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1.
Res Synth Methods ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32352639

RESUMO

It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta-analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double-blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta-Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two-dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010 and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs. This article is protected by copyright. All rights reserved.

2.
Mol Psychiatry ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404948

RESUMO

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

3.
BMC Med ; 18(1): 93, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32349753

RESUMO

BACKGROUND: Antidepressants may be used to manage a number of conditions in children and young people including depression, anxiety, and obsessive-compulsive disorder. UK guidelines for the treatment of depression in children and young people recommend that antidepressants should only be initiated following assessment and diagnosis by a child and adolescent psychiatrist. The aim of this study was to summarise visits to mental health specialists and indications recorded around the time of antidepressant initiation in children and young people in UK primary care. METHODS: The study used linked English primary care electronic health records and Hospital Episode Statistics secondary care data. The study included 5-17-year-olds first prescribed antidepressants between January 2006 and December 2017. Records of visits to paediatric or psychiatric specialists and potential indications (from a pre-specified list) were extracted. Events were counted if recorded less than 12 months before or 6 months after the first antidepressant prescription. Results were stratified by first antidepressant type (all, selective serotonin reuptake inhibitors (SSRIs), tricyclic and related antidepressants) and by age group (5-11 years, 12-17 years). RESULTS: In total, 33,031 5-17-year-olds were included. Of these, 12,149 (37%) had a record of visiting a paediatrician or a psychiatric specialist in the specified time window. The majority of recorded visits (7154, 22%) were to paediatricians. Of those prescribed SSRIs, 5463/22,130 (25%) had a record of visiting a child and adolescent psychiatrist. Overall, 17,972 (54%) patients had a record of at least one of the pre-specified indications. Depression was the most frequently recorded indication (12,501, 38%), followed by anxiety (4155, 13%). CONCLUSIONS: The results suggest many children and young people are being prescribed antidepressants without the recommended involvement of a relevant specialist. These findings may justify both greater training for GPs in child and adolescent mental health and greater access to specialist care and non-pharmacological treatments. Further research is needed to explore factors that influence how and why GPs prescribe antidepressants to children and young people and the real-world practice barriers to adherence to clinical guidelines.

4.
Pharmacol Ther ; : 107557, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32437828

RESUMO

There is increasing interest in clinical prediction models in psychiatry, which focus on developing multivariate algorithms to guide personalized diagnostic or management decisions. The main target of these models is the prediction of treatment response to different antidepressant therapies. This is because the ability to predict response based on patients' personal data may allow clinicians to make improved treatment decisions, and to provide more efficacious or more tolerable medications to the right patient. We searched the literature for systematic reviews about treatment prediction in the context of existing treatment modalities for adult unipolar depression, until July 2019. Treatment effect is defined broadly to include efficacy, safety, tolerability and acceptability outcomes. We first focused on the identification of individual predictor variables that might predict treatment response, and second, we considered multivariate clinical prediction models. Our meta-review included a total of 10 systematic reviews; seven (from 2014 to 2018) focusing on individual predictor variables and three focusing on clinical prediction models. These identified a number of sociodemographic, phenomenological, clinical, neuroimaging, remote monitoring, genetic and serum marker variables as possible predictor variables for treatment response, alongside statistical and machine-learning approaches to clinical prediction model development. Effect sizes for individual predictor variables were generally small and clinical prediction models had generally not been validated in external populations. There is a need for rigorous model validation in large external data-sets to prove the clinical utility of models. We also discuss potential future avenues in the field of personalized psychiatry, particularly the combination of multiple sources of data and the emerging field of artificial intelligence and digital mental health to identify new individual predictor variables.

