Positive And Negative Syndrome Scale Total Score Change Research Articles

Effectiveness and Safety of Switching from Oral Antipsychotics to Once-Monthly Paliperidone Palmitate (PP1M) in the Management of Schizophrenia: A Systematic Review and Meta-Analysis.

Considering the improvement in adherence and convenience, once-monthly paliperidone palmitate (PP1M) has been increasingly used in the treatment of schizophrenia. However, the outcomes for patients who switch from oral antipsychotics (OAPs) to PP1M have not been reliably assessed. The objective of this systematic review and meta-analysis was to investigate the efficacy and safety of PP1M in the management of patients with schizophrenia with a prior history of OAP use. We conducted a systematic search in PubMed, EMBASE, and the Cochrane Library on 19 July 2022 to identify eligible studies. All studies that examined the effectiveness and safety of switching from OAPs to PP1M in patients with schizophrenia were included. The primary outcomes were relapse rate, hospitalisation rate, and the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. The secondary outcomes included the changed number of inpatient visits, changed length of stay hospitalisation, change from baseline in the Clinical Global Impressions-Severity (CGI-S) score and the personal and social performance (PSP) total score, response rate, proportion of treatment discontinuation, and adverse events. We included randomised-controlled trials (RCTs), single-arm studies, and observational studies. Case reports, case series, and reviews were excluded. The quality assessment of included studies was performed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB2), the 9-point Newcastle-Ottawa Scale (NOS) instrument for non-randomised studies and cohort studies, and the 12-item National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) study without control group. Follow-up times were reported as short- (≤ 13 weeks), medium- (14-26 weeks), and long term (≥ 27 weeks). Data were pooled using meta-analysis. Fifteen studies with a total of 4740 patients were included. The long-term relapse rates and hospitalisation rates were 12% (95% CI 0.07-0.18) and 18% (95% CI 0.15-0.20), respectively. The short-, medium-, and long-term change in PANSS total score was - 21.69 (95% CI - 30.02 to -13.36), - 14.98 (95% CI - 21.45 to - 8.51) and - 17.88 (95% CI - 31.94 to -3.82), respectively. Approximately 50% of patients reported at least a 30% reduction in the PANSS score at the short-term follow-up. Improvements in CGI-S and PSP score were observed during various periods. There was a reduction in the length of stay hospitalisation and the number of inpatient visits at the medium- and long-term follow-ups. Low discontinuation and adverse event rates were reported. Based on our findings, this study may support the efficacy and safety of switching from OAPs to PP1M for the treatment of patients with schizophrenia. Future large-scale studies are warranted to confirm our findings.

ENHANCE: Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin for Schizophrenia in Patients With an Inadequate Response to Antipsychotic Treatment

AbstractInadequate response to antipsychotic treatment is common in patients with schizophrenia. This study evaluated pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, as adjunctive treatment in patients with inadequate response. This was a 6-week, randomized, double-blind, placebo-controlled, study conducted in North America and Europe. Adult outpatients with schizophrenia and inadequate response to current antipsychotic were enrolled. Inclusion criteria included Positive and Negative Syndrome Scale (PANSS) total score ≥65 and ≤110 and retrospective antipsychotic treatment stability of 8 weeks. Pimavanserin 20 mg/day or placebo added to ongoing antipsychotic was tested in a flexible-dose paradigm with dose adjustments allowed during the first 3 weeks. The primary efficacy endpoint, PANSS total score change from baseline to week 6, was not met, although improvement was greater with pimavanserin than placebo (LS mean difference: –2.1, [95% CI: –4.5, 0.4]; P = .094). As a hierarchical testing procedure was used, additional efficacy analyses were exploratory. Clear separation from placebo was observed with pimavanserin at week 6 for the PANSS Negative Symptoms subscale (LS mean difference: –0.7, [95% CI: –1.5, 0.0]) and Marder Negative Symptom Factor score (–0.9, [–1.7, –0.1]). Analysis of European sites (81.5% of patients) revealed a difference for pimavanserin versus placebo on PANSS total score (LS mean difference: –3.1, [95% CI: –5.8, –0.4]) and Clinical Global Impressions–Severity score (–0.2, [–0.4, –0.0]). Treatment-emergent adverse events occurred in 39.9% with pimavanserin and 36.4% with placebo. Although statistical significance for the primary endpoint was not met, a trend toward improvement in negative symptoms was observed with pimavanserin, warranting further study.

