What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?

The long‐term benefit‐to‐risk ratio of sustained antipsychotic treatment for schizophrenia has recently been questioned. In this paper, we critically examine the literature on the long‐term efficacy and effectiveness of this treatment. We also review the evidence on the undesired effects, the impact on physical morbidity and mortality, as well as the neurobiological correlates of chronic exposure to antipsychotics. Finally, we summarize factors that affect the risk‐benefit ratio. There is consistent evidence supporting the efficacy of antipsychotics in the short term and mid term following stabilization of acute psychotic symptoms. There is insufficient evidence supporting the notion that this effect changes in the long term. Most, but not all, of the long‐term cohort studies find a decrease in efficacy during chronic treatment with antipsychotics. However, these results are inconclusive, given the extensive risk of bias, including increasing non‐adherence. On the other hand, long‐term studies based on national registries, which have lower risk of bias, find an advantage in terms of effectiveness during sustained antipsychotic treatment. Sustained antipsychotic treatment has been also consistently associated with lower mortality in people with schizophrenia compared to no antipsychotic treatment. Nevertheless, chronic antipsychotic use is associated with metabolic disturbance and tardive dyskinesia. The latter is the clearest undesired clinical consequence of brain functioning as a potential result of chronic antipsychotic exposure, likely from dopaminergic hypersensitivity, without otherwise clear evidence of other irreversible neurobiological changes. Adjunctive psychosocial interventions seem critical for achieving recovery. However, overall, the current literature does not support the safe reduction of antipsychotic dosages by 50% or more in stabilized individuals receiving adjunctive psychosocial interventions. In conclusion, the critical appraisal of the literature indicates that, although chronic antipsychotic use can be associated with undesirable neurologic and metabolic side effects, the evidence supporting its long‐term efficacy and effectiveness, including impact on life expectancy, outweighs the evidence against this practice, overall indicating a favorable benefit‐to‐risk ratio. However, the finding that a minority of individuals diagnosed initially with schizophrenia appear to be relapse free for long periods, despite absence of sustained antipsychotic treatment, calls for further research on patient‐level predictors of positive outcomes in people with an initial psychotic presentation.     

The assessment and management of insomnia: an update

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non‐medication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines, “z‐drugs”, melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non‐selective antihistamines. A review of the available research indicates that rigorous double‐blind, randomized, controlled trials are lacking for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demonstrated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized. These interventions can form the basis for systematic, evidence‐based treatment of insomnia in clinical practice. We review this evidence base and highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients with insomnia.     

Treatment of bipolar depression

Antidepressants have insufficient effect in 20-40% of patients treated for depressive disorders. This is particularly true for psychotic and agitated depression. When administered on a long-term basis, antidepressants cause a switch into mania in 25-40% of patients and induce rapid cycling. Classical antipsychotics have exhibited good therapeutic efficacy in the treatment of various forms of depression, especially psychotic and agitated forms, albeit burdened with many, above all extrapyramidal, side effects. When administered over long periods of time, classical antipsychotics may have a depressogenic effect. Second-generation antipsychotics have started to be increasingly used in this indication for a variety of reasons including: their antidepressant effect attributable to raised concentrations of catecholamines in the prefrontal cortex, their impact on serotonin transmission, their antipsychotic effect due to their mode of action including the mesolimbic blockade of dopamine D2 receptors, and the low incidence of extrapyramidal and other side effects. The following text encompasses the results of controlled trials using second-generation antipsychotics in the treatment of acute depressive disorders.     

Treatment of acute agitation in psychotic disorders

Several psychotic disorders, including schizophrenia, may be associated with symptoms of acute agitation and aggression. While drug treatment of agitation is often essential, non-pharmacological interventions, both environmental and behavioral, also play important roles in the complex management of agitated patients. The most extensively used psychotropic drugs are parenteral formulas of conventional antipsychotics and benzodiazepines. Recently, injection forms of two second generation antipsychotics, olanzapine and ziprasidone, have become available. Both drugs have shown adequate efficacy and tolerability in several double-blind trials of intramuscular administration in acutely agitated psychotic patients. Compared to conventional medication, injection forms of the new antipsychotics may have a faster onset of action and more favorable profile of adverse events. Alternative approaches to injection administration include liquid drug formula, orally disintegrating tablets and wafers, treatment initiation with high doses, or rapid dose escalation. Evidence suggests that second-generation antipsychotics should be among the first-line choices in the treatment of agitation in acute psychosis.     

