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Roluperidone has antagonist properties for 5-HT 2A , sigma 2 , α 1A - and α 1B -adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia., Competing Interests: Declaration of competing interest Authors JR, MW, PH have received consultancy fees from Minerva Neurosciences. Authors JS, RK, MD, RL are employees of Minerva Neurosciences the sponsor of the trial and CS is an employee of PPRS the CRO of the study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We derived outlier-response pattern checks to flag possible careless PANSS (Positive and Negative Syndrome Scale) administrations based on analysis of 122,000 administrations from 29 registration trials of antipsychotics from NEWMEDS data repository. Flags identify outlier administrations based on frequency of endorsing a given response value, use of even or odd values, consecutive use of same value, variability of values, responses per specific item, and values on multiple items. Outlier flags were compared to published expert derived scoring inconsistency flags and tested in Monte Carlo simulated data, with known inconsistency, and appear to be useful at identifying administrations that require review., (Copyright © 2021 Elsevier B.V. All rights reserved.)

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Personal and Social Performance Scale (PSP). One hundred and forty seven flags were identified, 16 flag errors in deriving the PSP decile (i.e., total) score from the four individual domain scores, 74 flag inconsistencies between domain scores relative to Positive and Negative Symptom Scale (PANSS) item ratings and 57 flag inconsistencies between PSP decile score and PANSS items ratings. The flags were applied to assessments from randomized clinical trial data of antipsychotics in schizophrenia from almost 18,000 ratings. Twenty-two flags were raised in at least 5 of 1000 ratings. Nearly 20% of the PSP ratings had at least one inconsistency flag raised. Application of flags to clinical ratings may improve the reliability of ratings and validity of trials., Competing Interests: Declaration of competing interest Jonathan Rabinowitz has received research grant(s) support and/or travel support and/or speaker fees and/or consultant fees from Janssen Research and Development (J&J), Eli Lilly and Company, Pfizer, Lundbeck, Roche, Abraham Pharmaceuticals, Pierre Fabre, Intra-cellular Therapies, Minerva Foundation, Takeda and Amgen. Mark Opler is an employee and shareholder of WCG MedAvante-ProPhase Inc. and has received grant funding from Stanley Foundation, QNRF, and NIH. Alon A. Rabinowitz has no conflicts of interest to disclose. Selam Negash is an employee of WCG – MedAvante-ProPhase. Ariana Anderson has received grants or contracts from Janssen Research and Development and BlackThorn Therapeutics. Dong-Jing Fu is an employee of Janssen Research & Development, LLC and a stockholder of Johnson & Johnson. David Williamson is an employee of Janssen Scientific Affairs, LLC and a stockholder of Johnson & Johnson. Alan Kott is a Full time Employee of Signant Health, LLC. Lori L. Davis reports consulting income from Lundbeck, Otsuka, Janssen and research support from Alkermes, Aptinyx, Tonix. Nina R. Schooler has received honoraria and travel support for attendance at advisory board meetings or consultation from Alkermes, GW Pharmaceuticals, Intracellular Therapies, Lundbeck and Otsuka. She has received grant support from Otskua., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT 2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia., Method: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia., Results: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score., Conclusions: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

International Society for CNS Clinical Trials and Methodology convened an expert working-group that assembled consistency/inconsistency flags for the Positive and Negative Syndrome Scale (PANSS). Twenty-four flags were identified and divided based on extent to which they represent error (Possibly, Probably, Very probably or definitely). The flags were applied to assessments derived from the NEWMEDS data repository and the CATIE clinical trial data. Almost 40% of ratings had at least one inconsistency flag raised and 10% had two. Application of flags to clinical rating can improve reliability and validity of trials., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Emerging data from on imaging and genetic studies have generated interest in "clinically significant" biomarkers to predict response and prognosis. What constitutes "clinical significance" and how a biomarker would reach that threshold are unclear. To develop a benchmark we reviewed different approaches for defining "clinical significance" applied in schizophrenia research and identified that an improvement of 15 points on the PANSS Total is considered meaningful in clinical settings. Using this benchmark and we simulated thousands of schizophrenia trials, using characteristics derived from the NEWMEDS database with over 8000 patients with schizophrenia, to the kind of imaging, genetic, and other biomarkers that could attain clinical significance. We plotted the interaction between frequency-of-occurrence, the effect size of biomarkers and their relationship to the clinical significance threshold. Results show that categorical biomarkers are likely to attain clinical significance when they occur in 20-50% of the clinical population, and can predict at least a 8-10 point PANSS scale difference. Genetic markers are likely to have clinical significance when they occur in 20-50% of the population and can predict 7-9 points on the PANSS scale. A marker with a lower frequency or lesser effect size would find it hard to meet clinical significance thresholds for schizophrenia. The assumptions and limitations of this approach are discussed. Compared with standards in the rest of medicine, biomarkers that can attain this benchmark will be cost-effective and are likely to be adopted by clinical systems., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: Persistent negative symptoms are an important area of clinical research. However, there is limited consensus on how to define positive and negative symptom severity thresholds for inclusion in clinical trials. From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset we evaluated the performance of varying baseline negative and positive symptom thresholds on baseline symptom severity, change from baseline, and negative symptom variance attributable to positive symptom change., Methods: In CATIE, we first identified the group of subjects lacking an exacerbation prior to study enrollment. Six subsets with varying baseline positive and negative symptom thresholds were then identified. Baseline characteristics were summarized; negative and positive symptom change from baseline through month 3 was calculated both as crude change and change adjusted for corresponding baseline scores. Sensitivity analyses and correlations were calculated to assess the extent to which negative symptom variance was attributable to positive symptom change., Results: More restrictive baseline symptom severity thresholds yielded a considerably smaller sample size and higher negative and lower positive symptoms at baseline. Unadjusted negative symptom change was greater with more restrictive criteria; when adjusted for baseline severity the magnitude of change was comparable across subsets. The amount of variance in negative symptom change attributed to positive symptom change was also comparable across subsets., Conclusions: The use of restrictive positive and negative symptom thresholds yields a marked decrease in eligible sample size with no clear improvement in adjusted negative symptom change or amount of variance associated with positive symptom change., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety-depression symptoms). It is often claimed that antipsychotic medications are particularly helpful for positive symptoms, but not for the others, suggesting a differential efficacy for different aspects of the disorder. We formally tested this claim. Using Structural Equation Modeling in two large [1884 patients] clinical trials in schizophrenia, we compared the model of a common general effect of antipsychotics to models whereby the antipsychotics have multiple and differential effects on the different factors of the illness. We validated the generalizability of the model in further trials involving antipsychotics in chronic [1460 patients] and first-episode patients [1053 patients]. Across different populations, different trials and different antipsychotics - the best-fitting model suggests that symptom response in schizophrenia is underpinned by a single general effect with secondary and minor lower-order effects on specific symptom domains. This single-factor model explained nearly 80% of the variance, was superior to the assumption of unique efficacy for specific domains; and replicated across antipsychotics and illness stages. Despite theoretical and pharmacological claims the differential efficacy of antipsychotics on the various dimensions of schizophrenia is not supported in the prevailing data. The implication of this finding for the measurement of treatment response and our understanding of the neurobiology of antipsychotic action, for clinical practice and for future drug development are discussed., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Background: Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials., Objective: We aimed to understand determinants of response to antipsychotic treatment., Method: Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580)., Results: While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented., Conclusions: Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Outcomes in RCT's of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCT's. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p ≤ .05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question., (© 2013 Published by Elsevier B.V. and ECNP.)