Relationship between clinical outcomes measures and personal and social performance functioning in a prospective, interventional study in schizophrenia

ObjectivesTo explore clinical and demographic characteristics impacting patient functioning by determining extent of overlap in factors driving change in Personal and Social Performance (PSP) and other clinical outcomes.MethodsPost‐hoc analysis from a single‐arm trial of paliperidone extended release in adult patients with nonacute symptomatic schizophrenia. Psychosocial functioning measures: PSP, Clinical Global Impression–Severity (CGI‐S), Positive and Negative Syndrome Scale (PANSS), Short‐Form 36 (SF‐36), treatment satisfaction, sleep quality/daytime drowsiness, and Extrapyramidal Symptoms Rating Scale.ResultsHighest correlations with PSP total score change included PANSS total score change (Spearman's r = 0.607), PANSS general psychopathology change (r = 0.579), and CGI‐S change (r = 0.569). A PSP score change of −32 predicted 90% probability of deterioration in CGI‐S (score change of ≥1). The power of PSP change to predict PANSS total score change was lower. Linear stepwise regression demonstrated independent relationships for PSP change and: PANSS total change; CGI‐S change; SF‐36 Mental Component change; treatment satisfaction at endpoint; PSP at baseline; previous psychiatric hospitalizations. R 2 = 0.55 meant that 45% of PSP variation could not be explained by other clinical outcome measures.ConclusionsPsychosocial functioning improvement is important in schizophrenia. PSP may be valuable for assessing functioning; it encompasses psychosocial and clinical factors not measured by other established assessments.

M191. EFFECT OF BREXPIPRAZOLE ON ENGAGEMENT IN PATIENTS WITH SCHIZOPHRENIA: POST-HOC ANALYSIS OF THREE STUDIES

BackgroundIn schizophrenia, a patient’s quality of life and level of psychosocial functioning is dependent on two key domains: the severity of their psychotic symptoms, and the side effects of antipsychotic medication. In addition, people with schizophrenia experience motivation deficits, thus patient engagement is a key component of successful schizophrenia treatment outcomes.The present analyses investigated the effect of brexpiprazole (a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all at similar potency) on patient engagement. The concept of patient engagement stems from the collective post-marketing experience with brexpiprazole, and has been established in patients with MDD and an inadequate response to antidepressant treatments treated with adjunctive brexpiprazole.To explore the concept of engagement in schizophrenia, 11 out of the 30 items in the Positive and Negative Syndrome Scale (PANSS) were identified as relevant to capture patient improvement and well-being beyond an improvement of the core symptoms of schizophrenia.MethodsThe studies [Vector (NCT01396421), Beacon (NCT01393613) and Lighthouse (NCT01810380)] included patients aged 18–65 years experiencing an acute exacerbation of schizophrenia (DSM-IV-TR criteria), and who would benefit from hospitalization or continued hospitalization. Eligible patients were randomized to 6 weeks treatment with placebo or brexpiprazole ranging from doses of 0.25 to 4 mg/day depending on the study. The primary efficacy analysis in all three studies was the mean change in PANSS Total score from baseline (randomization) to Week 6. The PANSS was administered at weekly intervals.Items N1, N2, N3, N4, N5, N6, G6, G7, G13, G15, and G16 were selected from the PANSS as relevant items to capture patient engagement.In the present analysis, data were pooled for patients allocated to placebo and to a brexpiprazole dose in the range of 2–4 mg. Mean changes from baseline on the selected PANSS items were analyzed using a mixed model repeated measures approach. A Principal Component Analysis (PCA) was performed to validate whether changes in the selected items clustered together. Standardized effect sizes were also calculated.ResultsIn the short-term studies, the PANSS scale was completed at baseline by a total of 1,378 patients, brexpiprazole 2–4 mg (n=863); placebo (n=515). At Week 6, an improvement (p<0.05) was observed on 10 out of the 11 selected items from the PANSS scale, with LS mean differences versus placebo in the range of -0.11 to -0.24.The PCA showed that the majority of the selected items cluster together, confirming the importance of the selected items for patient engagement/re-engagement with their lives. The standardized effect size for brexpiprazole versus placebo was -0.31 for the combined 11 selected items and of a similar magnitude as the effect size of the PANSS Total score (-0.32).Discussion11 items from the PANSS scale were selected to capture patient re-engagement. The clustering, as shown by the PCA, validated the selection of the specific engagement items. The results of these exploratory post-hoc analyses suggest that treatment with brexpiprazole, in addition to improving symptoms of schizophrenia, has the potential to also improve patient well-being and engagement with life.

