Jensen 1999 (MTA).

Methods	The Multimodal Treatment Study of Children With ADHD (MTA) is a 14‐month multicentre, randomised, parallel clinical trial with 4 arms Medication Management (MGT) Behavioural Treatment (BEH) Combined Treatment (medication management + behavioural treatment) (COMB) Community Care (the control group) (CC) Phases: for the 2 groups receiving medication there was initially a 28‐day titration period. This titration phase was carried out as a randomised, double‐blind, placebo‐controlled, cross‐over trial with daily switching of MPH doses (placebo, low, middle, and high). Once the delivery of randomly assigned treatments by MTA staff stopped at 14 months, the MTA became an observational study in which participants and families were free to choose their own treatment but in the context of availability and barriers to care existing in their communities. The following follow‐up assessments took place after the RCT 10 months follow‐up (24 months after randomisation), 3‐year follow‐up, 8‐year follow‐up, 10‐year follow‐up In our review we will compare combined treatment with behavioural treatment (RCT) according to our protocol, and look at the medication treatment group as a cohort (observational)
Participants	Titration period (Greenhill 2001) The 28 day RCT (COMB + MGT group) N = 289 (MGT: n = 144, COMB: n = 145), N completed = 256 N not finishing titration = 33. Out of the completers, 198 were assigned to an individually best dose of MPH for the 14‐month trial, the rest on other medication or no medication Main study (Jensen 1999): Number of patients screened: 4541, N included = 579, N randomised to MPH + behavioural treatment (COMB) = 145, MPH: 144, behavioural treatment (BEH): 144, N followed up in each arm: combined treatment (COMB): 142; MPH: 136; behavioural treatment (BEH): 141, number of withdrawals/dropouts in each arm: combined treatment: 3; MPH: 8; behavioural treatment: 3 All the demographic data below is for the COMB, BEH, and MGT group: DSM‐IV diagnosis of ADHD (combined (100%)) Age: mean: 8.4 years (range: 7‐9.9). IQ: mean 100.4 Sex: m: 346, f: 87 MPH‐naïve (177/2) Ethnicity: white: 60.3%, African American: 20.6%, Hispanic: 8.8%, others: 10.4% Country: USA and Canada Comorbidity: anxiety disorder 35.1%, conduct disorder 14.1%, oppositional‐defiant disorder 38.8%, affective disorder 3.5%, tic disorder 10.2%, mania/hypomania 3%) Comedication (not stated) Sociodemographics (130 families on welfare. The population range widely in SES). There were no significant differences in baseline demographics between the 3 groups 10‐month follow‐up (MTA Group 2004) Number of patients followed up in each arm: MGT: 128, COMB: 138, BEH: 139 Age: mean: 8.4 years Sex: m: 322, f: 83 There were no difference from the demographic characteristics of the originally randomised 579 MTA participants and the participants who were assessed in the 10‐month follow‐up. The only statistically significant difference among treatment groups was a trivial difference in age (MHT was 0.3 years older that BEH) 3‐year follow‐up (Jensen 2007) Number of patients followed up in each arm: MPH: 115, combined: 127 Age: mean: 11.7 years (range: 10‐13) Sex: m: 291, f: 78 There were no significant differences in baseline characteristics between participants in the 36‐month assessment and those who were unable to follow 8‐year follow‐up (Molina 2008) Number of patients followed up in each arm: MGT: 101, COMB: 119. 32.5% of the MTA sample were medicated over 50% if days in the past year Age: mean: 16.8 years (range: 13‐16). At the 8‐year assessment, 55 MTA participants had turned 18 years. Only 30% of the sample still fulfilled an ADHD diagnosis. Participants lost to the 8‐year follow‐up, compared with those retained, were more often male, had younger mothers, had less educated parents, had lower parent income, and were more likely to have been on welfare at baseline 10‐year follow‐up, blood pressure (Vitiello 2012) Number of participants followed up in each arm: MGT: 77, COMB: 93. A comparison of patients who were retained through year 10 (n = 346) and those who were not (n = 233) showed a lower proportion of males in the retained group. Furthermore the participants were divided into groups based on the following criteria: never medicated, currently medicated, previously medicated. For the currently medicated group, the number of participants were respectively 184, 184, 108, 50, and 12 for 24 months, 36 months, 72 months, 96 months and 120 months follow‐up. Medication use during the previous 30 days was the criterion for positive medication status) Growth studies: at 24 months assessment (Jensen 2004) For both growth outcomes on the originally assigned, randomised, treatment groups were collected, and furthermore naturalistic subgroups had been made. The naturalistic subgroups consisted of those who had been medicated at all the assessment points up to 24 months (medication use during the previous 30 days was the criterion for positive medication status) and those who had not been medicated at the assessment points. Patients with consistent use of medication (med/med): 255, patients with no use of medication (NoMed/NoMed): 139 COMB: n = 135 mGT, n = 120 Growth studies: up to 36‐month assessment (Swanson 2007) Naturalistic subgroups were established based on the patterns of treatment with stimulant medication. If medication was used within a 30‐day period before the assessment medication status was positive (med) and otherwise negative (no med). If an individual's medication status changed at