Baseline Positive And Negative Syndrome Scale Scores Research Articles

Comparative Efficacy of Lorazepam and Risperidone in Hospitalized Cannabis-induced Psychotic Disorder

Abstract Background: There is a lack of a standardized treatment protocol for cannabis-induced psychotic disorder (CIPD). Current practice involves using antipsychotics and benzodiazepines concurrently for treating CIPD. Aim: The index study aimed to assess and compare the efficacy of lorazepam against risperidone in patients with CIPD. Methods: Hospitalized patients with a diagnosis of CIPD according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition were randomized to receive either lorazepam or risperidone orally. Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Cannabis Withdrawal Scale, and the Marijuana Craving Questionnaire were administered at baseline and daily to assess the improvement in psychopathology, withdrawal, and craving over a period of 10 days. Monitoring was also done for any adverse effects associated with treatment. Results: A total of 40 patients with a diagnosis of CIPD were included; 20 each in lorazepam and risperidone group. Both groups were comparable with respect to baseline PANSS (P = 0.13) and YMRS (P = 0.92) scores. The baseline withdrawal score was higher in the risperidone group (P = 0.03). There was a significant reduction in PANSS and YMRS scores in both groups by day 5 and day 10 (values of <0.001). However, there was no significant difference between the two groups. The degree of improvement during the initial 5 days was significantly more (P ≤ 0.001) than that observed from day 5 to day 10 in both groups. Conclusion: There was no statistically significant difference between lorazepam and risperidone groups in terms of improvement in PANSS and YMRS scores. The use of antipsychotic did not have any additional benefit in CIPD and was rather associated with more adverse effects.

Exploring Cariprazine’s Potential in Late-Stage Schizophrenia Treatment

IntroductionSchizophrenia is a chronic neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. There are important clinical differences between early-stage versus late-stage schizophrenia, like the predominant symptomatology. In later stages, negative, cognitive, and anxiety/depressive symptoms dominate the clinical picture, with relapses further potentiating the emergence of positive symptoms. Therefore, it is crucial to establish the efficacy of an antipsychotic medication in the later stages of schizophrenia as well. Cariprazine is a novel dopamine D3-preferring D3/D2 receptor partial agonist that has shown efficacy in treating schizophrenia across the symptom spectrum.ObjectivesThe aim of this poster is to present the findings of cariprazine’s efficacy in treating late-stage schizophrenia, especially in symptoms that are more commonly occurring in this phase of the disorder.MethodsThis poster reports the results of a post-hoc pooled analysis of three 6-week, double-blind, placebo-controlled trials (NCT01104766, NCT01104779, NCT00694707) that assessed the efficacy of cariprazine in schizophrenia. The primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) Total Scores from baseline to endpoint. The analysis focused on patients with late-stage schizophrenia (defined as having an illness-duration of more than 15 years) who received cariprazine at doses between 1.5 mg/day to 6.0 mg/day. The changes in PANSS-derived Marder Factor Scores for Negative, Disorganised Thought (i.e., Cognitive) and Anxiety/Depression symptoms were further examined. The least square mean differences (LSMDs) between cariprazine and placebo groups were calculated using mixed-models for repeated measures (MMRM).ResultsAltogether, 128 placebo-, and 286 cariprazine-treated patients were identified as having schizophrenia for more than 15 years. The mean age of patients was about 45 years, while the mean illness-duration was about 24 years. The mean baseline PANSS scores were the same between the two groups. In the late-stage schizophrenia population, at Week 6, cariprazine yielded statistically significantly greater reductions on the PANSS Total Score (LSMD -6.7, p<0.01). Cariprazine further showed superiority over placebo in reducing negative (LSMD -1.4, p<0.05), disorganised thought (LSMD -1.3, p<0.01), and anxiety/depression (LSMD -0.9, p<0.05) symptoms.ConclusionsCariprazine showed efficacy in treating patients with late-stage schizophrenia. It improved overall schizophrenia symptoms, as well as the negative, cognitive and anxiety/depression symptoms that are more prevalent in this phase of the disorder.Disclosure of InterestP. Falkai Consultant of: Janssen-Cilag, AstraZeneca, Lilly, and Lundbeck, Speakers bureau of: AstraZeneca, Bristol Myers Squibb, Lilly, Essex, GE Healthcare, GlaxoSmithKline, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Takeda, R. Csehi Employee of: Gedeon Richter Plc, K. Acsai Employee of: Gedeon Richter Plc, G. Németh Employee of: Gedeon Richter Plc