Review and Meta‐analysis of Pharmacotherapy for Binge‐eating Disorder

This study evaluated available controlled treatment studies to determine utility of pharmacotherapy for binge‐eating disorder (BED). The authors identified randomized placebo‐controlled trials testing pharmacotherapy‐only treatments and controlled trials testing pharmacotherapy with psychotherapy treatments. Meta‐analysis was performed on placebo‐controlled trials with data for attrition, remission, and weight loss. Qualitative review was performed on remaining controlled treatment literature. A total of 33 studies were considered of which 14 studies with a total of 1,279 patients were included in the meta‐analysis of pharmacotherapy‐only treatment and 8 studies with a total of 683 patients were included in the qualitative review of pharmacotherapy combined with psychotherapy interventions. No evidence suggested significant differences between medication and placebo for attrition. Evidence suggested that pharmacological treatments have a clinically significant advantage over placebo for achieving short‐term remission from binge eating (48.7% vs. 28.5%) and for weight loss, although weight losses are not substantial. No data exist to allow evaluation of longer‐term effects of pharmacotherapy‐only treatment for BED. Combining medications with psychotherapy interventions failed to significantly enhance binge outcomes, although specific medications (orlistat, topiramate) enhanced weight losses achieved with cognitive behavioral therapy and behavioral weight loss. In summary, BED patients can be advised that certain pharmacotherapies may enhance likelihood of stopping binge eating short term, but that longer‐term effects are unknown. Although some weight loss may occur, it is unlikely to be substantial with available medications. Combining medications with cognitive or behavioral treatments is unlikely to enhance binge outcomes, but specific medications (orlistat, topiramate) may enhance weight losses, albeit modestly.     

Psychological interventions to reduce positive symptoms in schizophrenia: systematic review and network meta‐analysis

Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta‐analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add‐on to antipsychotics. On average, patients were moderately ill at baseline. The network meta‐analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=?0.29; 95% CI: –0.55 to ?0.03), treatment as usual (SMD=?0.30; 95% CI: –0.45 to ?0.14) and supportive therapy (SMD=?0.47; 95% CI: –0.91 to ?0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers’ allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition.     

The impact of severe mental disorders and psychotropic medications on sexual health and its implications for clinical management

Sexual dysfunction often accompanies severe psychiatric illness and can be due to both the mental disorder itself and the use of psychotropic treatments. Many sexual symptoms resolve as the mental state improves, but treatment‐related sexual adverse events tend to persist over time, and are unfortunately under‐recognized by clinicians and scarcely investigated in clinical trials. Treatment‐emergent sexual dysfunction adversely affects quality of life and may contribute to reduce treatment adherence. There are important differences between the various compounds in the incidence of adverse sexual effects, associated with differences in mechanisms of action. Antidepressants with a predominantly serotonergic activity, antipsychotics likely to induce hyperprolactinaemia, and mood stabilizers with hormonal effects are often linked to moderate or severe sexual dysfunction, including decreased libido, delayed orgasm, anorgasmia, and sexual arousal difficulties. Severe mental disorders can interfere with sexual function and satisfaction, while patients wish to preserve a previously satisfactory sexual activity. In many patients, a lack of intimate relationships and chronic deterioration in mental and physical health can be accompanied by either a poor sexual life or a more frequent risky sexual behaviour than in the general population. Here we describe the influence of psychosis and antipsychotic medications, of depression and antidepressant drugs, and of bipolar disorder and mood stabilizers on sexual health, and the optimal management of patients with severe psychiatric illness and sexual dysfunction.     