6.
Schizophr Res ; 2020 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-32295752

RESUMO

The gut-microbiome has been hypothesised as a novel potential target for intervention for schizophrenia. We tested this hypothesis with a systematic review and meta-analysis of studies investigating the efficacy and acceptability of add-on strategies known to affect the gut-microbiome for the treatment of schizophrenia. Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobials, pre/probiotics, and faecal transplant in schizophrenia. Primary outcomes were severity of negative symptoms and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. We identified 28 eligible trials: 21 investigated antibiotics, 4 antimicrobials (Artemisinin, Artemether, and Sodium Benzoate), 3 pre/probiotics, none faecal transplant. Results showed no effect of D-Cycloserine (10 studies; SMD, -0.16; 95% CI -0.40, 0.08; P = .20; I2: 28.2%), Minocycline (7 studies; SMD: -0.35; 95% CI -0.70, 0.00; P = .05, I2:77.7%), other antibiotics (2 studies), probiotics alone (1 study), and Artemisinin (1 study) on negative symptoms of schizophrenia when compared to placebo. Limited evidence suggests efficacy on negative symptoms for Sodium benzoate (2 studies; SMD, -0.63; 95%CI -1.03, -0.23; P < .001; I2:0%), Artemether (1 study), and probiotics combined with Vitamin D (1 study) when compared to placebo. Acceptability of intervention was similar to placebo. Negative findings were mainly led by antibiotics trials, with paucity of evidence available on pre/probiotics. There is a need of expanding our knowledge on the clinical relevance of gut-microbiome-host interaction in psychosis before engaging in further trials.

7.
Lancet ; 395(10228): 998-1010, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199487

RESUMO

Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies might remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and might not collect patient-relevant outcomes. Regulators, in collaboration with the industry and patients, ought to ensure that the key questions unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators (for drugs and devices), notified bodies (for devices in Europe), health technology assessment organisations, and payers should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry impacting the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be large or when it is possible to reasonably infer the comparative benefits or risks in settings, in which doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous post-marketing research efforts. Last, financial incentives and penalties should be developed or more actively reinforced.


Assuntos
Aprovação de Equipamentos , Aprovação de Drogas/métodos , Segurança de Equipamentos , Vigilância de Produtos Comercializados/métodos , Tolerância a Medicamentos , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
8.
Lancet ; 395(10228): 986-997, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199486

RESUMO

Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.


Assuntos
Aprovação de Equipamentos/normas , Aprovação de Drogas/métodos , Segurança de Equipamentos , Segurança , Biomarcadores Farmacológicos/análise , Tolerância a Medicamentos , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
11.
Acta Neuropsychiatr ; : 1-8, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039743

RESUMO

OBJECTIVE: The aim of this paper was to provide a systematic review and update on the pharmacotherapy of social anxiety disorder (SAD), including the efficacy and tolerability of these agents, the ranking of interventions, and the grading of results by quality of evidence. METHODS: The Common Mental Disorder Controlled Trial Register and two trial registries were searched for randomised controlled trials (RCTs) comparing any pharmacological intervention or placebo in the treatment of SAD. We performed a standard pairwise meta-analysis using a random effects model and carried out a network meta-analysis (NMA) using the statistical package, R. Quality of evidence was also assessed. RESULTS: We included 67 RCTs in the review and 21 to 45 interventions in the NMA. Paroxetine was most effective in the reduction of symptom severity as compared to placebo. Superior response to treatment was also observed for paroxetine, brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline. Higher dropout rates were found for fluvoxamine. Brofaromine, escitalopram, fluvoxamine, paroxetine, pregabalin, sertraline, and venlafaxine performed worse in comparison to placebo for the outcome of dropouts due to adverse events. Olanzapine yielded a relatively high rank for treatment efficacy and buspirone the worse rank for dropouts due to any cause. CONCLUSION: The differences between drugs and placebo were small, apart from a significant reduction in symptom severity and response for paroxetine. We suggest paroxetine as a first-line treatment of SAD, with the consideration of future research on the drug olanzapine as well as brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline because we observed a response to treatment.