Factor Analysis Investigating the Efficacy of HP-3070 Transdermal System in Positive and Negative Syndrome Scale Five Adults With Schizophrenia

AbstractIntroductionHP-3070, a once-daily asenapine transdermal system, is FDA-approved for adults with schizophrenia. In a pivotal phase 3 randomized controlled study, patients with schizophrenia who were treated once daily with HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo. The PANSS score’s five-factor structure can also assess treatment efficacy across different domains. This post-hoc analysis of the pivotal study evaluated the efficacy of HP-3070 by examining these domains.MethodsIn the pivotal phase 3 study, adults with acute exacerbations of schizophrenia were randomized to 6 weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. Factor analysis of PANSS scores was performed using five domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.ResultsThe analysis included 607 patients. Least-squares mean estimates (standard error) of the difference from placebo in change from baseline to Week 6 for each factor were as follows: negative symptoms, 3.8mg/24h, -0.9 (0.43), P=0.045, and 7.6mg/24h, -0.4 (0.43), P=0.41; positive symptoms, 3.8mg/24h, -2.3 (0.57), P<0.001, and 7.6mg/24h, -2.0 (0.57), P<0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P<0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P<0.001, and 7.6mg/24h -0.9 (0.30), P=0.002; anxiety/depression, 3.8mg/24h, -0.5 (0.31), P=0.14, and 7.6mg/24h, -0.6 (0.31), P=0.07.ConclusionsHP-3070 demonstrated treatment effects on a PANSS five-factor model, with the results indicating impact on negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. These findings suggest that HP-3070 may address a broad range of symptoms in schizophrenia.FundingNoven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.

Pretreatment abnormalities in white matter integrity predict one-year clinical outcome in first episode schizophrenia

Schizophrenia is a serious mental illness for which the mainstay of treatment is antipsychotics. Up to 30% of schizophrenia patients show limited response to antipsychotics. Identifying these patients before treatment could guide individualized treatment for improving outcomes in those not likely to show robust benefit from antipsychotics. Diffusion tensor imaging was performed with 56 drug-naïve first-episode schizophrenia patients and 69 matched healthy controls. Patients were followed clinically after one-year of antipsychotic treatment and classified at that point into groups of 17 poor outcome and 39 good outcome patients based on whether they showed at least a 50% reduction of Positive and Negative Syndrome Scale (PANSS) scores from baseline. Tract-based spatial statistics were applied to assess white matter microstructure in the two patient subgroups and healthy controls. Poor outcome patients showed reduced pretreatment fractional anisotropy (FA) in left cingulum and anterior thalamic radiation and increased FA in right superior and inferior longitudinal fasciculus compared with good outcome patients. FA in each of these four tracts was decreased in both patient subgroups relative to healthy controls. Considered together, the four altered tracts showed promising ability to differentiate poor from good outcome patients (sensitivity = 74.4%, specificity = 95.2%, AUC = 0.90, p < 0.001), and superior prediction of clinical outcome to baseline PANSS scores (p < 0.015). Prediction of outcomes using DTI features was not related to duration of untreated psychosis. Baseline alterations in white matter integrity may identify schizophrenia patients less likely to respond to treatment, which could be useful information for stratification in clinical trials and for individualized treatment planning.

Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis

There is evidence that sodium benzoate (BZ) may be an effective adjunctive treatment for schizophrenia. The clinical efficacy of BZ has been investigated in chronic schizophrenia; however, the efficacy of this agent has not been studied in individuals with early psychosis. To examine the clinical efficacy of the adjunctive use of BZ for symptoms in people with early psychosis. Using a placebo-controlled double-masked parallel-group design, this randomized clinical trial was conducted from August 2015 to July 2018. Participants aged between 15 and 45 years experiencing early psychosis were enrolled from 5 major clinical sites in Queensland, Australia. Data analysis was conducted from October 2018 to February 2020. Participants were randomized 1:1 (50 participants in each group) to receive 500 mg of sodium benzoate twice daily or placebo for 12 weeks. The primary efficacy outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks. The key secondary efficacy measures were (1) the Clinical Global Impression score, (2) the Hamilton Depression Rating Scale for depression, (3) functioning as assessed by the clinician-rated Global Assessment of Function, and (4) the Assessment of Quality of Life Scale. The PANSS subscale scores and impact on selected amino acid concentrations were also assessed. The study comprised 100 participants with a mean (SD) age of 21.4 (4.1) years, of whom 73 (73%) were male individuals. The mean (SD) baseline PANSS score was 75.3 (15.4). We found no improvement in total PANSS score in the BZ group compared with the placebo group. The end result of least-squares mean difference (SE) for total PANSS was -1.2 (2.4) (P = .63). There were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. The dose of BZ was well tolerated without any clinically significant treatment-emergent adverse event differences between BZ and placebo groups. In this randomized clinical trial, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis. anzctr.org.au Identifier: ACTRN12615000187549.

M184. SOCIAL SKILLS TRAINING FOR TREATMENT-RESISTANT SCHIZOPHRENIA WITH PREDOMINANTLY NEGATIVE SYMPTOMS

BackgroundPoor social skills are a core characteristic of schizophrenia and are highly associated with the progression of negative symptoms. While positive symptoms have a good response to antipsychotics, the treatment of negative symptoms remains an unmet need.MethodsA randomized controlled trial to assess the efficacy of a 20-week social skills training (SST) program for the improvement of negative symptoms in patients with treatment-resistant schizophrenia (TRS) with predominantly negative persistent symptoms, with a score > 4 (moderate) in at least 3 items of the Negative Symptom Factor Score (NSFS) (blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, lack of spontaneity, motor retardation and active social avoidance).Each session lasted 60 minutes and included 6 to 9 participants. The SST sessions were conducted by trained psychologists, following topics previously outlined in a manual, and role-playing activities. The non-directive control group was conducted by nurses specialists in mental health, with the same duration but without role-playing activities. Control groups’ therapists were instructed not to give directions to the patients but to listen and redirect questions to the group.TRS was defined as the persistence of psychotic symptoms after at least two adequate trials with two different antipsychotics, All patients were taking clozapine. Blinded raters evaluated the patients at baseline, 20 weeks and after 6 months follow-up by the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) and the Social Skills Inventory (SSI). Longitudinal comparisons between groups were carried out using a linear mixed-effects model at pre, post and follow-up to assess differences between groups. Cohen’s d effect size was computed at each time point. Primary outcome measure was the PANSS negative subscale score.Social skill were assessed with the Social Skills Inventory.Results62 patients were randomized to SST (N=29) and control group (N=33). Subjects were predominantly male (70.96%) and single (88.70%). At baseline, groups showed no differences in terms of demographic variables and illness duration. Patients were moderately ill, with mean CGI = 4.10 (SD 0.78) in SST group and 4.34 (0.90) in the control group, and had a high baseline PANSS score, with a mean total PANSS 71.90 (10.83) in the SST group and 70.4 (13.8) in the control group. The mean PANSS negative subscale score was 25.48 (4.56) in SST group and 25.13 (6.34) in control group; in the SST group 28 patients completed the 20-week intervention and 24 were assessed after 6 months; in the control group, 18 completed the treatment and 16 were assessed at the follow-up. After the 20-week intervention period, the PANSS negative scores were 24.57 (4.92) in the SST group and 22.67 (6.59) in the control group. At the follow-up, the negative score was 23.92 (5.85) in the SST group and 22.97 (5.32) in the control. There was no improvement at any timepoint (p= 0.162) or any difference between groups (p= 0.864). Patients remained clinically stable during the study. The only symptom which showed a significant improvement was the control of aggressiveness (Cohen’s d at week 20 = 0.445 [IC 95% -0.140; 1.030]), which was maintained at follow-up (Cohen’s d = 0.682 [IC 95% 0.037; 1.327]).DiscussionThe study has limitations: the SSI was not designed to assess social skills in patients with psychosis, and we have not assessed the adherence to pharmacological treatment. Our findings suggest that SST is not effective to improve negative symptoms in patients with TRS with predominantly negative symptoms, but may be potentially useful for the control of aggressiveness in situations such as criticism and mockery, which frequently occur in social interactions.