Background: There is an increased interest in evaluating the impact of core symptoms of schizophrenia, both positive and negative, on functioning and burden of disease., Objective: To examine the extent to which prominent positive and prominent negative symptoms impact functional health, well-being, health-related quality of life (HRQoL), and family burden., Methods: Data on symptomatology, HRQoL, and resource use from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) were analyzed (n=1447). Patients were divided into four groups based on the Positive and Negative Syndrome Scale (PANSS) using published criteria as having (a) neither prominent positive nor prominent negative symptoms (n=575; 39.7%); (b) only prominent negative symptoms (n=274; 18.9%); (c) only prominent positive symptoms (n=295; 20.4%); or (d) both prominent positive and negative symptoms (n=303; 20.9%). Differences were examined for overall significance between the groups and for a linear trend., Results: There was a significant linear decline in the outcome measures with each subsequent symptom group, with the combination of prominent positive and negative symptoms incrementing the decline further on quality-adjusted life-years derived from the PANSS, Short-Form-12, Index of Functioning, HRQoL measures, and number of workdays missed by caregiver during the month prior to CATIE (all p<0.001)., Conclusions: Both prominent positive and prominent negative symptoms of schizophrenia are independently associated with significant decline in functionality, HRQoL, and caregiver lost workdays. An increased burden is observed in patients with highest symptomatology. Further research is needed to determine predictors of poor outcomes and burden of schizophrenia., (© 2013. Published by Elsevier B.V. All rights reserved.)

Background: Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus., Objectives: We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms., Method: Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome., Results: Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from "typical" trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics., Conclusions: Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A number of pharmacological agents for treating negative symptoms in schizophrenia are currently in development. Unresolved questions regarding the design of clinical trials in this area were discussed at an international meeting in Florence, Italy in April 2012. Participants included representatives from academia, the pharmaceutical industry, and the European Medicines Agency (EMA). Prior to the meeting, participants submitted key questions for debate and discussion. Responses to the questions guided the discussion during the meeting. The group reached agreement on a number of issues: (1) study subjects should be under the age of 65; (2) subjects should be excluded for symptoms of depression that do not overlap with negative symptoms; (3) functional measures should not be required as a co-primary in negative symptom trials; (4) information from informants should be included for ratings when available; (5) Phase 2 negative symptom trials should be 12weeks and 26weeks is preferred for Phase 3 trials; (6) prior to entry into a negative symptom study, subjects should demonstrate clinical stability for a period of 4 to 6months by collection of retrospective information; and (7) prior to entry, the stability of negative and positive symptoms should be confirmed prospectively for four weeks or longer. The participants could not reach agreement on whether predominant or prominent negative symptoms should be required for study subjects., (© 2013.)