Safety of 80 antidepressants,antipsychotics, anti‐attention‐deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta‐review of 78 adverse effects

Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis­orders in this age group and are used not infrequently off‐label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta‐review, we systematically searched network meta‐analyses and meta‐analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications – including antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity disorder (ADHD) medications and mood stabilizers – in children and adolescents with mental disorders. We included data from nine network meta‐analyses, 39 meta‐analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti‐ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti‐ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti‐ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta‐review of top‐tier evidence regarding the safety of antidepressants, antipsychotics, anti‐ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.     

Interventions to Improve Adherence in Patients with Immune-Mediated Inflammatory Disorders: A Systematic Review

Background

In patients with immune-mediated inflammatory disorders, poor adherence to medication is associated with increased healthcare costs, decreased patient satisfaction, reduced quality of life and unfavorable treatment outcomes.

Objective

To determine the impact of different interventions on medication adherence in patients with immune-mediated inflammatory disorders.

Design

Systematic review.

Data sources

MEDLINE, EMBASE and Cochrane Library.

Study eligibility criteria for selecting studies

Included studies were clinical trials and observational studies in adult outpatients treated for psoriasis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis or multiple sclerosis.

Study appraisal and synthesis methods

Intervention approaches were classified into four categories: educational, behavioral, cognitive behavioral, and multicomponent interventions. The risk of bias/study limitations of each study was assessed using the GRADE system.

Results

Fifteen studies (14 clinical trials and one observational study) met eligibility criteria and enrolled a total of 1958 patients. Forty percent of the studies (6/15) was conducted in patients with inflammatory bowel disease, half (7/15) in rheumatoid arthritis patients, one in psoriasis patients and one in multiple sclerosis patients. Seven out of 15 interventions were classified as multicomponent, four as educational, two as behavioral and two as cognitive behavioral. Nine studies, of which five were multicomponent interventions, had no serious limitations according to GRADE criteria. Nine out of 15 interventions showed an improvement of adherence: three multicomponent interventions in inflammatory bowel disease; one intervention of each category in rheumatoid arthritis; one multicomponent in psoriasis and one multicomponent in multiple sclerosis.

Conclusion

The assessment of interventions designed for increasing medication adherence in IMID is rare in the literature and their methodological quality may be improved in upcoming studies. Nonetheless, multicomponent interventions showed the strongest evidence for promoting adherence in patients with IMID.     

Quality of life in the long-term treatment and the role of second-generation antipsychotics

Health-related quality of life (QoL) represents important measure of treatment outcome in mental disorders. Numerous studies indicate that QoL of people with schizophrenia and bipolar disorder is similar to that of patients with chronic physical conditions. It has been shown that schizophrenia patients can themselves reliably assess their QoL; in addition to the objective scales various self-reporting instruments are used. Patients with bipolar disorder have QoL consistently higher than patients with schizophrenia and similar to that found in people with unipolar depression. Quality of life can be negatively affected by drug-induced side-effects and subjective treatment response. The second-generation antipsychotics (SGA) have superior efficacy on QoL over classical antipsychotics in approximately half of the studies with schizophrenia; in the other half those groups are comparable. However, in none of the trials novel antipsychotics were inferior. All SGA (clozapine, olanzapine, risperidone, amisulpride, quetiapine, ziprasidone, or remoxipride) have been found to be beneficial for patients well-being. The most investigated drugs that convincingly improve QoL in schizophrenia are olanzapine and risperidone (including depot form). Results of several studies indicate that individual antipsychotics may differ in their effects on QoL, with suggested superiority of olanzapine. In bipolar disorder, SGA consistently showed their superiority over placebo in effects on QoL. The most studied SGA in bipolar disorder is olanzapine. More long-term controlled double-blind trials are needed to definitively uphold superiority and different effects of individual SGA on QoL of patients with schizophrenia and bipolar disorder.     

