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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.)

It is unknown whether interim analyses portend final study results. Fatigue, pressure to complete trials and recruitment differences may mitigate against this. We examined the similarity of efficacy results of the first and second half of recruited patients to complete trials and explore possible intervening variables. Using data from the NewMeds repository of patient level data from placebo-controlled randomized trials of antipsychotics (AP) (22 studies, n=7056) and antidepressants (AD) (39 studies, n=12,217) we compared treatment effect size (placebo vs. active treatment) of the first and second half of patients recruited in completed trials. We found that in AP studies median difference in treatment effect between cohorts was -0.03, indicating that overall first and second cohorts yielded similar results. In AD studies, median difference between cohorts was 0.04, indicating that overall the second cohort had slightly larger active-placebo-difference. Overall, on average there were minimal differences in effect size between the first and the second cohorts, and in 30 of 39 trials interim results were a good estimate of the results on the 2nd cohort. In AD trials first and second cohort results were more similar when the proportion of patients per study centre and recruitment time of the two cohorts was similar. Results suggest that interim analyses in AD and AP studies may reliably serve to estimate ultimate effects and, at least in AD trials, are more accurate when the same sites are used to a similar extent and recruitment time of the two consequent cohorts is similar., (Copyright © 2015 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: 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: 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.)

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: The extent of heterogeneity in antipsychotic treatment response for over extended period is unclear. This study aimed to quantify treatment response trajectories and their characteristics up to 2 years in recent-onset psychosis., Method: Participants were from a double-blind randomized controlled trial of recent-episode psychosis (N = 263). Recurrent Positive and Negative Syndrome Scale (PANSS) administrations were used to index treatment response trajectories for up to 2 years. Trajectories were calculated with mixed-mode latent class regression modeling from which groups were derived. Group differences were examined on sex, age of first admission, duration of untreated psychosis, premorbid functioning, diagnoses of substance abuse and schizophrenia, and cognitive functioning., Results: Five trajectories based on PANSS total scores were identified at 2 years. In the trajectory group (23.1%) with the most improvement, approximately 62% met the PANSS 30% change criteria. Logistic regression modeling indicated that membership in the trajectory with the most improvement was significantly (P < 0.05) predicted by absence of a diagnosis of schizophrenia, better premorbid functioning, and higher cognitive scores. Membership in the trajectory with the least improvement was significantly predicted by higher PANSS baseline scores., Conclusions: Based on clinical trial data, treatment response in early episode psychosis seems to be characterized by amelioration and ongoing change. Premorbid functioning, cognitive functioning, and early symptom severity have prognostic value in predicting treatment response trajectories. Across trajectory studies, approximately 16% of patients experience a dramatic treatment response trajectory characterized by approximately a 60% to 80% symptom reduction.

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.

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: 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.

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: 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.

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.

Objectives: To examine the effect of risperidone on specific behavioral and psychological symptoms of dementia (BPSD) among patients with psychosis of Alzheimer's disease (AD)., Methods: Post hoc exploratory analysis of data on 479 nursing-home patients with psychosis of AD from three 12-week, double-blind, placebo-controlled clinical trials. Criteria for psychosis of AD were a diagnosis of AD or mixed dementia and a rating of >/= 2 on any delusion or hallucination item of the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) rating scale when entering the trial. Mean changes from baseline to endpoint were examined for items on the Cohen-Mansfield Agitation Inventory (CMAI) and BEHAVE- AD., Results: On the CMAI, risperidone was significantly more effective than placebo in treating cursing or verbal aggression (p = 0.004), hitting (p < 0.001), performing repetitious mannerisms (p < 0.001), pacing, aimless wandering (p = 0.017), hoarding things (p = 0.02), hiding things (p = 0.02) and repetitive sentences or questions (p = 0.025). On the BEHAVE-AD, risperidone was significantly more effective than placebo in treating physical threats and/or violence (p = 0.001), agitation (other) (p = 0.001) and verbal outbursts (p = 0.026). Although analysis on individual hallucination and delusional items did not demonstrate specific responses, analyses of a composite of delusional items revealed significant drug-placebo differences., Conclusions: These data indicate that risperidone is effective in treating a variety of symptoms associated with psychosis of AD.

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: 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.

