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BACKGROUND: Many people with schizophrenia do not reach a satisfactory clinical response with a standard dose of an initially prescribed antipsychotic drug. In such cases, clinicians face the dilemma of increasing the antipsychotic dose in order to enhance antipsychotic efficacy. OBJECTIVES: To examine the efficacy of increasing antipsychotic dose compared to keeping the same dose in the treatment of people with schizophrenia who have not responded (as defined in the individual studies) to an initial antipsychotic drug trial. We also examine the adverse effects associated with such a procedure. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (10 June 2014, 6 October 2015, and 30 March 2017). We examined references of all included studies for further trials. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs), reporting useable data, comparing increasing the antipsychotic dose rather than maintaining the original dose for people with schizophrenia who do not respond to their initial antipsychotic treatment. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data . We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their 95% CI. We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table. MAIN RESULTS: Ten relevant RCTs with 675 participants are included in this review. All trials were double blind except one single blind. All studies had a run-in phase to confirm they did not respond to their initial antipsychotic treatment. The trials were published between 1980 and 2016. In most studies the methods of randomisation, allocation and blinding were poorly reported. In addition sample sizes were often small, limiting the overall quality of the evidence. Overall, no clear difference was found between groups in terms of the number of participants who showed clinically relevant response (RR 1.09, 95% CI 0.86 to 1.40, 9 RCTs, N = 533, low-quality evidence), or left the study early due to adverse effects (RR 1.63, 95% CI 0.52 to 5.07, very low quality evidence), or due to any reason (RR 1.30, 95% CI 0.89 to 1.90, 5 RCTs, N = 353, low-quality evidence). Similarly, no clear difference was found in general mental state as measured by PANSS total score change (MD -1.44, 95% CI -6.85 to 3.97, 3 RCTs, N = 258, very low quality evidence). At least one adverse effect was equivocal between groups (RR 0.91, 95% CI 0.55 to 1.50, 2 RCTs, N = 191, very low quality evidence). Data were not reported for time in hospital or quality-of-life outcomes. Finally, subgroup and sensitivity analyses did not show any effect on the primary outcome but these analyses were clearly underpowered. AUTHORS' CONCLUSIONS: Current data do not show any clear differences between increasing or maintaining the antipsychotic dose for people with schizophrenia who do not respond to their initial antipsychotic treatment. Adverse effect reporting was limited and poor. There is an urgent need for further trials in order to determine the optional treatment strategy in such cases.
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Antipsicóticos/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/efectos adversos , Método Doble Ciego , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Método Simple Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Many people with schizophrenia do not respond to an initially prescribed antipsychotic drug. In such cases, one treatment strategy could be to increase the antipsychotic dose; and another strategy could be to switch to a different antipsychotic drug. OBJECTIVES: To examine the efficacy of increasing the antipsychotic dose versus switching the antipsychotic drug in the treatment of non-responsive people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (10 June 2014, 6 October 2015, and 30 March 2017). We examined references of all included studies for further trials. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) comparing increasing the antipsychotic dose versus switching to a different antipsychotic drug for people with schizophrenia who have not responded to their initial antipsychotic treatment. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data. We analysed dichotomous data using relative risks (RR) and their 95% confidence intervals (CIs). We analysed continuous data using mean differences (MD) and their 95% CIs. We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table. MAIN RESULTS: We include one RCT with relevant data on 29 participants in this review. The trial had a parallel design and was double-blind, but blinding procedures were not described. The trial included people who were non-responsive to fluphenazine 20 mg/day administered for 4 weeks. Participants were randomly assigned to continuing treatment with fluphenazine 20 mg/day, increasing the dose to fluphenazine 80 mg/day or switching to haloperidol 20 mg/day for four additional weeks. Data were reported only for 47 out of 58 initially randomised participants. The trial was published in 1993. The fact that only one RCT with a small sample size (N = 29) was included in the analysis limits the quality of the evidence. Overall, no clear difference was found between groups in terms of the three available outcomes: global state (number of participants with clinically relevant response (RR 1.63, 95% CI 0.17 to 15.99, very low quality evidence); general mental state (endpoint score, BPRS total) (MD 2.00, 95% CI -4.20 to 8.20, very low quality evidence); and negative symptoms (endpoint score, SANS) (MD 3.40, 95% CI -12.56 to 19.36). No data were reported for leaving the study early, adverse effects, time in hospital, quality of life, satisfaction with care and functioning. AUTHORS' CONCLUSIONS: There is extremely limited evidence and no clear conclusions can be drawn. There is an urgent need for further trials in order to determine the optimal treatment strategy for people with schizophrenia who do not respond to their initial antipsychotic treatment.
