The Elisabeth d'Ornano Association for ADHD

The prestigious American magazine specializing in child and adolescent psychiatry, published in its May 2009 issue three articles of great interest in connection with Attention Deficit and Hyperactivity Disorder (ADHD) and an editorial on the matter. All of them are summarized below, with the exception of the editorial, which because of its great importance, we reproduce in full:

THE FIRST: "The MTA at 8 Years: Prospective Follow-up of Children Treated for Combined-Type ADHD in a Multisite Study

In this article, Molina and colleagues give us an update of the MTA study conducted years ago in children who had been diagnosed with ADHD and that received different types of treatment (Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder) . This was performed at 8 years after the start of the study and monitored patients during those 8 years, at a time when participants were adolescents between 13 and 18 years.

In the original MTA study, 579 boys between 7 and 9.9 years of age were distributed across different treatment areas during 14 months:

• Treatment with systematic Methylphenidate
• Multi-Behavioral Therapy
• Combination of both (medication + behavioral therapy)
• Common Community Care

This article provides the results of the evolution of the boys who have been followed for 8 years. As in the follow-up after 3 years, at 6 to 8 years participants with ADHD did not differ depending on the treatment they received. There were no significant differences in academic performance, history of police arrests, psychiatric or other clinical variables. The authors emphasize that, despite the initial improvement in symptoms, patients with ADHD of combined type continued showing a significant deterioration over the course of adolescence. In addition, the overall result was predicted based on the best clinical presentation at the beginning (including severity of the symptoms of ADHD, conduct problems, intellectual level, social factors, and initial response to treatment) that depended on the type of treatment they received.

In the second article: " Medication Adherence in the MTA: Saliva Methylphenidate Samples Versus Parent Report and Mediating Effect of Concomitant Behavioral Treatment ", Jensen and colleagues evaluated the discrepancy between the information about the adherence to treatment (therapeutic compliance) from parent reports and from the physiological measures used in 254 MTA study participants. Although 89.8% of parents reported that their child adequately complied with medication, nearly one quarter of the saliva samples indicated that this was not the case and found that 24.8% of participants showed no adhesion in 50% or more of the salivary analysis. In this case, the authors found no significant associations with demographic factors.

The third article, " Clinical Responses to Atomoxetine in Attention-Deficit/Hyperactivity Disorder: The Integrated Data Exploratory Analysis (IDEA) Study, unrelated to the MTA study, Newcorn and his colleagues present a meta-analysis of 6 randomized trials with atomoxetine for treating ADHD, with a total of 618 participants. The data indicate that the overall response is bimodal, meaning that 47% greatly improved while 40% did not respond. No single factor at the start of the study could predict the response to treatment. Instead they only improvement in the 4th week of treatment predicted subsequent improvement, leading the authors to suggest that clinicians should consider increasing the dose or change the drug in patients who have not shown improvement at a week.

EDITORIAL: 8-Year Follow-up of the MTA Sample By: Philip L. Hazell, PhD.

(Given the importance of content, we included the editorial in its entirety).

A Dance to the Music of Time is the collective title given to a 12-volume series of novels by English author Anthony Powell that spans the period 1914-1971 and involves more than 300 characters. The work is notable for the way Powell advances the narrative while, at the same time, developing further background to the story through reminiscences of the narrator and conversations between the characters.

Reporting of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) is unfolding in a similar fashion. The MTA started with 579 children aged between 7 and 9.9 years who were randomized to receive one of 4 treatment conditions for 14 months. At the completion of the randomized phase of the trial, participating children and their families were free to resume or initiate treatment under the supervision of community clinicians. Their progress has been followed by the MTA study team. Eight primary articles have advanced the narrative by reporting the main findings of the study at successive waves of follow-up, whereas supplementary articles have developed the background to these main findings. Overall, more than 70 articles have been published on the MTA data set to date, creating a challenge for those wishing to keep the myriad of findings from this study in focus. Readers are directed to two recent articles that seek to review and integrate the MTA literature.This issue of the Journal includes a primary article reporting key outcomes at 6 and 8 years, and a supplementary article on the level of agreement between parental accounts of their child’s adherence to medication and objective assessment of adherence through salivary assay for methylphenidate.