Objective: The authors examined early onset of antipsychotic action and early prediction of nonresponse to antipsychotics in patients with first-episode schizophrenia., Method: Time to clinical response (>/=20% improvement in total score on the Positive and Negative Syndrome Scale [PANSS]) was determined in 522 participants in a randomized, controlled trial comparing risperidone and haloperidol. Median treatment length was 206 days., Results: Clinical response was achieved in 77% (N=400) of subjects. Among these patients, clinical response was achieved in 23.3%, 23.3%, 18.5%, and 12.5% at weeks 1, 2, 3, and 4, respectively, after treatment initiation. However, in 22.5% of patients, response was not achieved until after 4 weeks, and in 11.2%, it was not achieved until after 8 weeks. In 45% of patients, response was achieved with a dose of 1-2 mg/day, in 27% with 3 mg/day, in 17% with 4 mg/day, and in the remaining 11% with higher doses. Improvement in the PANSS total score of at least 30%, 40%, and 50%, respectively, were achieved by 63.0%, 44.8%, and 27.5% of patients., Conclusions: Time to antipsychotic response varied widely, suggesting that, in first-episode schizophrenia, longer treatment trials may be necessary.

Objective: Cognitive impairment is a major determinant of functional outcome in schizophrenia. Treatment of cognitive impairment at the time of the first episode may have the potential to change functional outcomes of the illness. This study examined changes associated with treatment with risperidone compared with haloperidol in aspects of cognitive functioning known to be associated with functional outcomes. The study was conducted in a large group of patients experiencing their first episode of schizophrenia., Method: Cognitive assessments were conducted in 533 patients experiencing their first episode of schizophrenia or a related psychosis who had been randomly assigned to receive low doses of risperidone or haloperidol. The cognitive assessments were repeated at several different follow-up intervals; 359 patients were reexamined at the 3-month follow-up. The assessments included examinations of verbal and visuospatial episodic memory, vigilance, executive functioning, processing speed, and verbal fluency. Patients' clinical symptoms were also rated with the Positive and Negative Syndrome Scale., Results: Improvements from baseline were found in the risperidone-treated patients for episodic memory, verbal fluency, vigilance, executive functioning, and visuomotor speed. Haloperidol-treated patients also showed improvements from baseline in episodic memory, vigilance, and visuomotor speed but not in executive functioning or verbal fluency. Comparison of differential treatment effects on a composite measure of cognitive functioning found that risperidone was significantly more beneficial than haloperidol after 3 months of treatment. Changes in Positive and Negative Syndrome Scale scores were correlated overall with improvement in the haloperidol-treated patients but not in the risperidone-treated patients., Conclusions: Treatment with risperidone at the time of the first episode of schizophrenia is associated with wide-ranging improvements in cognitive functioning. Overall improvement is significantly greater with risperidone than with haloperidol. Further, cognitive improvement associated with treatment with risperidone was not influenced by changes in symptoms, but that relationship was significant in haloperidol-treated patients.

Background: The extent to which antipsychotics improve patients' well-being is uncertain., Aims: To examine psychopathology and patient-rated functioning and well-being in patients treated with risperidone., Method: In a 1-year, open-label, international multicentre trial of long-acting risperidone in 615 stable adult patients with schizophrenia, self-rated functioning and well-being were measured every 3 months using the Short Form 36-item questionnaire (SF-36). Psychopathology was quantified using the Positive and Negative Syndrome Scale (PANSS)., Results: Significant improvements were found on the SF-36 mental component summary score and vitality and social functioning scales. PANSS and mental component summary scores were moderately correlated., Conclusions: Patient-reported functioning and well-being appear to differ from investigator-rated psychotic symptoms. Patient-rated well-being should be assessed with symptoms to help measure treatment outcomes.

