Antipsychotic-placebo separation on the PANSS-6 subscale as compared to the PANSS-30: a pooled participant-level analysis.
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ABSTRACT:
SUBMITTER: Hieronymus F
PROVIDER: S-EPMC8397783 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Modeling dose-response relationships of drugs is essential to understanding their safety effects on patients under realistic circumstances. While intention-to-treat analyses of clinical trials provide the effect of assignment to a particular drug and dose, they do not capture observed exposure after factoring in nonadherence and dropout. We develop a Bayesian method to flexibly model the dose-response relationships of binary outcomes with continuous treatment, permitting multiple evidence sources, treatment effect heterogeneity, and nonlinear dose-response curves. In an application, we examine the risk of excessive weight gain for patients with schizophrenia treated with the second-generation antipsychotics paliperidone, risperidone, or olanzapine in 14 clinical trials. We define exposure as total cumulative dose (daily dose × duration) and convert to units equivalent to 100 mg of olanzapine (OLZ doses). Averaging over the sample population of 5891 subjects, the median dose ranged from 0 (placebo randomized participants) to 6.4 OLZ doses (paliperidone randomized participants). We found paliperidone to be least likely to cause excessive weight gain across a range of doses. Compared with 0 OLZ doses, at 5.0 OLZ doses, olanzapine subjects had a 15.6% (95% credible interval: 6.7, 27.1) excess risk of weight gain; corresponding estimates for paliperidone and risperidone were 3.2% (1.5, 5.2) and 14.9% (0.0, 38.7), respectively. Moreover, compared with nonblack participants, black participants had a 6.8% (1.0, 12.4) greater risk of excessive weight gain at 10.0 OLZ doses of paliperidone. Nevertheless, our findings suggest that paliperidone is safer in terms of weight gain risk than risperidone or olanzapine for all participants at low to moderate cumulative OLZ doses.
| S-EPMC6786940 | biostudies-literature
Project description:Abstract Background About 40% of patients with Treatment-Resistant Schizophrenia (TRS) do not respond to an adequate trial with clozapine and are termed Clozapine- Resistant Schizophrenia (CRS). A metanalysis showed that clozapine augmentation with ECT is efficacious for CRS, but no studies with Sham-ECT were reported (1). We published a pilot single-blinded study trial, which, to our knowledge, is the first to evaluate the efficacy of electroconvulsive therapy (ECT) in comparison with Sham–ECT in CRS (2) (NCT02049021) (PS). In this PS, patients with CRS received ECT (n=12) or SHAM-ECT (n=7) and after 12 sessions, but no differences were found between both groups as measured by the total PANSS and subscales at the endpoint. Factors, obtained by factor analytic studies (3), as well as individual items of shorter versions of the PANSS (4), are considered more valid predictors of TRS than subscales. The aim of the present study is a reanalysis of our PS based either PANSS factors obtained through factors analysis as well as on the individual items of the PANSS-30 and the PANSS-6. Methods We used individual participant data (IPD) at the symptom level, based on a statistical approach of a study already published (5). We used PANSS-30 items, traditional subscales, as well as factor scores (Positive, Negative and Cognitive) derived from our factor analysis of patients with TRS (4). Additionally, we analyzed also all the PANSS-6 items and the sum of scores (hallucinatory behavior –P3 and lack of spontaneity and flow of conversation- N6) which identify severe cases. STATA, Comprehensive Metanalysis, and R were used for calculations of effect sizes (fixed effects) and power Results We obtained significant differences between groups with high effect sizes (>0.8) for three symptoms at endpoint: P3 (-0.993, 95% CI= -1.977 to -0.009, p= 0.048), N6 (-1.036, 95% CI= -2.025 to -0.047 p= 0.040), and Disorientation (G10) (-1.445, 95%CI=-2.48—0.40, p=0.006). The between-groups effect-sizes of other symptoms or factors showed no statistically significant differences Discussion The present reanalysis showed that patients with CRS do benefit from ECT treatment, with an improvement of their Hallucinatory Behavior or Lack of Spontaneity and Flow of Conversation, but suffer from some cognitive impairments (Disorientation). These findings are limited due to the small sample. We are conducting a trial with a much larger sample size to test the efficacy and tolerability of ECT vs Sham in CRS.
