Positive And Negative Syndrome Scale Items Research Articles

Unveiling altered connectivity between cognitive networks and cerebellum in schizophrenia

Cognitive functioning is a crucial aspect in schizophrenia (SZ), and when altered it has devastating effects on patients' quality of life and treatment outcomes. Several studies suggested that they could result from altered communication between the cortex and cerebellum. However, the neural correlates underlying these impairments have not been identified. In this study, we investigated resting state functional connectivity (rsFC) in SZ patients, by considering the interactions between cortical networks supporting cognition and cerebellum. In addition, we investigated the relationship between SZ patients' rsFC and their symptoms.We used fMRI data from 74 SZ patients and 74 matched healthy controls (HC) downloaded from the publicly available database SchizConnect. We implemented a seed-based connectivity approach to identify altered functional connections between specific cortical networks and cerebellum. We considered ten commonly studied resting state networks, whose functioning encompasses specific cognitive functions, and the cerebellum, whose involvement in supporting cognition has been recently identified. We then explored the relationship between altered rsFC values and Positive and Negative Syndrome Scale (PANSS) scores.The SZ group showed increased connectivity values compared with HC group for cortical networks involved in attentive processes, which were also linked to PANSS items describing attention and language-related processing. We also showed decreased connectivity between cerebellar regions, and increased connectivity between them and attentive networks, suggesting the contribution of cerebellum to attentive and affective deficits.In conclusion, our findings highlighted the link between negative symptoms in SZ and altered connectivity within the cerebellum and between the same and cortical networks supporting cognition.

Parkinsonism, Psychomotor Slowing, Negative and Depressive Symptoms in Schizophrenia Spectrum and Mood Disorders: Exploring Their Intricate Nexus Using a Network Analytic Approach.

Parkinsonism, psychomotor slowing, negative and depressive symptoms show evident phenomenological similarities across different mental disorders. However, the extent to which they interact with each other is currently unclear. Here, we hypothesized that parkinsonism is an independent motor abnormality showing limited associations with psychomotor slowing, negative and depressive symptoms in schizophrenia spectrum (SSD), and mood disorders (MOD). We applied network analysis and community detection methods to examine the interplay and centrality (expected influence [EI] and strength) between parkinsonism, psychomotor slowing, negative and depressive symptoms in 245 SSD and 99 MOD patients. Parkinsonism was assessed with the Simpson-Angus Scale (SAS). We used the Positive and Negative Syndrome Scale (PANSS) to examine psychomotor slowing (item #G7), negative symptoms (PANSS-N), and depressive symptoms (item #G6). In SSD and MOD, PANSS item #G7 and PANSS-N showed the largest EI and strength as measures of centrality. Parkinsonism had small or no influence on psychomotor slowing, negative and depressive symptoms in SSD and MOD. In SSD and MOD, exploratory graph analysis identified one community, but parkinsonism showed a small influence on its occurrence. Network Comparison Test yielded no significant differences between the SSD and MOD networks (global strength p value: .396 and omnibus tests p value: .574). The relationships between the individual domains followed a similar pattern in both SSD and MOD highlighting their transdiagnostic relevance. Despite evident phenomenological similarities, our results suggested that parkinsonism is more independent of negative and depressive symptoms than psychomotor slowing in both SSD and MOD.

Impact of Delusions and Hallucinations on Clinical Insight Dimensions in Schizophrenia Spectrum Disorders

Introduction: Insight in psychosis has been conceptualized as a continuous, dynamic, and multidimensional phenomenon. This study aims to determine the impact of delusions and hallucinations in different dimensions of clinical insight in schizophrenia spectrum disorders. Methods: Cross-sectional multicenter study including 516 patients (336 men) diagnosed with schizophrenia spectrum disorders. Based on dichotomized scores of Positive and Negative Syndrome Scale (PANSS) items P1 (delusions) and P3 (hallucinations), patients were assigned to four groups according to current clear presence of delusions (scores 4 or above 4 in PANSS item P1) and/or hallucinations (scores 4 or above 4 in PANNS item P3). Insight was assessed using the three main dimensions of the Scale of Unawareness of Mental Disorder (SUMD). Results: Around 40% of patients showed unawareness of illness; 30% unawareness of the need for treatment; and 45% unawareness of the social consequences of the disorder. Patients with current clear presence of delusions had higher overall lack of awareness, regardless of current clear presence of hallucinations. Similarly, the clear presence of delusions showed a greater predictive value on insight than the presence of hallucinations, although the implication of both in the prediction was modest. Conclusions: Our results confirm that lack of insight is highly prevalent in schizophrenia spectrum disorders, particularly when patients experience delusions. This study adds insight-related data to the growing symptom-based research, where specific types of psychotic experiences such as hallucinations and delusions could form different psychopathological patterns, linking the phenomenology of delusions to a lack of clinical insight.

