Improvement In Positive And Negative Syndrome Scale Total Score Research Articles

Subgroups of Clinical High Risk for Psychosis Based on Baseline Antipsychotic Exposure: Clinical and Outcome Comparisons Across a 2-Year Follow-up Period.

Antipsychotic (AP) prescription in clinical high risk for psychosis (CHR-P) subjects remains a divisive issue. Although official guidelines currently discourage AP treatment in CHR-P, it is common in clinical practice, especially for psychosis prevention. The aim of this study was to investigate whether baseline AP need (especially in high-dose) indexes a CHR-P subgroup with poorer prognosis and differs from AP-naïve subjects in terms of sociodemographic, clinical, and outcome parameters across a 2-year follow-up. CHR-P participants were treated within an "Early Intervention in Psychosis" program and completed the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale both at baseline and every 12 months. Individuals with baseline AP prescription were included in the high-dose or low-dose CHR-P-AP+ subgroup. The others were grouped as AP-naïve. Cox regression analyses and mixed-design ANOVA were performed. 180 CHR-P individuals were enrolled (32 high-dose, 60 low-dose, and 88 AP-naïve). Compared to AP-naive, CHR-P AP+ subgroups showed older age and more severe clinical presentation. High-dose subgroup also had grater functioning decline at entry and poorer functional recovery at follow-up. No inter-group differences in psychosis transition and symptomatic remission were found. Significant improvement in clinical outcomes were found over time in all subgroups. Baseline AP prescription was specifically associated with a more relevant improvement in PANSS total score, and in negative and disorganized symptoms. Our results suggest that baseline AP need is an important prognostic parameter in CHR-P and should be considered in risk/benefit calculators.

Safety and efficacy of KarXT (Xanomeline Trospium) in Schizophrenia in the Phase 3, Randomized, Double-Blind, Placebo-Controlled EMERGENT-2 Trial

AbstractIntroductionKarXT combines the M1/M4 preferring muscarinic receptor agonist xanomeline and the peripherally restricted anticholinergic trospium. In the phase 2 EMERGENT-1 study, KarXT met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS) total score through week 5 vs placebo, improved other key secondary efficacy measures, and was generally well tolerated.MethodsEMERGENT-2 was a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic patients with schizophrenia in the inpatient setting. Eligible patients were randomized 1:1 to KarXT or matched placebo. Dosing of KarXT (mg xanomeline/mg trospium) started at 50 mg/20 mg BID and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Key secondary endpoints included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, and PANSS negative Marder factor scores compared with placebo. Efficacy analyses were performed using the modified intent-to-treat population (patients with ≥1 dose of study medication, a baseline PANSS assessment, and ≥1 postbaseline PANSS assessment). All patients receiving ≥1 dose of study drug were included in safety analyses.Results252 US patients were enrolled. KarXT demonstrated a statistically significant and clinically meaningful 9.6-point reduction from baseline to week 5 (effect size=0.61) in PANSS total score vs placebo (p<0.0001); a significant improvement in PANSS total score was demonstrated starting at week 2 (first postbaseline rating) and continued through the study end. KarXT also met key secondary endpoints. Results at week 5 included a 2.9-point reduction in PANSS positive subscale score with KarXT vs placebo (p<0.0001), a 1.8-point reduction in PANSS negative subscale score with KarXT vs placebo (p=0.0055), and a 2.2-point reduction in PANSS negative Marder factor score with KarXT vs placebo (p=0.0022). KarXT was generally well tolerated. Overall discontinuation rates were similar with KarXT (25%) and placebo (21%). The overall treatment-emergent adverse events (TEAEs) rate for KarXT and placebo was 75% and 58%, respectively. Discontinuation rates related to TEAEs were similar between KarXT (7%) and placebo (6%). Rates of serious TEAEs were similar with KarXT and placebo (2%, each group); no serious TEAEs were determined to be drug related. The most common TEAEs (≥5%) with KarXT were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, blood pressure increases, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea. KarXT was not associated with sedation/somnolence, weight gain, and extrapyramidal symptoms.ConclusionsKarXT has the potential to be the first in a new class of treatments for patients with schizophrenia and a promising alternative to postsynaptic dopamine D2 receptor antagonists.FundingKaruna Therapeutics, Inc.

