Ole Jakob Storebø

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 Association Between ADHD and Antisocial Personality Disorder (ASPD): A Review

Objective: Children with ADHD have an increased risk of later developing personality disorders and criminal behavior. The object of the present review is to analyze the associations between ADHD and antisocial personality disorder (ASPD). Method: A review of literature was done using EMBASE, PsycINFO, and Medline databases. Results: Eighteen prospective studies (n = 5,501) showed that ADHD with and without comorbid conduct disorder (CD) is a strong predictor for the risk of later development of antisocial personality disorder (ASPD). Some of the 13 cross-sectional/retrospective studies (n = 2,451) suggested that ADHD and CD might be a separate subtype of ADHD, that especially impulsivity in ADHD is a predictor for later development of ASPD, or that callous-unemotional traits in the ADHD children are called for a risk factor for later ASPD. Conclusion: There is an increased risk for children with ADHD with or without comorbid CD to develop later onset of antisocial personality disorder.

Is ADHD an early stage in the development of borderline personality disorder

Abstract Background: Several studies report associations between adults with borderline personality disorder (BPD) and a history of attention-deficit hyperactivity (ADHD) symptoms in childhood. Aims: To explore the association between BPD and a history of ADHD in childhood. Method: A comprehensive search of EMBASE, PsychInfo and Medline and hand-searching yielded 238 “hits”. Fifteen articles were found to have sufficient quality and relevance to be included in the final review. The data were considered in six possible explanatory psychopathological models of the association between ADHD and BPD. Results: Most of the 15 articles showed a statistical association between ADHD and BPD. The data, most strongly provided a basis for the hypotheses that ADHD is either an early developmental stage of BPD, or that the two disorders share an environmental and genetic aetiology. Furthermore, one of the disorders seems to give a synergic effect, reinforce the other or complicate the disorders. In one prospective study, the risk factor for children with ADHD to develop BPD was as high as odds ratio 13.16. No studies have looked at treatment of ADHD as a mediator of the risk for BPD. Conclusions: Many studies pointed at shared aetiology or the risk for development of one disorder, when the other disorder is present. The data do not evaluate how treatment factors or other factors mediate the risk or how overlap of diagnostic criteria adds to the statistical association. More research is much needed, in particular studies looking at early intervention and which treatment of ADHD that might prevent later development of BPD.

Association Between Insecure Attachment and ADHD: Environmental Mediating Factors

Objective: Psychological theories have postulated an association between insecure attachment and ADHD. The objective of this study is to investigate possible association between insecure attachment and ADHD in children and adults. Method: Review of literature was performed using the PsycINFO, Medline, and EMBASE databases. Results: Twenty-nine studies were included in the review. Overall, the studies showed that parental attachment problems and environmental mediating factors were significantly associated with childhood ADHD. Adults with ADHD had a much higher incidence of insecure attachment styles than reported in the general population. Conclusion: There seems to be a clear association between ADHD and insecure attachment. It is likely that early intervention in the form of parent training and pharmacological treatment may prevent development of attachment problems. But such studies have not been carried out. Furthermore, adults with ADHD might need treatment for their lack of attachment competences as well. More research on this topic is much needed.

Social-Skills and Parental Training plus Standard Treatment versus Standard Treatment for Children with ADHD – The Randomised SOSTRA Trial

Objective To investigate the effects of social-skills training and parental training programme for children with attention deficit hyperactivity disorder (ADHD). Methods We conducted a randomized two-armed, parallel group, assessor-blinded superiority trial consisting of social-skills training plus parental training and standard treatment versus standard treatment alone. A sample size calculation showed at least 52 children should be included for the trial with follow up three and six months after randomization. The primary outcome measure was ADHD symptoms and secondary outcomes were social skills and emotional competences. Results 56 children (39 boys, 17 girls, mean age 10.4 years, SD 1.31) with ADHD were randomized, 28 to the experimental group and 27 to the control group. Mixed-model analyses with repeated measures showed that the time course (y  =  a + bt + ct2) of ADHD symptoms (p = 0.40), social skills (p = 0.80), and emotional competences (p = 0.14) were not significantly influenced by the intervention. Conclusions Social skills training plus parental training did not show any significant benefit for children with attention deficit hyperactivity disorder when compared with standard treatment. More and larger randomized trials are needed. Trial Registration ClinicalTrials.gov NCT00937469

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.