| S-EPMC7233989 | biostudies-literature
Project description:It was recently demonstrated in acutely exacerbated schizophrenia that a 6-item version (PANSS-6: P1 = delusions, P2 = conceptual disorganization, P3 = hallucinations, N1 = blunted affect, N4 = social withdrawal, N6 = lack of spontaneity/flow of conversation) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) was scalable (all items provide unique information regarding syndrome severity) and able to separate the effect of antipsychotics from placebo. Here, we tested the validity and sensitivity of PANSS-6 in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) outpatient study. We examined (1) the scalability of PANSS-6 and PANSS-30; (2) the correlation between PANSS-6 and PANSS-30 total scores; (3) whether PANSS-6 could identify symptom remission (Andreasen criteria); and (4) the effect of the 5 antipsychotics studied in CATIE Phase-1, using PANSS-6 and PANSS-30 total scores as outcomes. We found that for the 577 subjects with complete PANSS ratings at baseline, month 1, 3, and 6, PANSS-6 was scalable, whereas PANSS-30 was not. In the 1432 subjects in the intention-to-treat (ITT) sample, PANSS-6 and PANSS-30 total scores were highly correlated (Spearman correlation coefficient = 0.86). Based on 5080 ITT ratings, PANSS-6 identified symptom remission with an accuracy of 0.99 (95% confidence interval = 0.99-0.99). In ITT analyses, PANSS-6 and PANSS-30 identified the same statistically significant differences in antipsychotic efficacy, ie, olanzapine was superior to risperidone (P-value PANSS-6 = 0.0003 and PANSS-30 = 0.0003) and ziprasidone (P-value PANSS-6 = 0.0018 and PANSS-30 = 0.0046). In conclusion, PANSS-6 is a brief schizophrenia rating scale that adequately measures severity, remission, and antipsychotic efficacy related to core positive and negative symptoms in clinical trials. Prospective studies of PANSS-6 in clinical practice are required.
| S-EPMC5814988 | biostudies-literature
Project description:ImportanceProton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.ObjectiveTo assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.Data sourcesThe MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.Study selectionIn total, 45 1H-MRS studies contributed data.Data extraction and synthesisAssociations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.Main outcomes and measuresGlu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).ResultsIn total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.Conclusions and relevanceFindings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
| S-EPMC8060889 | biostudies-literature
Project description:BackgroundDaily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration.MethodsParticipant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models.ResultsAround 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels.ConclusionsUsing the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.
| S-EPMC10139701 | biostudies-literature
Project description:As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data discards information and violates the numerical nature of the scale. Here a longitudinal analysis based on Item Response Theory is presented using PANSS data from phase III clinical trials. Latent disease severity variables were derived from item-level data on the positive, negative, and general PANSS subscales each. On all subscales, the time course of placebo responses were best described with Weibull models, and dose-independent functions with exponential models to describe the onset of the full effect were used to describe paliperidone's effect. Placebo and drug effect were most pronounced on the positive subscale. The final model successfully describes the time course of treatment effects on the individual PANSS item-levels, on all PANSS subscale levels, and on the total score level.
| S-EPMC5572362 | biostudies-literature
Project description:Positive and Negative Syndrome Scale (PANSS) total score is the standard primary efficacy measure in acute treatment studies of schizophrenia. However, PANSS factors that have been derived from factor analytic approaches over the past several decades have uncertain clinical and regulatory status as they are, to varying degrees, intercorrelated. As a consequence of cross-factor correlations, the apparent improvement in key clinical domains (eg, negative symptoms, disorganized thinking/behavior) may largely be attributable to improvement in a related clinical domain, such as positive symptoms, a problem often referred to as pseudospecificity. Here, we analyzed correlations among PANSS items, at baseline and change post-baseline, in a pooled sample of 5 placebo-controlled clinical trials (N = 1710 patients), using clustering and factor analysis to identify an uncorrelated PANSS score matrix (UPSM) that minimized the degree of correlation between each resulting transformed PANSS factor. The transformed PANSS factors corresponded well with discrete symptom domains described by prior factor analyses, but between-factor change-scores correlations were markedly lower. We then used the UPSM to transform PANSS in data from 4657 unique schizophrenia patients included in 12 additional lurasidone clinical trials. The results confirmed that transformed PANSS factors retained a high degree of specificity, thus validating that low between-factor correlations are a reliable property of the USPM when transforming PANSS data from a variety of clinical trial data sets. These results provide a more robust understanding of the structure of symptom change in schizophrenia and suggest a means to evaluate the specificity of antipsychotic treatment effects.