From gut to brain: A network model of intestinal permeability, inflammation, and psychotic symptoms in schizophrenia.

Impaired intestinal permeability has recently been suggested as a possible source of chronic inflammation in schizophrenia, but its association with specific psychopathological features remains uncertain. This study aimed to explore the interaction between intestinal permeability, inflammation, and positive and negative symptoms in schizophrenia using a network analysis approach. The study sample comprised 281 adults with schizophrenia (age 40.29 ± 13.65 years, 63.0 % males), enrolled in a cross-sectional observational study assessing intestinal permeability. We estimated the network with a Gaussian graphical model, incorporating scores from 14 individual items of the Positive and Negative Syndrome Scale (PANSS), along with body mass index (BMI), and plasma C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) levels. We calculated strength centrality and expected influence and used bridge centrality statistics to identify the bridge nodes. Distinct but highly interconnected clusters emerged for positive and negative symptoms. The biological variables were closely associated with each other. LBP was positively linked with CRP and BMI, but only indirectly connected to psychopathology. CRP exhibited direct positive relationships with various PANSS items and bridged LBP and BMI with psychopathology. Bridge nodes included Conceptual Disorganisation (P2), Active Social Avoidance (G16), Suspiciousness/Persecution (P6), and CRP. These findings support the role of gut-derived inflammation as a mechanism underlying greater symptom severity in schizophrenia and emphasise the importance of addressing dietary habits not only to enhance physical health but also to contribute to improving psychotic symptoms.

Psychomotor slowing in schizophrenia is associated with cortical thinning of primary motor cortex: A three cohort structural magnetic resonance imaging study

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ.

Disorganization in first episode affective psychosis: Treatment response and clinical considerations from a 2-year follow-up study in a "real world" setting.

Disorganization is a crucial domain in affective psychoses. However, it has received poor research attention, especially at the illness onset. The aims of this study were: (a) to monitor the longitudinal course of disorganization in young people with first episode affective psychosis (FEAP) across 2 years of follow-up, and (b) to investigate any relevant correlation of disorganized symptoms with psychopathology, functioning and the specific treatment elements of an "Early Intervention in Psychosis" (EIP) protocol along the follow-up period. Seventy-five FEAP participants (aged 12-35 years) completed the Positive And Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). Spearman's rank correlation coefficients were calculated. During the follow-up, disorganized symptoms showed significant enduring positive correlations with PANSS items representing delusional thought content and uncooperativeness, as well as a persistent negative association with the GAF score. Across the 2-year follow-up period, FEAP individuals also had a relevant reduction in disorganization levels. This symptom decrease was specifically related with the combination of antipsychotic medication with the specific psychosocial components of our EIP intervention offered to FEAP patients during the first 12 months of treatment. Disorganization is relevant in FEAP subjects already at their enrollment in specialized EIP protocols. However, it decreases over time, together with the delivery of specific, combined (person-tailored) EIP interventions.

Symptoms and functioning: a content analysis of the PANSS under the ICF framework

Purpose The study aimed to compare the content of the Positive and Negative Syndrome Scale (PANSS) with that of the International Classification of Functioning, Disability, and Health (ICF) and to examine the extent to which PANSS items are represented in the ICF Core Sets (ICF-CS) for schizophrenia. Methods The 30 items of the PANSS were linked to the ICF using established rules by two health professionals experienced in applying the ICF conceptual framework. Results PANSS items were linked to 42 unique ICF categories, corresponding mainly to the Body functions component; categories b160 Thought functions and b152 Emotional functions from this component were the most frequently linked. Regarding the Activities and participation component, the second-level category d720 Complex interpersonal interactions was the most frequently linked to PANSS items. Overall, PANSS items covered 18% and 40% of the categories included, respectively, in the Comprehensive and Brief versions of the ICF-CSs for schizophrenia. No PANSS items were linked to categories from the Body structures or Environmental factors components. Conclusions The PANSS broadly covers the content of the ICF, especially as regards mental and movement-related functions, although it also covers some aspects of interpersonal relationships.