Early prediction of clinical response in first episode schizophrenia (FES) patients receiving olanzapine

Background: At present, schizophrenia guidelines recommend waiting for 8 weeks before considering a patient as non-responder. This study aims to detect the optimal early response threshold that best predict the final outcome of olanzapine.Methods: The study was conducted for 8-week, four points follow up (week 2,3,4, and 8) prospective observational study. A reduction of 20, 25, 30% in Positive and Negative Syndrome Scale (PANSS) score from the base line at week 2,3, and 4 respectively were considered as early response. A reduction of 50% at week 8 was considered as responders. Receiver Operating Characteristics (ROC) curves were performed to detect the optimal threshold.Results: Mean total baseline PANSS score was 106.66(95% CI; 100.4, 112.9). Week 2 (AUC = 50.5%, p > 0.964) and week 3 (AUC = 64.9, p > 0.13) responses failed to predict the 8th week response. Week 4 response (AUC = 92%, p < 0.001) can be taken for the prediction of 8th week response (specificity = 72%, sensitivity = 100%, Positive Predictive Value = 61.1%, Negative Predictive Value = 100% and Optimum Early Response (OER) = 29.4%). 25 patients (69%) achieved more than 50% reduction (responders) in PANSS score after 8 weeks of treatment.Conclusions: Our study suggests that patients with early response at week 4 are likely to achieve positive response after 8 weeks. This may help in appropriate clinical decision making for early non-responders.Key PointsThe early response can forecast the outcome at the endpoint for the treatment of FESA reduction of baseline PANSS score by 30% or more after four weeks are likely to have remission after week 8 with olanzapine therapy.

The Trend of Increasing Placebo Response and Decreasing Treatment Effect in Schizophrenia Trials Continues: An Update From the US Food and Drug Administration.

Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update in the trends observed in placebo response, treatment effect, and dropout rates for NDAs submitted from February 2009 to 2015 (ie, the post-2009 period). Clinical trial data from all acute schizophrenia trials that were submitted as part of NDAs to the US FDA during a 24-year period from 1991 to 2015. Aggregate trial-level efficacy data from multicenter, multiregional, randomized, placebo-controlled, 4- to 8-week, fixed- and flexible-dose trials in adult schizophrenia patients were compiled. There were 12 NDAs pre-2009 (32 trials, N = 11,567) and 3 NDAs post-2009 (14 trials, N = 6,434). Baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) were summarized and compared for the two time periods (pre-2009 and post-2009). The primary efficacy measure was mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis. Regional differences in placebo response and treatment effect were explored for the two time periods based on baseline patient characteristics, sample size, and dropout rates. Trials were predominantly multiregional (10/14; 71%) during the post-2009 period compared to the pre-2009 period (11/32; 34%). The overall trial success rates were 57% (8/14) and 78% (25/32) during the post-2009 and pre-2009 periods, respectively. Comparing the pre-2009 and post-2009 periods, the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5 and the mean treatment effect (drug response - placebo response) declined from -8.6 to -5.8 , with substantial differences observed especially in North American trials. In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009). The difference in placebo response (pre- and post-2009: -10.0 and -11.3 ) and treatment effect (pre and post-2009: -8.1 and -6.4 ) in multiregional trials for the two time periods remained minimal. Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100. Trials with higher mean baseline PANSS scores tended to show higher treatment effect irrespective of the time period and region. Post-2009, dropout rates were higher (55%) in North American trials compared with 33% in multiregional trials, similar to the pre-2009 trend. The continuing trend of increasing placebo responses and decreasing treatment effects in schizophrenia trials over the 24-year period does remain of great concern, especially with respect to North American trials. However, given the current global nature of drug development, close attention to trial conduct and reexamination of design elements for future trials may be warranted.