Movement disorders in first-episode psychosis are increasingly recognized; however, the prevalence and clinical correlates are uncertain. We compared antipsychotic exposed (< 12 weeks) with nonexposed first-episode patients, and report prevalence as well as clinical and demographic variables associated with extrapyramidal dysfunction. Data are baseline assessments from a multicentre, international drug trial of first-episode psychosis (n = 535). Analysis included the Extrapyramidal Symptom Rating Scale, Premorbid Adjustment Scale, and the Positive and Negative Syndrome Scale. Of non-exposed patients, 28.1% (n = 47/167) had at least one mild sign of extrapyramidal dysfunction, as did 46.3% (n = 169/365) of previously exposed patients. Hypokinetic Parkinsonism was the most prevalent disorder. The severity of movement disorders and negative symptoms were correlated; however, the effect sizes were small. Logistic regression analysis indicated that the salient risk factors for all patients were: previous antipsychotic exposure [odds ratio (OR) = 2.4; 95% confidence interval (CI) 1.6-3.6] and poor premorbid functioning (OR = 1.8; 95% CI 1.2-2.6). For the non-exposed group (n = 167), the significant risk factors were: having severe mental illness in the family (OR = 2.9; 95% CI 1.2-7.2) and poor premorbid functioning (OR = 2.3; 95% CI 1.0-5.3). For the previously exposed group (n = 368), the significant variables were: poor premorbid functioning (OR = 1.8; 95%CI 1.2-2.8) and shorter duration of untreated psychosis (OR = 0.78; 95% CI 0.64-0.94). Although antipsychotic exposure was associated with extrapyramidal signs, the results indicate that many first-episode patients with no exposure to antipsychotics also had extrapyramidal dysfunction. In this group, family history and poor premorbid functioning appear to be associated with increased risk for movement disorders.

Objective: The first episode of psychotic illness is a key intervention point. The initial experience with medication can affect willingness to accept treatment. Further, relapse prevention is a treatment cornerstone during the first years of illness because active psychotic illness may affect lifetime outcomes. Thus, initial treatment of active symptoms and subsequent relapse prevention are central goals of pharmacotherapy. This study compared long-term effectiveness of risperidone versus haloperidol in first-episode psychosis patients., Method: First-episode psychosis patients (N=555, mean age=25.4 years) participated in a double-blind, randomized, controlled flexible-dose trial that compared risperidone (mean modal dose=3.3 mg) and haloperidol (mean modal dose=2.9 mg). The median treatment length was 206 days (maximum=1,514)., Results: Positive and Negative Syndrome Scale scores and Clinical Global Impression ratings improved significantly relative to baseline, with no significant differences between groups. Three-quarters of the patients achieved initial clinical improvement, defined as >20% reduction in total Positive and Negative Syndrome Scale score. However, among those who achieved clinical improvement, 42% of the risperidone group experienced a relapse compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone-treated subjects and 205 days for those given haloperidol. These differences were statistically significant based on Kaplan-Meier survival analysis. Adverse effects distinguished the treatments: there were significantly more extrapyramidal signs and symptoms and adjunctive medication use in the haloperidol group and greater prolactin elevation in the risperidone group. There was less weight gain with haloperidol initially but no significant differences between groups at endpoint., Conclusions: Relatively low doses of antipsychotic drugs lead to significant symptom amelioration in the majority of first-episode psychosis patients. In the long term, risperidone prevents relapse in more patients and for a longer time and also induces less abnormal movements than haloperidol.

Objective: To examine the effect of risperidone on specific behavioral and psychological symptoms of dementia (BPSD)., Method: We conducted a post hoc exploratory analysis of an integrated database from 3 randomized, controlled trials of risperidone versus placebo in treating 1150 nursing home residents with BPSD. Changes in scores were measured for items on the Cohen-Mansfield Agitation Inventory (CMAI) and Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD)., Results: On the CMAI, risperidone was significantly more effective in treating hitting (p = .000), hurt self or other (p = .005), cursing or verbal aggression (p = .000), repetitive sentences or questions (p = .001), scratching (p = .041), general restlessness (p = .001), grabbing onto people (p = .028), constant request for attention (p = .041), pacing and aimless wandering (p = .013), and performing repetitious mannerisms (p = .045). On the BEHAVE-AD, risperidone was significantly more effective in treating physical threats and/or violence (p = .000), verbal outbursts (p = .000), other anxieties (p = .01), agitation (p = .000), tearfulness (p = .03), and nonparanoid delusions (p = .02)., Conclusions: The items from the BEHAVE-AD and CMAI that were improved with risperidone included psychotic, agitated, and aggressive symptoms. These data suggest that risperidone is more effective than placebo in treating a variety of symptoms associated with dementia.