12.
JAMA Psychiatry ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32074273

RESUMO

Importance: Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors. Objectives: To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication. Data Sources: Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals. Study Selection: Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study's end point. Data Extraction and Synthesis: Baseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019. Main Outcomes and Measures: With the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year. Results: In the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent. Conclusions and Relevance: Individual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.

13.
Arch Osteoporos ; 15(1): 21, 2020 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-32088774

RESUMO

We compared the cumulative network meta-analyses with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA. There was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vitamin D and calcium, when we used cumulative NMAs as references. PURPOSE: To compare the results of cumulative network meta-analyses (NMAs) with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched to retrieve randomized controlled trials (RCTs) in July 2017. The Agency for Healthcare Research and Quality's National Guideline Clearinghouse and associated society websites were searched to retrieve guidelines in June 2018. We used the Medical Expenditure Panel Survey (MEPS) to analyze prescription data from 1996 to 2015. Two independent investigators selected eligible RCTs. One investigator selected potential eligible guidelines, which were confirmed by another investigator. Two independent investigators extracted data from included RCTs. One investigator extracted recommendations from guidelines, which were confirmed by another investigator. (Registration: UMIN000031894) RESULTS: We analyzed data from 1995, 2000, 2005, 2010, and 2015. We chose hip fracture as the primary outcome of cumulative NMAs. We included 51 trials, 17 guidelines, and 5099 postmenopausal osteoporosis patients from the MEPS. Bisphosphonate, including alendronate, and combination of vitamin D and calcium (vDCa) were consistently recommendable from an efficacy viewpoint in NMAs and recommended in guidelines. Alendronate was the most prescribed drug (more than 30% over the observation period); however, vDCa was seldom prescribed. The maximum proportion was 5.3% from 2011 to 2015. CONCLUSIONS: In postmenopausal osteoporosis, there was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vDCa, when we used cumulative NMAs as references.

14.
Evid Based Ment Health ; 23(1): 21-26, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32046989

RESUMO

BACKGROUND: Utilisation of routinely collected electronic health records from secondary care offers unprecedented possibilities for medical science research but can also present difficulties. One key issue is that medical information is presented as free-form text and, therefore, requires time commitment from clinicians to manually extract salient information. Natural language processing (NLP) methods can be used to automatically extract clinically relevant information. OBJECTIVE: Our aim is to use natural language processing (NLP) to capture real-world data on individuals with depression from the Clinical Record Interactive Search (CRIS) clinical text to foster the use of electronic healthcare data in mental health research. METHODS: We used a combination of methods to extract salient information from electronic health records. First, clinical experts define the information of interest and subsequently build the training and testing corpora for statistical models. Second, we built and fine-tuned the statistical models using active learning procedures. FINDINGS: Results show a high degree of accuracy in the extraction of drug-related information. Contrastingly, a much lower degree of accuracy is demonstrated in relation to auxiliary variables. In combination with state-of-the-art active learning paradigms, the performance of the model increases considerably. CONCLUSIONS: This study illustrates the feasibility of using the natural language processing models and proposes a research pipeline to be used for accurately extracting information from electronic health records. CLINICAL IMPLICATIONS: Real-world, individual patient data are an invaluable source of information, which can be used to better personalise treatment.

15.
Aust N Z J Psychiatry ; 54(1): 29-45, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729893

RESUMO

OBJECTIVE: Ketamine may reduce suicidal ideation in treatment-resistant depression. But it is not known how quickly this occurs and how long it persists. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality. METHOD: CENTRAL, EMBASE, Medline, and PsycINFO were searched until 12 December 2018. Randomised controlled trials of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included. Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Standardised mean difference was used for continuous outcomes. RESULTS: Twenty-five reports from 15 independent trials, with a total of 572 participants diagnosed with predominately affective disorders, were included. The evidence was rated moderate to low. In most trials, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. Only a single trial of intranasal esketamine was identified. At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardised mean difference = -0.51, 95% confidence interval = [-1.00, -0.03]), which persisted until 72 hours post-infusion (time points between 12 and 24 hours: standardised mean difference = -0.63, 95% confidence interval = [-0.99, -0.26]; between 24 and 72 hours: standardised mean difference = -0.57, 95% confidence interval = [-0.99, -0.14]), but not thereafter. However, there was marked heterogeneity of results. In a single trial of esketamine, marginal effects on suicidal ideation were observed. In terms of actual suicidal behaviour, there were virtually no data on effects of ketamine or esketamine. CONCLUSION: A single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts. While confirmation of these results in further trials is needed, they suggest possible use of ketamine to treat acute suicidality. Means of sustaining any anti-suicidal effect need to be found.