Objective: BL-1020 is a γ-aminobutyric acid (GABA)-enhanced antipsychotic that combines dopamine antagonism with GABA agonist activity. On the basis of animal models, we tested the hypotheses that BL-1020 would be effective in ameliorating both psychotic symptoms and cognitive impairments, with a favorable safety profile in acutely ill schizophrenia patients., Method: 363 hospital-based psychiatric patients in India, Romania, and United States aged 18 to 65 years and meeting criteria for DSM-IV-TR diagnosis of chronic schizophrenia were randomized double-blind to receive BL-1020 10 mg/d, BL-1020 20-30 mg/d, placebo, or risperidone (2-8 mg/d) for 6 weeks. The main outcome measures were the positive and negative syndrome scale (PANSS), brief assessment of cognition in schizophrenia, readiness for discharge questionnaire, clinical global impressions scale (CGI) , and extrapyramidal symptom rating scale. The study ran from July 2008 to June 2009., Results: BL-1020 20-30 mg was significantly better than placebo on PANSS (P = .02) and CGI (P < .001) measurements, with no significant differences noted between BL-1020 20-30 mg and risperidone. There were no significant differences in the maximum change on extrapyramidal symptom rating scale between risperidone and BL-1020 20-30 mg, and both were significantly worse (P < .001) than placebo. BL-1020 20-30 mg was associated with significantly greater improvements on cognitive functioning as measured by the brief assessment of cognition in schizophrenia composite score when compared to placebo (effect size = 0.50, P = .009), risperidone (effect size = 0.43, P = .019), and BL-1020 10 mg (effect size = 0.42, P = .013) after 6 weeks., Conclusions: BL-1020 appears to be an effective antipsychotic with possible procognitive effects that will need to be further tested for short- and long-term effects. A further randomized controlled trial using the U.S. Food and Drug Administration-recommended Measurement and Treatment Research to Improve Cognition in Schizophrenia cognitive battery is ongoing., Trial Registration: ClinicalTrials.gov identifier: NCT00567710., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Increased attention has been given to treatment of negative symptoms and its potential impact on functional outcomes, however previous inferences have been confounded by the fact that measures of functional outcomes often use items similar to those of negative symptoms. We attempted to discern the relative effects of negative symptoms on functioning, as compared to other symptoms, using data from the National Institute of Mental Health CATIE trial of chronic schizophrenia (n=1447) by examining correlations of Positive and Negative Syndrome Scale factors, Calgary Depression Rating Scale and select items from Heinrich's and Lehman's Quality of Life Scales measuring aspects of functioning that did not overlap with negative symptoms. Baseline functioning and change in functioning were more strongly related to PANSS negative factor than any of the other symptoms - though the amount of variance explained by symptom changes in general was small. The data suggests that improvement in negative symptoms may have a distinctive and independent effect on functional outcome relative to other symptoms. This should be further tested in studies where negative symptoms improve without concomitant improvement of other symptoms., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Trajectory studies highlight heterogeneity in treatment response, although they are yet to systematically differentiate between antipsychotic medications., Aims: To compare treatment response trajectories across antipsychotic medication groups., Method: Data were analyzed from Phase 1 of CATIE, an 18-month double-blind randomized controlled trial of chronic schizophrenia. Change on recurrent Positive and Negative Syndrome Scale (PANSS) administrations for 1124 patients was used to index treatment response trajectories up to 18 months. Trajectory groups were identified with mixed-mode latent class regression modeling. Groups were derived for all participants, and separately for completers, dropouts, and each antipsychotic medication (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone) and then characterized., Results: Trajectory analysis of the entire sample identified that 18.9% of participants belonged to a group of responders. This figure increased to 31.5% for completers, and fell to 14.5% for dropouts. Olanzapine treated patients were significantly more likely than other treatment groups to belong to the trajectory of responders (n=69, 32.55%; Chi=20.13, df=2, p<.01). Separate trajectory analyses of each medication group showed that all medication groups showed two trajectories except olanzapine that had three trajectories and the only trajectory that attained a 20% PANSS reduction by endpoint., Conclusions: Trajectories of treatment response differ between antipsychotic medications and demonstrate substantial heterogeneity in chronic schizophrenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Population-based studies of cognitive and behavioral premorbid functioning in psychotic disorders generally focus on late adolescence in schizophrenia and most are based on IQ test scores., Aims: To examine differences in school grades at the ages of 13-14 between persons hospitalized during adulthood for schizophrenia or affective disorders and their peers., Methods: Ten years of school report data were ascertained on 8th grade children (n=21,448) in the city of Jerusalem (1978-1988). During adulthood cases with schizophrenia (n=194, 0.9%) or an affective disorder (n=41, 0.19%) were identified based on psychiatric hospitalizations in the National Psychiatric Hospitalization Case Registry of the State of Israel. School assessments of academic performance, nonacademic topics, and teacher ratings of classroom behavior were compared between peers without illness and cases, and their association with illness was examined., Results: Children subsequently hospitalized with schizophrenia had significantly lower nonacademic performance (ES=.20, p=.007) and teacher ratings on behavior (ES=.18, p=.02) than controls and numerically lower teacher behavior ratings than people subsequently hospitalized for an affective disorder (ES=.25, p=.19). Cox regression modeling showed that poorer nonacademic and lower behavioral ratings were significantly associated with earlier age of onset of schizophrenia., Conclusions: Premorbid behavior and nonacademic deficits are evident in early adolescence among persons subsequently hospitalized with schizophrenia and different from those hospitalized with affective disorders. This suggests that these ratings may have diagnostic specificity between schizophrenia and affective disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: Generally, immigrant status and male sex are separately documented to increase the risk of schizophrenia; although population-based risk trends by sex and immigration over time have not been examined. This study aims to examine the extent to which immigration acts as a risk factor for schizophrenia, delineated by origin, sex and year, using national population-based data over 15 years., Method: Data on all first psychiatric admissions from 1978 to 1992 (n = 10,892) from the National Psychiatric Hospitalization Case Registry of the State of Israel were merged with aggregate national data from the Israeli Central Bureau of Statistics., Results: Compared to native-born Israelis, people who migrated prior to the age of 15 (n = 2,335) were at a greater risk of schizophrenia (n = 8,557; RR = 1.6, 95% CI = 1.53; 1.68), particularly those from Far Eastern (RR = 2.43, 95% CI = 1.91; 3.1) and Caribbean and South American (RR = 1.94, 95% CI = 1.51; 2.51) countries. Aggregate risk was higher among female than male immigrants and over the 15-year study immigration-related risk declined across the sexes., Conclusion: The current findings replicate past research showing that immigrants, particularly from a social minority, as suggested by the social defeat-hypothesis, are at an increased risk of schizophrenia, and extend past findings to show that risk at least in Israel has decreased with time irrespective of sex.