Efficacy and Safety of Lumateperone for Treatment of Schizophrenia

Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects. To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States. Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks. The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression-Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed. The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], -4.2; 95% CI, -7.8 to -0.6; P = .02; effect size [ES], -0.3) and the CGI-S (LSMD, -0.3; 95% CI, -0.5 to -0.1; P = .003; ES, -0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was -2.6 (95% CI, -6.2 to 1.1; P = .16; ES, -0.2) on the PANSS total score and -0.2 (95% CI, -0.5 to 0.0; P = .02; ES, -0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo. Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile. ClinicalTrials.gov identifier: NCT02282761.

M102 - VARIATION IN VOLTAGE-GATED CALCIUM CHANNEL GENES IS ASSOCIATED WITH ANTIPSYCHOTIC TREATMENT RESPONSE IN A SOUTH AFRICAN FIRST EPISODE SCHIZOPHRENIA COHORT

Background Voltage-gated calcium channels have been implicated in schizophrenia aetiology, however little is known about their involvement in antipsychotic treatment response. This study investigated variants within the calcium channel subunit genes for association with antipsychotic treatment response in a first episode schizophrenia cohort. Methods The patient cohort included 103 unrelated South African FES patients (80% South African Coloured, 12% Xhosa and 8% European descent). Treatment response was assessed using the positive and negative syndrome scale (PANSS) over a period of 12 months, with measurements taken biweekly for the first six weeks, and every three months thereafter. Variants within the calcium channel subunit genes (α1, α2δ, β and γ subunits) were mined from available GWAS data produced using the Infinium OmniExpressExome-8 Kit (Illumina, California, USA). In total 1830 variants were identified within 10 CACNA1 genes, four CACNB genes, four CACNA2D genes and eight CACNG genes. Linear mixed-effects models were used to investigate the effect of genetic variants on change in PANSS scores for each domain (positive, negative, general and total) over the twelve-month period, adjusting for age, gender, proportion ancestry, and baseline PANSS scores. Multiple modes of inheritance were considered and the best-fit model was selected for further analysis. Results Twelve regulatory variants were shown to be significantly associated with treatment outcome. Most notably the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C-allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect. Discussion These results implicate the calcium channel subunits in antipsychotic treatment response and suggest that increased activation of these channels may be explored to enhance or predict antipsychotic treatment outcome.

Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines

BackgroundBiomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients.MethodsThis research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment.ResultsThe administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes.A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group.ConclusionsThe DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined.

Motor sequencing abnormalities are the trait marking neurological soft signs of schizophrenia

We describe the profile of NSS across the one-year course of schizophrenia in 84 Nigerian first-episode patients. They were assessed at baseline and 3 monthly for 12 months using the Neurological Evaluation Scale and the Positive and Negative Syndrome Scale (PANSS), and treated with flupenthixol decanoate. The pattern of NSS total and sub-category scores obtained from repeated measurements were investigated for responders (≥ 50% reduction of baseline PANSS scores) and non-responders using the method of repeated measures analysis of variance. Trait-like features of NSS categories were quantified using intraclass correlation coefficients (ICCs). NSS were present in 96.4% of the patients at baseline (mean 21.5 ± 11.1). The motor-sequencing sub-category was found unrelated to changes in schizophrenia psychopathology with treatment (positive, r=0.19, p=0.136., negative, r=0.12, p=0.350; disorganization, r=0.16, p=0.245; overall, r=0.20, p=0.112). Regardless of decrements in psychopathology, motor-sequencing scores remained relatively unchanged across the course of the disease (main effects: 'responders' F=2.44, p=0.930, 'poor responders' F=0.27, p=0.764, entire sample F=1.87, p=0.160). ICC was "substantial" at 0.8 (95% C.I=0.6-0.9). Only the motor-sequencing NSS appear to be trait marker of schizophrenia in this sample. Other NSS seem to reflect symptomatic states of the disorder.