Objective: The presence of cognitive dysfunction in schizophrenia has been well documented, but questions remain about whether there are relationships between this dysfunction and clinical symptomatology. If present, such relationships should be most clearly observable in patients with first episode schizophrenia; that is, before the effects of chronic illness, institutionalization, or treatment might confound them., Method: 307 schizophrenia subjects in their first episode of illness were recruited to participate in a clinical trial comparing the long-term efficacy of haloperidol and risperidone. The psychopathology, cognitive functioning, early treatment history, and duration of untreated psychosis of these subjects were assessed prior to their assignment to randomized, double-blind treatment. Approximately two-thirds of the subjects were receiving antipsychotic treatment at the time of assessment; however, the duration of treatment was limited to 12 weeks or less., Results: The severity of negative symptoms at the time of assessment was associated with deficits in memory, verbal fluency, psychomotor speed and executive function. Positive symptoms were not associated with cognitive deficits. Also, the duration of untreated illness (DUI) prior to assessment was not significantly associated with cognitive impairment., Conclusions: The results of this study of first episode schizophrenia patients suggest that a relationship exists between negative symptoms and cognitive dysfunction. However, that relationship accounts for only a minor portion of the variance (i.e., 10-15%) in the severity of cognitive dysfunction after controlling for a number of potentially confounding factors. This finding provides support for the theory that the neurobiological processes that give rise to symptomatology and cognitive dysfunction in schizophrenia are partially overlapping.

Background: Chronic schizophrenia patients have been sampled for factor analytic studies to identify the factor structure of the Positive and Negative Syndrome Scale (PANSS). Many of these studies have identified a cognitive factor, which may provide useful information about patients for whom formal neuropsychological testing is unavailable. However, the relationship between the clinically rated cognitive factor and performance-based cognitive test scores has not been thoroughly examined, particularly in patients who are early in the course of illness., Objectives: The validity of the PANSS cognitive factor was examined in a sample of antipsychotic naïve, first-episode psychosis patients and the PANSS items that best predicted cognitive functioning were identified., Method: PANSS scores and performance on a battery of cognitive tests from the baseline assessment of a clinical trial of 167 neuroleptic naïve patients with schizophrenia-like illnesses were analyzed., Results: Factor analysis revealed a five-factor model that was consistent with previously described factor models from samples of chronically treated patients. There were modest correlations (less than r=0.44) between the derived cognitive factor and six of the neuropsychological test variables (Wisconsin Card Sorting Test total errors and number of categories correctly sorted, WMS-R immediate and delayed recall scores, Category Fluency total score, and WAIS-R digit symbol). Five PANSS items (P6, N5, N6, G2, and G10) were identified that predicted global cognitive functioning; however, 66% of the variance in cognitive functioning remained unexplained., Conclusions: A PANSS cognitive factor can be identified in first-episode, neuroleptic naïve patients. However, clinical ratings of cognitive deficits lack sensitivity and specificity and thus should not be relied upon fully.

Background: Evidence on efficacy of antipsychotic medications comes primarily from controlled trials which select eligible consenting patients for experimental and regimented treatments, who do not abuse drugs, and are in good general health. Thus, it is not clear to what extent results are generalizable to most individuals treated for a psychotic illness who may not be eligible for such trials., Objective: This study compared characteristics of patients treated in a large randomized trial of persons with early psychosis to a cohort from a large epidemiological study of first episode psychosis., Methods: Included were the 535 patients enrolled in a controlled trial of antipsychotic medication and 179 similarly diagnosed persons from the Suffolk County Mental Health epidemiological study. Drug trial exclusion criteria were used to estimate the number of patients from the epidemiological study who would have been ineligible for the drug trial. The two samples were compared on key characteristics., Results: Thirty-three percent (n=59) of the epidemiological sample did not meet inclusion criteria for the drug trial (due to antidepressant treatment, n=26; current substance abuse, n=18; recent suicide attempt, n=9; and for more than one reason, n=6). There were no significant differences between the two study samples on age of onset, age, gender and premorbid functioning. Drug trial patients had higher Brief Psychiatric Rating Scale (BPRS), slightly lower Clinical Global Impression (CGI), and less formal education than those in the epidemiological study., Conclusions: While some patients in the epidemiological sample would have been excluded from the drug trial, patients in the two studies were similar on several key variables.