Background: Data on attaining and maintaining symptom remission associated with specific antipsychotic medications are rare and variant., Aims: To examine remission rates and their variation by antipsychotic medication in chronic schizophrenia in the National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) given it has an 18-month duration and representative antipsychotic medications., Methods: Symptom remission was examined using the Remission in Schizophrenia Working Group remission criteria of attaining and maintaining for 6 months with mild ratings on 8 specific Positive and Negative Syndrome Scale (PANSS) items. Remission rates were assessed (a) up to 18 months across CATIE's switching phases (n = 1332); and (b) in phase 1 (that involved double-blind randomization to one of five antipsychotic medications) to compare antipsychotic medication differences in attaining and maintaining remission among patients not in remission at baseline (n = 941)., Results: At baseline 16.2% of patients were in symptomatic remission. Across the medication phases of CATIE only 11.7% attained and then maintained at least 6 months of symptomatic remission, and 55.5% (n = 623) experienced no symptom remission at any visit. During the first medication randomization phase, attaining and maintaining remission for 6 months was highest for the olanzapine (12.4%) medication group followed by the quetiapine (8.2%), perphenazine (6.8%), ziprasidone (6.5%), and risperidone (6.3%) groups., Conclusions: As currently defined, remission appears to be a very difficult therapeutic target to attain and maintain in chronic schizophrenia and may differ by antipsychotic medication. Pragmatically, remission gradients may be effectively studied by applying modified duration and symptom criteria., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Premorbid functioning may be associated with treatment response, but this is confounded by a lack of prospective longitudinal data and controls for medication compliance. This study tested the hypothesis that good premorbid functioning will be associated with better antipsychotic treatment response after controlling for drug adherence by using a long-acting injectable antipsychotic. This was a 6-month, open label, multicenter, phase IV trial in recent-onset schizophrenia treated with flexible doses of risperidone long-acting injectable (25-50 mg every 14 days). Premorbid functioning was assessed with the Premorbid Adjustment Scale (PAS)-Structured Interview; efficacy was evaluated with clinician-rated Positive and Negative Syndrome Scale, Clinical Global Impression scale of Severity of Illness, Clinical Global Impression scale of Change, Global Assessment of Functioning Scale, and trial participant completed SF-36. Analyses controlled for baseline scores and demographics. With the use of a priori PAS scoring criteria, the participants' premorbid functioning was categorized as stable-good (n = 142), stable-poor (n = 116), and deteriorating (n = 36). At baseline, the stable-good group had the best functioning on most efficacy measures. All groups showed significant improvement on efficacy measures with treatment. Improvement was significantly higher for the stable-good group. The PAS global assessment of highest level of functioning scale (excellent, n = 75; good, n = 117; fair, n = 78; and poor, n = 31) showed a strong association with baseline functioning and improvement and had a significant linear association with meeting Remission in Schizophrenia Working Group symptom criteria at baseline (P = 0.003) and attained and sustained remission for 3 months during study (47.7%, 49.3%, 29.6%, and 22.2%; P = 0.006). Good premorbid functioning corresponds with better treatment response in recent-onset psychosis as captured on both clinician and patient-reported measures.

Background: Insight is increasingly seen as an important variable for study in psychotic illness, particularly in relation to treatment adherence. This study aims to quantify the association of insight with outcome, sociodemographic variables and diagnosis in a large stable patient sample., Method: Data are from a one-year, open-label, international, multicenter trial (n=670) of long-acting risperidone in adult symptomatically stable patients with schizophrenia or schizoaffective disorder. Psychopathology and insight were quantified using the Positive and Negative Syndrome Scale (PANSS). Patients were assessed at four time points over the year of the study., Results: 31.2% of the sample showed clinically significant deficits in insight at baseline. There were no differences based on sex, but significant differences in age and diagnosis, with oldest patients and schizophrenia patients (cf., schizoaffective disorder) showing more deficits. Baseline insight impairment was correlated with change in PANSS score at one year (r=-0.243, p<0.001). Recursive partitioning showed that, of those whose symptoms improved, those whose insight also improved were more likely to complete the trial., Conclusions: Insight is important above and beyond the effects of symptoms for predicting continuation in drug trials. This may have implications for the design and analysis of such trials, as well as suggesting the importance of targeting insight in treatment to increase likelihood of adherence to treatment. There also appear to be small but significant differences in insight based on age and diagnosis within the schizophrenia spectrum.

Background: The associations of insight into illness and clinical and socio-demographic variables in schizophrenia have been examined, yet little attention has been given to premorbid functioning, insight change and outcomes., Objectives: We examined these associations in a large cohort of recent onset schizophrenia spectrum disorder patients., Methods: This was a prospective 6-month, open-label, multicentre, phase IV trial in 303 subjects with recent onset (

Background: Persons with psychotic illnesses have an increased risk for suicide, especially early in the illness. Sufficient knowledge allowing for early recognition is lacking., Objectives: To describe suicide behaviors before and during the 4 years following first psychiatric hospitalization, examine associations of demographic and psychiatric risk factors, and develop a suicide risk index., Method: Data came from the Suffolk County Mental Health Project, a first-admission cohort (n = 529). Cox regression was used to study associations of risk factors to suicide behaviors; a summary suicide behavior risk index was also tested., Results: Prior to first admission, 28.0% (n = 148) of the cohort had attempted suicide. During the 4-year follow-up, 13.6% (n = 72) of the cohort attempted suicide (29.7% of those with previous attempts and 7.3% making their first attempt) and 3 respondents died of suicide. The significant predictors at index admission of subsequent attempts were prior attempts or ideation, severity of depressive symptoms and thought disorder, lifetime substance abuse, and younger age. Suicide ideation was predicted by the same variables with the addition of insight into illness and with the exception of age at admission. A 3-category risk index was created; 61.1% of those who made a suicide attempt were in the highest risk group (n = 44/72)., Conclusion: The current study confirms and extends previous research showing that risk factors early in the course of illness are predictive of subsequent ideation and attempts. The risk index may be a useful adjunct in identifying individuals likely to benefit from preventive interventions.