16.
Lancet Psychiatry ; 7(1): 64-77, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31860457

RESUMO

BACKGROUND: Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment. METHODS: We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change. FINDINGS: Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m2 (-0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035). INTERPRETATION: Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians. FUNDING: UK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre.


Assuntos
Antipsicóticos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metanálise em Rede , Esquizofrenia , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Ganho de Peso/efeitos dos fármacos
17.
Aging Dis ; 10(6): 1311-1319, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788342

RESUMO

As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

18.
Cochrane Database Syst Rev ; 10: CD004052, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31621892

RESUMO

BACKGROUND: Bipolar disorder is a severe and common mental disorder where patients experience recurrent symptoms of elevated or irritable mood, depression, or a combination of both. Treatment is usually with psychiatric medication, including mood stabilisers, antidepressants and antipsychotics. Valproate is an effective maintenance treatment for bipolar disorder. However, evidence assessing the efficacy of valproate in the treatment of acute mania is less robust, especially when comparing it to some of the newer antipsychotic agents. This review is an update of a previous Cochrane Review (last published 2003) on the role of valproate in acute mania. OBJECTIVES: To assess the efficacy and tolerability of valproate for acute manic episodes in bipolar disorder compared to placebo, alternative pharmacological treatments, or a combination pharmacological treatments, as measured by the treatment of symptoms on specific rating scales for individual episodes in paediatric, adolescent and adult populations. SEARCH METHODS: We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 28 September 2018. We had also conducted an earlier search of these databases in the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all years to 6 June 2016). We also searched the World Health Organization (WHO) trials portal (ICTRP) and clinicaltrials.gov in September 2018, to identify any additional unpublished or ongoing studies. SELECTION CRITERIA: Single- and double-blind, randomised controlled trials comparing valproate with placebo, alternative antimanic treatments, or a combination of pharmacological treatments. We also considered studies where valproate was used as an adjunctive treatment in combination with another agent separately from studies where it was used in monotherapy. We included male and female patients of all ages and ethnicity with bipolar disorder. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and methodological quality assessment. For analysis, we used the odds ratio (OR) for binary efficacy outcomes and the mean difference (MD) or standardised mean difference (SMD) for continuously distributed outcomes. MAIN RESULTS: Twenty-five trials (3252 participants) compared valproate with either placebo or alternative antimanic treatments to alleviate the symptoms of acute mania. For efficacy, our primary outcome was response rate. For tolerability, our primary outcome was the number of participants with any adverse effect. This meta-analysis included studies focusing on children, adolescents, as well as adults with a range of severity of manic symptoms. The majority of studies focused on adult men and women (aged 18 and above), were conducted in inpatient settings and completed in the US. Five studies in this review focused on children and adolescents (aged 18 and under) so that the review covers an age range from 3 - 82 years. Seven studies contained outpatient participants in some form. Nine studies included data that has been collected outside the US, namely Iran (4 studies), India (3 studies), China (1 study), or across several international countries (1 study).In adults, high-quality evidence found that valproate induces a slightly higher response compared to placebo (45% vs 29%, OR 2.05, 95% CI 1.32 to 3.20; 4 studies, 869 participants). Moderate-quality evidence found there was probably little or no difference in response rates between valproate and lithium (56% vs 62%, OR 0.80, 95% CI 0.48 to 1.35; 3 studies, 356 participants). In adults, low-quality evidence found there may be little or no difference in response rate between valproate and olanzapine (38% vs 44%, OR 0.77, 95% CI 0.48 to 1.25; 2 studies, 667 participants).In the children and adolescent population, the evidence regarding any difference in response rates between valproate and placebo was uncertain (23% vs 22%, OR 1.11, 95% CI 0.51 to 2.38; 1 study, 151 participants, very low-quality evidence). Low-quality evidence found that the response rate of participants receiving valproate may be lower compared to risperidone (23% vs 66%, OR 0.16, 95% CI 0.08 to 0.29; 1 study, 197 participants). The evidence regarding any difference in response rates between valproate and lithium was uncertain (23% vs 34%, OR 0.57, 95% CI 0.31 to 1.07; 1 study, 197 participants, very low-quality evidence).In terms of tolerability in adults, moderate-quality evidence found that there are probably more participants receiving valproate who experienced any adverse events compared to placebo (83% vs 75%, OR 1.63, 95% CI 1.13 to 2.36; 3 studies, 745 participants). Low-quality evidence found there may be little or no difference in tolerability between valproate and lithium (78% vs 86%, OR 0.61, 95% CI 0.25 to 1.50; 2 studies, 164 participants). We did not obtain primary tolerability outcome data on the olanzapine comparison.Within the children and adolescent population, the evidence regarding any difference between valproate or placebo was uncertain (67% vs 60%, OR 1.39, 95% CI 0.71 to 2.71; 1 study, 150 participants, very low-quality evidence). We did not obtain primary tolerability outcome data on the lithium or risperidone comparisons. AUTHORS' CONCLUSIONS: There is evidence that valproate is an efficacious treatment for acute mania in adults when compared to placebo. By contrast, there is no evidence of a difference in efficacy between valproate and placebo for children and adolescents. Valproate may be less efficacious than olanzapine in adults, and may also be inferior to risperidone as a monotherapy treatment for paediatric mania. Generally, there is uncertain evidence regarding whether valproate causes more or less side effects than the other main antimanic therapies. However, evidence suggests that valproate causes less weight gain and sedation than olanzapine.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31645364