Efficacy and Acceptability of Cariprazine in Acute Exacerbation of Schizophrenia: Meta-Analysis of Randomized Placebo-Controlled Trials.

The purpose of this study was to assess the efficacy and acceptability of cariprazine treatment in acute exacerbation of schizophrenia. This review included randomized controlled trials of patients with acute exacerbation of schizophrenia in relation to efficacy and acceptability. The efficacy outcomes were assessed by pooling standardized mean differences (SMDs) calculated from the difference in the reduction in the mean of the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive and negative scores, and response rate. The primary acceptability outcomes were determined by pooling the risk ratios (RRs) of discontinuation for any reason, the incidence of serious adverse events, and treatment emergent events. Four randomized controlled trials consisting of 1843 patients met all inclusion and exclusion criteria. Efficacy analysis showed significant positive effects in relation to cariprazine therapy (SMD: -0.37, P < 0.00001 for PANSS total score change; SMD: -0.32, P < 0.00001 for PANSS positive score change; SMD: -0.32, P < 0.0001 for PANSS negative score change; RR, 1.41; 95% confidence interval [CI], 1.19-1.67; P < 0.0001 for response rate). For primary acceptability outcomes, less patients taking cariprazine discontinued treatment for any reason compared with patients receiving placebo (RR, 0.90; 95% CI, 0.78-1.04; P = 0.16). Significantly less patients on cariprazine had serious adverse events during the double-blind treatment period compared with patients taking placebo (RR, 0.55; 95% CI, 0.34-0.89; P = 0.01). Significantly more patients on cariprazine had treatment emergent events compared with those receiving placebo (RR, 1.10; 95% CI, 1.03-1.18; P = 0.006). Results suggest that cariprazine may be an effective and acceptable treatment for schizophrenia and future research is warranted.

Pregnenolone as an adjunct to risperidone for treatment of women with schizophrenia: A randomized double-blind placebo-controlled clinical trial

There have been few studies of pregnenolone therapy in schizophrenia and those that exist have been subject to several critical limitations, thus yielding inconsistent results. We attempted to assess the therapeutic effect of pregnenolone in a patient sample as homogeneous as possible. In this randomized double-blind clinical trial, 82 female inpatients with chronic schizophrenia, who had discontinued their antipsychotic medications for at least one week in case of any oral antipsychotic medication or a month for any depot antipsychotic medication, received risperidone plus either pregnenolone (50 mg/day) or placebo for 8 weeks. Inclusion criteria were acute illness with a baseline Positive and Negative Syndrome Scale (PANSS) negative subscale score of ≥20. Exclusion criteria were the presence of severe depression or other concomitant psychiatric disorders. Primary outcome was defined as the difference in the PANSS total score change from baseline to week 8 in the pregnenolone group compared to the placebo group. No significant difference was found in the PANSS total score changes between the two arms (mean difference (CI 95%) = −9.41 (−20.24 to 1.41); p = 0.087). Significant differences were initially found for PANSS negative change scores (mean difference (CI 95%) = −2.61 (−5.03 to −0.19); p = 0.035) and general psychopathology change scores (mean difference (CI 95%) = −5.93 (−11.37 to −0.48); p = 0.033). However, these findings did not survive Bonferroni correction for multiple testing. While this trial may suggest a potential effect of pregnenolone on schizophrenia symptoms, further studies are warranted.

Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia.

Although clozapine has been shown to be the treatment of choice in people with schizophrenia that are resistant to treatment, one third to two thirds of people still have persistent positive symptoms despite clozapine monotherapy of adequate dosage and duration. The need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine is the most common reason for simultaneously prescribing a second antipsychotic drug in combination with clozapine.To determine the efficacy and tolerability of various clozapine combination strategies with antipsychotics in people with treatment resistant schizophrenia.We searched the Cochrane Schizophrenia Group Trials Register (March 2008) and MEDLINE (up to November 2008). We checked reference lists of all identified randomised controlled trials and requested pharmaceutical companies marketing investigational products to provide relevant published and unpublished data.We included only randomised controlled trials recruiting people of both sexes, aged 18 years or more, with a diagnosis of treatment-resistant schizophrenia (or related disorders) and comparing clozapine plus another antipsychotic drug with clozapine plus a different antipsychotic drug.Two review authors independently extracted data and resolved disagreement by discussion with third member of the team. When insufficient data were provided, we contacted the study authors.Three small (range of number of participants 28 to 60) randomised controlled trials were included in the review. Even though results from individual studies did not find that one combination strategy is better than the others, the methodological quality of included studies was too low to allow authors to use the collected data to answer the research question correctly.In this review we considered the risk of bias too high because of the poor quality of the retrieved information (small sample size, heterogeneity of comparisons, flaws in the design, conduct and analysis). Although clinical guidelines recommend a second antipsychotic in addition to clozapine in partially responsive patients with schizophrenia, the present systematic review was not able to show if any particular combination strategy was superior to the others. New, properly conducted, randomised controlled trials independent from the pharmaceutical industry need to recruit many more patients to give a reliable estimate of effect or of no effect of antipsychotics as combination treatment with clozapine in patients who do not have an optimal response to clozapine monotherapy.

Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies

Brexpiprazole, a serotonin-dopamine activity modulator, is a partial agonist at 5-HT1A and dopamine D2 receptors, and antagonist at 5-HT2A and noradrenaline α1B and α2C receptors, all at similar potency. Efficacy of brexpiprazole was evaluated in patients with acutely exacerbated schizophrenia in three short-term, randomized, double-blind, placebo-controlled studies.In a Phase 2 study, patients were randomized to brexpiprazole 0.25mg (fixed dose), 1.0±0.5mg, 2.5±0.5mg, 5.0±1mg (flexible-dose ranges), placebo, or aripiprazole 15±5mg. In two Phase 3 studies, patients were randomized to fixed-dose brexpiprazole 0.25mg, 1mg, 2mg, or 4mg, or placebo. For this review, brexpiprazole 2mg and 4mg arms from the Phase 3 studies were combined. Primary efficacy endpoint was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline at week 6; key secondary endpoint was change in Clinical Global Impression-Severity of illness (CGI-S) score at week 6. Primary outcome moderator analyses explored effects of sex, age, race, and illness duration.There were no statistically significant differences vs. placebo in the Phase 2 brexpiprazole and aripiprazole groups for primary and key secondary endpoints. Combined brexpiprazole 2mg (n=359) and 4mg (n=359) were superior to placebo (n=358) in change in PANSS total score (least square mean difference from placebo: −5.46, p=0.0004, and −6.69, p<0.0001, respectively) and CGI-S (−0.25, p=0.0035, and −0.38, p<0.0001, respectively). Changes from baseline in efficacy endpoints were minimal in the 0.25mg group, while the 1mg group exhibited suboptimal improvement. No relevant moderators were identified.Meta-analysis of the pivotal studies indicates brexpiprazole 2mg and 4mg are effective in treating acute schizophrenia.