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Antipsicóticos/administración & dosificación , Sustitución de Medicamentos , Flufenazina/administración & dosificación , Haloperidol/administración & dosificación , Humanos , Esquizofrenia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Despite evidence for their comparable efficacy, psychotherapy faces a dramatic decline relative to pharmacotherapy in psychiatry. A deep ideological reason for this decline centres on the belief that psychotherapy is a psychosocial treatment whereas pharmacotherapy is a biological treatment. Modern cognitive neuroscience demonstrates that this distinction is a myth.
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Quimioterapia/tendencias , Trastornos Mentales/psicología , Trastornos Mentales/terapia , Psicoterapia/tendencias , Humanos , Trastornos Mentales/tratamiento farmacológico , Estados UnidosRESUMEN
BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, and valproate is one of these. OBJECTIVES: To examine whether:1. valproate alone is an effective treatment for schizophrenia and schizoaffective psychoses; and2. valproate augmentation of antipsychotic medication is an effective treatment for the same illnesses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (July 2002; February 2007; July 2012; March 04, 2016). We also contacted pharmaceutical companies and authors of relevant studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials comparing valproate to antipsychotics or to placebo (or no intervention), whether as the sole agent or as an adjunct to antipsychotic medication for the treatment of people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible, abstracts, ordered papers, and re-inspected and quality-assessed these. At least two review authors independently extracted data. We analysed dichotomous data using risk ratio (RR) and its 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their 95% CI. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table. MAIN RESULTS: The 2012 update search identified 19 further relevant studies, most of which were from China. Thus the review currently includes 26 studies with a total of 2184 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With the exception of two studies, the studies were small, the participants and personnel were not blinded (neither was outcome assessment), and most were short-term and incompletely reported.For this update we prespecified seven main outcomes of interest: clinical response (clinically significant response, aggression/agitation), leaving the study early (acceptability of treatment, overall tolerability), adverse events (sedation, weight gain) and quality of life.Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (14 RCTs, n = 1049, RR 1.31, 95% CI 1.16 to 1.47, I2 = 12%, low-quality evidence). However, this effect was removed after excluding open RCTs in a sensitivity analysis. In terms of acceptability of treatment (measured by the number of participants leaving the study early due to any reason) valproate was just as acceptable as placebo (11 RCTs, n = 951, RR 0.76, 95% CI 0.47 to 1.24, I2 = 55%). Also overall tolerability (measured by the number of participants leaving the study early for adverse events) between valproate and placebo was similar (6 RCTs, n = 974, RR 1.33, 95% CI 0.90 to 1.97, I2 = 0).Participants in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (3 RCTs, n = 186, MD -2.55, 95% CI -3.92 to -1.19, I2 = 82%, very low-quality evidence). Participants receiving valproate more frequently experienced sedation (8 RCTs, n = 770, RR 1.38, 95% CI 1.07 to 1.79, I2 = 0, low-quality evidence) but were no more likely to gain weight than those receiving placebo (4 RCTs, n = 427, RR 1.17, 95% CI 0.76 to 1.82, I2 = 0, low-quality evidence). No study reported on the important outcome of quality of life. AUTHORS' CONCLUSIONS: There is limited evidence, based on a number of trials, that the augmentation of antipsychotics with valproate may be effective for overall clinical response, and also for specific symptoms, especially in terms of excitement and aggression. However, this evidence was entirely based on open RCTs. Moreover, valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups. Further randomised studies which are blinded are necessary before any clear recommendation can be made. Ideally these would focus on people with schizophrenia and aggression, on those with treatment-resistant forms of the illness and on those with schizoaffective disorders.
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Antimaníacos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Antipsicóticos/uso terapéutico , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The vastness of clinical data and the progressing specialization of medical knowledge may lead to misinterpretation of medication efficacy. To show a realistic perspective on drug efficacy we present meta-analyses on some of the most commonly used pharmacological interventions. For each pharmacological intervention we present statistical indexes (absolute risk or response difference, percentage response ratio, mean difference, standardized mean difference) that are often used to represent efficacy. We found that some of the medications have relatively low effect sizes with only 11 out of 17 of them showing a minimal clinically important difference. Efficacy was often established based on surrogate outcomes and not the more relevant patient-oriented outcomes. As the interpretation of the efficacy of medication is complex, more training for physicians might be needed to get a more realistic view of drug efficacy. That could help prevent harmful overtreatment and reinforce an evidence-based, but personalized medicine.