Depression trajectories and cytokines in schizophrenia spectrum disorders - A longitudinal observational study

Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.

Impaired insight in schizophrenia: impact on patient-reported and physician-reported outcome measures in a randomized controlled trial

BackgroundImpaired insight poses a challenge in the treatment of patients with schizophrenia because of its potential to jeopardize therapeutic engagement and medication adherence. This study explored how insight impairment, graded from none to extreme, is related to patient-reported mental health status, depression, and neurocognition in schizophrenia.MethodsIn a post hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (NCT00014001), insight was measured using the Positive and Negative Syndrome Scale (PANSS) Item G12 (lack of insight). Additional assessments for this analysis included the 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS), physician- and patient-reported Clinical Global Impression–Severity (CGI-S), MATRICS Consensus Cognitive Battery, and Calgary Depression Scale for Schizophrenia. Relationships between patient-reported outcomes and PANSS total and Item G12 ratings were evaluated.ResultsAmong 1431 CATIE study participants in this analysis, increasingly impaired insight at baseline was significantly associated with better patient-reported quality of life (QoL), lower baseline depression, and greater divergence between physician- and patient-reported illness severity. Patients with more severely impaired insight reported milder illness compared with physician reports, particularly those with moderate-severe to extreme impairment (PANSS Item G12 rating ≥ 5), approximately 10% (138/1431) of CATIE participants. For the 90% of patients with PANSS Item G12 ratings < 5, patient-reported QoL decreased with increasing symptoms. SF-12 MCS scores were linearly related to baseline PANSS total score only in patients with PANSS total score < 90 (moderately ill or better), and better symptom scores were associated with higher QoL. No significant relationship between insight and neurocognition was observed.ConclusionsIn the small subgroup (10%) of CATIE study patients with schizophrenia and PANSS Item G12 ratings ≥5, moderate-severe–severe/extreme insight impairment was associated with significantly more positive perception of QoL and illness severity by the patient versus the treating physician. This was not observed in the remaining 90% of patients with normal to moderately impaired insight, suggesting that poor insight as a threat to the validity of self-report is uncommon.

FDA Approves First Six-Month LAI Antipsychotic

Back to table of contents Previous article Next article Clinical & ResearchFull AccessFDA Approves First Six-Month LAI AntipsychoticNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:29 Nov 2021https://doi.org/10.1176/appi.pn.2021.12.7AbstractJanssen’s new formulation of paliperidone palmitate will necessitate just two injections a year.iStock/Alernon77The “long” in long-acting injectable (LAI) antipsychotics extended its reach this past fall, as the U.S. Food and Drug Administration (FDA) approved the first twice-yearly injectable of paliperidone palmitate (marketed as Invega Hafyera by Janssen). Prior to this approval, the longest coverage offered by an LAI was three months.“This twice-yearly injectable enables us to provide more continuous medication coverage than ever before, while further reducing self-stigma among schizophrenia patients,” said Dean Najarian, Pharm D., an associate field director for Neuroscience Medical Affairs at Janssen. “Fewer injections each year means fewer trips to the mental health clinic just for medication, fewer instances of families asking patients if they took their daily antipsychotic, and fewer reminders overall that someone has an illness.”The FDA approval was based on data from a large phase 3 study comparing the safety and efficacy of three-month paliperidone with six-month paliperidone. Over 700 adults with schizophrenia who were clinically stable and already taking one- or three-month paliperidone were randomized to receive 12 months of either the three-month or six-month formulation. The participants’ symptoms were measured throughout the study using the Positive and Negative Syndrome Scale (PANSS) as well as other measures of functioning. Patients were considered to have relapsed if PANSS total scores or specific PANSS items rose over two consecutive assessments and/or if they had any events of psychiatric hospitalization, self-injury, violent behavior, and/or suicidal/homicidal ideation. Outcomes between the two groups were comparable, with 92.5% of the patients treated with the six-month LAI and 95% treated with the three-month LAI remaining relapse-free after one year.The safety profile of the six- and three-month LAI was also similar in terms of the frequency and type of treatment-related side effects. The most common side effects in patients were upper respiratory tract infections, injection site reactions, and weight gain.Najarian said he hopes that these robust relapse findings can help change the paradigm on when to use LAI antipsychotics with patients. “Right now, the average patient is 38 years old and has tried four oral medications before injectables are even discussed,” he said. “Rather than reserve LAIs for people who have experienced multiple relapses, let’s use them to delay time to relapse in the first place.”John Lauriello, M.D., the Daniel Lieberman Professor and Chair of Psychiatry at Thomas Jefferson University, said that he believes the arrival of a six-month injectable represents significant progress in the research and development of LAIs. “It’s great that we have extended the injectable lifespan [of LAI antipsychotics] from two weeks to six months in less than two decades,” he said. “However, I would not describe the new formula as a game changer; it’s more of a graduation program for those already taking an LAI.”Lauriello noted that many patients will not respond to or tolerate paliperidone, so this is not an option for them. Also, the six-month paliperidone formulation is only recommended for patients who are stable on one-month or three-month paliperidone formulations, not patients needing acute stabilization of their psychotic symptoms.Jeffrey Lieberman, M.D., the Lawrence C. Kolb Professor and Chair of Psychiatry at Columbia University, agreed that the potential impacts of the six-month injectable are likely to be modest. “The longer duration adds a convenience factor, so it will benefit remote individuals, those with limited health care access, and people who do not like injections,” he told Psychiatric News. “But while the clinical data show the six-month injection is not inferior to the three-month one, there is no indication that it is any better.”Lauriello believes the added stability offered by a twice-yearly injection could be beneficial for some patients, and he hopes Janssen or insurance groups offer pricing incentives to encourage expanded use of both three- and six-month formulations. He also believes Invega Hafyera and other LAIs would be more widely used if they could be administered at home, currently by a visiting nurse but possibly family members or even the patient themselves.“We let patients self-inject a lot of powerful drugs like insulin; if we could feel comfortable putting antipsychotic injections in patient hands that may make them feel more a part of their treatment and more time can be spent with other aspects of care like psychotherapy or occupational therapy.”Neither Lauriello or Lieberman were involved with the development of Invega Hafyera and do not report any existing conflicts with Janssen. ■“A Randomized, Double-Blind, Multicenter, Noninferiority Study Comparing Paliperidone Palmitate 6-month Versus the 3-month Long-Acting Injectable in Patients With Schizophrenia” is posted here. ISSUES NewArchived