Cariprazine in the treatment of schizophrenia: a proof-of-concept trial.

This 6-week, double-blind, placebo-controlled, proof-of-concept study evaluated the efficacy, safety, and tolerability of low-dose (1.5–4.5 mg/day) and high-dose (6–12 mg/day) cariprazine in patients with acute exacerbation of schizophrenia (NCT00404573). The primary efficacy measure was change in the Positive and Negative Syndrome Scale (PANSS) total score, analyzed using a last observation carried forward approach. Other efficacy measures included the Clinical Global Impression-Severity (secondary) and PANSS subscales (additional). There were no significant differences between the two doses of cariprazine and placebo in PANSS total score change or any other efficacy parameter after multiplicity adjustment. However, low-dose cariprazine versus placebo showed significantly greater reductions in PANSS total (P=0.033) and PANSS negative (P=0.027) scores without multiplicity adjustment. Common treatment-emergent adverse events (incidence≥5% and twice that in the placebo group in either cariprazine dose group) were akathisia, restlessness, tremor, back pain, and extrapyramidal disorder. In this study, the overall cariprazine treatment effect was not statistically significant, but patients treated with low-dose cariprazine showed significantly greater improvement in schizophrenia symptoms relative to placebo-treated patients. Cariprazine was generally well tolerated. Results of this study suggest that cariprazine may be effective in treating schizophrenia and future research is warranted.

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine.

The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤ 5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Of 396 patients, 65.2% were men, mean age was 40.0 ± 12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥ 20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8 ± 5.2 kg at endpoint, and a clinically relevant weight gain of ≥ 7% occurred in 8.0% of patients. Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

Activation of Th17 cells in drug naïve, first episode schizophrenia

The present study was to examine the role of pro-inflammatory T helper 17 (Th17) cells in drug naïve, first episode schizophrenia. Patients with normal weight, drug naïve, first episode schizophrenia and healthy controls were enrolled in the study. Flow cytometric analysis was performed to analyze the proportion of Th17 cells among the CD4(+) T cells. Plasma levels of interleukin-17 (IL-17), interferon-γ (IFN-γ) and interleukin-6 (IL-6) were examined using enzyme-linked immunosorbent assay (ELISA). Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). All measures were repeated for the patient group after 4 weeks of risperidone treatment. Sixty-nine patients with normal weight, drug naïve, first episode schizophrenia and 60 healthy controls were enrolled. At baseline, the patient group hadz significantly higher proportions of Th17 cells and plasma levels of IFN-γ and IL-6 compared with the control group (p's<0.01). Within the patient group, there were significant positive relationships between the proportion of Th17 cells, plasma levels of IL-17, IFN-γ, IL-6 and the PANSS total score after controlling for potential confounding variables (p's<0.05). After 4weeks of risperidone treatment, the proportion of Th17 cells decreased significantly (p <0.001), and there was a significant positive relationship between the PANSS total score change rate and the change in proportion of Th17 cells (p = 0.039). Patients with normal weight, drug naïve, first episode schizophrenia present activation of Th17 cells, which might be associated with therapeutic response after risperidone treatment.

Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia

Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = -0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia.

