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Noninferiority of perphenazine vs. three second-generation antipsychotics in chronic schizophrenia.

ABSTRACT: Noninferiority analysis is a statistical method of growing importance in comparative effectiveness research that has rarely been used in psychopharmacology. This method is used here to evaluate whether first-generation antipsychotics are clinically not inferior to second-generation antipsychotics (SGAs) using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). A conservative noninferiority margin (NIM) on the Positive and Negative Syndrome Scale (PANSS) was derived from the smallest published value for the minimal clinically important difference, further reduced by 25%. This NIM was used to assess whether perphenazine is noninferior to olanzapine, risperidone, and quetiapine on the basis of the 95% confidence intervals of differences in mean PANSS outcomes (N = 1049). Perphenazine was noninferior to all three SGAs during 18 months of intention-to-treat analysis and in several subanalyses. Noninferiority can be evaluated from studies designed as superiority trials. Power was available in the CATIE to conduct noninferiority analysis.

SUBMITTER: Rosenheck R

PROVIDER: S-EPMC4635461 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Noninferiority of perphenazine vs. three second-generation antipsychotics in chronic schizophrenia.

Rosenheck Robert R Lin Haiqun H

The Journal of nervous and mental disease 20140101 1

Noninferiority analysis is a statistical method of growing importance in comparative effectiveness research that has rarely been used in psychopharmacology. This method is used here to evaluate whether first-generation antipsychotics are clinically not inferior to second-generation antipsychotics (SGAs) using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). A conservative noninferiority margin (NIM) on the Positive and Negative Syndrome Scale (PANSS) was derived ...[more]

PMID: 24375207

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Project description:Few controlled trials compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) regarding relapse prevention in schizophrenia. We conducted a systematic review/meta-analysis of randomized trials, lasting ?6 months comparing SGAs with FGAs in schizophrenia. Primary outcome was study-defined relapse; secondary outcomes included relapse at 3, 6 and 12 months; treatment failure; hospitalization; and dropout owing to any cause, non-adherence and intolerability. Pooled relative risk (RR) (±95% confidence intervals (CIs)) was calculated using random-effects model, with numbers-needed-to-treat (NNT) calculations where appropriate. Across 23 studies (n=4504, mean duration=61.9±22.4 weeks), none of the individual SGAs outperformed FGAs (mainly haloperidol) regarding study-defined relapse, except for isolated, single trial-based superiority, and except for risperidone's superiority at 3 and 6 months when requiring ?3 trials. Grouped together, however, SGAs prevented relapse more than FGAs (29.0 versus 37.5%, RR=0.80, CI: 0.70-0.91, P=0.0007, I(2)=37%; NNT=17, CI: 10-50, P=0.003). SGAs were also superior regarding relapse at 3, 6 and 12 months (P=0.04, P<0.0001, P=0.0001), treatment failure (P=0.003) and hospitalization (P=0.004). SGAs showed trend-level superiority for dropout owing to intolerability (P=0.05). Superiority of SGAs regarding relapse was modest (NNT=17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several key outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors.

Project description:Objective:Second-generation antipsychotics (SGAs) have a high risk of causing metabolic syndrome (MetS). There is accumulating evidence supporting the fact that the activation of inflammatory pathway contributes to the development of MetS and further aggravates cognitive impairment. This study aimed to investigate the relationship between interleukin-6 (IL-6), cognitive function, and MetS in schizophrenia patients treated with SGAs. Methods:One hundred and seventy-four patients with schizophrenia using SGAs were divided into MetS and non-MetS group, based on the criteria of the National Cholesterol Education Program's Adult Treatment Panel III. Cognitive function was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A total of 138 patients and 29 healthy controls were examined in the plasma IL-6 levels. Results:The prevalence of MetS in schizophrenia patients treated with SGAs was 33% in this study. There were no significant differences in cognitive functions (both RBANS total score and subscale score) between MetS and non-Mets patients (P>0.05). Patients with MetS had higher plasma levels of IL-6 compared to non-MetS patients (P=0.019). However, such difference was only found in male patients (male: P=0.012; female: P=0.513). The partial correlational analysis further showed that IL-6 levels were notably negative related to the HDL levels in male schizophrenia patients after age, years of education, body mass index (BMI), age of onset, total disease course, and equal dose of olanzapine were controlled (male: P=0.009; female: P=0.450). In addition, the multiple regression analysis (stepwise model) performed in the male patient subgroup showed that IL-6 (beta =-0.283, t=-2.492, P=0.015) was an independent contributor to the HDL levels. However, the IL-6 was not an independent contributor to the HDL levels in female patients. Conclusion:Our findings provide evidence suggesting that the immune-inflammatory effect of IL-6 on SGAs-induced MetS may be in a gender manner.

