Summary Background Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled ...trials to compare the effects of these two types of drugs in patients with schizophrenia. Methods We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation. Findings We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride −0·31 95% CI −0·44 to −0·19, p<0·0001, clozapine −0·52 −0·75 to −0·29, p<0·0001, olanzapine −0·28 −0·38 to −0·18, p<0·0001, and risperidone −0·13 −0·22 to −0·05, p=0·002). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication. Interpretation Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost. Funding National Institute of Mental Health.
We conducted a systematic review and meta-analysis of randomized controlled trials that compared second-generation antipsychotic (SGA) drugs with placebo in schizophrenic patients and which ...considered 13 different outcome measures. Thirty-eight randomized controlled trials with 7323 participants were included. All SGA drugs were more effective than placebo, but the pooled effect size (ES) for overall symptoms (primary outcome) was moderate (-0.51). The absolute difference (RD) in responder rates was at 18% (41% responded to drug compared with 24% to placebo, number needed to treat=6). Similar ESs were found for the other efficacy parameters: negative symptoms (ES=-0.39), positive symptoms (ES=-0.48), depression (ES=-0.26), relapse (RD 20%) and discontinuation due to inefficacy (RD 17%). Curiously, the efficacy of haloperidol for negative and depressive symptoms was similar to that of the SGA drugs. In contrast to haloperidol, there was no difference in terms of EPS between any SGA drugs and placebo, and there was also no difference in terms of dropouts due to adverse events. Meta-regression showed a decline in treatment response over time, and a funnel plot suggested the possibility of publication bias. We conclude that the drug versus placebo difference of SGA drugs and haloperidol in recent trials was moderate, and that there is much room for more efficacious compounds. Whether methodological issues account in part for the relatively low efficacy ESs and the scarcity of adverse event differences compared with placebo needs to be established.
Summary Background The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy ...based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. Methods We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. Findings We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73–1·03; amisulpride 0·66, 0·53–0·78; olanzapine 0·59, 0·53–0·65; risperidone 0·56, 0·50–0·63; paliperidone 0·50, 0·39–0·60; zotepine 0·49, 0·31–0·66; haloperidol 0·45, 0·39–0·51; quetiapine 0·44, 0·35–0·52; aripiprazole 0·43, 0·34–0·52; sertindole 0·39, 0·26–0·52; ziprasidone 0·39, 0·30–0·49; chlorpromazine 0·38, 0·23–0·54; asenapine 0·38, 0·25–0·51; lurasidone 0·33, 0·21–0·45; and iloperidone 0·33, 0·22–0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. Interpretation Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. Funding None.
Ferroelasticity involves the generation of spontaneous strain in a solid by the application of mechanical stress. The phenomenon has been well‐studied in metal alloys but relatively neglected in ...organic solid‐state chemistry. Herein we present multiple discrete modes of mechanical twinning and a mechanistic analysis of ferroelasticity in 1,4‐diethoxybenzene. Single crystals of the compound can be almost freely deformed, as multiple different twin domains are generated simultaneously. Within each domain, single‐crystal character is preserved. Such extremely versatile, ferroelastic deformability is unprecedented in single crystals of any kind and defies the fragility and anisotropic mechanical behaviour of most organic crystals. The dissipated energy and critical stress associated with twinning deformation in 1,4‐diethoxybenzene suggests that organic solids could be developed for absorbing weak mechanical shocks in such applications as mechanical damping and soft robotics.
Twinning ways: Ferroelastic single crystals of 1,4‐diethoxybenzene can be almost freely deformed by simultaneously accessing multiple modes of mechanical twinning. Within each twin domain, single‐crystal character is preserved. Such extremely versatile, ferroelastic deformability is unprecedented in single crystals of any kind and defies the fragility and anisotropic mechanical behaviour of most organic crystals.
The Saccharomyces Genome Database (SGD, http://www.yeastgenome.org) is the community resource for the budding yeast Saccharomyces cerevisiae. The SGD project provides the highest-quality manually ...curated information from peer-reviewed literature. The experimental results reported in the literature are extracted and integrated within a well-developed database. These data are combined with quality high-throughput results and provided through Locus Summary pages, a powerful query engine and rich genome browser. The acquisition, integration and retrieval of these data allow SGD to facilitate experimental design and analysis by providing an encyclopedia of the yeast genome, its chromosomal features, their functions and interactions. Public access to these data is provided to researchers and educators via web pages designed for optimal ease of use.
The total number of glomeruli is a fundamental parameter of kidney function but very difficult to determine using standard methodology. Here, we counted all individual glomeruli in murine kidneys and ...sized the capillary tufts by combining in vivo fluorescence labeling of endothelial cells, a novel tissue-clearing technique, lightsheet microscopy, and automated registration by image analysis. Total hands-on time per organ was <1 hour, and automated counting/sizing was finished in <3 hours. We also investigated the novel use of ethyl-3-phenylprop-2-enoate (ethyl cinnamate) as a nontoxic solvent-based clearing reagent that can be handled without specific safety measures. Ethyl cinnamate rapidly cleared all tested organs, including calcified bone, but the fluorescence of proteins and immunohistochemical labels was maintained over weeks. Using ethyl cinnamate-cleared kidneys, we also quantified the average creatinine clearance rate per glomerulus. This parameter decreased in the first week of experimental nephrotoxic nephritis, whereas reduction in glomerular numbers occurred much later. Our approach delivers fundamental parameters of renal function, and because of its ease of use and speed, it is suitable for high-throughput analysis and could greatly facilitate studies of the effect of kidney diseases on whole-organ physiology.
What does the PANSS mean? Leucht, Stefan; Kane, John M.; Kissling, Werner ...
