Craig Whittington

Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data

BACKGROUND Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs. METHODS We did a meta-analysis of data from randomised controlled trials that evaluated an SSRI versus placebo in participants aged 5-18 years and that were published in a peer-reviewed journal or were unpublished and included in a review by the Committee on Safety of Medicines. The following outcomes were included: remission, response to treatment, depressive symptom scores, serious adverse events, suicide-related behaviours, and discontinuation of treatment because of adverse events. FINDINGS Data for two published trials suggest that fluoxetine has a favourable risk-benefit profile, and unpublished data lend support to this finding. Published results from one trial of paroxetine and two trials of sertraline suggest equivocal or weak positive risk-benefit profiles. However, in both cases, addition of unpublished data indicates that risks outweigh benefits. Data from unpublished trials of citalopram and venlafaxine show unfavourable risk-benefit profiles. INTERPRETATION Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. Clinical guideline development and clinical decisions about treatment are largely dependent on an evidence base published in peer-reviewed journals. Non-publication of trials, for whatever reason, or the omission of important data from published trials, can lead to erroneous recommendations for treatment. Greater openness and transparency with respect to all intervention studies is needed.

Early intervention services, cognitive–behavioural therapy and family intervention in early psychosis: systematic review

Background Early intervention services for psychosis aim to detect emergent symptoms, reduce the duration of untreated psychosis, and improve access to effective treatments. Aims To evaluate the effectiveness of early intervention services, cognitive–behavioural therapy (CBT) and family intervention in early psychosis. Method Systematic review and meta-analysis of randomised controlled trials of early intervention services, CBT and family intervention for people with early psychosis. Results Early intervention services reduced hospital admission, relapse rates and symptom severity, and improved access to and engagement with treatment. Used alone, family intervention reduced relapse and hospital admission rates, whereas CBT reduced the severity of symptoms with little impact on relapse or hospital admission. Conclusions For people with early psychosis, early intervention services appear to have clinically important benefits over standard care. Including CBT and family intervention within the service may contribute to improved outcomes in this critical period. The longer-term benefits of this approach and its component treatments for people with early and established psychosis need further research.

Does theory influence the effectiveness of health behavior interventions? Meta-analysis.

OBJECTIVE To systematically investigate the extent and type of theory use in physical activity and dietary interventions, as well as associations between extent and type of theory use with intervention effectiveness. METHODS An in-depth analysis of studies included in two systematic reviews of physical activity and healthy eating interventions (k = 190). Extent and type of theory use was assessed using the Theory Coding Scheme (TCS) and intervention effectiveness was calculated using Hedgess g. Metaregressions assessed the relationships between these measures. RESULTS Fifty-six percent of interventions reported a theory base. Of these, 90% did not report links between all of their behavior change techniques (BCTs) with specific theoretical constructs and 91% did not report links between all the specified constructs with BCTs. The associations between a composite score or specific items on the TCS and intervention effectiveness were inconsistent. Interventions based on Social Cognitive Theory or the Transtheoretical Model were similarly effective and no more effective than interventions not reporting a theory base. CONCLUSIONS The coding of theory in these studies suggested that theory was not often used extensively in the development of interventions. Moreover, the relationships between type of theory used and the extent of theory use with effectiveness were generally weak. The findings suggest that attempts to apply the two theories commonly used in this review more extensively are unlikely to increase intervention effectiveness.

Brief psychological therapies for anxiety and depression in primary care: meta-analysis and meta-regression

BackgroundPsychological therapies provided in primary care are usually briefer than in secondary care. There has been no recent comprehensive review comparing their effectiveness for common mental health problems. We aimed to compare the effectiveness of different types of brief psychological therapy administered within primary care across and between anxiety, depressive and mixed disorders.MethodsMeta-analysis and meta-regression of randomized controlled trials of brief psychological therapies of adult patients with anxiety, depression or mixed common mental health problems treated in primary care compared to primary care treatment as usual.ResultsThirty-four studies, involving 3962 patients, were included. Most were of brief cognitive behaviour therapy (CBT; n = 13), counselling (n = 8) or problem solving therapy (PST; n = 12). There was differential effectiveness between studies of CBT, with studies of CBT for anxiety disorders having a pooled effect size [d -1.06, 95% confidence interval (CI) -1.31 to -0.80] greater than that of studies of CBT for depression (d -0.33, 95% CI -0.60 to -0.06) or studies of CBT for mixed anxiety and depression (d -0.26, 95% CI -0.44 to -0.08). Counselling for depression and mixed anxiety and depression (d -0.32, 95% CI -0.52 to -0.11) and problem solving therapy (PST) for depression and mixed anxiety and depression (d -0.21, 95% CI -0.37 to -0.05) were also effective. Controlling for diagnosis, meta-regression found no difference between CBT, counselling and PST.ConclusionsBrief CBT, counselling and PST are all effective treatments in primary care, but effect sizes are low compared to longer length treatments. The exception is brief CBT for anxiety, which has comparable effect sizes.