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.

Identifying strategies to improve PANSS based dimensional models in schizophrenia: Accounting for multilevel structure, Bayesian model and clinical staging

BackgroundDimensional approaches can decompose a construct in a set of continuous variables, improving the characterization of complex phenotypes, such as schizophrenia. However, the five-factor model of the Positive and Negative Syndrome Scale (PANSS), the most used instrument in schizophrenia research, yielded poor fits in most confirmatory factor analysis (CFA) studies, raising concerns about its applications. Thus, we aimed to identify dimensional PANSS CFA models with good psychometric properties by comparing the traditional CFA with three methodological approaches: Bayesian CFA, multilevel modeling, and Multiple Indicators Multiple Causes (MIMIC) modeling. MethodsClinical data of 700 schizophrenia patients from four centers were analyzed. We first performed a traditional CFA. Next, we tested the three techniques: 1) a Bayesian CFA; 2) a multilevel analysis using the centers as level; and 3) a MIMIC modeling to evaluate the impact of clinical staging on PANSS factors and items. ResultsCFA and Bayesian CFA produced poor fit models. However, when adding a multilevel structure to the CFA model, a good fit model emerged. MIMIC modeling yielded significant differences in the factor structure between the clinical stages of schizophrenia. Sex, age, age of onset, and duration of illness did not significantly affect the model fit. ConclusionOur comparison of different CFA methods highlights the need for multilevel structure to achieve a good fit model and the potential utility of staging models (rather than the duration of illness) to deal with clinical heterogeneity in schizophrenia. Large prospective samples with biological data should help to understand the interplay between psychometrics concerns and neurobiology research.

Effects of Cariprazine on Cognition in Patients With Bipolar Mania or Mixed States: Post Hoc Analysis From 3 Randomized, Controlled Phase III Studies

AbstractIntroductionCariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, is approved for the treatment of schizophrenia and for depressive, manic, or mixed episodes associated with bipolar I disorder. Previous post hoc analyses have demonstrated that cariprazine was effective versus placebo for improving cognitive symptoms in patients with schizophrenia or bipolar depression. This post hoc analysis evaluated the effects of cariprazine on cognitive symptoms in patients with acute manic or mixed bipolar episodes.MethodsData from 3 phase II/III, randomized, double-blind, placebo-controlled studies in patients with manic or mixed episodes associated with bipolar I disorder (NCT00488618, NCT01058096, NCT01058668) were pooled and analyzed. Patients were randomized to placebo or flexibly dosed cariprazine (3-12 mg/d, 3-6 mg/d, or 6-12 mg/d [1 study only]) for 3 weeks of double-blind treatment; all dose groups were combined for the pooled analysis. Cognitive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) Cognitive subscale (sum of PANSS items P2, N5, N7, G10, G11); a score of 15 or greater at baseline indicated the presence of cognitive symptoms. Mean changes from baseline to week 3 in PANSS cognitive subscale/item scores and Young Mania Rating Scale (YMRS) total score were evaluated in the overall intent-to-treat (ITT) population and in the subgroup of patients with baseline cognitive symptoms. A mixed-effects model for repeated measures (MMRM) was used to impute missing values.ResultsOf the 1012 patients in the ITT population, 174 (placebo=71; cariprazine=103) had a PANSS Cognitive subscale score of 15 or greater at baseline. At week 3, the cariprazine group demonstrated significantly greater mean improvement than the placebo group on PANSS cognitive subscale scores in both the ITT population (−2.2 vs −1.3; P&lt;.0001) and the subgroup with baseline cognitive symptoms (−4.0 vs −1.9; P=.0002). In patients with baseline cognitive symptoms, improvement was significantly greater for cariprazine- versus placebo-treated patients on YMRS total score (−16.7 vs −8.2; P&lt;.0001) and the individual PANSS cognitive subscale items of conceptual disorganization (−1.1 vs −0.5; P=.0004), difficulty in abstract thinking (−0.8 vs −0.3; P=.0044), stereotyped thinking (−0.3 vs −0.1; P=.0350), and poor attention (−1.1 vs −0.6; P=.0043).ConclusionIn patients with manic or mixed episodes associated with bipolar I disorder, cariprazine versus placebo was effective in improving cognitive symptoms in the overall patient population as well as in patients with baseline cognitive symptoms. In addition, cariprazine versus placebo also demonstrated efficacy in improving manic symptoms in patients with baseline cognitive symptoms. These results suggest that cariprazine may provide benefits for the treatment of cognitive symptoms in patients with bipolar I mania.FundingAbbVie Inc.

Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications

Facilitating the development of safe and effective medications for schizophrenia is a public health imperative. To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia and to offer perspective on an alternative regulatory pathway to the historically accepted trial duration and response assessment. A database was created consisting of clinical trial data from 32 placebo-controlled RCTs of 8 atypical antipsychotic drugs approved by the US Food and Drug Administration (FDA) between January 1, 2001, and December 31, 2015. The database included information on total and individual PANSS item ratings, demographic characteristics, disposition, and adverse events (AEs). All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected. Quality control checks were performed to ensure that the collected data were consistent with the reported results of each trial. Data were collected from March 15, 2015, to September 30, 2015. Data analysis was conducted from October 1, 2015, to June 20, 2016. The following analyses were performed: (1) longitudinal assessment of mean change from baseline in total PANSS score, (2) correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, (3) concordance analyses of outcomes across trials between week 6 and earlier time points using total PANSS and modified PANSS, and (4) analyses of time course of treatment-emergent AEs. The final database contained data from 14 219 participants enrolled in 32 drug trials; 9805 of 14 219 participants (69.0%) were male and were either white (7183 [50.5%]) or black (4346 [30.6%]) individuals. The mean (SD) age during treatment was 38.9 (10.9) years, and the mean (SD) age at schizophrenia diagnosis was 25 (8.5) years. Statistically significant separation between treatment response and placebo response was observed after 1 week of treatment. The overall concordance rate across treatment groups steadily increased from week 1 to week 4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4). Trends in AE occurrence were evident by week 1 and percentage of AEs were similar across weeks 3, 4, and 6. The overall concordance rate between change from baseline in the modified PANSS score and change from baseline in the total PANSS score was 93.0% (80 of 86 treatment groups) at week 4 and 97.7% (84 of 86 treatment groups) at week 6. Shortening the trial duration to 4 weeks increased the required sample size to 502 participants. Using the modified PANSS as the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial. Findings from this analysis suggest that there is the potential to streamline the design of schizophrenia drug clinical trials. Trial sponsors may consider incorporating these strategies and are encouraged to consult with the FDA early in the drug development process.