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Resultado del Tratamiento , Humanos , Metaanálisis como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: As the number of systematic reviews is growing rapidly, we systematically investigate whether meta-analyses published in leading medical journals present an outline of available evidence by referring to previous meta-analyses and systematic reviews. METHODS: We searched PubMed for recent meta-analyses of pharmacological treatments published in high impact factor journals. Previous systematic reviews and meta-analyses were identified with electronic searches of keywords and by searching reference sections. We analyzed the number of meta-analyses and systematic reviews that were cited, described and discussed in each recent meta-analysis. Moreover, we investigated publication characteristics that potentially influence the referencing practices. RESULTS: We identified 52 recent meta-analyses and 242 previous meta-analyses on the same topics. Of these, 66% of identified previous meta-analyses were cited, 36% described, and only 20% discussed by recent meta-analyses. The probability of citing a previous meta-analysis was positively associated with its publication in a journal with a higher impact factor (odds ratio, 1.49; 95% confidence interval, 1.06 to 2.10) and more recent publication year (odds ratio, 1.19; 95% confidence interval 1.03 to 1.37). Additionally, the probability of a previous study being described by the recent meta-analysis was inversely associated with the concordance of results (odds ratio, 0.38; 95% confidence interval, 0.17 to 0.88), and the probability of being discussed was increased for previous studies that employed meta-analytic methods (odds ratio, 32.36; 95% confidence interval, 2.00 to 522.85). CONCLUSIONS: Meta-analyses on pharmacological treatments do not consistently refer to and discuss findings of previous meta-analyses on the same topic. Such neglect can lead to research waste and be confusing for readers. Journals should make the discussion of related meta-analyses mandatory.
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Metaanálisis como Asunto , Literatura de Revisión como Asunto , HumanosRESUMEN
BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary anti-psychotic drug treatment. In these cases, various add-on medications are used, among them lithium. OBJECTIVES: To assess whether:1. Lithium alone is an effective treatment for schizophrenia, schizophrenia-like psychoses and schizoaffective psychoses; and2. Lithium augmentation of antipsychotic medication is an effective treatment for the same illnesses. SEARCH METHODS: In July 2012, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. This search was updated on January 20, 2015. For the first version of the review, we also contacted pharmaceutical companies and authors of relevant studies to identify further trials and obtain original participant data. SELECTION CRITERIA: Randomised controlled trials (RCTs) of lithium compared with antipsychotics or placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication, in the treatment of schizophrenia or schizophrenia-like psychoses or both. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data, we calculated random-effects meta-analyses, risk ratios (RRs), and 95% confidence intervals (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and 95% confidence intervals. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to create 'Summary of findings' tables and assessed risk of bias for included studies. MAIN RESULTS: The update search in 2012 detected two further studies that met our inclusion criteria. We did not find any further studies that met our inclusion criteria in the 2015 search. This review now includes 22 studies, with a total of 763 participants (median mean age: 35 years, range: 26 to 72 years). Most studies were small, of short duration, and incompletely reported. As we detected a high risk of bias in many studies, the overall methodological quality of the included sample was rather low.Three small studies comparing lithium with placebo as the sole treatment showed no difference in any of the outcomes we analysed.In eight studies comparing lithium with antipsychotic drugs as the sole treatment, more participants in the lithium group left the studies early (eight RCTs; n = 270, RR 1.77, 95% CI 1.01 to 3.11, low quality evidence).Thirteen studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (10 RCTs; n = 396, RR 1.81, 95% CI 1.10 to 2.97, low quality evidence). However, this effect became non-significant when we excluded participants with schizoaffective disorders in a sensitivity analysis (seven RCTs; n = 272, RR 1.64, 95% CI 0.95 to 2.81), when we excluded non-double-blind studies (seven RCTs; n = 224, RR 1.82, 95% CI 0.84 to 3.96), or when we excluded studies with high attrition (nine RCTs; n = 355, RR 1.67, CI 0.93 to 3.00). The overall acceptability of treatment (measured by the number of participants leaving the studies early) was not significantly different between groups (11 RCTs; n = 320, RR 1.89, CI 0.93 to 3.84, very low quality evidence). Few studies reported on side effects. There were no significant differences, but the database is too limited to make any judgement in this regard. For example, there were no data on thyroid dysfunction and kidney problems - two major and well-known side effects of lithium. AUTHORS' CONCLUSIONS: The evidence base for the use of lithium in schizophrenia is limited to 22 studies of overall low methodological quality. There is no randomised trial-based evidence that lithium on its own is an effective treatment for people with schizophrenia. There is some GRADE low quality evidence that augmentation of antipsychotics with lithium is effective, but the effects are not significant when more prone-to-bias open RCTs are excluded. Nevertheless, further large and well-designed trials are justified. These should concentrate on two target groups: (1) people with no affective symptoms, so that trialists can determine whether lithium has an effect on the core symptoms of schizophrenia, and (2) people with schizoaffective disorders for whom lithium is widely used in clinical practice, although there is no evidence to support this use.