This article examined suicide attempt rates at first psychiatric hospitalization and risk factors for subsequent suicide attempts over the early course of schizophrenia in national population-based data. Data were extracted from the National Psychiatric Hospitalization Case Registry of the State of Israel that contains all first psychiatric admissions with schizophrenia 1989-1992 and were followed up to 1996 (N=2293). Attempted suicide rates were: 8.5% (n=196) at the time of first psychiatric hospitalization and 6.6% (n=151) over the follow-up period of 4 to 7 years. Of those with a suicide attempt at first admission, 31.6% (n=62) made a subsequent suicide attempt during the follow-up period (OR=10.44, 95% CIs=7.22 to 15.09). Risk profiles were derived using recursive partitioning to predict sub-groups at risk of a subsequent suicide attempt. Those characterized by an attempt at the time of first admission were college educated, female and not married (45.9% (17/37), OR=13.46, 95% CIs=6.89 to 26.3). The risk profiles together correctly classified 90.7% (137/151) of subsequent suicide attempts. Suicide attempts at first admission and premorbid years of education have long-term prognostic utility and risk profiles are available., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Little is known about the extent of heterogeneity of symptomatology in treated early-onset psychosis. The current study aims to quantify the extent of heterogeneity in trajectories of treated symptom severity in early-episode psychosis and their antecedents., Methods: Data were from 491 persons with early-episode psychosis from a clinical trial of haloperidol and risperidone. Positive and Negative Syndrome Scale (PANSS) administrations were used to measure symptom severity trajectories for (a) rapid treatment response scores over 4 weeks and (b) medium-term course over 24 weeks. Baseline antecedents included sex, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis, age of onset, the Premorbid Adjustment Scale, and a cognitive test battery. Symptom severity trajectories were calculated with mixed mode latent class regression modeling from which groups were derived., Results: Five groups based on PANSS scores over time were identified. Over 4 weeks, 3 groups with varied baseline PANSS scores (54-105) did not surpass 30% PANSS improvement. Another group improved and then was stable (n = 76,15.3%), and another showed marked improvement (n = 94,18.9%). Logistic regression showed that membership in the best response trajectory was associated with not having a diagnosis of schizophrenia, good premorbid functioning, and higher cognitive functioning, whereas membership in the poor response trajectory was associated with earlier age of onset and poorer cognitive functioning., Conclusion: Amelioration generally characterizes treated symptom severity. Age of onset, diagnosis, cognitive functioning, and premorbid functioning have prognostic value in predicting treatment response trajectories.

Background: Mounting evidence suggests that compromised neurocognitive function is a central feature of schizophrenia. There are, however, schizophrenia patients with a normal neuropsychological (NP) performance, but estimates of the proportion of NP normal patients vary considerably between studies. Neurocognitive dysfunction is also a characteristic of other psychotic disorders, yet there are inconsistencies in the literature regarding the similarity to impairments in schizophrenia. NP normality in psychotic affective disorders has not been systematically studied., Methods: Data came from the Suffolk County Mental Health Project, an epidemiological study of first-admission patients with psychotic disorders. Respondents with a diagnosis of schizophrenia (N = 94) or schizoaffective disorder (N = 15), bipolar disorder (N = 78), and major depressive disorder (N = 48) were administered a battery of NP tests assessing 8 cognitive domains 2 years after index admission. Patients' performance profile was compared, and their NP status was classified based on 3 previously published criteria that vary in their stringency., Results: The 4 diagnostic groups had comparable NP performance profile patterns. All groups demonstrated impairments in memory, executive functions, and attention and processing speed. However, schizophrenia patients were more impaired than the other groups on all cognitive domains. Results were not attenuated when IQ was controlled. Prevalence of NP normality ranged between 16% and 45% in schizophrenia, 20% and 33% in schizoaffective disorder, 42% and 64% in bipolar disorder, and 42% and 77% in depression, depending on the criterion employed., Conclusions: Evidence suggests that differences in NP performance between schizophrenia and psychotic affective disorders are largely quantitative. NP impairment is also common in psychotic affective disorders. A significant minority of schizophrenia patients are NP normal.

Dropout is often used as an outcome measure in clinical trials of antipsychotic medication. Previous research is inconclusive regarding (a) differences in dropout rates between first- and second-generation antipsychotic medications and (b) how trial design features reduce dropout. Meta-analysis of randomized controlled trials (RCTs) of antipsychotic medication was conducted to compare dropout rates for first- and second-generation antipsychotic drugs and to examine how a broad range of design features effect dropout. Ninety-three RCTs that met inclusion criteria were located (n = 26 686). Meta-analytic random effects models showed that dropout was higher for first- than second-generation drugs (odds ratio = 1.49, 95% confidence interval: 1.31-1.66). This advantage persisted after removing study arms with excessively high dosages, in flexible dose studies, studies of patients with symptom exacerbation, nonresponder patients, inpatients, and outpatients. Mixed effects models for meta-analysis were used to identify design features that effected dropout and develop formulae to derive expected dropout rates based on trial design features, and these assigned a pivotal role to duration. Collectively, dropout rates are lower for second- than first-generation antipsychotic drugs and appear to be partly explained by trial design features thus providing direction for future trial design.

Background: Social and intellectual premorbid functioning are generally estimated retrospectively, and related to clinical or hospitalization outcomes in schizophrenia. Yet the relationship between premorbid functioning assessed prior to psychiatric hospitalization and postmorbid functional outcomes has not been examined., Objectives: To test competing models of the relationship between (a) functional outcomes with (b) premorbid functioning assessed on nationally administered tests prior to psychiatric hospitalization, postmorbid intellectual functioning and symptomatology using a historical prospective design., Methods: Ninety one inpatient and outpatient males with schizophrenia or schizoaffective disorder, aged 19 to 35, were examined using the Positive and Negative Syndrome Scale, the WAIS-III and Strauss and Carpenter social and occupational functional outcome scale. Premorbid intelligence and social functioning data were obtained from national standardized tests administered during high school prior to first hospitalization for schizophrenia., Results: Path modeling showed that premorbid intelligence and behavioral functioning directly predicted postmorbid IQ and negative symptoms, and indirectly predicted postmorbid social and occupational functioning via negative symptoms. Item level analysis indicated that better social and occupational outcomes occurred in a group with few negative symptoms., Conclusions: Premorbid functioning, postmorbid IQ and negative symptoms are related, yet the relationship between premorbid functioning and postmorbid functional outcomes appears to be mediated by postmorbid negative symptoms.