The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses

OBJECTIVE We evaluated the inter-rater reliability (IRR) of assessing the quality of evidence (QoE) using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. STUDY DESIGN AND SETTING On completing two training exercises, participants worked independently as individual raters to assess the QoE of 16 outcomes. After recording their initial impression using a global rating, raters graded the QoE following the GRADE approach. Subsequently, randomly paired raters submitted a consensus rating. RESULTS The IRR without using the GRADE approach for two individual raters was 0.31 (95% confidence interval [95% CI] = 0.21-0.42) among Health Research Methodology students (n = 10) and 0.27 (95% CI = 0.19-0.37) among the GRADE working group members (n = 15). The corresponding IRR of the GRADE approach in assessing the QoE was significantly higher, that is, 0.66 (95% CI = 0.56-0.75) and 0.72 (95% CI = 0.61-0.79), respectively. The IRR further increased for three (0.80 [95% CI = 0.73-0.86] and 0.74 [95% CI = 0.65-0.81]) or four raters (0.84 [95% CI = 0.78-0.89] and 0.79 [95% CI = 0.71-0.85]). The IRR did not improve when QoE was assessed through a consensus rating. CONCLUSION Our findings suggest that trained individuals using the GRADE approach improves reliability in comparison to intuitive judgments about the QoE and that two individual raters can reliably assess the QoE using the GRADE system.

Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine: a meta-analysis.

Objectives: To conduct a meta-analysis of randomized placebo-controlled trials (RCTs) of clozapine augmentation with another antipsychotic drug in patient with schizophrenia who partially respond to clozapine and compare the results with the findings of relevant open studies. Methods: A systematic literature search was conducted to identify eligible RCTs. All baseline, posttreatment, and change scores in these trials were included in the meta-analysis. For change in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale total scores, the effect size was calculated, and for the proportion of patients with a reduction in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale scores of 20% or more, the relative risk was calculated. Results: There was a total of 166 participants in the 4 eligible RCTs. Pooling effect sizes across these studies revealed clinically important heterogeneity (I2 = 63.5%). Analyzing by duration accounted for the heterogeneity (I2 = 0%), whereas analyzing by drug did not (I2 = 57.5%). The 2 RCTs lasting 10 weeks or more gave an odds ratio of response to treatment of 4.41 (95% confidence interval, 1.38 to 14.07). In 8 open studies identified, the same pattern of response was seen. The main treatment-emergent side effects reported were extrapyramidal side effects and raised serum prolactin. Conclusions: Augmentation of clozapine with another antipsychotic drug in patients with schizophrenic illness that has partially responded to clozapine is worthy of an individual clinical trial. This trial may need to be longer than the 4 to 6 weeks usually recommended for acute antipsychotic monotherapy.

Memory Deficits in Parkinson's Disease

The purpose of this study was to investigate deficits in recognition, recall, and prospective memory among Parkinson’s disease (PD) patients, and to ascertain whether task difficulty and disease severity moderate these deficits. Comparisons were made between 41 nondemented PD participants, divided into early-stage and advanced-stage groups, and 41 matched controls. PD participants exhibited deficits in recognition, recall, and prospective memory. The advanced-stage PD group produced greater deficits than the early-stage PD group in all tasks, suggesting that these deficits increase in step with overall disease severity. The results of the task difficulty manipulation provide a partial explanation for the inconsistencies in the literature concerning the existence of recognition memory deficits in PD. This research was supported by the Massey University Research Fund Grant 1-0575-67302A, the Massey University Research Equipment Fund Grant 1–0575–98025, and the School of Psychology at Massey University. Parts of this article were presented in 2000 at the annual conference of the British Psychological Society, Winchester, England.

Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: A systematic review and network meta-analysis

Previous meta‐analyses of psychotherapies for child and adolescent depression were limited because of the small number of trials with direct comparisons between two treatments. A network meta‐analysis, a novel approach that integrates direct and indirect evidence from randomized controlled studies, was undertaken to investigate the comparative efficacy and acceptability of psychotherapies for depression in children and adolescents. Systematic searches resulted in 52 studies (total N=3805) of nine psychotherapies and four control conditions. We assessed the efficacy at post‐treatment and at follow‐up, as well as the acceptability (all‐cause discontinuation) of psychotherapies and control conditions. At post‐treatment, only interpersonal therapy (IPT) and cognitive‐behavioral therapy (CBT) were significantly more effective than most control conditions (standardized mean differences, SMDs ranged from −0.47 to −0.96). Also, IPT and CBT were more beneficial than play therapy. Only psychodynamic therapy and play therapy were not significantly superior to waitlist. At follow‐up, IPT and CBT were significantly more effective than most control conditions (SMDs ranged from −0.26 to −1.05), although only IPT retained this superiority at both short‐term and long‐term follow‐up. In addition, IPT and CBT were more beneficial than problem‐solving therapy. Waitlist was significantly inferior to other control conditions. With regard to acceptability, IPT and problem‐solving therapy had significantly fewer all‐cause discontinuations than cognitive therapy and CBT (ORs ranged from 0.06 to 0.33). These data suggest that IPT and CBT should be considered as the best available psychotherapies for depression in children and adolescents. However, several alternative psychotherapies are understudied in this age group. Waitlist may inflate the effect of psychotherapies, so that psychological placebo or treatment‐as‐usual may be preferable as a control condition in psychotherapy trials.

Recognition, intervention, and management of antisocial behaviour and conduct disorders in children and young people: summary of NICE-SCIE guidance

Antisocial behaviour and conduct disorders (including oppositional defiant disorder and conduct disorder) are the most common mental and behavioural problems in children and young people globally, with the frequency increasing in Western countries.1 In the United Kingdom 5% of mental and behavioural problems in children and young people (≤ 18 years) meet criteria for a conduct disorder, as do almost 40% of looked-after children, children who have been abused, and those on child protection or safeguarding registers.2 Conduct disorders are strongly associated with poor performance at school, social isolation, substance misuse, and involvement with the criminal justice system.3 A large proportion of children and young people with a conduct disorder will go on to be antisocial adults with impoverished and destructive lifestyles,3 especially if the conduct problems develop early,4 and a large minority will be diagnosed with antisocial personality disorder.5 Antisocial behaviour and conduct disorders often coexist with other mental health problems, place a heavy personal and economic burden on individuals and society,6 and involve a wide range of health, social care, educational, and criminal justice services. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on recognising and managing antisocial behaviour and conduct disorders in children and young people.7 The guideline was developed jointly with the Social Care Institute for Excellence (SCIE). NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Working safely and effectively Health and social care professionals working with children and young people who present with behaviour suggestive of a conduct disorder, …

Network Meta-Analysis with Competing Risk Outcomes

BACKGROUND Cost-effectiveness analysis often requires information on the effectiveness of interventions on multiple outcomes, and commonly these take the form of competing risks. Nevertheless, methods for synthesis of randomized controlled trials with competing risk outcomes are limited. OBJECTIVE The aim of this study was to develop and illustrate flexible evidence synthesis methods for trials reporting competing risk results, which allow for studies with different follow-up times, and that take account of the statistical dependencies between outcomes, regardless of the number of outcomes and treatments. METHODS We propose a competing risk meta-analysis based on hazards, rather than probabilities, estimated in a Bayesian Markov chain Monte Carlo (MCMC) framework using WinBUGS software. Our approach builds on existing work on mixed treatment comparison (network) meta-analysis, which can be applied to any number of treatments, and any number of competing outcomes, and to data sets with varying follow-up times. We show how a fixed effect model can be estimated, and two random treatment effect models with alternative structures for between-trial variation. We suggest methods for choosing between these alternative models. RESULTS We illustrate the methods by applying them to a data set involving 17 trials comparing nine antipsychotic treatments for schizophrenia including placebo, on three competing outcomes: relapse, discontinuation because of intolerable side effects, and discontinuation for other reasons. CONCLUSIONS Bayesian MCMC provides a flexible framework for synthesis of competing risk outcomes with multiple treatments, particularly suitable for embedding within probabilistic cost-effectiveness analysis.