RESUMO

INTRODUCTION: Matching treatment to specific patients is too often a matter of trial and error, while treatment efficacy should be optimised by limiting risks and costs and by incorporating patients' preferences. Factors influencing an individual's drug response in major depressive disorder may include a number of clinical variables (such as previous treatments, severity of illness, concomitant anxiety etc) as well demographics (for instance, age, weight, social support and family history). Our project, funded by the National Institute of Health Research, is aimed at developing and subsequently testing a precision medicine approach to the pharmacological treatment of major depressive disorder in adults, which can be used in everyday clinical settings. METHODS AND ANALYSIS: We will jointly synthesise data from patients with major depressive disorder, obtained from diverse datasets, including randomised trials as well as observational, real-world studies. We will summarise the highest quality and most up-to-date scientific evidence about comparative effectiveness and tolerability (adverse effects) of antidepressants for major depressive disorder, develop and externally validate prediction models to produce stratified treatment recommendations. Results from this analysis will subsequently inform a web-based platform and build a decision support tool combining the stratified recommendations with clinicians and patients' preferences, to adapt the tool, increase its' reliability and tailor treatment indications to the individual-patient level. We will then test whether use of the tool relative to treatment as usual in real-world clinical settings leads to enhanced treatment adherence and response, is acceptable to clinicians and patients, and is economically viable in the UK National Health Service. DISCUSSION: This is a clinically oriented study, coordinated by an international team of experts, with important implications for patients treated in real-world setting. This project will form a test-case that, if effective, will be extended to non-pharmacological treatments (either face-to-face or internet-delivered), to other populations and disorders in psychiatry (for instance, children and adolescents, or schizophrenia and treatment-resistant depression) and to other fields of medicine.

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