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Antipsicóticos/uso terapéutico , Compuestos de Litio/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Perazine is an old phenothiazine derivative used for the treatment of people with schizophrenia and is reputed to have a low level of extrapyramidal adverse effects. As far as we are aware, its use is limited to Germany, Poland, the former Yugoslavia and the Netherlands. OBJECTIVES: To examine the effects of perazine for those with schizophrenia or related psychoses in comparison with placebo, no treatment or other antipsychotic medications. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register, which includes relevant randomised controlled trials from the bibliographic databases Biological Abstracts, CINAHL, The Cochrane Library, EMBASE, MEDLINE, PsycLIT, LILACS, PSYNDEX, Sociological Abstracts and Sociofile. We searched the references of all included studies for further trials. We contacted pharmaceutical companies and authors of trials. We updated this search on 16th July 2012. SELECTION CRITERIA: We selected all randomised controlled trials that compared perazine with other treatments for people with schizophrenia or schizophrenia-like psychoses, or both. DATA COLLECTION AND ANALYSIS: The review authors (SL, BH, BHe) independently inspected the citations and where possible abstracts and ordered papers for re-inspection and quality assessment. We independently extracted data. We calculated the risk ratio (RR) and 95% confidence interval (CI) using a random-effects model. For continuous data, we calculated mean differences (MD). We inspected all data for heterogeneity, assessed trials for risk of bias and created summary of findings tables using GRADE. MAIN RESULTS: The review now includes seven trials with a total of 479 participants. In only one trial, with 95 participants, perazine appeared superior to 'active placebo' (trimipramine) at five weeks for the outcome of 'no important global improvement' (n = 95, RR 0.43 CI 0.2 to 0.8, low quality evidence), but there was no statistically significant difference in most measures of mental state. Perazine did not induce more general adverse events than placebo but more participants received at least one dose of antiparkinson medication (n = 95, RR 4.50 CI 1.0 to 19.5, very low quality evidence).Six small trials comparing perazine with other antipsychotics, including 384 participants in total, were incompletely reported and the outcomes were presented in various ways so that meta-analysis was not possible on most occasions. In the six studies, a similar number of participants receiving perazine or comparator antipsychotics (amisulpride, haloperidol, olanzapine, ziprasidone, zotepine) left the studies early (n = 384, RR 0.97 CI 0.68 to 1.38, low quality evidence). The results on efficacy could not be meta-analysed because the authors presented their results in very different ways. No obvious differences in adverse events between perazine and other antipsychotics could be derived from the limited data. Two haloperidol comparisons did not present extrapyramidal side-effects in a way that was suitable for use in meta-analysis, but three small comparisons with the second-generation antipsychotics zotepine and amisulpride showed no higher risk of akathisia (n = 111, RR 0.31 CI 0.1 to 1.1), dyskinesia (n = 111, RR 0.47 CI 0.1 to 3.5), parkinsonism (n = 81, RR 1.21 CI 0.5 2.8) or tremor (n = 40, RR 0.80 CI 0.3 to 2.6) with perazine. AUTHORS' CONCLUSIONS: The number, size and reporting of randomised controlled perazine trials are insufficient to present firm conclusions about the properties of this antipsychotic. It is possible that perazine is associated with a similar risk of extrapyramidal side-effects as some atypical antipsychotics but this is based on small comparisons. This should be clarified in larger, well-designed trials.