Schizophrenia research,
11/2005, Letnik:
79, Številka:
2
Journal Article
Recenzirano
Despite the frequent use of the Positive and Negative Syndrome Scale (PANSS) for rating the symptoms of schizophrenia, the clinical meaning of its total score and of the cut-offs that are used to ...define treatment response (e.g. at least 20% or 50% reduction of the baseline score) are as yet unclear. We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions (CGI).
PANSS and CGI ratings at baseline (
n
=
4091), and after one, two, four and six weeks of treatment taken from a pooled database of seven pivotal, multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking.
Being considered “mildly ill” according to the CGI approximately corresponded to a PANSS total score of 58, “moderately ill” to a PANSS of 75, “markedly ill” to a PANSS of 95 and severely ill to a PANSS of 116. To be “minimally improved” according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively. The corresponding figures for a CGI rating “much improved” were 40%, 45%, 51% and 53%.
The results provide a better framework for understanding the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations. Such studies may ideally use at least a 50% reduction from baseline cut-off to define response rather than lower thresholds. In treatment resistant populations, however, even a small improvement can be important, so that a 25% cut-off might be appropriate.
Objective:The authors examined the safety and efficacy of antidepressants added to antipsychotic drugs in the treatment of schizophrenia.Method:Multiple databases and previous publications were ...searched through June 2015 to identify all randomized controlled trials of any add-on antidepressants compared with placebo or no-treatment in schizophrenia. Depressive and negative symptoms (primary outcomes), overall symptoms, positive symptoms, side effects, exacerbation of psychosis, and responder rates were examined. Subgroup, meta-regression, and sensitivity analyses were performed, as well as investigations of publication bias and risk of bias.Results:Eighty-two randomized controlled trials with a total of 3,608 participants were included. Add-on antidepressants appeared more efficacious than controls for depressive symptoms (standardized mean difference: –0.25, 95% CI=–0.38 to –0.12), negative symptoms (standardized mean difference: –0.30, 95% CI=–0.44 to –0.16), overall symptoms (standardized mean difference: –0.24, 95% CI=–0.39 to –0.09), positive symptoms (standardized mean difference: –0.17, 95% CI=–0.33 to –0.01), quality of life (standardized mean difference: –0.32, 95% CI=–0.57 to –0.06), and responder rate (risk ratio: 1.52, 95% CI=1.29 to 1.78; number-needed-to-treat-to-benefit: 5, 95% CI=4 to 7). The effects on depressive and negative symptoms appeared more pronounced when minimum thresholds of these symptoms were inclusion criteria (standardized mean difference: –0.34, 95% CI=–0.58 to –0.09 and standardized mean difference: –0.58, 95% CI=–0.94 to –0.21, respectively). There were no significant differences between antidepressants and controls in terms of exacerbation of psychosis, premature discontinuation, and the number of participants with at least one adverse event. More patients taking add-on antidepressants suffered from abdominal pain, constipation, dizziness, and dry mouth.Conclusions:Analysis of primary outcomes (depressive and negative symptoms) suggests small, beneficial effects of adjunctive antidepressants. It would appear that this augmentation can be accomplished with a low risk of exacerbation of psychosis and adverse effects. However, secondary and subgroup analyses should be interpreted cautiously and considered exploratory.
Urea is frequently surface applied to winter wheat (Triticum aestivum L.) during cold weather months (October–April) in the semiarid northern Great Plains. This study was conducted to quantify NH3 ...volatilization loss from surface-applied urea (100 kg N ha−1) and urea amended with N-(n-butyl) thiophosphoric triamide (NBPT) during this period. Ammonia emissions were quantified by a micrometeorological integrated horizontal flux method with samplers placed on a mast in the center of circular plots (20-m radius). Cumulative NH3 losses from urea varied but averaged 20.5% of applied N across 12 trials. The largest losses (30–44% of applied N) occurred after urea was applied to high-water-content soil surfaces, followed by a period of slow drying with little or no precipitation. Emissions occurred for a prolonged period often lasting >42 d. Periods (1–2 wk) of high NH3 flux (>30 g N ha−1 h−1) frequently occurred when mean daily soil temperatures (1-cm depth) were –2 to 5°C. In one trial, 24.3% of applied N was lost after urea was applied to a 140-mm snowpack. Ammonia losses were moderated by applying urea to dry soil surfaces. If precipitation events that followed were light (<8 mm), losses were reduced to 10 to 20% of applied N. If the events were heavy (>18 mm), then losses were <10%. Coating urea with NBPT (1 g kg−1) reduced cumulative NH3 losses by 66%. Volatilization protection lasted 2 to 3 wk on acidic soils, and >7 wk on an alkaline soil. This study demonstrated that significant NH3 losses from surface-applied urea could occur during cold weather months.
Phase diagram mapping is a useful method for predicting and rationalizing unusual thermally and mechanically triggered crystal transition phenomena. Here we focus on crystals of pimelic acid, which ...is known to exist as at least three polymorphs: modifications I–III. Modification III exhibits twinning ferroelasticity and a polymorphic transition, involving superelastic behavior by shearing. Additionally, a phase transition from modification III to modification II by heating involves a rapid expansion of crystals. The reverse transition from the metastable modification II to the thermally stable modification III at ambient temperature by mechanical stimuli involves rapid shrinkage, causing crystals to jump or rapidly fragment. For the first time a comprehensive phase diagram has been presented that accounts for the three different mechanical responses observed for pimelic acid: jumping/fragmentation, superelasticity, and ferroelasticity. Both thermal and mechanical transitions have been rationally mapped on the phase diagram.
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