A meta‐review of “lifestyle psychiatry”: the role of exercise,smoking, diet and sleep in the prevention and treatment of mental disorders

There is increasing academic and clinical interest in how “lifestyle factors” traditionally associated with physical health may also relate to mental health and psychological well‐being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta‐review of the top‐tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta‐analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta‐reviews, and two meta‐analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress‐related disorders, schizophrenia, bipolar disorder, and attention‐deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non‐pharmacological sleep‐focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.     

Long‐term effectiveness of oral second‐generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta‐analysis of direct head‐to‐head comparisons

Second‐generation antipsychotics (SGAs) are recommended for maintenance treatment in schizophrenia. However, comparative long‐term effectiveness among SGAs is unclear. Here we provide a systematic review and meta‐analysis of randomized trials lasting ≥?6 months comparing SGAs head‐to‐head in schizophrenia and related disorders. The primary outcome was all‐cause discontinuation. Secondary outcomes included efficacy and tolerability, i.e., psychopathology, inefficacy‐related and intolerability‐related discontinuation, relapse, hospitalization, remission, functioning, quality of life, and adverse events. Pooled risk ratio and standardized mean difference were calculated using random‐effects models. Across 59 studies (N=45,787), lasting 47.4±32.1 weeks (range 24‐186), no consistent superiority of any SGA emerged across efficacy and tolerability outcomes. Regarding all‐cause discontinuation, clozapine, olanzapine and risperidone were significantly (p<0.05) superior to several other SGAs, while quetiapine was inferior to several other SGAs. As to psychopathology, clozapine and olanzapine were superior to several other SGAs, while quetiapine and ziprasidone were inferior to several other SGAs. Data for other efficacy outcomes were sparse. Regarding intolerability‐related discontinuation, risperidone was superior and clozapine was inferior to several other SGAs. Concerning weight gain, olanzapine was worse than all other compared non‐clozapine SGAs, and risperidone was significantly worse than several other SGAs. As to prolactin increase, risperidone and amisulpride were significantly worse than several other SGAs. Regarding parkinsonism, olanzapine was superior to risperidone, without significant differences pertaining to akathisia. Concerning sedation and somnolence, clozapine and quetiapine were significantly worse than some other SGAs. In summary, different long‐term SGA efficacy and tolerability patterns emerged. The long‐term risk‐benefit profiles of specific SGAs need to be tailored to individual patients to optimize maintenance treatment outcomes.     

Two‐year Follow‐up in 21,784 Overweight Children and Adolescents With Lifestyle Intervention

Although randomized controlled trials demonstrated the long‐term efficacy of lifestyle interventions in overweight children, the effects of these interventions in clinical practice under real‐life conditions are largely unknown. One hundred twenty‐nine centers specialized in outpatient pediatric obesity care participated in this quality assessment. All patients presenting before the year 2006 for lifestyle intervention of at least 6 months duration in these institutions were analyzed in a 2‐year follow‐up. A total of 21,784 (45% male) overweight children and adolescents aged 2–20 years (mean BMI 30.4 kg/m², mean SDS‐BMI 2.51, mean age 12.6 years) were included in the analysis. Based on an intention‐to‐treat analysis with variables set back to baseline in lost of follow‐up, 22% of the children reduced their SDS‐BMI after 6 months, 15% after 12 months, and 7% after 24 months, but only in 24, 17, and 8% of children, respectively, complete data were available. In the five treatment centers with the best outcome (518 patients), 83% of the children reduced their overweight after 6 months, 67% after 12 months, and 51% after 24 months. Under real‐life conditions, most treatment centers cannot prove the long‐term efficacy of their interventions due to high drop‐out rate or lack of documentation. Conversely, some institutions achieved a reduction of overweight in nearly the half of their patients 24 months after baseline demonstrating the great heterogeneity in outcome. To improve the effectiveness of lifestyle interventions in real‐life studying, the process and structure quality as well as their long‐term results is urgently needed.     