Adjunctive Use of Nonsteroidal Anti-inflammatory Drugs for Schizophrenia: A Meta-analytic Investigation of Randomized Controlled Trials

To meta-analytically assess the efficacy and tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs) vs placebo in schizophrenia. Searching PubMed, PsycINFO, ISI Web of Science, and the US National Institute of Mental Health clinical trials registry from database inception to December 31, 2012, we conducted a systematic review/meta-analysis of randomized placebo-controlled studies assessing the efficacy of adjunctive NSAIDs. Primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included change in PANSS positive and negative subscores, all-cause discontinuation, and tolerability outcomes. Random effects, pooled, standardized mean changes (Hedges' g) and risk ratios were calculated. Across 8 studies, including 3 unpublished reports (n = 774), the mean effect size for PANSS total score was -0.236 (95% CI: -0.484 to 0.012, P = .063, I(2) = 60.6%), showing only trend-level superiority for NSAIDs over placebo. The mean effect sizes for the PANSS positive and negative scores were -0.189 (95% CI: -0.373 to -0.005, P = .044) and -0.026 (95% CI: -0.169 to 0.117, P = .72), respectively. The relative risk for all-cause discontinuation was 1.13 (95% CI: 0.794 to 1.599, P = .503). Significant superiority of NSAIDs over placebo regarding PANSS total scores was moderated by aspirin treatment (N = 2, P = .017), inpatient status (N = 4, P = .029), first-episode status (N = 2, P = .048), and (in meta-regression analyses) lower PANSS negative subscores (N = 6, P = .026). These results indicate that adjunctive NSAIDs for schizophrenia may not benefit patients treated with first-line antipsychotics judged by PANSS total score change. NSAIDs may have benefits for positive symptoms, but the effect was minimal/small. However, due to a limited database, further controlled studies are needed, especially in first-episode patients.

Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses.

BackgroundA considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ).MethodsPost hoc analyses were done based on two randomized studies (one short-term, one long-term) conducted in patients suffering from schizophrenia and treated with OLAI. The short-term study was an 8-week placebo-controlled, double-blind trial in acute patients, and the long-term study was a 2-year, oral olanzapine-controlled, open-label, follow-up of stabilized outpatients.ResultsThese analyses used data from 62 OLAI-treated patients (12 switched from OLZ, 50 from non-OLZ) from the short-term study and 190 OLAI-treated patients (56 switched from OLZ, 134 from non-OLZ) from the long-term study. Kaplan–Meier survival analyses of time to all-cause discontinuation of OLAI treatment did not differ significantly between OLZ and non-OLZ patients in the short-term study (P=0.209) or long-term study (P=0.448). Similarly, the proportions of OLZ and non-OLZ patients that discontinued OLAI were not statistically different in the short-term (16.7% versus 36.0%, respectively; P=0.198) or long-term (57.1% versus 47.8% respectively; P=0.238) studies. In the short-term study, no significant differences were detected between the patient groups in mean change in Positive and Negative Syndrome Scale (PANSS) total score (−13.4 OLZ versus −20.8 non-OLZ; P=0.166). In the long-term study, mean change in PANSS total score (3.9 OLZ versus −3.6 non-OLZ; P=0.008) was significantly different between the non-OLZ and OLZ groups. Rates of treatment-emergent adverse events were similar in OLZ and non-OLZ groups per study.ConclusionThese post hoc analyses suggest that no significant differences in clinical effectiveness were seen after switching from non-OLZ or OLZ to OLAI. However, these findings should be interpreted with care, due to small sample sizes and differences in patients’ clinical profiles.