| S-EPMC5890480 | biostudies-literature
Project description:ImportanceBecause increasing placebo response rates decrease drug-placebo differences and increase the number of failed trials, it is imperative to determine what is causing this trend.ObjectivesTo investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables.Data sourcesMEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of antipsychotic medications published from 1960 to July 2013.Study selectionIncluded were randomized clinical trials lasting 4 to 24 weeks, contrasting antipsychotic medication with placebo or an active comparator, and enrolling patients 18 years of age or older with schizophrenia or schizoaffective disorder.Data extraction and synthesisStandardized mean change scores were calculated for each treatment arm, plotted against publication year, and tested with Spearman rank correlation coefficients. Hierarchical linear modeling identified factors associated with the standardized mean change across medication and placebo treatment arms.Main outcomes and measuresWe hypothesized that the mean change in placebo-treated patients would significantly increase from 1960 to the present, that a greater change would be observed in active comparator vs placebo-controlled trials, and that more protocol visits would increase the symptom change observed.ResultsIn the 105 trials examined, the mean change observed in placebo arms increased significantly with year of publication (n=39, r=0.52, P=.001), while the mean change in effective dose medication arms decreased significantly (n=208, r=-0.26, P<.001). Significant interactions were found between assignment to effective dose medication and publication year (t260=-5.55, P<.001), baseline severity (t260=5.08, P<.001), and study duration (t260=-3.76, P<.001), indicating that the average drug-placebo difference significantly decreased over time, with decreasing baseline severity and with increasing study duration. Medication treatment in comparator studies was associated with significantly more improvement than medication treatment in placebo-controlled trials (t93=2.73, P=.008).Conclusions and relevanceThe average treatment change associated with placebo treatment in antipsychotic trials increased since 1960, while the change associated with medication treatment decreased. Changes in randomized clinical trials leading to inflation of baseline scores, enrollment of less severely ill participants, and higher expectations of patients may all be responsible.
| S-EPMC4256120 | biostudies-literature
Project description:BackgroundCanagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age.MethodsPooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids.ResultsCanagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets.ConclusionsCanagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM.Trial registrationClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.
| S-EPMC4021426 | biostudies-literature
Project description:After over a hundred years of research, the question whether the symptoms of schizophrenia are rather trait-like (being a relatively stable quality of individuals) or state-like (being substance to change) is still unanswered. To assess the trait and the state component in patients with acute schizophrenia, one group receiving antipsychotic treatment, the other not. Data from four phase II/III, 6-week, randomized, double-blind, placebo-controlled trials of similar design that included patients with acute exacerbation of schizophrenia were pooled. In every trial, one treatment group received a third-generation antipsychotic, cariprazine, and the other group placebo. To assess symptoms of schizophrenia, the Positive and Negative Symptom Scale (PANSS) was applied. Further analyses were conducted using the five subscales as proposed by Wallwork and colleagues. A latent state-trait (LST) model was developed to estimate the trait and state components of the total variance of the observed scores. All symptom dimensions behaved more in a trait-like manner. The proportions of all sources of variability changed over the course of the observational period, with a bent around weeks 3 and 4. Visually inspected, no major differences were found between the two treatment groups regarding the LST structure of symptom dimensions. This high proportion of inter-individual stability may represent an inherent part of symptomatology that behaves independently from treatment status.
| S-EPMC11362189 | biostudies-literature