pooled data from nine identified risperidone long-acting injection studies. The second analysis was a "sensitivity analysis," using only the most similar studies, one for olanzapine long-acting injection and one for risperidone long-acting injection, which shared near-identical study designs and involved study cohorts with near-identical patient characteristics. Pearson Chi-square tests assessed group differences on treatment-completion rates.Comparison of olanzapine long-acting injection data (931 patients) with the pooled data from the nine risperidone long-acting injection studies (3950 patients) provided almost identical 12-month treatment-completion rates (72.7% versus 72.4%; P = 0.87). When the two most similar studies were compared, the 12-month completion rate for olanzapine long-acting injection was significantly higher than for risperidone long-acting injection (81.3% versus 47.0%; P < 0.001). However, any conclusions drawn from this comparison may be limited by differences in the studies' geographic catchment areas.Using treatment-completion rates as a proxy measure of medication effectiveness, olanzapine long-acting injection did not differ significantly from risperidone long-acting injection when including all eligible studies. However, the findings of this exploratory analysis should be interpreted with caution, considering the methodological limitations of these indirect, cross-study comparisons.

Project description:Obesity induced by antipsychotics severely increases the risk of many diseases and significantly reduces quality of life. Genome Wide Association Studies has identified fat-mass and obesity-associated (FTO) gene associated with obesity. The relationship between the FTO gene and drug-induced obesity is unclear.Two hundred and fifty drug naïve, Chinese Han patients with first-episode schizophrenia were enrolled in the study, and genotyped for four single nucleotide polymorphisms (SNPs rs9939609, rs8050136, rs1421085 and rs9930506) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Body weight and body mass index (BMI) were measured at baseline and six months after risperidone treatment.At baseline, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609; body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p's < 0.05). After 6 months of risperidone treatment, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609 (p's <0.01); body weight and BMI of CC homozygotes were lower than those of A allele carriers in rs8050136 (p's < 0.05); body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p's < 0.05). After controlling for age, gender, age of illness onset, disease duration, weight at baseline and education, weight gain of TT homozygotes at 6 months remained to be lower than those of A allele carriers in rs9939609 (p < 0.01); weight gain of CC homozygotes at 6 months was lower than those of A allele carriers in rs8050136 (p = 0.01). Stepwise multiple regression analysis suggested that, among 4 SNPs, rs9939609 was the strongest predictor of weight gain after 6 months of risperidone treatment (p = 0.001).The FTO gene polymorphisms, especially rs9939609, seem to be related to weight gain after risperidone treatment in Chinese Han patients with first episode schizophrenia.

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Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia.

Publications

Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia.

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