Association Between Hippocampal Subfields and Clinical Symptoms of First-Episode and Drug Naive Schizophrenia Patients During 12 Weeks of Risperidone Treatment

Small hippocampal size may be implicated in the pathogenesis and psychopathology of schizophrenia (SCZ). However, does the volume of hippocampal subfields in SCZ patients affect response to antipsychotic treatment? In this study, we used risperidone to treat first-episode drug naïve (FEDN) SCZ patients for 12 weeks, and then explored the relationship between baseline hippocampal subfield volumes, as well as any changes in these hippocampal subfield volumes during treatment, and improvement in their psychopathological symptoms. By adopting a state-of the-art automated algorithm, the hippocampal subfields were segmented in 43 FEDN SCZ inpatients at baseline and after 12 weeks of risperidone monotherapy, as well as in 30 matched healthy controls. We adopted the Positive and Negative Syndrome Scale (PANSS) to assess psychopathological symptoms in patients at baseline and at post-treatment. Before treatment, SCZ patients had no significant differences in total or subfield hippocampal volumes compared with healthy volunteers. However, we found a significant correlation between a smaller left CA1 at baseline and a lower PANSS total score and general psychopathology sub-score at post-treatment (both p < 0.05). Furthermore, the left CA1 at baseline was significantly smaller in responders, who had >50% improvement in PANSS total score, than in non-responders (p < 0.05). Our results suggest that smaller left CA1 volume may be a predicator for improvement in psychotic symptoms of FEDN SCZ patients.

PANSS Individual Item and Marder Dimension Analyses From a Pivotal Trial of RBP-7000 (Monthly Extended-Release Risperidone) in Schizophrenia Patients.

Background: Positive and Negative Syndrome Scale (PANSS) data from a pivotal phase 3 study in participants with schizophrenia of RBP-7000, a recently marketed long-acting subcutaneous injectable risperidone formulation, were examined to determine if dose-response relationships existed for different items of the PANSS.Methods: Changes in the 30 PANSS items were analyzed individually and using the 5 factor-analysis-derived dimensions defined by Marder and colleagues. Subgroups of patients who could benefit from the RBP-7000 120 mg dose were investigated.Results: 337 participants were randomized and received study medication (RBP-7000 90 mg n = 111, RBP-7000 120 mg n = 114, placebo n = 112). Dose-dependent responses were observed in items from the study-specified PANSS positive and general psychopathology exploratory subscales. Dose-dependent responses were observed across all 5 Marder dimensions, with the largest effect sizes observed with the 120 mg dose in the uncontrolled hostility/excitement (UHE) and anxiety/depression dimensions. Participants with baseline UHE dimension scores ≥ 9 demonstrated greater improvement in PANSS total score at the 120 mg dose compared to the 90 mg dose.Conclusions: RBP-7000 demonstrated efficacy across both the primary and exploratory PANSS study endpoints and the post hoc Marder dimensions. Schizophrenia patients with higher baseline Marder UHE scores may benefit from initiation of treatment at the 120 mg dose.Trial Registration: ClinicalTrials.gov identifier: NCT02109562.

Antipsychotic medication versus psychological intervention versus a combination of both in adolescents with first-episode psychosis (MAPS): a multicentre, three-arm, randomised controlled pilot and feasibility study

SummaryBackgroundEvidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis.MethodsWe did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433.FindingsOf 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial.InterpretationThis trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence.FundingNational Institute for Health Research.