Background: Few studies have compared long-acting injectable second-generation antipsychotics with oral antipsychotics. Long-acting injectable antipsychotics-developed specifically to address the problem of adherence-might have an important role to play in treating early psychosis., Objective: The effects of oral antipsychotics versus risperidone long-acting injection (RLAI) were compared between 2 similar studies lasting 2 years each that were conducted at our site in South Africa., Methods: Results of an open-label study in which patients were treated with flexible doses of RLAI were compared with the results of a randomized controlled trial of flexible doses of oral risperidone or haloperidol. Inclusion criteria for both studies were age 16 to 45 years; confirmed diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder;

Recently proposed criteria for remission by a 'Remission in Schizophrenia Working Group' have generated considerable interest. We assessed rates, predictors, and correlates of remission in a sample of patients with first-episode schizophrenia treated with injectable, long-acting risperidone. This allowed us to examine remission among patients known to be receiving medication. This was a single-site open-label study in which 50 newly diagnosed cases of schizophreniform disorder or schizophrenia aged 16 to 43 years were treated with injectable, long-acting risperidone 25-50 mg every 2 weeks for 2 years. Remission, according to Remission in Schizophrenia Working Group criteria, was achieved in 64% of the patients. Of those achieving remission, 97% maintained this status until study completion. Remission was associated with greater improvements in other symptom domains, insight, and social and occupational functioning. Patients in remission received lower doses of antipsychotic medication, had fewer extrapyramidal symptoms, and a more favorable attitude toward medication. The results of this open-label study suggest that a majority of first-episode patients who receive long-acting injectable antipsychotic medication may achieve sustained remission. Double-blind-controlled studies using long-acting injectable antipsychotics in early psychosis are warranted to further test this.

Background: Often, outcomes in clinical trials of antipsychotic medications are examined using last observation carried forward (LOCF). One limitation of LOCF and other common approaches is that they overlook the meaning underpinning trial completion and noncompletion. Noncompletion often relates to lack of drug tolerability. Because long-term treatment is often indicated, noncompletion is an important outcome. An alternative approach is to test the composite hypothesis of the difference between (a) completion rates and (b) efficacy of complete cases. Studies to date have not applied this relatively new method., Objective: To illustrate the composite approach, we applied it to a systematic review of studies and compared the results with the reported LOCF analysis., Methods: A systematic search of the Schizophrenia Module of the Cochrane Library and Medline was conducted that identified 127 relevant randomized clinical trials of antipsychotic medications conducted since 1995. Extracted from study reports were the P values of a difference in dropout and the P value of a difference in improvement among complete cases. These P values were combined using standard approaches., Results: We identified 11 trials with 5339 participants that provided the necessary information to adequately apply the composite approach. In 2 trials, (18.2%) in which the LOCF results were not significant, the composite results were significant., Conclusions: The composite approach was more sensitive to change than LOCF and conceptually answers a more relevant question. It is likely that applying the composite approach would change how results of many trials are interpreted.

Background: The aim of the current study was to test the predictive and concurrent validity of the Premorbid Adjustment Scale (PAS) by comparing it with another similar but more elaborate retrospective measure and with data collected during late adolescence., Methods: We compared PAS late adolescence scores (age 16-18 years) of 91 males with schizophrenia or schizoaffective disorder with data on behavior collected in adolescence, before the first psychotic episode as part of standardized Draft Board screening, and with the same measure readministered during adulthood and modified to collect the same data again retrospectively., Results: The correlation of the PAS social withdrawal and social relations items with the social behavior scale of the Draft Board were .76 and .80, respectively, for the concurrent ratings and .52 and .53, respectively, for the data collected at age 17 years. The correlation of the PAS school achievements and school adjustment items with the functioning in structured environments scale of the Draft Board were .71 and .72, respectively, for the concurrent ratings and .43 and .47, respectively, for the data collected at age 17 years., Conclusions: Our results support the predictive and concurrent validity of the PAS and the validity of self-reported data on premorbid functioning in persons with schizophrenia.

Objective: The extent to which noncompletion of a clinical trial relates to outcomes has implications for choosing the most appropriate method for contending with missing data due to dropout. We examined whether dropout relates to outcome in clinical trials of antipsychotic medication., Methods: Data from 5 large clinical trials of schizophrenia (n=3483) were examined separately. Patients were aggregated into groups based on their final study visit. Group mean Positive and Negative Syndrome Scale (PANSS) total scores for each visit were computed and graphed. Change from baseline to end point for each group was computed and examined using ANCOVA. Cox regression modeling was used to examine baseline PANSS total and change as predictors of time to dropout., Results: In all 5 trials there was a statistically significantly relationship between time in trial and improvement. The longer the patients remained in the trial the more that they improved, with trial completers showing the most improvement at each time point. Higher baseline PANSS scores and symptom deterioration indicated by increased PANSS preceding the final study visit prior to dropout corresponded significantly with a greater likelihood of dropout., Conclusions: Dropout in clinical trials of antipsychotic medications corresponds with efficacy outcomes, the dynamics of symptom change and baseline symptom severity. Therefore, methods for statistical analysis should examine both efficacy and dropout and cannot assume that missing data due to dropout are completely at random.

