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The opening session of MoM VII highlighted the consideration of ADHD as a long-term disorder, presenting longitudinal research into the associates and treatment of ADHD.

The Multimodal Treatment of ADHD (MTA) study

Professor Scott H Kollins (Duke University, North Carolina, USA) gave a comprehensive overview of the MTA study, reviewing the rationale behind the initial concept of the research and highlighting key findings.

MTA study – initial design1

The MTA study was a multisite co-operative agreement sponsored by the National Institute of Mental Health.1 The study comprised four comprehensively managed treatment groups administered over a 14-month period:

  1. Medication (n=144): 1-month blind titration with methylphenidate, open titration with other drugs if necessary and monthly maintenance visits with dose adjustment1
  2. Psychosocial (behavioural) (n=144): parent training, teacher consultations, 8-week summer treatment programme, behavioural specialist in the classroom1
  3. Combined (n=144): 1 and 2 combined1
  4. Community care (n=144): treated as per local community standard.1

A comprehensive assessment battery was planned to take place at baseline, 3 months, 9 months, 14 months (MTA treatment endpoint) and 24 months (10-month follow-up), to support analyses of effects of severity, comorbidity, sex, socioeconomic status, ethnicity, parental psychopathology and domains of dysfunction on treatment outcome, palatability and compliance.1

The MTA study was initiated to understand the impacts of the different treatments/combinations of treatments on the domains of child functioning, and under what circumstances (and with what child characteristics) these impacts are experienced: for how long, and to what extent.2

Key results at 14 months (MTA treatment endpoint), as selected by Professor Kollins, indicated that:

  • The Medication and Combined groups performed significantly better than the Psychosocial or Community care groups in terms of improved parent- and teacher-reported core symptoms3
  • The Combined group was superior to the Psychosocial group or Community care group in terms of improved oppositional/aggressive symptoms, internalising symptoms, social skills and parent–child relations3
  • Behavioural treatment yielded better outcomes than Community care in children with anxiety disorders versus those without4
  • Treatment acceptance/attendance was particularly important for outcomes of the Medication group.4

However, follow-up assessments undertaken after the MTA treatment endpoint (when patients received random, naturalistic treatment) indicated that the groups with the greatest improvements at the end of the 14-month MTA treatment period (Medication and Combination) deteriorated, whilst the other two groups (Psychosocial and Community care) did not.5

  • Changes in medication use after the 14-month MTA treatment period appeared to mediate the 14- to 24-month change in ADHD symptoms, with those that reported stopping medication showing the largest deterioration.5

Professor Kollins concluded that stimulant medication can significantly reduce ADHD symptoms, but only when carefully and comprehensively managed; with behavioural therapy an important component of an effective ADHD treatment plan to help mitigate symptoms/impairments not optimally managed by medication (particularly for certain patient subgroups, such as those with anxiety disorder). Notably, long-term and consistent treatment is associated with better outcomes. However, Professor Kollins noted that as the therapies administered during the MTA study are very carefully and comprehensively managed, it is important to consider how such interventions can be relevant to/implemented in the real world. In addition, it is possible that the biggest predictors of treatment outcome may not be related to the treatment per se; but rather to characteristics of the patient and initial response to treatment. Furthermore, children with ADHD may be at significant risk for adverse outcomes many years after initial treatment.

In a commentary of the MTA study findings, Professor Jan K Buitelaar (Radboud University Medical Center, Nijmegen, Netherlands) noted that the evidence for long-term advantages of medication was limited beyond symptom control (with advantages in social functioning, academic achievement, employment status and psychiatric outcomes unclear). Furthermore, Professor Buitelaar highlighted that clinical decisions regarding starting, continuing and stopping medication for patients with ADHD should be made on an individual basis. Medication-free periods should be implemented to regularly assess the need for, and ongoing benefit of, medication.

What can Danish and Swedish registry studies tell us about ADHD?

Professor Henrik Larsson (Karolinska Institutet, Sweden) discussed the opportunities held by longitudinal Swedish and Danish registries to study the adverse health outcomes of ADHD and the real-world effectiveness of ADHD medications on such outcomes. To illustrate this, Professor Larsson presented such research into the following adverse outcomes associated with ADHD: mortality and accidents; criminality; and suicidal behaviours. Although longitudinal studies offer benefits such as large sample sizes, long time scales, and information on health outcomes related to the general public; they must be considered in the light of several limitations. These include the limited observational design within a specific demographic (i.e. within those people whose information is registered); and incomplete data presentation (e.g. lack of follow-up data).