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Antipsicóticos/uso terapéutico , Perazina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/efectos adversos , Humanos , Perazina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with just antipsychotic drug treatment and various adjunct medications are used to promote additional response. The antiepileptic carbamazepine is one such drug. OBJECTIVES: To examine whether carbamazepine or oxcarbazepine alone is an effective treatment for schizophrenia and schizoaffective psychoses and whether carbamazepine or oxcarbazepine augmentation of neuroleptic medication is an effective treatment for the same illnesses. SEARCH METHODS: For the original version we searched The Cochrane Schizophrenia Group's Register of Trials (December 2001), The Cochrane Library (Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1980-2001), Biological Abstracts (1980-2001), PsycLIT (1886-2001) and PSYNDEX (1974-2001). For the most recent update we searched the Cochrane Schizophrenia Group's Register of Trials in July 2012. We also inspected references of all identified studies for further trials and contacted relevant pharmaceutical companies and authors for additional data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing carbamazepine or compounds of the carbamazepine family with placebo or no intervention, whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizoaffective psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For homogenous dichotomous data we calculated fixed-effect, risk ratio (RR), with 95% confidence intervals (CIs) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD). We assessed the risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The updated search did not reveal any further studies that met our inclusion criteria. The number of included studies therefore remains at 10 with the number of participants randomised still 283.One study comparing carbamazepine with placebo as the sole treatment for schizophrenia was abandoned early due to high relapse rate with 26 out of 31 participants relapsing by three months. No effect of carbamazepine was evident with no difference in relapse between the two groups (1 RCT n = 31, RR 1.07 CI 0.78 to 1.45). Another study compared carbamazepine with antipsychotics as the sole treatment for schizophrenia. No differences in terms of mental state were found when comparing 50% reduction in Brief Psychiatric Rating Scale (BPRS) scores (1 RCT n = 38, RR 1.23 CI 0.78 to 1.92). A favourable effect for carbamazepine was found when more people who received the antipsychotic (perphenazine) had parkinsonism (1 RCT n = 38, RR 0.03 CI 0.00 to 0.043). Eight studies compared adjunctive carbamazepine versus adjunctive placebo, we were able use GRADE for quality of evidence for these results. Adding carbamazepine to antipsychotic treatment was as acceptable as adding placebo with no difference between the numbers leaving the study early from each group (8 RCTs n = 182, RR 0.47 CI 0.16 to 1.35, very low quality evidence). Carbamazepine augmentation was superior compared with antipsychotics alone in terms of overall global improvement, but participant numbers were low (2 RCTs n = 38, RR 0.57 CI 0.37 to 0.88). There were no differences for the mental state outcome of 50% reduction in BPRS scores (6 RCTs n = 147, RR 0.86 CI 0.67 to 1.12, low quality evidence). Less people in the carbamazepine augmentation group had movement disorders than those taking haloperidol alone (1 RCT n = 20, RR 0.38 CI 0.14 to 1.02). No data were available for the effects of carbamazepine on subgroups of people with schizophrenia and aggressive behaviour, negative symptoms or EEG abnormalities or with schizoaffective disorder. AUTHORS' CONCLUSIONS: Based on currently available randomised trial-derived evidence, carbamazepine cannot be recommended for routine clinical use for treatment or augmentation of antipsychotic treatment of schizophrenia. At present large, simple well-designed and reported trials are justified - especially if focusing on people with violent episodes and people with schizoaffective disorders or those with both schizophrenia and EEG abnormalities.
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Antimaníacos/uso terapéutico , Antipsicóticos/uso terapéutico , Carbamazepina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Terapia Combinada/métodos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , RecurrenciaRESUMEN
INTRODUCTION: Commercial milk formula manufacturers often emphasise their role in supporting infant and young child nutrition and breastfeeding, but their commercial goals to increase volume and profit margin of formula sales conflict with these declarations. Healthcare professional associations have an important role in healthcare worker education, shaping clinical practice. When healthcare professional associations enter into financial relationships with formula manufacturers, conflicts of interest arise, which may undermine education and practice that promotes optimal infant and young child feeding. The World Health Assembly calls on all parties to avoid such conflicts of interest, but it is uncertain how often this recommendation is followed. This protocol documents a systematic method to identify funding from the commercial milk formula industry among international, regional and national associations of healthcare professionals. METHODS AND ANALYSIS: Using systematic search strategies in the Gale Directory Library and Google, we will identify international healthcare professional associations relevant to maternal and child health. Data regarding funding relationships with the commercial milk formula industry over the past 24 months will be extracted from the official websites or, in their absence, social media accounts by two independent analysts. The analysis will focus on the presence of conflict of interest or sponsorship policies and type of funding, such as sponsorship or payment for services. ETHICS AND DISSEMINATION: This study does not require ethical approval and will use data available in the public domain. The results will be disseminated through peer-reviewed journal articles, at conferences and among the healthcare professional associations.
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Conflicto de Intereses , Fórmulas Infantiles , Humanos , Fórmulas Infantiles/economía , Industria de Alimentos/economía , Lactante , Estudios Transversales , Lactancia Materna/economía , Proyectos de Investigación , Personal de SaludRESUMEN
There is growing scientific interest in immunity mandates/passports (IMP) for viral diseases in light of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. IMP isolate those who remain nonimmune from various settings to reduce nonhousehold transmissions from the nonimmune and reduce severe/critical illness among the nonimmune. A major limitation in the scientific literature is that there are currently no methods to quantify how many nonimmune individuals need to be isolated to achieve these purported benefits. This paper develops a procedure for estimating the benefits of IMP using a novel variant of the number needed to treat which we call the number needed to isolate (NNI). We use data from the SARS-CoV-2 pandemic to demonstrate the properties and utility of the NNI and to inform the debate about IMP. We focus on data from the European Union, United Kingdom, United States, Canada, Australia, and Israel during the fall 2021 when the Delta (B.1.617.2) variant predominated.