Objective: Research based on pooling data from clinical trials suggests that it is possible to extrapolate from a CGI-S to a PANSS severity score and from the CGI-I to a PANSS percentage change score. This research has not been replicated nor examined in individual trials. This study aims to examine the feasibility of extrapolation from the CGI to the PANSS across and within 4 large clinical trials of antipsychotic medication., Methods: Equipercentile linking is used to examine extrapolation (a) from CGI-S to PANSS severity ratings and (b) from CGI-I to PANSS percentage change (n=2698). Linking is conducted at baseline and after 2, 4, 6 and 8 weeks of treatment from ITT clinical trial participants with schizophrenia., Results: Across weeks 2, 4, 6 and 8, being considered 'not ill' according to the CGI-S corresponded to PANSS scores of 31-2. The relationship between the CGI-S and the PANSS followed an increasing trend, such that 'very mild' corresponded with 41-7, 'mild' corresponded with 55-62, 'moderate' corresponded with 71-7, 'marked' corresponded with 88-94, 'severe' corresponded with 105-110, and 'extremely severe' corresponded with 126-134. The relationship between CGI-I ratings and percentage change followed a linear trend, such that 'very much improved' corresponded to PANSS percentage change scores from 79 to 75, 'much improved' corresponded with 45 to 49, 'minimally improved' corresponded with 21 to 23, 'unchanged' corresponded with 2 to 3, 'minimally worse' corresponded with -15 to -20, 'much worse' corresponded with -44 to -51. Generally, within the trials the cut-off ranges identified overlapped within around 10 points of those found in the pooled analysis., Conclusions: Despite trial heterogeneity, the results support the extrapolation from the CGI-I to PANSS percentage change. Extrapolation of the CGI-S to the PANSS is observed, except in the case of severe symptomatology which is rare. Collectively, the results support the extrapolation between the PANSS and CGI.

Background: Information on premorbid functioning is often based on patients recalling their past. Premorbid functioning is relevant as it is associated with treatment response and other outcomes. The extent to which memory impairments of persons with schizophrenia may bias such reporting has not been investigated. The purpose of the current study was to assess the extent to which persons with schizophrenia might exhibit biased reporting relative to controls., Methods: Seventy males with schizophrenia or schizoaffective disorder and 51 males with no psychiatric symptoms participated in the study. Contemporaneous and retrospective reports from a behavioral functioning assessment conducted as part of the Israeli Draft Board were compared. This assessment routinely administered to all 17 years old males in the country assesses social functioning, individual autonomy, organizational ability, physical activity and functioning in structured environments. We compared the groups on the Draft Board behavioral measures at age 17 and at re-assessment. We also examined the relationship between symptom severity, neuropsychological performance and differences between age 17 and current behavioral assessment scores., Results: In a repeated measures MANCOVA of the five measures there was no overall significant difference in accuracy of reporting between persons with schizophrenia and those without. Both groups showed a slight tendency to glorify their past. Consistency of reporting was not significantly correlated with neuropsychological performance or levels of psychotic symptoms., Conclusions: We found that when reporting on personal and social functioning during teen age years persons with schizophrenia report with the same level of consistency as persons without schizophrenia. This suggests that self-report of premorbid functioning of persons with schizophrenia can be trusted as being reasonably accurate.

Background: Inconsistent findings obscure understanding the relationship between socioeconomic status (SES) and schizophrenia. The aim of the current study was to test the association between individual and community SES at birth and risk of schizophrenia., Method: Population-based longitudinal follow forward study of a 13-year birth cohort (n = 71 165). Effects of individual and community socioeconomic variables were examined using multilevel regression in MLwiN., Results: Years of education of fathers and mothers, respectively, (0-8 vs 13+ odds ratio [OR] = 1.17, P < .0001; OR = 1.14, P < .001) lower occupational status of fathers (OR = 1.29, P = .036), and poorer residential area SES (OR = 1.26, P = .012) were risk factors for schizophrenia., Conclusions: Individual- and community-level SES at the time of birth are associated with an increased risk of schizophrenia.

Background: The Positive and Negative Syndrome Scale (PANSS) is a widely used instrument to measure severe psychopathology in schizophrenia. Recently, its widely accepted 5-factor solution is questioned using confirmatory factor analysis (CFA). This article examines the appropriateness of applying CFA to PANSS data and the dimensionality of the PANSS in a large sample of persons with chronic schizophrenia, schizophreniform disorder, and schizoaffective disorder., Materials and Methods: Data reduction was conducted on PANSS baseline assessments from 2 multicenter clinical trials consisting of 1284 persons' available PANSS data at baseline and Week 8. Supplementary analyses were conducted for separate trials and for noncompleters at baseline (n = 1872)., Results: Examination of the data indicated that the statistical requirements of CFA (eg, multivariate normality) were not met by the data. Multidimensional scaling and a scree plot of principal components superimposed on simulated random data converged to indicate that 5 dimensions are generally a parsimonious fit to the PANSS at baseline, whereas 4 dimensions emerged after 8 weeks of treatment. The components included negative symptoms, positive symptoms, disorganized (baseline only), anxiety/depression, and excited., Conclusions: The results demonstrate realistic alternatives to CFA when studying the PANSS, support a 5-component model of PANSS ratings at baseline, and indicate that the structure of symptoms change after 8 weeks of treatment. These results seem to be robust because they generally replicate within trials for completers and at baseline for the entire sample.

Background: Previous work suggests that the association between urbanicity and schizophrenia may be greatest in those with pre-existing vulnerability., Aims: To test for synergism in risk of schizophrenia between population density and a combined exposure of poor premorbid social and cognitive functioning., Method: For 371 603 adolescent males examined by the Israeli Draft Board on social and cognitive functioning, data on population density of place of residence and later hospitalisation for schizophrenia were obtained from population-based registries., Results: There was an interaction between population density (five levels) and poor premorbid social and cognitive functioning (interaction chi(2)=4.6, P=0.032). The adjusted increase in cumulative incidence associated with one unit change in population density was 0.10% in the vulnerable group (95% CI 0.019-0.18, P=0.015), nine times larger than that in the non-vulnerable group (0.011%, 95% CI 0.0017-0.020, P=0.021)., Conclusions: Risk of schizophrenia may increase when people with a genetic liability to the disorder, expressed as poor social and cognitive functioning, need to cope with city life.