Therapie mitochondrialer Erkrankungen

Although there have been major advances in understanding the pathogenesis of mitochondrial disorders, current treatment is largely supportive and there is still no cure. A variety of pharmacological agents, vitamins and cofactors, dietary modifications and interventions are under investigation, including attempts to bypass blocks in the respiratory chain, antioxidative effects, supplementation of deficiencies of specific compounds or the removal of noxious metabolites. There is currently no clear evidence supporting the use of any of these interventions. However, replacement of deficient metabolites or elimination of toxic molecules might be beneficial in specific disorders. Moreover, current data suggest that idebenone might be useful in Leber??s hereditary optic neuropathy (LHON). Only few randomized controlled trials had been conducted to date, and future controlled trials are strongly needed to establish the role of therapeutic approaches in homogeneous study populations. Gene therapy is a challenge, but promising experimental approaches are being pursued.     

Psychotherapies for depression in low‐ and middle‐income countries: a meta‐analysis

Most psychotherapies for depression have been developed in high‐income Western countries of North America, Europe and Australia. A growing number of randomized trials have examined the effects of these treatments in non‐Western countries. We conducted a meta‐analysis of these studies to examine whether these psychotherapies are effective and to compare their effects between studies from Western and non‐Western countries. We conducted systematic searches in bibliographical databases and included 253 randomized controlled trials, of which 32 were conducted in non‐Western countries. The effects of psychotherapies in non‐Western countries were large (g=1.10; 95% CI: 0.91‐1.30), with high heterogeneity (I²=90; 95% CI: 87‐92). After adjustment for publication bias, the effect size dropped to g=0.73 (95% CI: 0.51‐0.96). Subgroup analyses did not indicate that adaptation to the local situation was associated with the effect size. Comparisons with the studies in Western countries showed that the effects of the therapies were significantly larger in non‐Western countries, also after adjusting for characteristics of the participants, the treatments and the studies. These larger effect sizes in non‐Western countries may reflect true differences indicating that therapies are indeed more effective; or may be explained by the care‐as‐usual control conditions in non‐Western countries, often indicating that no care was available; or may be the result of the relative low quality of many trials in the field. This study suggests that psychotherapies that were developed in Western countries may or may not be more effective in non‐Western countries, but they are probably no less effective and can therefore also be used in these latter countries.     

Oral and long‐acting antipsychotics for relapse prevention in schizophrenia‐spectrum disorders: a network meta‐analysis of 92 randomized trials including 22,645 participants

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia‐spectrum disorders, but evidence‐based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long‐acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head‐to‐head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random‐effects pairwise and network meta‐analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta‐analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, “high” confidence in the results was found for (in descending order of effect magnitude) amisulpride‐oral (OS), olanzapine‐OS, aripiprazole‐LAI, olanzapine‐LAI, aripiprazole‐OS, paliperidone‐OS, and ziprasidone‐OS. “Moderate” confidence in the results was found for paliperidone‐LAI 1‐monthly, iloperidone‐OS, fluphenazine‐OS, brexpiprazole‐OS, paliperidone‐LAI 1‐monthly, asenapine‐OS, haloperidol‐OS, quetiapine‐OS, cariprazine‐OS, and lurasidone‐OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing “moderate” confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia‐spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best‐performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low‐ and middle‐income countries and constrained‐resource settings, where few medications may be selected. Results from this network meta‐analysis can inform clinical guidelines and national and international drug regulation policies.     

Bias and Sensitivity Analysis When Estimating Treatment Effects from the Cox Model with Omitted Covariates

Summary

Omission of relevant covariates can lead to bias when estimating treatment or exposure effects from survival data in both randomized controlled trials and observational studies. This paper presents a general approach to assessing bias when covariates are omitted from the Cox model. The proposed method is applicable to both randomized and non‐randomized studies. We distinguish between the effects of three possible sources of bias: omission of a balanced covariate, data censoring and unmeasured confounding. Asymptotic formulae for determining the bias are derived from the large sample properties of the maximum likelihood estimator. A simulation study is used to demonstrate the validity of the bias formulae and to characterize the influence of the different sources of bias. It is shown that the bias converges to fixed limits as the effect of the omitted covariate increases, irrespective of the degree of confounding. The bias formulae are used as the basis for developing a new method of sensitivity analysis to assess the impact of omitted covariates on estimates of treatment or exposure effects. In simulation studies, the proposed method gave unbiased treatment estimates and confidence intervals with good coverage when the true sensitivity parameters were known. We describe application of the method to a randomized controlled trial and a non‐randomized study.     