Meta-Analyses of the Efficacy of Asenapine for Acute Schizophrenia

Asenapine is an approved treatment for schizophrenia in the United States. Meta-analyses were conducted to evaluate the efficacy of asenapine in acute schizophrenia compared with placebo and other antipsychotics. Four asenapine trials from the asenapine development program were pooled for the meta-analysis. To compare asenapine versus placebo treatment effect with other antipsychotics, we added integrated asenapine data to a previously published meta-analysis. For comparative efficacy of asenapine versus other second-generation antipsychotics (SGAs), data from a second published meta-analysis were combined with the 4 asenapine trials. To evaluate efficacy, mean change in Positive and Negative Syndrome Scale (PANSS) total score was examined in asenapine and other antipsychotics. To assess clinical relevance, PANSS response rates and associated odds ratios (ORs) for treatment response were assessed. To assess the relative efficacy of SGAs, a network meta-analysis with PANSS total score change was conducted by using data from the 2 published meta-analyses together with asenapine data. Asenapine was superior to placebo with regard to mean change in PANSS total score (last observation carried forward [LOCF]: -3.6, P = .002; mixed model for repeated measures [MMRM]: -4.1, P = .001), an effect comparable to active controls from the same trials (LOCF: -4.0, P = .002; MMRM: -4.8, P = .001). PANSS responder rates were significantly better with asenapine versus placebo (OR, 1.9; P < .001) and comparable to active controls (OR, 1.7; P = .002). Effect sizes for asenapine were somewhat lower than those reported in the literature for other SGAs. Network meta-analysis also demonstrated that the efficacy of asenapine was comparable to that of other SGAs; estimated differences between asenapine and other SGAs ranged from 3.9 points (95% CI, 0.3 to 7.4) greater than ziprasidone to 2.9 points (95% CI, -0.1 to 5.9) less than olanzapine. These meta-analyses indicate that the efficacy of asenapine for acute schizophrenia is superior to placebo and comparable to several other SGAs.

Efficacy and Safety of Quetiapine in Adolescents with Schizophrenia Investigated in a 6-Week, Double-Blind, Placebo-Controlled Trial

The purpose of this study was to evaluate the efficacy and safety of acute quetiapine monotherapy in adolescents with schizophrenia. Patients ages 13-17 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score ≥60 were randomized to 6 weeks of quetiapine (400 or 800 mg/day) or placebo treatment. The primary efficacy measure was change in PANSS total score from baseline to day 42. Safety endpoints included adverse events and assessments of clinical chemistry values, suicidality, and extrapyramidal symptoms. The intent-to-treat population included 220 patients. Least-squares mean change in PANSS total score from baseline to endpoint was -27.31 with quetiapine 400 mg/day, -28.44 with quetiapine 800 mg/day, and -19.15 with placebo (p=0.043 and 0.009 for quetiapine 400 and 800 mg/day, respectively, vs. placebo; mixed-model, repeated-measures analysis). Several secondary efficacy outcomes, including Clinical Global Impressions-Improvement score, supported the primary outcome measure in demonstrating significantly greater improvement in quetiapine groups than in the placebo group. Mean changes in body weight at day 42 were 2.2 kg and 1.8 kg for quetiapine 400 and 800 mg/day, respectively, and -0.4 kg for placebo. Mean changes in certain clinical chemistry parameters, including total cholesterol and triglycerides, were numerically greater in the quetiapine groups than in the placebo group. Adverse events associated with quetiapine were mostly mild to moderate in intensity and were consistent with its known profile in adults with schizophrenia. In this 6-week study of adolescent patients, quetiapine at doses of 400 and 800 mg/day provided significant improvements in symptoms associated with schizophrenia in adolescent patients, including the primary efficacy measure of PANSS total score change. Quetiapine was generally well tolerated with a profile broadly similar to that reported in adult and adolescent populations. Quetiapine Fumarate (SEROQUEL(™)) Compared to Placebo in the Treatment of Adolescent Patients With Schizophrenia (ANCHOR 112). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00090324?term=quetiapine+112&rank=1.

Safety of quetiapine fumarate extended release in the treatment of Korean patients with acute schizophrenia