Background: Speed of onset of therapeutic effect is an important dimension of drugs employed to treat psychosis and schizophrenia. Faster onset is desirable to reduce the anguish caused by delusions and hallucinations and to protect patients and others from the consequences of poor judgment associated with psychotic exacerbation. Although sufficient studies have demonstrated that novel antipsychotics have advantages over clinically employed doses of classic drugs in terms of tolerability and aspects of efficacy, less is known about differences in speed of onset of therapeutic effect. This report consists of a post hoc subanalysis of data from a large double-blind, randomized pivotal trial in which we compared onset of therapeutic effect between risperidone and haloperidol., Method: During an 8-week period, 227 patients with DSM-III chronic schizophrenia received 4 mg/day of risperidone and 226 patients received 10 mg/day of haloperidol. Symptoms were assessed 6 times (days 0, 7, 14, 28, 42, and 56) using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and the Clinical Global Impressions-Severity of Illness scale (CGI-S). Data were analyzed using analysis of variance for multiple dependent variables and repeated-measures multivariate analysis of variance., Results: The analyses revealed that patients receiving risperidone improved more rapidly than those receiving haloperidol as measured by PANSS total and CGI-S scores. Differences were most pronounced during the first week of treatment., Conclusion: Results suggest that risperidone offers a more rapid response than haloperidol, particularly during the active phase of illness when time to response can be crucial.

Objective: The purpose of this study was to compare the rehospitalization rates of patients discharged from the hospital while being treated with risperidone, olanzapine, or conventional antipsychotics., Method: By using Israel's National Psychiatric Hospitalization Case Registry, rehospitalization status was monitored for all patients with schizophrenia who were discharged from any inpatient psychiatric facility in Israel while taking risperidone (N=268) or olanzapine (N=313) between Jan. 1, 1998, and Dec. 31, 1998, and a group of patients discharged during that time who were treated with conventional antipsychotics (N=458). Time to readmission over the course of 2 years was measured by the product-limit (Kaplan-Meier) formula., Results: The readmission rate for patients discharged while taking conventional antipsychotics was higher than the rates for patients treated with either risperidone or olanzapine. At 24 months, 67% of the risperidone-treated patients and 69% of the olanzapine-treated patients remained in the community, as compared to 52% of the patients treated with conventional antipsychotics., Conclusions: This study suggests that the rehospitalization rates of patients taking the novel antipsychotics risperidone and olanzapine are not different from each other and are considerably lower than the rate for patients treated with conventional antipsychotics. The results confirm findings of previous studies suggesting that the levels of overall effectiveness of risperidone and olanzapine are not very different and offers evidence that these drugs are more effective in preventing rehospitalization than conventional antipsychotic drugs.

Converging evidence indicates that, in controlled drug trials, individuals receiving novel antipsychotic medications have fewer adverse effects than those receiving conventional antipsychotic medications. This in turn may lead to greater patient treatment satisfaction. This study examines patient satisfaction and burden of adverse effects in a county-wide epidemiologic study of first admission psychotic persons with psychosis who were receiving novel antipsychotic drugs (n = 42). Comparisons were made within this group, and between 25 of these persons and 25 others with the same diagnosis and sex, from the same epidemiologic study, who were receiving a comparable regimen of conventional antipsychotic drugs. Patients receiving novel antipsychotics were significantly more satisfied and were significantly less burdened by adverse effects than those receiving conventional antipsychotics. Among the group receiving novel antipsychotics, dosage was not related to satisfaction or burden of adverse effects. For those treated with risperidone (n = 27), there was a difference, approaching statistical significance, for greater satisfaction and less adverse effect burden among those persons with dosages less than 5 mg daily as compared to higher dosages.