Less than 2 years have passed since the publication of the MTA 3-year follow-up data. This was the first in the sequence of primary articles to show that differences in key outcomes attributable to treatment group assignment during the first 14 months of the trial had vanished. The authors were careful to point out that the study had not been designed to demonstrate benefits of the randomized treatments beyond 14 months. After all, in the intervening 22 months, under the supervision of community clinicians, the treatment received by the participants available to follow-up had grown to look not identical but similar. Gradual extinction of the effect of assigned treatment as evaluated by intent-to-treat analyses was predicted after the 24-month follow-up. Nevertheless, the authors of the article in this issue of the Journal tested the hypothesis that there may be a sleeper effect, with the benefits of assigned treatment emerging again later in development. A betting person would give short odds against this being the case, and they are correct. There were no differences between the four assigned treatment groups after 6 and 8 years on repeated measures of psychiatric symptoms, academic function, and social functioning. Nor were there differences on new measures salient to adolescence such as grade point average, arrest by the police, or psychiatric hospitalization. The minority of participants who continued with medication at 8 years was at no clear advantage over those who did not, but as the study was no longer controlled, the finding should be interpreted with caution. Fresh attempts to elucidate the mechanism underlying the convergence in outcome of the four assigned treatment groups are unwarranted, given the effort already directed to the interpretation of the convergence at 3-year follow-up.3 We accept that the absence of a sleeper effect is a reflection of the reality and not the consequence of bias in the study. The authors are correct in their statement that it is purely speculative whether persistence of intensive treatment beyond 14 months would have led to sustained differences between the assigned treatments.

The article by Molina et al. reports two secondary analyses. The first involved the grouping of participants not by assigned treatment but according to trends in attention-deficit/hyperactivity disorder (ADHD) symptoms from baseline through 14, 24, and 36 months, as described by Swanson et al.8 Evaluable data were available for 485 participants. On first pass, it may seem that an initial large improvement in ADHD symptoms that then plateaus over 36 months is associated with more favorable clinical, academic, and social outcomes after 8 years than other trends in ADHD symptoms, such as slow gradual improvement or initial improvement followed by deterioration. This, however, may be an artifact arising from the fact that participants with an initial and sustained improvement in ADHD symptoms had milder problems at baseline than other MTA participants. The mundane interpretation is that patients with milder problems in middle childhood are likely to continue to have milder problems in mid-adolescence. An additional analysis involved the comparison of MTA participants with a sample of local normal controls matched for age and sex distribution. Although the MTA participants showed improvement from baseline in clinical, academic, and social measures, their scores remained significantly different from those of the normal controls. The finding confirms previous research that has demonstrated symptomatic, if not syndromal, persistence of ADHD into late adolescence. It also confirms that treatments for ADHD, like those for diabetes or asthma, even when highly structured and intense, provide symptomatic improvement, not a cure.

The second MTA article in this issue of the Journal reports that one quarter of participants in the two medication arms of the study were inadequately adherent with treatment during the 14-month randomized phase of the trial.5 Furthermore, contemporaneous reports by parents substantially overestimated adherence. The reader should take these data with a grain of salt, as saliva samples were inconsistently obtained, making the definition of physiological adherence somewhat arbitrary. However, the data do point to unplanned variability in treatment, even in the intensive first 14 months of the study. Why was there a discrepancy in the estimates of adherence obtained by parental report and by analysis of the saliva samples? My guess is that parents were simply unaware that their children were not compliant. The participants themselves may have had a part to play. At age 10 years, if you had to make a choice between getting in trouble from your parents for not taking your medication, or running the risk of having your fib detected years later, what would you have done? We will never know, but one wonders whether there was even poorer adherence to medication in the nonexperimental community care arm of the study. Perhaps this contributed to the lower efficacy of treatment in the community care group, even in the face of higher prescribed (but not necessarily ingested) doses of medication.

The fact that the 6- and 8-year follow-up article includes both primary and secondary analyses signals a departure from the pattern established in previous MTA articles. In the future, there will be less attention given to analyses based on the four assigned treatment groups. The emphasis will shift to the reporting of a high-quality cohort study involving subjects who met criteria for ADHD in middle childhood, shared a common experience of participation in the acute phase of the MTA, and have subsequently followed varying trajectories. We could liken them to the characters of A Dance to the Music of Time, who were exposed to a common and binding experience (in their case, the impact of World War II) and then moved on through the vicissitudes of marriage, work, aging, and ultimately death.