Maria Skoog

Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials

Study question Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? Methods Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. Study answer and limitations The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) −0.77, n=1698), corresponding to a mean difference of −9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD −0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. What this study adds The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. Funding, competing interests, data sharing Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial

BackgroundEvery year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2.Methods/DesignSafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events.DiscussionCerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia.Trial registrationClinicalTrial.gov, NCT01590316

Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial.

BACKGROUND The CLARICOR trial reported that clarithromycin compared with placebo increased all-cause mortality in patients with stable coronary heart disease. This study investigates the effects of clarithromycin versus placebo during 10years follow up. METHODS The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2weeks of clarithromycin 500mg a day versus placebo. 10year follow up was performed through Danish public registers and analysed with Cox regression. RESULTS Clarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10years (HR: 1.19, 95% CI: 1.02-1.38). The increased mortality and morbidity were restricted to patients not on statin at entry (HR: 1.16, 95% CI: 1.04-1.31, and HR: 1.25, 95% CI: 1.03-1.50). The assumption of constant HR during the 10years was violated for cardiovascular death (P=0.01) and cardiovascular death outside hospital (P<0.0005). Analyses of the effects over time showed that clarithromycin increased cardiovascular mortality during the first three years (HR: 1.42, 95% CI: 1.09-1.84) due to increased cardiovascular mortality outside hospital in patients not on statin (HR: 2.36, 95% CI: 1.60-3.50). During the last 4years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88). CONCLUSION Clarithromycin increased mortality due to cardiovascular death outside hospital and cerebrovascular morbidity in patients with stable coronary heart disease who were not on statin. The increased cardiovascular mortality was years later compensated, likely through frailty attrition.

Attachment Competences in Children With ADHD During the Social-Skills Training and Attachment (SOSTRA) Randomized Clinical Trial

Objective: To investigate the effects of social-skills training and a parental training program on children with ADHD as measured by the children’s attachment competences. Method: The SOSTRA trial is a randomized, parallel-group, outcome-assessor-blinded, superiority trial evaluating 8 weeks social-skills training and parental training plus standard treatment versus standard treatment alone for 8- to 12-year old children with ADHD. Results: There were no significant differences in attachment competences at 6 months between the experimental (n = 25) and the control (n = 22) groups (odds ratio = 1.06, 95% confidence interval = [0.31, 3.58], p = .91). In total, 17 children (36%) changed their entry status, 1 (2%) from secure to insecure attachment, while 16 (34%) changed from insecure to secure attachment. Conclusion: The experimental treatment does not seem to affect attachment competences compared with standard treatment alone. Children in the SOSTRA trial improved their attachment competences significantly at 6-month follow-up.

Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial

BACKGROUND Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other. METHODS In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014. FINDINGS Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (p<0·0001). Weight gain was more rapid with quetiapine-ER (p=0·0008), with an adjusted mean weight group difference at week 12 of 3·33 kg (SD 7·23; effect size 0·64; p<0·0001). The HOMA-IR group difference at week 12 favoured aripiprazole (adjusted mean log-transformed group difference 0·259 [SD 0·906]; effect size 0·35; p=0·0060). Akathisia was more common with aripiprazole at week 2 (observed in 34 [60%] of 57 patients; estimated 63·5%) than with quetiapine-ER (15 [30%] of 50; estimated 31·3%; p=0·0021), but not at other timepoints. Sedation proportions did not change significantly over time with either intervention (observed at weeks 2, 4, and 12, respectively, for quetiapine-ER in 43 [83%] of 52, 40 [83%] of 48, and 34 [72%] of 47 patients and for aripiprazole in 49 [89%] of 55, 52 [96%] of 54, and 44 [92%] of 48 patients), and the overall estimated probability combining all timepoints was significantly higher for aripiprazole (97·1%) than for quetiapine-ER (89·2%; p=0·012). In addition to sedation and akathisia, the most common adverse events were tremor (42 [79%] patients in the quetiapine-ER group vs 52 [91%] patients in the aripiprazole group), increased duration of sleep (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]). INTERPRETATION This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment. FUNDING The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.

Osteoprotegerin independently predicts mortality in patients with stable coronary artery disease: The CLARICOR trial

Abstract Objectives. To elucidate the prognostic power of serum osteoprotegerin (OPG) in patients with stable coronary artery disease (CAD). Methods. Serum OPG levels were measured in the CLARICOR trial cohort of 4063 patients with stable CAD on blood samples drawn at randomization. The follow-up was 2.6 years for detailed cardiovascular events and 6 years for all-cause mortality. Results. OPG levels were significantly increased in non-survivors (21%) compared to survivors (median [quartiles] 2092 ng/L [1636; 2800] compared to 1695 ng/L [1322; 2193, p < 0.0001]). The 2.6-year follow-up showed that OPG adds to the prediction of both cardiovascular and all-cause mortality in combination with clinical risk factors (HR [one log10 unit increase] 6.1 [95% CI 2.4–15.6, p = 0.0001]) and HR 6.5 [95% CI 3.4–12.5, p < 0.0001], respectively). Similar, in the 6-year follow-up, OPG was found to be a strong predictor for all-cause mortality. Importantly, OPG remained an independent predictor of mortality even after adjustment for both clinical and conventional cardiovascular risk markers (HR 2.5 [95% CI 1.6–3.9, p < 0.0001]). Conclusions. Serum OPG has a long-lasting independent predictive power as to all-cause mortality and cardiovascular death in patients with stable CAD. Trial registration: ClinicalTrials.gov identifier: NCT00121550.

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

Objectives To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. Methods and findings We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. Conclusion Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found.

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents: assessment of harmful effects in non-randomised studies

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the harmful effects of methylphenidate treatment for children and adolescents with attention deficit hyperactivity disorder (ADHD) in non-randomised studies. 1 Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents assessment of harmful effects in nonrandomised studies (Protocol) Copyright