Aggressiveness is associated with excitement on the five-factor model of the positive and negative syndrome scale and prefrontal function in patients with stable schizophrenia

Aggressiveness is a clinical concern in the stable phase of schizophrenia, as well as in the acute phase. The factors that affect aggressiveness during the stable phase remain unclear. This study investigated factors associated with aggressiveness in patients with stable schizophrenia. Sixty-six patients with schizophrenia who were in the stable phase without acute exacerbation were assessed for aggressiveness using the Buss–Perry Aggression Questionnaire; impulsivity using the Barratt Impulsiveness Scale Version 11, psychotic symptoms using the five-factor model of the Positive and Negative Syndrome Scale (PANSS) including positive symptoms, negative symptoms, disorganization, excitement, and emotional distress; and prefrontal hemodynamic responses using near-infrared spectroscopy. Multivariate regression analyses showed that the excitement factor of the PANSS five-factor model, which comprised four PANSS items (poor impulse control, hyperactivity, hostility, and uncooperativeness), and delayed prefrontal hemodynamic responses were associated with elevated aggressiveness. These findings suggest that in patients with stable schizophrenia, excitement symptoms and prefrontal dysfunction are associated with elevated aggressiveness. Furthermore, the impact of impulsive traits on aggressiveness is less relevant. Our results shed light on a specific aspect of aggressiveness in patients with stable schizophrenia and may indicate factors to consider in the clinical setting.

T206. ANTIPSYCHOTIC EFFECTIVENESS FOCUSING ON INSIGHT

BackgroundImpaired insight is common among patients with schizophrenia, and a major obstacle for treatment adherence and improvement. Previous studies have investigated the effect of antipsychotics on insight, but findings are indecisive due to small or homogeneous samples, non-randomized design or short follow- up.The aim of this study was to investigate if there were differential effects on insight among different antipsychotic medications, and whether the effect was directly related to improvement in insight or indirectly through reduction of psychosis symptoms.MethodsData was derived from the Bergen-Stavanger-Innsbruck-Trondheim study (BestIntro). This is a randomized, rater-blinded, naturalistic study with a head- to head comparison of three antipsychotic medications: amisulpride, aripiprazole and olanzapine. Inclusion criteria were adults with a F20-F29 ICD-10 diagnosis being actively psychotic defined as a score of ≥4 on items P1, P3, P5, P6, or G9 on the Positive And Negative Syndrome Scale (PANSS). Insight was measured by PANSS item G12. We used a modified version of PANSS to assess psychosis symptoms (PANSS total score minus item G12, mPANSS). Level and change in insight and psychosis symptoms were estimated in latent growth curve models. The pattern of change indicated a piecewise model with the initial phase from baseline to week six and the long-term phase from week six to one year. The study drugs were used as predictors.ResultsA total of 144 participants were included, 35% female and 61% had previously used antipsychotic medication. Mean insight score at baseline was 3.36. Preliminary findings show differential effects on insight among the three medications, where aripiprazole was the least effective drug. The effect on insight was related to improvement in psychosis symptoms for all study drugs. In addition, we found a direct effect on insight in the long-term phase for amisulpride and olanzapine. In the same phase, the aripiprazole group showed a slight increase in impaired insight.DiscussionThis is the first randomized study with a heterogeneous sample to find an effect of antipsychotics on insight that exceeds the contribution of reduction of psychosis symptoms. Although we have not investigated the association between increased insight and medication adherence, our results imply that patients with impaired insight will benefit from antipsychotic treatment. More specifically, treatment with amisulpride or olanzapine may be more helpful in improving insight over time.