Project description:BackgroundPrevious studies have reported an increased risk of stroke in patients taking antipsychotics. However, most of these studies have been conducted in the elderly population.ObjectiveWe estimated stroke risk in new users of any first-generation antipsychotic or haloperidol, vs second-generation antipsychotics among patients aged 18-64 years without a recent dementia diagnosis and, separately, regardless of a recent dementia diagnosis.MethodsData were obtained from IBM MarketScan® Commercial Database (1 January, 2001-31 December, 2017). Among new users without a recent dementia diagnosis, stroke risk for first-generation antipsychotics (FGAw/oD cohort) or haloperidol (HALw/oD cohort) was compared with second-generation antipsychotics (SGAw/oD cohort). A similar comparison was conducted among new users regardless of dementia diagnosis: first-generation antipsychotics (FGA cohort) or haloperidol (HAL cohort) vs second-generation antipsychotics (SGA cohort). Crude incident stroke rates within each cohort were determined. For hazard ratios, three propensity score matching strategies were used: unadjusted (crude), Sentinel propensity score strategy, and large-scale regularized regression model (adapted propensity score strategy).ResultsEach cohort included ≥12,000 patients. The incident rates for stroke per 1000 person-years were 3.10 (FGAw/oD), 5.99 (HALw/oD), 0.85 (SGAw/oD), 3.14 (FGA), 6.12 (HAL), and 0.90 (SGA). Pre-planned analysis with adapted propensity score strategy matching yielded calibrated hazard ratios for stroke: FGAw/oD vs SGAw/oD: 2.05 (calibrated confidence interval 1.13-3.89); HALw/oD vs SGAw/oD: 2.47 (1.14-5.48), FGA vs SGA: 1.64 (0.94-2.97), and HAL vs SGA: 1.98 (0.99-4.00). A post-hoc sensitivity analysis to address potential bias introduced by the 2015 change from the International Classification of Diseases, Ninth Revision to the International Classification of Diseases, Tenth Revision yielded calibrated hazard ratios for FGAw/oD vs SGAw/oD: 1.59 (0.87-3.01), HALw/oD vs SGAw/oD: 2.79 (1.24-6.42), FGA vs SGA: 1.41 (0.79-2.62), and HAL vs SGA: 3.47 (1.63-7.92).ConclusionsAmong adults aged ≤64 years, without a recent dementia diagnosis, stroke risk is higher among those exposed to haloperidol compared with those exposed to second-generation antipsychotics.

Project description:Because early treatment choice is critical in first-episode schizophrenia-spectrum disorders (FES), this meta-analysis compared efficacy and tolerability of individual second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) in FES. We conducted systematic literature search (until 12 December 2010) and meta-analysis of acute, randomized trials with ?1 FGA vs. SGA comparison; patients in their first episode of psychosis and diagnosed with schizophrenia-spectrum disorders; available data for psychopathology change, treatment response, treatment discontinuation, adverse effects, or cognition. Across 13 trials (n = 2509), olanzapine (seven trials) and amisulpride (one trial) outperformed FGAs (haloperidol: 9/13 trials) in 9/13 and 8/13 efficacy outcomes, respectively, risperidone (eight trials) in 4/13, quetiapine (one trial) in 3/13 and clozapine (two trials) and ziprasidone (one trial) in 1/13, each. Compared to FGAs, extrapyramidal symptom (EPS)-related outcomes were less frequent with olanzapine, risperidone and clozapine, but weight gain was greater with clozapine, olanzapine and risperidone. Pooled SGAs were similar to FGAs regarding total psychopathology change, depression, treatment response and metabolic changes. SGAs significantly outperformed FGAs regarding lower treatment discontinuation, irrespective of cause, negative symptoms, global cognition and less EPS and akathisia, while SGAs increased weight more (p < 0.05-0.01). Results were not affected by FGA dose or publication bias, but industry-sponsored studies favoured SGAs more than federally funded studies. To summarize, in FES, olanzapine, amisulpride and, less so, risperidone and quetiapine showed superior efficacy, greater treatment persistence and less EPS than FGAs. However, weight increase with olanzapine, risperidone and clozapine and metabolic changes with olanzapine were greater. Additional FES studies including broader-based SGAs and FGAs are needed.

Project description:ObjectivesTo examine the association between use of second-generation antipsychotics (SGA) and the risk of chronic kidney disease (CKD).DesignPopulation-based case-control study.SettingRoutinely collected laboratory, prescription and diagnostic information on all inhabitants with creatinine measurements residing on the island of Funen, Denmark (2001 to 2015).Participants21 434 cases with incident CKD matched with 85 576 CKD-free population controls by risk-set sampling using age, sex and calendar year.Primary and secondary outcome measuresCKD was defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m2 in a period longer than 3 months. Information on drug exposure and comorbidities were obtained from the Danish National Prescription Register and the Danish National Patient Register. We calculated OR for the association between SGA use and CKD using conditional logistic regression.ResultsUse of SGAs was associated with increased risk of CKD among ever users (OR 1.24, 95% CI: 1.12 to 1.37) and current users (OR 1.26, 95% CI: 1.12 to 1.42). We found no clear evidence of dose-response relationship. Both short duration (one to two antipsychotic prescriptions; OR 1.22, 95% CI: 1.01 to 1.48) as well as long-term use (>30 prescriptions; OR 1.45, 95% CI 1.19 to 1.76) were associated with an increased risk of CKD. Both use of SGAs with mild and high risk of metabolic disturbances was associated with increased risk of CKD (OR 1.21, 95% CI: 1.06 to 1.39 and OR 1.36, 95% CI: 1.11 to 1.68, respectively). Recent use of non-steroidal anti-inflammatory drugs, prior use of lithium, hypertension or prior acute kidney injury were not clearly associated with development of CKD connected to SGA exposure. The highest risk of CKD was found for clozapine (OR 1.81, 95% CI: 1.22 to 2.69).ConclusionUse of SGA is associated with a small-to-moderately increased risk of incident CKD. All investigated SGAs, except for aripiprazole, were associated with an increased risk of CKD.

Project description:ImportanceRecent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice.ObjectiveTo conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies.Data sourcesSystematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018.Study selectionNonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder.Data extraction and synthesisIndependent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data.Main outcomes and measuresCoprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies.ResultsOf 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90).Conclusions and relevanceIn cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.

Dataset Information

Noninferiority of perphenazine vs. three second-generation antipsychotics in chronic schizophrenia.

Publications

Noninferiority of perphenazine vs. three second-generation antipsychotics in chronic schizophrenia.

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