M41. TRAJECTORIES AND PREDICTORS OF OUTCOME IN SCHIZOPHRENIA: THE BENEFICIAL ROLE OF AMISULPRIDE

BackgroundSchizophrenia is a serious illness and treatment with antipsychotic drugs remains one of the most effective types of treatment. The course of schizophrenia, however, is highly heterogeneous and currently it is not possible to predict which patient will respond adequately to which antipsychotic drug. The aim of our study was to define trajectories regarding response to antipsychotic drug treatment in patients with schizophrenia spectrum disorders. A second aim was to evaluate demographic factors and antipsychotic drugs as predictors for the different trajectories.MethodsBest Intro is a randomized, rater-blind, head-to-head comparison of amisulpride, aripiprazole and olanzapine. Adult patients with a diagnosis in the schizophrenia spectrum (ICD-10 diagnoses F20-29) were included. Participants had symptoms of ongoing psychosis as determined by a score of four or more on at least one of the following PANSS (Positive and Negative Syndrome Scale) items: P1 (delusions), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution) or G9 (unusual thought content). Patients were followed over a period of 52 weeks and the assessment points were at baseline, after one week, three weeks, six weeks, three months, six months, nine months, and 12 months. Totally 359 patients were assessed for eligibility, and 144 of them were enrolled and randomized to one of the study drugs. We used the R statistical program to define trajectories of antipsychotic response.ResultsWe identified three different trajectories regarding the reduction of PANSS total score, with Bayesian information criterion (BIC) = 6157 (BIC for two groups=6164 and for four groups=6171). A large group of patients (N=106, 74%) showed a trajectory of good improvement in PANSS total score over the first 26 weeks of follow-up and maintained it after one year with a total of 35% reduction in PANSS total score (Good response group). A second group of patients (N=19, 13%) followed a trajectory of quick response (already at one week) and a large reduction of PANSS total score (Strong response group). After one year, the reduction of PANSS total score was 58%. There was a difference in the starting point for PANSS total score in these two groups with a higher value at baseline in the Strong response group, but the ending point was quite similar. A third group of patients (N= 19, 13%) followed a trajectory of poor improvement and a 9% reduction in PANSS total score over the studied period (Slight response group).The demographic variables age, sex, civil status and living alone, or drug naivety did not predict participants grouping in the various trajectories. Furthermore, we examined the predictive value of different antipsychotic drug treatment for the different trajectories with the “Intention to treat” method. There was a statistically significant difference in favor of amisulpride treatment for belonging to the Strong response group, while olanzapine strongly predicted the belonging to the Slight response group. There was no significant difference among the antipsychotic drugs regarding the Good response group.DiscussionMost patients (74%) with a schizophrenia spectrum diagnosis showed a good response during the one year follow-up and another 13% showed a remarkable strong improvement. That means that a total of 87% of patients had a satisfactory course of illness during the first year. Use of amisulpride predicts a better course compared to aripiprazole and olanzapine. This finding can be useful for clinicians when selecting antipsychotic drugs for their patients.

Switching to Lurasidone following 12\u2009months of treatment with Risperidone: results of a 6-month, open-label study

BackgroundPatients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome, which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone. A secondary aim was assessment of the effect of long-term lurasidone on the Positive and Negative Syndrome Scale (PANSS).MethodsThe treatment sample in the current study consisted of clinically stable patients with schizophrenia (N = 223) who had completed a 12-month, double-blind study of lurasidone vs. risperidone. In the current extension study, all patients received 6 months of open-label treatment with lurasidone, either continuing lurasidone assigned during the preceding double-blind trial, or switching from double-blind risperidone to lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests.ResultsSix months of OL treatment with lurasidone was generally well-tolerated, with a low incidence of parkinsonism (4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation versus risperidone switch groups, change from OL baseline to 6-month endpoint (observed case) was observed in mean body weight (− 0.6 vs. -2.6 kg), median total cholesterol (− 4.0 vs. + 4.5 mg/dL), triglycerides (− 4.5 vs. -5.5 mg/dL), glucose (0.0 vs. -3.0 mg/dL) and prolactin (males, + 0.15 vs. -11.2 ng/mL; females, + 1.3 vs. -30.8 ng/mL). Improvement in PANSS total score was maintained, from OL baseline to endpoint in the continuation vs. switch groups (+ 1.0 vs. -1.0; OC).ConclusionsIn this 6-month extension study, lurasidone treatment was generally well-tolerated and associated with minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety parameters experienced during the previous 12 months of treatment with risperidone.Trial registrationClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).