S37. CROSS-CULTURAL DIFFERENCES IN PANSS ITEM RATINGS: COMPARISONS OF SIX GEO-CULTURAL REGIONS

BackgroundWhile schizophrenia is observed in different parts of the world across countries, ethnicities, and races, research indicates cultural factors play significant roles in the phenomenology of this illness. Cultural norms and values affect manifestations of this pathology; more specifically, they affect how symptoms are expressed, experienced, and interpreted. Given that culture affects manifestations of schizophrenia, cultural factors should be considered in the assessment of its symptoms in clinical trials. This study explores the differences and patterns in the Positive and Negative Syndrome Scale (PANSS) item ratings across different geocultural regions. Identifying such patterns can give insights into culturally sensitive assessment practices and aid in developing more effective rater training and data surveillance that consider unique cultural factors.MethodsData were obtained from an international group of raters from 37 different countries, representing 6 geocultural regions across 13 different studies. As part of the rater training and qualification process for each of these studies, raters viewed and scored the 30-item PANSS based on a video-recorded PANSS interview that was administered using the Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-PANSS). Raters were deemed qualified if their scores fell within the defined acceptable item score ranges. Given the cultural diversity of the raters, the acceptable passing score ranges for each country were determined by a combination of expert opinion scores, group modal scores, and clinical analyses. Only the scores from raters who achieved qualification on their first scoring attempt were analyzed. The number of raters per geocultural regions included: Asia Pacific, n = 397; Eastern Europe, n = 412; Latin America, n = 88; Middle East/Africa, n = 29; North America, n = 339; and Western Europe, n = 129.ResultsA Shapiro-Wilk test for normality was conducted on the scores for each PANSS item and found all significantly different from a normal distribution (all ps < .0001). A Kruskal-Wallis test for rank-ordered differences was conducted for each item for the influence of region on item score. Most items showed a significant influence of region on score after a Bonferroni correction was applied; most ps < .0001 with the following exceptions: N1, p < .001; G15, p < .05; P2, P7, N6, N7, G1, G6, G10, G12, and G13 were not significant. The most significant cross-regional differences were found with P1, P3 and P6, and these items were analyzed further with a post hoc Dunn test to understand cross-regional patterns. On P1, Asia Pacific and Eastern Europe were significantly lower than Latin America, North America, and Western Europe (all ps < .0008) but not Mideast/Africa. On P3, Western Europe were significantly lower than all other regions (all ps < .0005); Asia Pacific were significantly lower than Eastern Europe, North America, and Western Europe (all ps < .006). On P6, Asia Pacific and Eastern Europe were significantly lower than all other regions (all ps < .03).DiscussionThe present study suggests that ratings of schizophrenia symptoms are influenced by cultural factors. Cultural beliefs and behaviors seem to influence interpretations of schizophrenia pathology. Given that the PANSS is not standardized for cross-cultural contexts, it is important to consider cultural factors when using this scale in clinical studies. In addition, when developing rater training and data surveillance programs, adjustment of acceptable item score ranges for key PANSS items highlighted above for different geocultural region is recommended. Future studies should explore country-level patterning of ratings of the PANSS.

M47. AKATHISIA AND ATYPICAL ANTIPSYCHOTICS: EXPLORING ASSOCIATIONS TO SUICIDALITY AND AGITATION

BackgroundAntipsychotic associated akathisia is a highly relevant clinical phenomenon. The common side effect can be stigmatizing, cause subjective distress and depression, lead to medication noncompliance and be potentially disabling for patients with psychosis. Associations between akathisia and both suicide, depression and agitation has been suggested in research literature, but inconsistently. This study investigates the level of akathisia at hospital discharge/first follow-up for consecutively admitted patients with acute phase psychosis, comparing four atypical antipsychotics (AAPs) regarding the presence of akathisia, and explores possible associations between akathisia and both suicidality, depression and agitation.MethodsThis study is a sub-study of the Bergen Psychosis Project (BPP), a pragmatic, rater-blind, randomized trial comparing head-to-head ziprasidone, olanzapine, risperidone and quetiapine. The present study reports cross-sectional data at discharge/first follow-up after acute admission to hospital for patients with psychosis. Patients were assessed with The Positive And Negative Syndrome Scale (PANSS). We applied the validated PANSS Excited Component (PANSS-EC) factor to assess agitation. The PANSS-EC consists of the five PANSS items: P4 Excitement, P7 Hostility, G4 Tension, G8 Uncooperativeness and G14 Poor impulse control. To assess depression in general and suicidality specifically we used the validated Calgary Depression Scale for Schizophrenia (CDSS).Furthermore the Clinical Global Impression – Severity Scale (CGI-S), and the patient-administered version of the UKU Side Effect Self-Rating Scale (UKU SERS Pat).ResultsA total of 109 patients were included of which 35 (32.1 %) were females, mean age was 34.0 (12.4). The mean total PANSS score was 54.9 (14.4), the mean CGI-S was 3.7 (1.1) and the mean total CDSS score was 3.9 (4.0). Our preliminary results show that a total of 58 (53.3%) patients had used antipsychotics before entering the study. Some level of akathisia was reported by ¼ of the patients, meaning a score of 1 or more on the UKU SERS Pat. There was a statistically significant difference between ziprasidone and olanzapine, with higher akathisia level in the ziprasidone group. Furthermore, there were statistically significant correlations between akathisia and suicidality and between akathisia and depression. We found no significant correlation between akathisia and the PANSS-EC factor or between akathisia and the PANSS general item G14 Poor impulse control. Statistical details will be presented on the poster.DiscussionOur study shows that akathisia is a prevalent side effect in a clinically relevant sample of patients with acute phase psychosis treated with atypical antipsychotics. The prevalence of antipsychotic associated akathisia ranges widely across studies due to, among others, methodological heterogeneities and varieties in measurement tools. In our study, akathisia was significantly associated with both depression and suicidality. The finding of a significant correlation between akathisia and suicidality supports a previous finding that even a mild to moderate experience of akathisia in first episode patients had an increase in the likelihood to be suicidal. We found no relationship with agitation in our study. As akathisia may go unrecognized in clinical practice and may contribute to medication noncompliance, systematic assessment for symptoms of akathisia is warranted.ConclusionAkathisia is still a prevalent phenomenon in a substantial proportion of patients treated with atypical antipsychotics. Special attention is called for regarding the association towards suicidality.