Examination of the Positive and Negative Syndrome Scale factor structure and longitudinal relationships with functioning in early psychosis.

We examined the factor structure of the Positive and Negative Syndrome Scale (PANSS) in early-episode psychosis and its relationships with functioning at baseline and follow-up. A total of 240 consecutive admissions to an early intervention in psychosis clinic were assessed at intake to the program with the PANSS, Global Assessment of Functioning (GAF) and Social and Occupational Functioning Assessment Scale (SOFAS). Seventy individuals were reassessed at follow-up. A maximum likelihood factor analysis was conducted on baseline PANSS scores and the ability of each factor to predict baseline and follow-up GAF and SOFAS was examined. A five-factor model with varimax rotation was the best fit to our data and was largely congruent with factors found previously. The negative symptom factor was the best predictor of GAF and SOFAS at baseline and follow-up. Negative symptoms are the best symptomatic predictor of functioning in individuals with early psychosis and are an important treatment target to improve recovery.

Minimum Clinically Important Difference in the Positive and Negative Syndrome Scale With Data From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)

Establishing the minimum clinically important difference in the Positive and Negative Syndrome Scale (PANSS) is important to the interpretation of the research and clinical work conducted with this scale. This study employed both anchor-based and distributive methods to estimate the minimum clinically important difference for the PANSS by using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, a large, multicenter trial for patients with schizophrenia. By using an equipercentile method, data from 1,442 individuals linked PANSS scores with both clinician and patient ratings on the Clinical Global Impressions scale (CGI). Data were also used to investigate the magnitude of the standard error of measurement (SEM), offering another estimate of the minimum clinically important difference. Cross-sectional, clinician-rated CGI-Severity of illness scores of 1 through 7 linked to PANSS scores of 32.4, 42.2, 57.5, 74.5, 93.0, 110.9, and 131.0, respectively. The minimum clinically important difference for PANSS scores using this scale equaled a 15.3-point (34.0%) change from baseline. A 1.96 SEM on the PANSS corresponded to a 16.5-point (36.2%) change from baseline. The minimum clinically important difference for a subsample with above-median baseline PANSS scores was 38% higher than a sample with lower baseline scores. With the patient-rated CGI as the anchor, PANSS scores were higher for CGI scores of 1 through 4, and the minimum clinically important difference was lower, 11.2 points (24.6%). Minimum clinically important difference estimates from a longer-term effectiveness trial were consistent with previous efforts from shorter-term efficacy trials. Minimum clinically important difference estimates can help clinicians and researchers design future studies and interpret treatment change in future research and clinical work.

Aripiprazole and Dehydroaripiprazole Plasma Concentrations and Clinical Responses in Patients With Schizophrenia

Aripiprazole is widely used to treat schizophrenia. Plasma levels of aripiprazole and its active metabolite dehydroaripiprazole and their clinical responses in patients were explored. Forty-five (male/female: 19/26) patients with schizophrenia were treated with aripiprazole after a washout period of at least 3 days. There was no concomitant psychotropic except benzodiazepines for insomnia. The Positive and Negative Syndrome Scale (PANSS) was used to measure the clinical response at baseline and at weeks 2, 4, and 6. Blood was drawn at week 6 to measure the plasma concentrations of aripiprazole and dehydroaripiprazole. Patients with a PANSS score that decreased by more than 20% were defined as responders after 6 weeks of treatment. There was no difference in baseline PANSS scores or the daily dosage used between responders (n = 28) and nonresponders (n = 17) (15.0 ± 5.9 vs 12.9 ± 6.9 mg, respectively; P = 0.203). The responders showed a trend toward a higher plasma concentration of aripiprazole than nonresponders (234.4 ± 156.7 vs 163.5 ± 77.2 ng/mL, respectively; P = 0.117) and a significantly higher plasma concentration of dehydroaripiprazole (101.6 ± 58.0 vs 66.0 ± 48.4, respectively; P = 0.023). Higher plasma concentrations of aripiprazole and its active metabolite dehydroaripiprazole were noted in responders than nonresponders. Compared with Western patients, Oriental patients had higher plasma concentrations of aripiprazole and dehydroaripiprazole at the same dose. We suggest that therapeutic drug monitoring of aripiprazole will help improve the response in clinical practice.