Analysis of early response to the antipsychotic treatment and related factors in acute schizophrenia patients

Objective: The objective was to assess the relationship between early response and later response to antipsychotics, and the relationship between antipsychotics and early response. Methods: Data were retrospectively analyzed from patients with schizophrenia and they were hospitalized in the Second Affiliated Hospital of Xinxiang Medical College from May, 2013 to September, 2015.The patients were divided into theearly response group (PANSS total score improvement ≥20% at week 2) and early nonresponse group.General information, the use of drug and the Positive and Negative Syndrome Scale (PANSS) on before and 2, 4, 6 weeks after treatment were compared between the two groups.The relation between early response and late response and the effect of drug selection on early response were analyzed by correlation analysis and regression analysis. Results: Relative to early nonresponders, early responders were significantly more likely to have lower PANSS scores (total scores on 2, 4, 6 weeks after treatment 66.2±11.8 vs 84.5±10.9, 55.9±13.2 vs 70.9±13.7, 48.9±13.1 vs 60.6±14.9, all P<0.05) and higher PANSS scores improvement at 2, 4, 6 weeks after treatment (total scores improvement on 2, 4, 6 weeks after treatment (37±14)% vs (9±7)%, (56±19)% vs (32±18)%, (68±20)% vs (49±21)%, all P<0.05). The correlation coefficient between PANSS total score improvement at week 2 and at week 4, 6 were 0.730 and 0.541, respectively (all P<0.05). Olanzapine had more PANSS total score improvement than aripiprazole, quetiapine and ziprasidone (2 weeks after treatment (29±19)% vs (19±16)%, (18±15)%, (17±15)%, 4 weeks after treatment (51±21)% vs (37±25)%, (39±18)%, (37±22)%, all P<0.05). The protective factor for early response was olanzapine (P<0.05). Conclusions: Early responders are associated with faster and greater improvement in symptoms, the type of antipsychotic has impacts on early response, early non-responders can benefit from adjustment of treatment.

Cognitive-behavioural therapy for patients with schizophrenia: a multicentre randomized controlled trial in Beijing, China.

Meta-analyses support the efficacy of cognitive-behavioural therapy (CBT) for schizophrenia in western cultures. This study aimed to compare the efficacy of CBT and supportive therapy (ST) for patients with schizophrenia in China. A multicentre randomized controlled, single-blinded, parallel-group trial enrolled a sample of 192 patients with schizophrenia. All patients were offered 15 sessions of either CBT or ST over 24 weeks and followed up for an additional 60 weeks. All measures used were standardized instruments with good reliability and validity. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptoms of schizophrenia. The Schedule for Assessing Insight (SAI) was used to assess patients' insight and the Personal and Social Performance Scale (PSP) was used to assess their social functioning. Effect-size analysis showed that patients made rapid improvements in all symptoms, insight and social functioning as measured by the PANSS, SAI and PSP at 12 and 24 weeks and maintained these improvements over the course of the study to 84 weeks. Patients in the CBT group showed significantly greater and more durable improvement in PANSS total score (p=0.045, between-group d=0.48), positive symptoms (p=0.018, between-group d=0.42) and social functioning (p=0.037, between-group d=0.64), with significant differences emerging after completion of therapy. Both CBT and ST combined with medication had benefits on psychopathology, insight and social functioning of patients with schizophrenia. CBT was significantly more effective than ST on overall, positive symptoms and social functioning of patients with schizophrenia in the long term.

P.3.d.029 Analyzing the efficacy of second-generation antipsychotic drugs in treatment-resistant schizophrenia: a meta-analysis

Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis.We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433.Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial.This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence.National Institute for Health Research.

Paliperidone extended-release in patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics

Objective: This study explores relevant outcomes with flexibly dosed paliperidone extended-release (ER) in a real-world design.Research design and methods: Patients were recruited from 23 countries. Adults with non-acute schizophrenia (n = 1812), previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER and prospectively treated for 6 months.Main outcome measures: Primary efficacy outcome for patients switching for the main reason of lack of efficacy was ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for main reasons other than lack of efficacy, primary outcome was non-inferiority in efficacy compared with the previous medication.Results: Among the lack-of-efficacy group, 61% achieved a ≥ 20% improvement in PANSS total scores from baseline to endpoint. For switchers from other than the lack-of-efficacy group, efficacy maintenance after switching to paliperidone ER was confirmed. Clinically relevant and statistically significant symptomatic improvements occurred for each patient group based on main reason for switching.Conclusion: Paliperidone ER was well tolerated and associated with a meaningful clinical response in patients who switched from other oral antipsychotics, with insomnia and anxiety as most frequent side-effects.