Background: Because risperidone and olanzapine have similar efficacy and tolerability in the treatment of schizophrenia, costs, physician experience, and preference become relevant considerations in making treatment decisions. The purpose of this paper is to compare daily treatment costs of risperidone and olanzapine, and to examine psychiatrists' clinical preferences., Method: Dosage information was obtained from a national Ministry of Health registry and a national survey of psychiatrists. In addition, psychiatrists' clinical preference of antipsychotic medication and dosage for patient subtypes were examined by the national survey., Results: Data from the registry and national survey estimated the mean daily dose of risperidone to be one-third that of olanzapine, irrespective of patient subtype. Taking into account drug costs and dosage requirements, the average daily retail price was US $6.85 for risperidone and US $13.60 for olanzapine. Psychiatrists preferred risperidone for first-episode psychosis and elderly psychosis, and olanzapine for patients sensitive to EPS. They rated the drugs equally effective on positive and negative symptoms, for chronic patients, for treatment-refractory patients and relapse prevention., Conclusions: Risperidone has a substantial cost advantage over olanzapine, and was preferred by psychiatrists for more indications.

Objective: The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment., Method: The subjects were 322 patients with schizophrenia or schizoaffective disorder who were consecutively admitted to a university hospital-based research program., Results: Analysis of variance showed significant relationship between age at onset and both gender and longterm responsivity to neuroleptic drugs. The mean ages at onset in the neuroleptic-responsive men (mean = 21.2 years, SD = 6.1, N = 75), neuroleptic-resistant men (mean = 19.4 years, SD = 4.7, N = 119), and neuroleptic-resistant women (mean = 20.1 years, SD = 6.3, N = 77) were fairly similar, whereas that of the neuroleptic-responsive women (mean = 24.2 years, SD = 8.7, N = 51) was significantly greater than for all other groups. A simple effects model indicated that male and female neuroleptic-resistant patients did not differ significantly in mean age at onset, whereas male and female neuroleptic-responsive patients did. The effect of gender and neuroleptic responsivity on age at onset was related to schizophrenic subtype., Conclusions: These results confirm previous data indicating neuroleptic resistance is associated with early onset. The finding that the difference in age at onset between males and females is smaller in neuroleptic-resistant patients than in neuroleptic-responsive patients suggests that neuroleptic-resistant patients differ premorbidly as well as after onset of illness.

Objective: The hypothesis that clozapine reduced serious physically and verbally aggressive behavior of persons with schizophrenia whose symptoms did not respond to typical neuroleptic treatment was tested., Method: Incident reports of aggression and restraint of 75 such inpatients were reviewed for 3 months before clozapine treatment and for 6 months of clozapine treatment. BPRS scores were also examined. Twenty-eight patients with no incidents were removed from study., Results: There were significantly fewer incidents of physical aggression per month per patient on clozapine than before clozapine (mean +/- S.D. = 0.13 +/- 0.25 vs. 0.54 +/- 0.93; t = 3.4, df = 46, p < 0.002) and a similar decline in verbal aggression (0.21 +/- 0.31 vs. 0.73 +/- 0.83; t = 4.3, df = 46, p < 0.000). On clozapine, 49% (n = 23) of patients had fewer incidents of physical aggression, 36% (n = 17) showed no change and 15% (n = 7) showed more. Seventy percent (n = 33) of patients had fewer incidents of verbal aggression, 4% (n = 2) showed no change and 25% (n = 12) had more. During the 3 months before clozapine, 14 patients (30%) were restrained a total of 40 times. During the first 6 months of clozapine treatment, three patients (6%) were restrained a total of six times. There were significant decreases in BPRS hostility, positive, negative and psychosis scores., Conclusion: Clozapine appears to reduce serious aggression among some patients.

Background: Clozapine's effectiveness in reducing symptoms and facilitating discharge among patients with chronic schizophrenia who were resistant to neuroleptics was studied., Method: All 169 such patients in a public psychiatric hospital were given clozapine. BPRS ratings (0-5 scale) were completed before treatment and 21 months later. Patients were followed for about 2.5 years., Results: Clozapine was discontinued in 37.8% of cases due to non-compliance, non-response, or side-effects. At follow-up 41% of clozapine recipients and 25.9% of the drop-outs were discharged and remained so, and 33% of recipients and 24.1% of drop-outs were being prepared for discharge. Longer treatment was associated with more improvement. Decline in average BPRS total scores of recipients was significantly more than drop-outs (32.7, s.d. 16.8 v. 12.1, s.d. 14.1, d.f. = 155, t = 7.5, P = 0.000)., Conclusions: Clozapine appears to be effective for treating some chronic neuroleptic nonresponding schizophrenic patients.