A PROSPECTIVE STUDY OF THE CLINICAL OUTCOME FOLLOWING TREATMENT DISCONTINUATION AFTER 2 YEARS IN FIRST-EPISODE SCHIZOPHRENIA

Background: An important unanswered question in the management of schizophrenia is how long antipsychotic treatment should be continued after a first psychotic episode. This study assessed the clinical consequences of antipsychotic discontinuation after 2 years of uninterrupted treatment in patients treated for a first episode of schizophrenia or related illness. This is a pre-specified interim analysis after 1 year of treatment discontinuation. Methods: This study is an extension of a previously published 24month, open-label study in which 50 patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated with flexible doses of risperidone long-acting injection (RLAI). At the completion of that study, patients were offered enrolment in this follow-up study evaluating the effects of treatment discontinuation. Patients opting to participate in the discontinuation trial had RLAI tapered over a period of up to 6 weeks, with follow-up while off antipsychotic therapy or until relapse, defined operationally. Following RLAI discontinuation, patients were assessed every 2 months. RLAI was immediately re-instituted when relapse was identified. This is a pre-specified interim analysis of all subjects who completed 1 year of follow-up. Relapse rates, time to relapse, and antecedents to relapsewere evaluatedwith Positive and Negative Syndrome Scale (PANSS) and Patient-assessed Global Impression of Change (PGI-C) scores. Results: Of the 50 patients who completed the 2-year treatment study,19men and 14women (mean age 27.5±7.9 years and baseline PANSS score of 45.0±7.4) entered the discontinuation study and were followed for 1 year or until relapse. At baseline, 28 patients (84.8%) were in remission. 26 patients (79%) relapsed within 1 year. Kaplan-Meier estimate of median time to relapse was 163 days (95% CI 96–199). 8 patients were hospitalized as a result of relapse. There were no differences between those who relapsed and those who did not in terms of baseline PANSS scores or remission status. PANSS total scores remained similar to those at baseline up until (and including) the visit prior to relapse. Discussion: Similar to previously reported studies with oral and depot antipsychotics,2,3 relapse rates were high within 1 year of treatment discontinuation in patients who had been treated with RLAI for firstepisode of schizophrenia for 2 years. First relapses occurred suddenly, without clear-cut warning signs. These findings have important clinical implications, suggesting that antipsychotic discontinuationafter 2 years of treatment may not be in the best interest of the majority of patients.

Modeling the Effectiveness of Paliperidone ER and Olanzapine in Schizophrenia: Meta‐Analysis of 3 Randomized, Controlled Clinical Trials

The time course of Positive and Negative Syndrome Scale (PANSS) scores in adult schizophrenia patients was modeled, and the effectiveness of paliperidone extended-release tablets (paliperidone ER) and olanzapine was quantified. Data from 3 randomized, double-blind phase III studies were used. Patients received paliperidone ER (3, 6, 9, 12, or 15 mg), olanzapine 10 mg, or matched placebo once daily for 6 consecutive weeks. An indirect response model implemented using a nonlinear mixed effects approach described the time course of the PANSS. Deterioration rate was modeled as a function of baseline PANSS score, placebo, and drug effects, and the dropout effect. An exponential decrease of the placebo response was also implemented. Paliperidone ER and olanzapine treatment were characterized by a long-lasting drug effect (13%), with a larger but short-lasting placebo effect (40%) and a notable dropout rate. The covariate exploration failed to identify any clinically relevant factors. The nonparametric bootstrap analysis confirmed the acceptable precision of parameter estimates. The visual predictive check supported the model's adequacy to reproduce observed PANSS time courses. The population model describes the time course of PANSS scores in schizophrenia patients and is appropriate for use in clinical trial simulation activities.