The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder

A Cochrane systematic review on immediate-release methylphenidate for adults with attention deficit hyperactivity disorder (ADHD) was withdrawn from the Cochrane Library on 26 May 2016 after substantial criticism of its methods and flawed conclusions. Retraction of scientific papers on this basis is unusual but can be necessary. We provide a summary of the criticism that led to the withdrawal. We detail the methodological flaws of the withdrawn Cochrane systematic review and general issues of bias and shortcomings of the included ADHD trials: cross-over designs compared with parallel-group designs, exclusion of participants with psychiatric comorbidity, absence of ‘functional outcomes’ and use of clinical outcomes with limited relevance, short trial duration and small trial populations, broken blinding caused by easily recognisable side effects, combining outcome assessments by trial investigators and participants, outcome reporting bias, poor evaluation of cardiovascular and psychiatric harms and conflicts of interest of trialists and systematic reviewers. The withdrawal of the Cochrane systematic review signals recognition of previous unreliable clinical ADHD research. We conclude that clinical trials of immediate-release methylphenidate in adults with ADHD are of very low quality. We urgently need well-conducted long-term trials free of bias to assess the benefits and harms of central stimulant treatment in adult ADHD.

Evidence on methylphenidate in children and adolescents with ADHD is in fact of ‘very low quality’

Banaschewski and colleagues from the European Attention Deficit Hyperactivity Disorder (ADHD) guideline group make a number of critical comments regarding our systematic review on methylphenidate for children and adolescents with ADHD. In this article, we present our views, showing that our trial selection was not flawed and was undertaken with scientific justification. Similarly, our data collection and interpretation was systematic and correct. We have followed a sound methodology for assessing risk of bias and our conclusions are not misleading. We acknowledge that different researchers might make risk of bias judgments at higher or lower thresholds, but we have been consistent and transparent in applying our pre-defined and per reviewed protocol. Although we made minor errors, we demonstrate that the effects are negligible and not affecting our conclusions. We are happy to correct such errors and to engage in debate on methodological and ethical issues. In terms of clinical implications, we are advocating that clinicians, patients and their relatives should weight carefully risks and benefits of methylphenidate. Clinical experience seems to suggest that there are people who benefit from this medication. Our systematic review does, however, raise questions regarding the overall quality of the methylphenidate trials.

The evidence base of methylphenidate for children and adolescents with attention-deficit hyperactivity disorder is in fact flawed

In an editorial on our Cochrane systematic review on methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD) [1], Hoekstra and Buitelaar raise several points [2]. We thank them for drawing attention to our review and for agreeing with us that there are several caveats regarding the evidence trying to underpin the use of the drug for ADHD [2]. They also raise several critical comments on our review. Here we shall try to explain our standpoints on inclusion of trials; bias due to vested interests; bias risks derived by lack of blinding; and nocebo.

Methylphenidate for Attention-Deficit/Hyperactivity Disorder-Reply

know about the risks of the procedure. Do the benefits outweigh the risks? Jurors in states with the reasonablepatient standard can ask themselves, “Would I have wanted to know about this risk?” “Would it have affected my decision making?” Drs Drolet and Brower also express concerns about operationalizing the reasonable-patient standard. They argue that each patient’s informational needs are unique and that barriers to understanding this heterogeneity undermine the real-world experience of implementing a common standard. In the courts, the fixed normative reference point for a reasonable patient is what the jury (or, in the United Kingdom, the judge, because medical malpractice cases do not go before a jury) decides after hearing expert medical testimony and after deliberation about what a reasonable patient would deem material to the decision-making process. In clinical practice, there is undoubtedly variation in patients’ informational needs. Nonetheless, it is possible to identify the material information that reasonable patients value in making an intelligent decision, as evidenced by decision aids developed with input from patients and health professionals to support shared decision making.2 The development of decision aids has shown that complex and even anxiety-producing information can be effectively communicated to patients, a factor cited in the Montgomery case for why the risk of shoulder dystocia was not shared with the patient. Thus, decision aids can help address barriers to patient-physician communication and reduce variation in what physicians deem reasonable to communicate to patients. In the physician-based standard for informed consent, there are no fixed normative reference points. Still, physicians need training.3 Additionally, there is a need for high-quality informed consent tools like patient decision aids to be integrated into the clinical workflow. In linking informed consent to shared decision making, reasonable-patient standards can be defined and implemented, ensuring that patients receive care aligned with their preferences, values, and goals.