Introduction: Approximately one third of schizophrenia patients show partial or no response to pharmacotherapy. Despite intensive investigations, the phenomenological and biological characteristics of such patients are far from elucidated. This study examined the premorbid behavioral and intellectual functioning of schizophrenia patients who showed poor response to antipsychotic treatment., Method: One hundred twenty-nine schizophrenia patients who showed poor response to treatment were ascertained from a national register and matched by gender, age and education to 129 patients who showed adequate response. The groups were compared on premorbid measures of behavioral and intellectual functions., Results: As a group, treatment-resistant male patients had significantly lower (worse) social functioning [p=0.002], and individual autonomy [p<0.0001] scores before the onset of the illness compared to treatment non-resistant patients. Male and female treatment-resistant patients did not differ from non-resistant patients in premorbid intellectual functioning [p>0.1]., Conclusions: Low premorbid social functioning and individual autonomy, but not intellectual functioning, could serve as predictors of poor treatment response in schizophrenia.

Background: Schizophrenia may follow a course of amelioration, deterioration or stability. It is possible that deterioration at the aggregate level may be due to a sub-group of patients with a tendency to deteriorate., Aims: To examine the course of schizophrenia in a national population-based cohort., Methods: All first admissions for schizophrenia in Israel 1978-1986 were followed for readmissions in the Israeli psychiatric hospitalization registry for 10 years (n=6865). Readmission rates were examined using cluster analysis. This was followed by an examination of changes in readmission patterns., Results: Cluster analysis identified a small cluster of patients who spent more days in the hospital over time and two clusters that improved. A priori classification of the patients into deteriorating, improving and stable (based on days hospitalized per year) revealed that approximately 75% of patients improved over time., Conclusions: Over time a majority of patients appear to improve and a minority appear to deteriorate.

Background: Recently, the "Remission in Schizophrenia Working Group" proposed remission criteria consisting of a reduction to mild levels on key symptoms for at least 6 months., Aims: This study applied these remission criteria to a large first-episode psychosis sample in order to (1) determine the rates of remission; (2) explore predictors of remission; and (3) test the external validity of these criteria., Methods: We analyzed data from 462 subjects with a first-episode of psychosis who participated in a long-term, multinational, randomized, double-blinded trial of risperidone and haloperidol over 2 to 4 years., Results: At some time point in the study 323 (70%) of the 462 subjects had a reduction to mild levels on the key symptoms as measured by the PANSS although only 109 (23.6%) maintained this level for at least 6 months thereby meeting remission criteria. The two strongest predictors of remission were shorter duration of untreated psychosis (p=0.01) and treatment response at 6 weeks (p=0.001). Compared to non-remitted patients, those in remission experienced greater improvement on all PANSS subscales (p<.0001), CGI-S (p<.0001), better quality of life (p=0.006), fewer relapses (p<.0001), displayed a more favorable attitude towards their medication (p=.002), had lower EPS levels according to the ESRS (p=<.0001) and received lower doses of antipsychotic medication (p=0.003). The remission and non-remission groups did not differ significantly regarding composite cognitive scores, suicidality and body mass index., Conclusions: The results suggest that the remission criteria, although based solely on core symptom improvement, can effectively identify patients who have a more favorable overall outcome.

Background: Despite suggestions that an earlier age of onset and being male confer to a poorer course of schizophrenia, evidence regarding when these effects are most salient appears to be ambiguous., Aims: To examine the relationship of age of first hospitalization and sex with the course of hospitalization in a population based cohort., Method: All first admissions for schizophrenia in a national population based cohort in Israel from 1978 to 1992 were followed through 1996 (n=12,071) using data from the National Psychiatric Hospitalization Case Registry of the State of Israel, a complete national registry of psychiatric admissions. Recursive partitioning was conducted to empirically determine cut-off points for age groups showing the greatest difference on the variables of interest., Results: A younger age of first hospital admission was associated with a greater likelihood of having more than one hospital admission, longer first admissions, more hospital admissions and more inpatient days per year. Of patients with age of first admission below 17, 82.5% had more than one admission which decreased for subsequent age groups to 73.54% (18-28), 69.36% (29-31), 62.88% (32-45), and 50.77% (over 45). Men had an earlier first admission than women, and had slightly more cut-off values. Irrespective of sex, the relationship between age at first admission and later hospitalization conformed to a linear trend., Conclusions: An earlier onset corresponds linearly with the severity of the course of illness and appears to have prognostic value.

Studies suggest that better premorbid functioning is associated with better outcomes in chronic schizophrenia. Yet first admission studies, which are more appropriate to examine this, are less conclusive. Also, little attention has been given to whether these findings hold for other psychoses. We examined the relationship of premorbid functioning using the Premorbid Adjustment Scale and outcomes in first admission psychoses (schizophrenia, N = 177; bipolar disorder, N = 106; major depression, N = 68) in the Suffolk County-wide mental health project. Poor premorbid functioning was associated with worse outcomes in all three diagnostic groups. Specifically, it was associated with more negative symptoms early in the course of illness, less improvement in negative symptoms, poorer overall clinical functioning, and poorer social functioning. Consistent with new epidemiological research, early assessment of premorbid functioning could provide an avenue for targeted interventions that might improve outcomes.

Background: Investigating the relationship between premorbid functioning and treatment response in schizophrenia is relevant to understanding the illness and predicting treatment outcomes., Aims: To examine the relationship between premorbid characteristics and treatment response of people with recent-onset schizophrenia., Method: Data came from a large, double-blind trial of recent-onset psychosis treated with a flexible dose of risperidone or haloperidol. Median treatment length was 206 days. Premorbid functioning was categorised using the Cannon-Spoor Premorbid Adjustment Scale., Results: There were significant differences between the premorbid groups on change on the Positive and Negative Syndrome Scale, Clinical Global Impression severity and cognitive functioning and Extrapyramidal Symptoms Rating Scale. Patients in the ;stable-good' premorbid group (n = 251) improved more than those in the'stable-poor' (n = 198) and 'declining' (n = 81) groups. The ;stable-good' group received the lowest doses of antipsychotic and had the least extrapyramidal symptoms. Patients in the 'declining' group had the highest dosages and the most extrapyramidal symptoms., Conclusions: In first-episode psychosis good premorbid functioning is associated with better response to treatment and fewer extrapyramidal symptoms.