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Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

ABSTRACT: The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6_Mage [2.9] years; 21 women; placebo group: 39; 18.3_Mage [2.7]; 22 women); and 42 healthy controls (19.2_Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; η_p² = 0.062; verbal learning: p = 0.015; η_p² = 0.072 both medium effects; delayed recall: p = 0.001; η_p² = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).

SUBMITTER: Allott K

PROVIDER: S-EPMC10257667 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

Allott Kelly K Yuen Hok Pan HP Baldwin Lara L O'Donoghue Brian B Fornito Alex A Chopra Sidhant S Nelson Barnaby B Graham Jessica J Kerr Melissa J MJ Proffitt Tina-Marie TM Ratheesh Aswin A Alvarez-Jimenez Mario M Harrigan Susy S Brown Ellie E Thompson Andrew D AD Pantelis Christos C Berk Michael M McGorry Patrick D PD Francey Shona M SM Wood Stephen J SJ

Translational psychiatry 20230610 1

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperido ...[more]

PMID: 37301832

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Project description:PURPOSE:Reducing the dosing frequency of antipsychotics (APs) with long-acting injectables (LAIs) such as once-monthly paliperidone palmitate (PP1M) can improve adherence and clinical outcomes for schizophrenia patients. This US study compared physical and psychiatric comorbidity-related outcomes, AP adherence, healthcare resource utilization (HRU), and costs pre- and post-transition to PP1M among schizophrenia patients treated with oral risperidone/paliperidone pre-PP1M transition. METHODS:Health insurance claims from the IQVIA™ PharMetrics Plus database (01/01/2012-07/31/2018) were used to identify adults with???2 schizophrenia diagnoses,???1 claim for PP1M, and???30 days of treatment with oral risperidone/paliperidone in the 60 days before the first PP1M claim (i.e., the index date). Comorbidity-related outcomes, adherence to APs (measured via the proportion of days covered [PDC]), all-cause per-patient-per-month (PPPM) HRU, and all-cause PPPM medical, pharmacy, and total costs (i.e., sum of medical and pharmacy costs) during the 6-month periods pre- and post-transition to PP1M were compared using generalized estimating equation models adjusted for repeated measurements. Analyses were replicated in the subset of patients with???1 all-cause inpatient stay pre-PP1M transition. FINDINGS:Among 427 schizophrenia patients transitioning from oral risperidone/paliperidone to PP1M, the mean age was 41.1 years and 37.9% were female. Following the PP1M transition, patients were less likely to have claims with a diagnosis for psychoses (odds ratio [OR] 0.41; P?<?0.001), hypertension (OR 0.80; P?=?0.011), depression (OR 0.70; P?<?0.001), drug abuse (OR 0.60; P?<?0.001), substance-related and addictive disorders (OR 0.73; P?=?0.003), bipolar and related disorders (OR 0.59; P?<?0.001), sleep-wake disorders (OR 0.68; P?=?0.017), anxiety disorders (OR 0.78; P?=?0.034), and other conditions that may require a focus of clinical attention (OR 0.58; P?<?0.001). Mean PDC by APs was higher post-PP1M (mean?=?0.81) versus pre-PP1M (mean?=?0.68) transition. Post-PP1M, patients were less likely to have an all-cause emergency room visit (OR 0.51; P?<?0.001) or inpatient stay (OR 0.39; P?<?0.001) compared to pre-PP1M. All-cause total healthcare costs remained similar post- versus pre-transition to PP1M (mean monthly cost difference [MMCD]?=?$228; P?=?0.260). Pharmacy costs increased post-PP1M (MMCD?=?$960; P?<?0.001), but were offset by decreasing medical costs (MMCD?=?- $732; P?<?0.001), largely driven by lower costs related to inpatient stays (MMCD?=?- $695; P?<?0.001) and emergency room visits (MMCD?=?- $63; P?<?0.001). For patients with???1 all-cause inpatient stay pre-PP1M transition (N?=?177), a more pronounced improvement in comorbidity-related outcomes, a more pronounced reduction in HRU, and a reduction in total healthcare costs (MMCD?=?- $1308; P?<?0.001) were observed post-transition to PP1M. IMPLICATIONS:Among schizophrenia patients in the US, transitioning to PP1M following oral risperidone/paliperidone treatment was associated with improved comorbidity-related outcomes, higher adherence, and a reduction in HRU, while remaining cost neutral. Furthermore, patients with???1 all-cause inpatient stay pre-PP1M transition had significantly lower total healthcare costs post-PP1M transition.

Project description:BackgroundRisperidone is the first new-generation antipsychotic drug made available in the market in its generic form.ObjectivesTo determine the clinical effects, safety and cost-effectiveness of risperidone compared with placebo for treating schizophrenia.Search methodsOn 19th October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. We checked the references of all included studies and contacted industry and authors of included studies for relevant studies and data.Selection criteriaRandomised clinical trials (RCTs) comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia-like psychoses.Data collection and analysisTwo review authors independently screened studies, assessed the risk of bias of included studies and extracted data. For dichotomous data, we calculated the risk ratio (RR), and the 95% confidence interval (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and the 95% CI. We created a 'Summary of findings table' using GRADE (Grading of Recommendations Assessment, Development and Evaluation).Main resultsThe review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence).When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low-quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects.Authors' conclusionsBased on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality.

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: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.

Dataset Information

Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

Publications

Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

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