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COVID-19 , Humanos , SARS-CoV-2 , Enfermedad Crítica , Conducta de Reducción del RiesgoRESUMEN
(1) Background: The use of benzodiazepines for the treatment of acute mania remains prevalent. This systematic review and meta-analysis provides an updated assessment of Clonazepam's antimanic efficacy, tolerability, and acceptability. (2) Methods: A systematic search of multiple databases and clinical trial registries was conducted, aiming to identify any controlled studies of Clonazepam vs. placebo or any other pharmacotherapy for the treatment of acute mania. Pairwise meta-analytic evaluations were performed. (3) Results: Six studies were included with a total number of 192 participants, all of which were randomized controlled trials. Clonazepam may be superior to a placebo in the acute phase of treatment and no different to Lithium and Haloperidol in terms of efficacy, both acutely and in the medium to long term. Clonazepam may be an acceptable and well-tolerated treatment for acute mania, especially when used as an augmentation strategy. Comparisons were underpowered, with minimal sample sizes and only one study per comparison in many cases, thus limiting the generalizability of our findings and hindering firm clinical conclusions. (4) Conclusions: Given the prevalence of benzodiazepine use in current practice, more and larger studies are urgently needed.
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BACKGROUND: Atypical arousal regulation may explain slower mean reaction time (MRT) in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder compared with typical development. The locus coeruleus-norepinephrine system (LC-NE) underlies arousal regulation and adapts its activity to the utility of a task. LC-NE tonic and phasic activity are indexed by baseline pupil size (BPS) and stimulus-evoked pupillary response (SEPR). METHODS: The study assessed pupillometry in ASD (n = 31, 3 female/28 male), attention-deficit/hyperactivity disorder (n = 28, 3 female/25 male), and typically developing control subjects (n = 31, 16 female/15 male) during a visuospatial reaction-time task that manipulates arousal by conditions with low and high task utility. We estimated linear mixed models of BPS, SEPR, and MRT in a per-trial analysis to investigate arousal regulation of task performance. RESULTS: Slower MRT occurred in the ASD group compared with the typically developing control group during low-utility conditions while controlling for dimensional ASD and attention-deficit/hyperactivity disorder symptoms. In low-utility conditions, BPS and SEPR were inversely related and both were associated with faster MRT. Increased ASD symptoms across groups were associated with higher BPS during low-utility conditions. Changes in BPS and SEPR between task-utility conditions were smaller in the ASD group. CONCLUSIONS: Slower visuospatial task performance in ASD is specific to low task utility. Arousal was associated with task performance and showed altered activity in ASD. Increased BPS during low-utility conditions suggested increased LC-NE tonic activity as an ASD symptom marker in children. Smaller changes in BPS and SEPR in ASD indicated attenuated LC-NE activity adaptation in response to high-utility conditions. Slower performance and atypical arousal regulation are probably associated with attenuated LC-NE activity adaptation.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Masculino , Niño , Femenino , Locus Coeruleus/fisiología , Trastorno del Espectro Autista/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Nivel de Alerta/fisiologíaRESUMEN
INTRODUCTION: Clinicians caring for adults with borderline personality disorder (BPD) in acute settings such as the emergency department (ED) have little evidence/guidance to base decisions on. Specific/detailed guidance for managing BPD in the ED is needed given the morbidity and mortality risks, high service utilisation, unique challenges and risk of iatrogenic interventions. The primary objective of this study is to use a consensus method to develop a guideline for managing adults with BPD in the ED. This protocol and the key questions for the guideline were developed with the advice of people with BPD and their family members/support persons. METHODS AND ANALYSIS: We will perform a four-phase Delphi study of an expert panel of clinicians, researchers, adults with BPD and their family members/support persons. Various disciplines (psychiatry, psychology, emergency medicine, nursing, social work) and treatment approaches will be included in the expert panel. An online questionnaire will be developed from systematic reviews, qualitative assessments of pivotal literature, and opinions suggested by the panel (phase 1). The panel will rate their agreement on opinions for each key question covering areas of emergency care of adults with BPD using two rounds of this questionnaire (phases 2 and 3). Opinions meeting predefined thresholds for consensus will be brought to consensus meetings moderated by an independent chair (phase 4). The purpose of these meetings is to finalise the set and phrasing of the opinions for each area of emergency care. These final opinions will be the recommendations in the guideline. If there are significant differences of opinion, the guideline will present both recommendations alongside one another. ETHICS AND DISSEMINATION: This study has received ethics approval by the Hamilton Integrated Research Ethics Board in Hamilton, Ontario, Canada. The results of this study will be disseminated through peer-reviewed publications, conferences and national professional and patient/family/support associations.