The aim of this study was to evaluate the efficacy and safety of quetiapine fumarate extended release (XR) in the treatment of Korean subjects with acute schizophrenia. This was an 8-week, multi-center, open-label, non-comparative study to evaluate the efficacy and safety of quetiapine fumarate XR at a daily dose of 400-800 mg. Changes in total scores on the Positive and Negative Syndrome Scale (PANSS) from baseline to week 8 were analyzed to evaluate the efficacy of quetiapine XR. Additionally, the Clinical Global Impression scale and the Montgomery-Åsberg Depression Rating Scale were administered. The mean change in PANSS total scores was -26.8, and the mean PANSS total score at the endpoint was significantly lower than that at baseline. The mean PANSS positive score, negative score, and general score showed statistically significant reductions at the end of the study. Statistically significant changes were also observed in Clinical Global Impression-Severity and Montgomery-Åsberg Depression Rating Scale scores. The most common treatment-related adverse events in the group receiving quetiapine XR were sedation (10.6%) and constipation (9.6%). In this study of Korean patients with acute schizophrenia, quetiapine XR showed clinical efficacy and relatively good tolerability.

A Randomized, Double-Blind Study of Paliperidone Extended-Release in Treatment of Acute Schizophrenia in Adolescents

Paliperidone extended-release (ER) is approved for treatment of schizophrenia in adults but has not been evaluated in adolescents. In this 6-week, double-blind, parallel-group study, participants (n = 201) aged 12 to 17 years, with a Positive and Negative Syndrome Scale (PANSS) total score of 60 to 120 were randomly allocated (1:1:1:1) to receive either placebo or one of three weight-based, fixed doses of paliperidone ER, once-daily (patients weighing 29 to < 51 kg at baseline: 1.5 mg [Low], 3 mg [Medium], or 6 mg [High]; patients weighing ≥ 51 kg: 1.5 mg [Low], 6 mg [Medium], or 12 mg [High]). The mean (SD) change in PANSS total score from baseline to endpoint (primary efficacy variable) was significant for the paliperidone ER Medium-treatment (-17.3 [14.33]; p < .05; n = 54) but not for Low- (-9.8 [16.31]; n = 48) or High-treatment groups (-13.8 [15.74]; n = 47) versus placebo (-7.9 [20.15]; n = 51). By actual dose, the mean (SD) change in PANSS total score was significant for the 3-, 6-, and 12-mg doses (3 mg: -19.0 [15.45]), 6 mg: -13.8 [14.75], and 12 mg: -16.3 [15.41;] all ps < .05), compared with placebo (-7.9 [20.15]). The total percentages of treatment-emergent adverse events were dose-related for the three weight-based treatment groups. With weight-based treatment, only paliperidone ER Medium-treatment (3-6 mg) resulted in significant improvement in symptoms of schizophrenia in adolescents, as did 3, 6, and 12 mg by actual dose strengths. Weight-based dosing of paliperidone ER in adolescents with schizophrenia does not appear to be necessary. Paliperidone ER (1.5-12 mg, once daily) was tolerable, and no new safety concerns were reported.

Med Check

Med Check

Oral Paliperidone

Oral paliperidone extended or prolonged release (Invega®) is an atypical antipsychotic, and is the first agent approved for the treatment of schizoaffective disorder. Paliperidone (or 9-hydroxyrisperidone) is the major active metabolite of the well known atypical antipsychotic risperidone, and its mechanism of action is thought to be the antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors. The clinical efficacy of paliperidone was demonstrated in two 6-week, randomized, double-blind, placebo-controlled, multicentre trials in patients with schizoaffective disorder. One trial was flexible dose in design (3-12 mg/day) and the other was fixed dose in design (3-6 and 9-12 mg/day). Compared with placebo, the change from baseline at study end in the Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint) was significantly greater with paliperidone 3-12 mg/day in one trial and with 9-12 mg/day (but not 3-6 mg/day) in the other trial. However, pooled analyses reported a significantly greater change in PANSS total score across all paliperidone dosages than with placebo. Paliperidone was generally well tolerated in the 6-week trials, and no unexpected adverse events were reported. The most commonly reported treatment-emergent adverse events were headache, tremor, dizziness, insomnia, nausea, akathisia, dyspepsia, hypertonia, somnolence and sedation. Although long-term efficacy and tolerability data and comparisons with other antipsychotics are needed, paliperidone appears to be a useful agent for the short-term management of patients with schizoaffective disorder.