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.

S221. THE EFFICACY OF LUMATEPERONE 42 MG IN THE TREATMENT OF SCHIZOPHRENIA SYMPTOMS ASSOCIATED WITH SOCIAL FUNCTIONING: POST HOC ANALYSIS OF AN ACUTE PLACEBO- AND ACTIVE-CONTROLLED TRIAL

BackgroundDeficits in social functioning are a core feature of schizophrenia and may be due to the interaction of multiple factors including negative symptoms, depression symptoms, and deficits in social cognition. Social and functional impairment in schizophrenia can be difficult to treat, may not correlate with improvements in psychotic symptoms, and has been associated with poor long-term patient outcomes.Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel agent for the treatment of schizophrenia that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. Lumateperone was shown to be efficacious and well tolerated in 2 acute placebo-controlled studies and its safety and effectiveness was further supported in a long-term open-label study.The effects of lumateperone 42 mg (ITI-007 60 mg) on schizophrenia symptoms associated with social function were investigated in a post hoc analysis of a study that included risperidone 4 mg as an active control (Study 005, NCT01499563). Symptoms associated with social functioning were assessed with the Positive and Negative Syndrome Scale (PANSS)-derived Prosocial factor (PANSS items P3, P6, N2, N4, N7, G16), which has been utilized previously to evaluate the efficacy of various antipsychotics on this functional domain.MethodsThis is a post hoc analysis of data from a positive placebo- and active-controlled study in patients with an acute exacerbation of schizophrenia. Change from baseline in the PANSS Prosocial factor was assessed in the intent-to-treat (ITT) population and in patients with prominent negative symptoms (PNS, score ≥4 on at least 3 negative symptom items) or moderate-to-severe depression symptoms (Calgary Depression Scale for Schizophrenia [CDSS] ≥6) at baseline. Inferential analysis was conducted using a mixed-effects model for repeated measures (MMRM).ResultsThe ITT population comprised 231 patients (placebo, n=80; lumateperone 42 mg, n=76; risperidone 4 mg, n=75); the PNS and CDSS ≥6 populations comprised 110 and 54 patients, respectively. Lumateperone 42-mg treatment was associated with significantly greater improvement compared with placebo on the PANSS Prosocial factor (least-squares mean difference [LSMD] vs placebo = −2.7; P<.001). Risperidone also was superior to placebo on the PANSS Prosocial factor (LSMD= −1.8; P=.011). Similar treatment effects for lumateperone 42 mg were seen on the PANSS Prosocial factor in patients with PNS at baseline (LSMD −2.6, P=.006). Conversely, in patients with PNS, risperidone treatment showed small and non-significant treatment effects on the PANSS Prosocial factor (LSMD= −0.4; P=.707). In patients with moderate-to-severe depression symptoms at baseline, marked and significant improvements on the PANSS Prosocial factor were seen in lumateperone-treated patients (LSMD= −4.9; P<.001) but not in risperidone-treated patients (LSMD=−1.3; P=.397).DiscussionLumateperone 42 mg significantly improved schizophrenia symptoms related to social functioning. In contrast to risperidone, lumateperone was associated with similar or greater treatment effects on the PANSS Prosocial factor in patients with prominent negative symptoms or moderate-to-severe depression symptoms at baseline. These results suggest that lumateperone may have benefits on schizophrenia symptoms associated with social function.