An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: A phase II, randomized clinical trial

IntroductionCariprazine is an orally active and potent D3 and D2 partial agonist with preferential binding to D3 receptors in development for the treatment of schizophrenia and bipolar mania. This study (NCT00694707) evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia. MethodsThis study was a multinational, double-blind, randomized, placebo- and active-controlled, fixed-dose trial. Patients were randomized to receive placebo, cariprazine 1.5mg/d, cariprazine 3.0mg/d, cariprazine 4.5mg/d, or risperidone 4.0mg/d (for assay sensitivity) for 6weeks of double-blind treatment and 2weeks of safety follow-up. Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total and Global Impressions-Severity of Illness (CGI-S) scores, respectively. Safety parameters included adverse events (AEs), vital signs, laboratory measures, and extrapyramidal symptom (EPS) scales. ResultsOf 732 randomized patients, 64% completed the study. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5mg/d, 3.0mg/d, and 4.5mg/d (least squares mean difference [LSMD]: −7.6, −8.8, −10.4, respectively; p<0.001; LOCF) and risperidone (−15.1, p<0.001; LOCF); significant improvement on CGI-S was demonstrated for all active treatments (p<0.05). The most frequent cariprazine AEs (≥5% and at least twice the rate of the placebo group) were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation. Mean changes in metabolic parameters were small and similar between groups. ConclusionThe results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.

EPA-1547 - Once monthly paliperidone palmitate – tolerability and treatment response in recently diagnosed versus chronic non-acute schizophrenia patients switched from previously unsuccessful treatment with oral antipsychotics

To explore tolerability and treatment response of flexibly dosed once-monthly paliperidone palmitate (PP) in recently diagnosed versus chronic adult non-acute schizophrenia patients previously unsuccessfully treated with oral antipsychotics. International prospective 6-month open-label study. Patients were stratified by years since diagnosis [≤3 versus >3 years]. Outcomes were changes from baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression- Change Scale (CGI-C), Extrapyramidal Symptom Rating Scale (ESRS) and treatment-emergent adverse events (TEAEs). N=233 recently diagnosed (63.9% male, mean age 32.2±10.3 years, mean time since diagnosis 1.2±0.9 years) and n=360 chronic patients (62.5% male, mean age 42.4±11.0, mean time since diagnosis 13.9±9.3 years) were included. 71% of recently diagnosed and 59% of chronic patients showed a ≥20% improvement in PANSS total score at endpoint. Mean changes in PANSS total score at endpoint were - 15.1±15.6 and -9.6±15.7, respectively (between-group difference p<0.0001). Changes in PANSS positive, negative and general subscores were consistently higher in recently diagnosed patients (all p≤0.001). At endpoint, 52.4% of recently diagnosed patients were rated much or very much improved on CGI-C compared to 38.1% in the chronic group (p=0.0008). TEAEs ≥5% in both subgroups (recently diagnosed and chronic) were injection site pain (12.9% vs. 11.9%), insomnia (9.9% vs. 7.8%), anxiety (6.4% vs. 6.9%), and headache (6.0% vs.5.3%). These data suggest that both recently diagnosed and chronic patients previously unsuccessfully treated with oral antipsychotics benefit from paliperidone palmitate, with recently diagnosed patients showing consistently higher treatment response and lower disease severity at endpoint.

Add-on Treatment of Benzoate for Schizophrenia

In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of d-amino acids by blocking their metabolism. Sodium benzoate is a d-amino acid oxidase inhibitor. To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer. Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment. Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for d-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.

P.3.d.008 Reproductive side effects of antipsychotic-induced hyperprolactinemia; a cross-sectional study – preliminary results