Mortality and accidents

  • A Danish Registry study (n=1.92 million children [n=32,061 with ADHD]) found that there was a two-fold increased risk of mortality in individuals with ADHD versus those without (mortality rate [n=5,580 individuals died]: 5.85 vs 2.21, respectively; p<0.0001)6
    • The excess mortality in ADHD was found to be largely driven by deaths from unnatural causes, such as accidents6
  • A within-individual analysis of a Swedish Patient Register (n=17,408 individuals with ADHD) indicated that in males, treatment with ADHD medication reduced the rate of accidents by 58% (hazard ratio 0.41; 95% confidence interval [CI] 0.23–0.75).7

Criminality

  • Criminal conviction data (Danish National Crime Register) collected from a clinical sample of Danish children with ADHD (n=206) indicated that in adulthood (mean age 31.1 years), 47% had criminal convictions8
    • Comparison of these data with the general population indicated that all children with ADHD were ~5 times more likely to sustain criminal convictions (rate ratio 5.6; 95% CI 5.2–6.1) in adulthood, and male children with ADHD were ~12 times more likely to sustain violent convictions (rate ratio 11.9; 95% CI 9.8–14.4) in adulthood8
  • A within-individual analysis of a Swedish Patient Register (n=25,656 individuals with ADHD) indicated that compared with non-medicated periods, the criminality rate significantly decreased by 32% (hazard ratio 0.68; 95% CI 0.63–0.73) for men and 41% (hazard ratio 0.59; 95% CI 0.50–0.70) for women when they received ADHD medication.9

Suicidal behaviours

  • Results of a meta-analysis of clinical trials, and a retrospective cohort study, have suggested that an increased risk of suicidal behaviour in individuals with ADHD may be explained by ADHD medications10,11
  • However, a within-individual analysis of a Swedish Patient Register (n=37,936 individuals with ADHD) found that ADHD medication reduced the rate of suicide-related events by 11% (hazard ratio 0.89; 95% CI 0.79–1.00)12
  • Furthermore, a population-based Swedish study (n=51,707 individuals with ADHD identified in patient/prescribed drug registers) revealed evidence for familial risk factors in suicidal behaviours. The highest familial risk was observed among first-degree relatives (attempted suicide: odds ratio [OR] 2.42 [95% CI 2.36–2.49] among parents of individuals with ADHD and OR 2.28 [2.17–2.40] among full siblings of individuals with ADHD; completed suicide: OR 2.24 [2.06–2.43] and OR 2.23 [1.83–2.73], respectively), whereas the risk was considerably lower among more genetically distant relatives (attempted suicide: OR 1.59 [1.47–1.73] among maternal half siblings, OR 1.57 [1.45–1.70] among paternal half siblings, and OR 1.39 [1.35–1.43] among cousins; completed suicide: OR 1.51 [1.08–2.10], OR 2.02 [1.47–2.79], and OR 1.51 [1.36–1.67], respectively). Researchers in this study, and Professor Larsson, concluded that pleiotropic effects could provide an explanation for these findings, possibly reflecting genetic variants associated with impulsivity.13

Professor Per Hove Thomsen (Aarhus University, Denmark) commented that although such registry studies are limited by patient selection (private clinics are not included) and may not convey the full treatment picture of individuals, the large patient numbers and potential to link with other registers to provide additional information are key strengths. Clinical implications of registry study data may include opportunities for early detection of ADHD and early intervention/support for those affected (in homes, schools, workplaces and prisons).

  1. Arnold LE, Abikoff HB, Cantwell DP, et al. National Institute of Mental Health Collaborative Multimodal Treatment study of children with ADHD (the MTA) – Design challenges and choices. Arch Gen Psychiatry 1997; 54: 865-870.
  2. Richters JE, Arnold LE, Jensen PS, et al. NIMH collaborative multisite Multimodal Treatment study of children with ADHD: I. Background and rationale. J Am Acad Child Adolesc Psychiatry 1995; 34: 987-1000.
  3. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56: 1073-1086.
  4. The MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the Multimodal Treatment Study of children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56: 1088-1096.
  5. The MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004; 113: 762-769.
  6. Dalsgaard S, Ostergaard SD, Leckman JF, et al. Mortality in children, adolescents and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190-2196.
  7. Chang Z, Lichtenstein P, D’Onofrio B, et al. Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study. JAMA Psychiatry 2014; 71: 319-325.
  8. Dalsgaard S, Mortensen PB, Frydenberg M, et al. Long-term criminal outcome of children with attention deficit hyperactivity disorder. Crim Behav Ment Health 2013; 23: 86-98.
  9. Lichtenstein P, Halldner L, Zettergvist J, et al. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med 2012; 367: 2006-2014.
  10. Bangs ME, Tauscher-Wisniewski S, Polzer J, et al. Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psych 2008; 47: 209-218.
  11. McCarthy S, Cranswick N, Potts L, et al. Mortality associated with attention-deficit hyperactivity disorder (ADHD) drug treatment: a retrospective cohort study of children, adolescents and young adults using the general practice research database. Drug Saf 2009; 32: 1089-1096.
  12. Chen Q, Sjolander A, Runeson B, et al. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study. BMJ 2014; 348: g3769.
  13. Ljung T, Chen Q, Lichtenstein P, et al. Common etiological factors of attention-deficit/hyperactivity disorder and suicidal behaviour: a population-based study in Sweden. JAMA Psychiatry 2014; 71: 958-964.
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