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Trastorno de Personalidad Limítrofe , Humanos , Adulto , Técnica Delphi , Trastorno de Personalidad Limítrofe/terapia , Proyectos de Investigación , Servicio de Urgencia en Hospital , OntarioRESUMEN
OBJECTIVES: To review available health and nutrition claims for infant formula products in multiple countries and to evaluate the validity of the evidence used for substantiation of claims. DESIGN: International cross sectional survey. SETTING: Public facing and healthcare professional facing company owned or company managed formula industry websites providing information about products marketed for healthy infants delivered at full term in 15 countries: Australia, Canada, Germany, India, Italy, Japan, Nigeria, Norway, Pakistan, Russia, Saudi Arabia, South Africa, Spain, the United Kingdom, and the United States in 2020-22. MAIN OUTCOME MEASURES: Number and type of claims made for each product and ingredient. References cited were reviewed and risk of bias was assessed for registered clinical trials using the Cochrane risk of bias tool, and for systematic reviews using the Risk Of Bias in Systematic reviews tool. RESULTS: 757 infant formula products were identified, each with a median of two claims (range from 1 (Australia) to 4 (US)), and 31 types of claims across all products. Of 608 products with ≥1 claims, the most common claim types were "helps/supports development of brain and/or eyes and/or nervous system" (323 (53%) products, 13 ingredients), "strengthens/supports a healthy immune system" (239 (39%) products, 12 ingredients), and "helps/supports growth and development" (224 (37%) products, 20 ingredients). 41 groups of ingredients were associated with ≥1claims, but many claims were made without reference to a specific ingredient (307 (50%) products). The most common groups of ingredients cited in claims were long chain polyunsaturated fatty acids (278 (46%) products, 9 different claims); prebiotics, probiotics, or synbiotics (225 (37%) products, 19 claims); and hydrolysed protein (120 (20%) products, 9 claims). 161/608 (26%) products with ≥1 claims provided a scientific reference to support the claim-266 unique references were cited for 24 different claim types for 161 products. The reference types most frequently cited were clinical trials (50%, 134/266) and reviews (20%, 52/266). 28% (38/134) of referenced clinical trials were registered, 14% (19/134) prospectively. 58 claims referred to 32 registered clinical trials, of which 51 claims (27 trials) related to a randomised comparison. 46 of 51 claims (90%) referenced registered clinical trial outcomes at high risk of bias, and all cited systematic reviews and pooled analyses, carried a high risk of bias. CONCLUSIONS: Most infant formula products had at least one health and nutrition claim. Multiple ingredients were claimed to achieve similar health or nutrition effects, multiple claims were made for the same ingredient type, most products did not provide scientific references to support claims, and referenced claims were not supported by robust clinical trial evidence.
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Fórmulas Infantiles , Probióticos , Lactante , Humanos , Estudios Transversales , Revisiones Sistemáticas como Asunto , PrebióticosRESUMEN
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in adults are often undiagnosed and overlap in psychopathology. Here we investigated the transdiagnostic traits of emotion recognition and mind wandering in a sample of 103 adults (43 with ADHD and 14 with ASD). The ability to correctly identify a facial expression of anger, fear, disgust or surprise was no different between the adults with ADHD or ASD and neurotypical (NT) adults. However, adults with ADHD or ASD were on average almost 200 ms slower in making a correct decision, suggesting a larger speed-accuracy trade-off in facial emotion recognition compared to NT adults. General processing speed was associated with excessive mind wandering in adults with ADHD, but not with ASD. The deficits in emotional processing were independent from mind wandering in both adults with ADHD or ASD. Emotional dysregulation and functional impairment scales separated adults with ADHD and ASD from the NT adults, but not from each other. When controlling for self-reported ADHD and ASD symptom severity, mind wandering in ADHD was independent from both ADHD and ASD symptom severity. In ASD, mind wandering was related to ASD but not ADHD symptom severity. Our results suggest that ASD and ADHD share a slower ability to recognize emotions, which is exacerbated by excessive mind wandering in ADHD, and by decreased processing speed in ASD.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Reconocimiento Facial , Adulto , Trastorno del Espectro Autista/complicaciones , Cognición , Emociones , HumanosRESUMEN