Cariprazine is an orally active and potent D3 and D2 partial agonist with preferential binding to D3 receptors in development for the treatment of schizophrenia and bipolar mania. This study (NCT00694707) evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.This study was a multinational, double-blind, randomized, placebo- and active-controlled, fixed-dose trial. Patients were randomized to receive placebo, cariprazine 1.5 mg/d, cariprazine 3.0 mg/d, cariprazine 4.5 mg/d, or risperidone 4.0 mg/d (for assay sensitivity) for 6 weeks of double-blind treatment and 2 weeks of safety follow-up. Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total and Global Impressions-Severity of Illness (CGI-S) scores, respectively. Safety parameters included adverse events (AEs), vital signs, laboratory measures, and extrapyramidal symptom (EPS) scales.Of 732 randomized patients, 64% completed the study. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5 mg/d, 3.0 mg/d, and 4.5 mg/d (least squares mean difference [LSMD]: − 7.6, − 8.8, − 10.4, respectively; p < 0.001; LOCF) and risperidone (− 15.1, p < 0.001; LOCF); significant improvement on CGI-S was demonstrated for all active treatments (p < 0.05). The most frequent cariprazine AEs (≥ 5% and at least twice the rate of the placebo group) were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation. Mean changes in metabolic parameters were small and similar between groups.The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.

P.2.b.018 Post hoc analyses of levomilnacipran SR 40, 80, and 120 mg on functional outcomes in major depressive disorder

Cariprazine is an orally active and potent D3 and D2 partial agonist with preferential binding to D3 receptors in development for the treatment of schizophrenia and bipolar mania. This study (NCT00694707) evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.This study was a multinational, double-blind, randomized, placebo- and active-controlled, fixed-dose trial. Patients were randomized to receive placebo, cariprazine 1.5 mg/d, cariprazine 3.0 mg/d, cariprazine 4.5 mg/d, or risperidone 4.0 mg/d (for assay sensitivity) for 6 weeks of double-blind treatment and 2 weeks of safety follow-up. Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total and Global Impressions-Severity of Illness (CGI-S) scores, respectively. Safety parameters included adverse events (AEs), vital signs, laboratory measures, and extrapyramidal symptom (EPS) scales.Of 732 randomized patients, 64% completed the study. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5 mg/d, 3.0 mg/d, and 4.5 mg/d (least squares mean difference [LSMD]: − 7.6, − 8.8, − 10.4, respectively; p < 0.001; LOCF) and risperidone (− 15.1, p < 0.001; LOCF); significant improvement on CGI-S was demonstrated for all active treatments (p < 0.05). The most frequent cariprazine AEs (≥ 5% and at least twice the rate of the placebo group) were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation. Mean changes in metabolic parameters were small and similar between groups.The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.

Lurasidone for the treatment of acutely psychotic patients with schizophrenia: A 6-week, randomized, placebo-controlled study

Despite the availability of established antipsychotic agents for the treatment of schizophrenia, continued unmet needs exist for effective medications with lower adverse-effect burden. The present study evaluated the efficacy, safety, and tolerability of treatment with the atypical antipsychotic lurasidone for patients with an acute exacerbation of schizophrenia. Patients were randomized to 6 weeks of double-blind treatment with lurasidone 40 mg/day, 80 mg/day, or 120 mg/day, or placebo. Changes in Positive and Negative Syndrome Scale (PANSS) scores were evaluated using mixed-model repeated-measures (MMRM) analysis. Vital signs, laboratory parameters, extrapyramidal symptoms, and electrocardiogram were assessed. Treatment with lurasidone 80 mg/day resulted in significantly greater improvement in PANSS total score compared with placebo (−23.4 versus −17.0; p < 0.05) at study endpoint (MMRM); lurasidone 40 mg/day and 120 mg/day achieved clinically meaningful overall PANSS score reductions from baseline (−19.2 and −20.5), but not significant separation from placebo. Differences between all lurasidone groups and placebo for changes in laboratory parameters and electrocardiographic measures were minimal. Weight gain ≥7% occurred in 8.2% of patients receiving lurasidone and 3.2% receiving placebo. Modest increases in prolactin (median increase, 0.7 ng/mL) and extrapyramidal symptoms were observed following treatment with lurasidone compared with placebo. Akathisia was the most commonly reported adverse event with lurasidone (17.6%, versus 3.1% with placebo). In this study, in which a large placebo response was observed, lurasidone 80 mg/day, but not 40 mg/day or 120 mg/day, was statistically superior to placebo in treating acute exacerbation of chronic schizophrenia. All lurasidone doses were generally well tolerated.

Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia: A randomized, double-blind, placebo- and active-controlled trial

ObjectiveThis study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80mg/day and 160mg/day) in the treatment of an acute exacerbation of schizophrenia. MethodsParticipants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6weeks of fixed-dose, double-blind treatment with lurasidone 80mg (n=125), lurasidone 160mg (n=121), quetiapine XR 600mg (QXR-600mg; n=119; active control included to test for assay sensitivity), or placebo (n=121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure). ResultsTreatment with both doses of lurasidone or with QXR-600mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80mg (65%; p<0.001), lurasidone 160mg (79%; p<0.001), and QXR-600mg (79%; p<0.001) compared with placebo (41%). The proportion of patients experiencing ≥7% weight gain was 4% for each lurasidone group, 15% for the QXR-600mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p<0.001), LDL cholesterol (p<0.01), and triglycerides (p<0.05). ConclusionsLurasidone 80mg and 160mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated.

Efficacy, tolerability and cost effectiveness of zotepine versus olanzapine in patients of acute schizophrenia

Background: Schizophrenia is a functional psychosis with severe personality changes and thought disorders without cerebral damage . No reports are available in literature regarding efficacy and tolerability of atypical antipsychotic drug zotepine over olanzapine a preferred drug worldwide for the treatment of schizophrenia. Therefore, present study is undertaken to evaluate efficacy, tolerability and cost effectiveness of zotepine over olanzapine in patients suffering from schizophrenia. Methods: A prospective, randomized, single blind, parallel, 6 weeks clinical study was conducted on a total of 112 patients, of schizophrenia attending psychiatry outpatient department at G. R. Medical College, Gwalior, India randomized into two groups (56 in each). Patients received either olanzapine (10-20mg) or zotepine (75-150mg) per day for a period of 6 week. Efficacy was measured by Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scale whereas tolerability was measured by dropout rate and frequency of adverse effects. Cost effectiveness was calculated in terms of cost incurred for improvement at the end of treatment period. Results: Both the drugs showed significant (P&lt;0.05) improvement in PANSS total score as compared to their respective baseline scores however, there was no significant difference between the two groups (P&gt;.0.05). Olanzapine showed significantly better (P&lt;0.05) positive subscale and CGI scale score improvement as well as response rate when compared to zotepine. Incidences of adverse effects like weight gain, somnolence and hyperglycemia were 42, 32 and12 % respectively with olanzapine and 39, 30 and 9% respectively with zotepine with no significant difference (P&gt;0.05) between the two groups. Incidence of akathisia and drop out (16% and 23%) with zotepine were significant (P&lt;0.05) as compared to olanzapine (2% and 11%) respectively. Conclusions: Though the efficacy of both the drugs is comparable, olanzapine appears to have better tolerability and cost effectiveness than zotepine in patients of schizophrenia.

Does early improvement predict response to the fast-dissociating D2 receptor antagonist JNJ-37822681 in patients with acute schizophrenia? ☆

Early predictability of sustained response to atypical antipsychotics in patients with schizophrenia has important implications for clinical decision making. In order to investigate whether early onset of efficacy correlates with week-6 response for the selective fast-dissociating D2 receptor antagonist JNJ-37822681, we analysed data from a 12-week placebo- and active-controlled (olanzapine) study designed to evaluate efficacy and safety of JNJ-37822681. Factors, including baseline Positive and Negative Syndrome Scale (PANSS) total score, waist circumference, weight, body mass index group, number of previous hospitalisations, age at diagnosis, race, sex and age at study entry, and relative (%) change from baseline on day 3 (early improvement) in PANSS total score, were analysed using logistic regression models and receiver operator characteristic (ROC) curve analysis, to predict the week-6 efficacy response (≥30% improvement in PANSS total score). Results showed that week-6 response with JNJ-37822681 30mg bid treatment could be reliably predicted by improvement in PANSS total score on day 3, the number of previous hospitalisations, and race (80% accuracy [ROC area under curve]). Early improvement (day 3) in PANSS score had the highest predictive value as a single factor across all JNJ-37822681 doses. At a specificity of 70%, sensitivity for predicting week-6 response was: 0.60, 0.64, and 0.74 in the 10-, 20-, and 30mg bid JNJ-37822681 groups, respectively; 0.40 in olanzapine group. Early improvement in PANSS may be a simple and reliable way to predict sustained response with JNJ-37822681 in patients with acute schizophrenia.