Clinical utility of ICD‐11 diagnostic guidelines for high‐burden mental disorders: results from mental health settings in 13 countries

In this paper we report the clinical utility of the diagnostic guidelines for ICD‐11 mental, behavioural and neurodevelopmental disorders as assessed by 339 clinicians in 1,806 patients in 28 mental health settings in 13 countries. Clinician raters applied the guidelines for schizophrenia and other primary psychotic disorders, mood disorders (depressive and bipolar disorders), anxiety and fear‐related disorders, and disorders specifically associated with stress. Clinician ratings of the clinical utility of the proposed ICD‐11 diagnostic guidelines were very positive overall. The guidelines were perceived as easy to use, corresponding accurately to patients’ presentations (i.e., goodness of fit), clear and understandable, providing an appropriate level of detail, taking about the same or less time than clinicians’ usual practice, and providing useful guidance about distinguishing disorder from normality and from other disorders. Clinicians evaluated the guidelines as less useful for treatment selection and assessing prognosis than for communicating with other health professionals, though the former ratings were still positive overall. Field studies that assess perceived clinical utility of the proposed ICD‐11 diagnostic guidelines among their intended users have very important implications. Classification is the interface between health encounters and health information; if clinicians do not find that a new diagnostic system provides clinically useful information, they are unlikely to apply it consistently and faithfully. This would have a major impact on the validity of aggregated health encounter data used for health policy and decision making. Overall, the results of this study provide considerable reason to be optimistic about the perceived clinical utility of the ICD‐11 among global clinicians.     

Vitamin D and overall mortality

Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of genes. Several meta‐analyses of epidemiological studies support the evidence that low vitamin D serum level, which is highly prevalent worldwide, could be a ‘new’ risk factor for many chronic diseases including cancer, and for all‐cause mortality. A meta‐analysis in healthy subjects suggested that current doses of vitamin D supplements could be associated with decrease in total mortality rates. However, these associations are insufficient to establish causality between vitamin D and all‐cause mortality. Furthermore, long‐term health effects of high doses of vitamin D, that is, prolonged supplementation and association with different baseline vitamin D levels, remain to be investigated. Several trials are ongoing but population‐based, placebo‐controlled randomized trials with total mortality as the main endpoint should be planned to confirm a real beneficial effect of vitamin D for non‐skeletal diseases and to prove causality.     

Trends in publications regarding evidence-practice gaps: A literature review

Background

Well-designed trials of strategies to improve adherence to clinical practice guidelines are needed to close persistent evidence-practice gaps. We studied how the number of these trials is changing with time, and to what extent physicians are participating in such trials.

Methods

This is a literature-based study of trends in evidence-practice gap publications over 10 years and participation of clinicians in intervention trials to narrow evidence-practice gaps. We chose nine evidence-based guidelines and identified relevant publications in the PubMed database from January 1998 to December 2007. We coded these publications by study type (intervention versus non-intervention studies). We further subdivided intervention studies into those for clinicians and those for patients. Data were analyzed to determine if observed trends were statistically significant.

Results

We identified 1,151 publications that discussed evidence-practice gaps in nine topic areas. There were 169 intervention studies that were designed to improve adherence to well-established clinical guidelines, averaging 1.9 studies per year per topic area. Twenty-eight publications (34%; 95% CI: 24% - 45%) reported interventions intended for clinicians or health systems that met Effective Practice and Organization of Care (EPOC) criteria for adequate design. The median consent rate of physicians asked to participate in these well-designed studies was 60% (95% CI, 25% to 69%).

Conclusions

We evaluated research publications for nine evidence-practice gaps, and identified small numbers of well-designed intervention trials and low rates of physician participation in these trials.