Trajectories and Antecedents of Treatment Response Over Time in Early-Episode Psychosis

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. 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. 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. Amelioration generally characterizes treated symptom severity. Age of onset, diagnosis, cognitive functioning, and premorbid functioning have prognostic value in predicting treatment response trajectories.

A Multiple-Center, Randomized, Double-Blind, Placebo-Controlled Study of Oral Aripiprazole for Treatment of Adolescents With Schizophrenia

Aripiprazole is a dopamine partial agonist approved for use in adults for short- and long-term treatment of schizophrenia and bipolar disorder. This study was designed to examine the acute efficacy, safety, and tolerability of aripiprazole for adolescents with schizophrenia. This was a 6-week multicenter, double-blind, randomized, placebo-controlled trial. Subjects 13 to 17 years old with a DSM-IV diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score of 70 or more were randomly assigned (1:1:1 ratio) to placebo or 10 or 30 mg/day of aripiprazole. The primary endpoint was mean change from baseline to endpoint (last observation carried forward) in PANSS total score. Assessments of safety and tolerability included spontaneously reported adverse events, extrapyramidal symptom scores, serum prolactin concentration, body weight, and metabolic measures. Of 302 patients, 85% completed the 6-week study. The mean baseline PANSS score was 94.1. At the end of the study, both aripiprazole doses showed statistically significant differences from placebo in reduction in PANSS total score. Adverse events occurring in more than 5% of either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorder, somnolence, and tremor. Mean changes in prolactin were -8.45, -11.93, and -15.14 ng/ml for placebo and 10 mg and 30 mg of aripirazole, respectively. Mean body weight changes were -0.8, 0.0, and 0.2 kg for placebo and 10 mg and 30 mg of aripiprazole, respectively. Both 10- and 30-mg/day doses of aripiprazole were superior to placebo in the acute treatment of adolescents with schizophrenia. Aripiprazole was generally well tolerated.

Dimensions of Psychosis in Patients with Bipolar Mania as Measured by the Positive and Negative Syndrome Scale

Background: Psychosis is present in 50% or more of patients with bipolar mania and is commonly evaluated in clinical research by means of the Positive and Negative Syndrome Scale (PANSS). The aim of the present analysis was to investigate the psychotic dimensions of bipolar disorder and its contributing symptoms based on a factor analysis of baseline PANSS scores and to compare them with those identified in studies of patients with schizophrenia and bipolar disorder. Sampling and Methods: Baseline data were analyzed from two 3-week, double-blind, placebo-controlled studies of risperidone monotherapy for acute mania associated with bipolar I disorder (n = 535). Inclusion criteria were a DSM-IV diagnosis of bipolar I disorder with manic features, with or without psychotic features, age ≧18 years, and mean baseline Young Mania Rating Scale scores ≧20. A principal component analysis of the 30 PANSS item scores of the 535 patients with a diagnosis of a manic episode at baseline was conducted. Results: Five factors were extracted by the analysis: anxiety (13.4% of the variance), negative symptoms (12.3%), depression (10.5%), excitement (10.3%), and positive symptoms (8.7%). Similar factors, in particular the negative, excitement, and positive factors, have been identified in patients with schizophrenia. There was an absence of a cognitive factor supporting the notion that bipolar patients may present fewer cognitive symptoms. Conclusion: The results of the present analysis and those of other studies indicate similarities in psychotic symptom domains, as measured by the PANSS, in patients with bipolar mania and schizophrenia. Future analyses will address the effects of treatment on the identified factors.