OBJECTIVE: To systematically review the conduct and reporting of formula trials. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1 January 2006 to 31 December 2020. REVIEW METHODS: Intervention trials comparing at least two formula products in children less than three years of age were included, but not trials of human breast milk or fortifiers of breast milk. Data were extracted in duplicate and primary outcome data were synthesised for meta-analysis with a random effects model weighted by the inverse variance method. Risk of bias was evaluated with Cochrane risk of bias version 2.0, and risk of undermining breastfeeding was evaluated according to published consensus guidance. Primary outcomes of the trials included in the systematic review were identified from clinical trial registries, protocols, or trial publications. RESULTS: 22 201 titles were screened and 307 trials were identified that were published between 2006 and 2020, of which 73 (24%) trials in 13 197 children were prospectively registered. Another 111 unpublished but registered trials in 17 411 children were identified. Detailed analysis was undertaken for 125 trials (23 757 children) published since 2015. Seventeen (14%) of these recently published trials were conducted independently of formula companies, 26 (21%) were prospectively registered with a clear aim and primary outcome, and authors or sponsors shared prospective protocols for 11 (9%) trials. Risk of bias was low in five (4%) and high in 100 (80%) recently published trials, mainly because of inappropriate exclusions from analysis and selective reporting. For 68 recently published superiority trials, a pooled standardised mean difference of 0.51 (range -0.43 to 3.29) was calculated with an asymmetrical funnel plot (Egger's test P<0.001), which reduced to 0.19 after correction for asymmetry. Primary outcomes were reported by authors as favourable in 86 (69%) trials, and 115 (92%) abstract conclusions were favourable. One of 38 (3%) trials in partially breastfed infants reported adequate support for breastfeeding and 14 of 87 (16%) trials in non-breastfed infants confirmed the decision not to breastfeed was firmly established before enrolment in the trial. CONCLUSIONS: The results show that formula trials lack independence or transparency, and published outcomes are biased by selective reporting. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2018 CRD42018091928.
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Ensayos Clínicos como Asunto , Fórmulas Infantiles , Proyectos de Investigación , Lactancia Materna/estadística & datos numéricos , Ensayos Clínicos como Asunto/ética , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Exactitud de los Datos , Humanos , Lactante , Fórmulas Infantiles/clasificación , Fórmulas Infantiles/normas , Proyectos de Investigación/normas , Proyectos de Investigación/estadística & datos numéricosRESUMEN
BACKGROUND: We investigated whether adults with attention-deficit/hyperactivity disorder (ADHD) show pseudoneglect-preferential allocation of attention to the left visual field (LVF) and a resulting slowing of mean reaction times (MRTs) in the right visual field (RVF), characteristic of neurotypical (NT) individuals -and whether lateralization of attention is modulated by presentation speed and incentives. METHOD: Fast Task, a four-choice reaction-time task where stimuli were presented in LVF or RVF, was used to investigate differences in MRT and reaction time variability (RTV) in adults with ADHD (n = 43) and NT adults (n = 46) between a slow/no-incentive and fast/incentive condition. In the lateralization analyses, pseudoneglect was assessed based on MRT, which was calculated separately for the LVF and RVF for each condition and each study participant. RESULTS: Adults with ADHD had overall slower MRT and increased RTV relative to NT. MRT and RTV improved under the fast/incentive condition. Both groups showed RVF-slowing with no between-group or between-conditions differences in RVF-slowing. CONCLUSION: Adults with ADHD exhibited pseudoneglect, a NT pattern of lateralization of attention, which was not attenuated by presentation speed and incentives.
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Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Atención , Lateralidad Funcional , Percepción Espacial , Adulto , Femenino , Humanos , Masculino , Motivación , Tiempo de ReacciónRESUMEN
BACKGROUND: Adults with attention deficit hyperactivity disorder (ADHD) frequently suffer from sleep problems and report high levels of daytime sleepiness compared to neurotypical controls, which has detrimental effect on quality of life. METHODS: We evaluated daytime sleepiness in adults with ADHD compared to neurotypical controls using an observer-rated sleepiness protocol during the Sustained Attention Response Task as well as electroencephalogram (EEG) slowing, a quantitative electroencephalographic measure collected during a short period of wakeful rest. RESULTS: We found that adults with ADHD were significantly sleepier than neurotypical controls during the cognitive task and that this on-task sleepiness contributed to cognitive performance deficits usually attributed to symptoms of ADHD. EEG slowing predicted severity of ADHD symptoms and diagnostic status, and was also related to daytime sleepiness. Frontal EEG slowing as well as increased frontal delta were especially prominent in adults with ADHD. We have validated and adapted an objective observer-rated measure for assessing on-task sleepiness that will contribute to future sleep research in psychology and psychiatry. CONCLUSIONS: These findings indicate that the cognitive performance deficits routinely attributed to ADHD and often conceptualized as cognitive endophenotypes of ADHD are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. Daytime sleepiness plays a major role in cognitive functioning of adults with ADHD.