any assessment point, then they were placed in the inconsistently medicated group. Patients with Med, n = 70. At the baseline at 14‐, 24‐, 36‐month assessment points, respectively, the percentages of medicated children taking methylphenidate were the following: 85.4%, 79.7%, 76.8%, 73.5%. The naturalistic subgroups did not differ on initial size at birth (birth weight), age, parent or teacher ratings of ADHD symptoms, sex, expected adult size (mid‐parent size), welfare status, or maternal smoking Inclusion criteria: Boys and girls between ages of 7‐9.9 years In grades 1 through 4 In residence with the same primary caretaker(s) for the last 6 months or longer Meeting the DSM‐IV criteria for ADHD combined type Exclusion criteria: Child currently in hospital Child currently in another study Below 80 on all WISC‐III scales and on SIBBipolar disorder, psychosis, or personality disorder Chronic serious tics or Tourette syndrome OCD serious enough to require separate treatment Neuroleptic medication in previous 6 months Major neurological or medical illness History of intolerance to MTA medications Ongoing or previously unreported abuse Missed 1/4 of school days in previous 2 months Same classroom as child already in MTA study Parental stimulant abuse in previous 2 years Non‐English speaking primary caretaker Another child in same household in MTA study No telephone Suicidal or homicidal
Interventions	Titration period (Greenhill 2001) Mean MPH dose during titration period: COMB: 32.1 mg/d MGT: 28.9 mg/d. Medication management started with a 4‐day single‐blind, safety lead‐in period, during which participants were exposed to 3 progressively higher daily MPH doses given 3 times daily. This was followed by a 28‐day, double‐blind, daily, switch titration of methylphenidate hydrochloride, using 5 randomly ordered repeats each of placebo, 5 mg, 10 mg, and 15 mg or 20 mg. Cross‐site teams of experienced clinicians blindly reviewed graphs portraying parent and teacher ratings of responses to each of the 4 doses and by consensus selected each child's best dose Compliance: not stated. 29 of the 32 placebo responders had to go back to taking MPH during the maintenance period Main study (Jensen 1999) Participants were randomly assigned to MGT, COMB, or BEH. Mean MPH dosage during the main study: COMB 31.2 mg/d, MGT: 37.8 mg/d. Administration schedule: 3 times a day; breakfast, lunch and in the afternoon. Duration of intervention: 14 months. Treatment compliance: monthly pill counts, intermittent saliva measurements to monitor taking methylphenidate, and encouragement of families to make up missed visits. "the study achieved a high degree of adherence to protocol." NB: for participants not obtaining an adequate response to MPH during titration, alternate medications were titrated openly in the following order until a satisfactory one was found: dextroamphetamine, pemoline, imipramine, and if necessary, others approved by a cross‐site panel. Thus 256 participants successfully completed titration; of these, 198 of 289 participants were assigned to an individually titrated best dose of MPH. 26 were titrated to dextroamphetamine, 32 given no medication because of a robust placebo response 10 months follow‐up (MTA Group 2004) Duration of intervention: 24 months (10 months follow‐up from the 14 months RCT) Treatment compliance: not stated. From end of treatment to the first follow‐up, the percentage of participants on medication decreased for COMB (87% vs 70%) and MPH (93% vs 72%) but increased for behavioural (23% to 38%) 3‐year follow‐up (Jensen 2007) Duration of intervention: 3 years (36 months follow‐up from the 14 months RCT). Treatment compliance: not stated. At 36 months the percentage of participants on medication were 70% for the combined group, 72% for the MPH group and 45% for the behavioural intervention group 8‐year follow‐up (Molina 2009) Duration of intervention: 8 years. Mean MPH dose: 44.93 mg 10‐year follow‐up (Vitello 2012) Duration of intervention: 10 years. Treatment compliance: not stated. Mean MPH dosage: 54.3 mg
Outcomes	Titration period (Greenhill 2001) CLAM (with inattention/overactive (I/O), Aggressive/defiant (A/D) and mixed (I/O + A/D) subscales). Sssessed daily by parents and teachers SKAMP (with attention and deportment subscales) rated daily by parents and teachers) Main study (Jensen 1999) SNAP Inattention and hyperactivity‐impulsivity subscale, both parent and teacher. Assessed at baseline, 3, 9, and 14 months SNAP oppositional‐defiant disorder subscale, both parent and teacher rated. Assessed at baseline, 3, 9, and 14 months Abikoff Classroom Observational System (ADHD and oppositional/aggressive symptoms), blind ratings by blind observer Serious adverse events: Main study (Jensen 1999) 6 of 11 reported severe side effects could have been due to non‐medication factors 3 deaths were recorded among the ADHD participants during the 10 years of observation: a suicide at age 14 (the patient was on MPH), a fatal car accident at age 17 (the patient was the driver and was on MPH), and a sudden unexplained death at age 17 (the patient was found dead in bed; no specific cause of death could be determined; he had been previously treated with MPH and had been off medication for more than 1 year when he died Non‐serious adverse events Main study (Jensen 1999) Participants had up to 8 additional sessions provided when needed to address clinical emergencies or instances of possible study attrition Pittsburgh Side Effects Rating Scale, monitored monthly, reviewed by the pharmacotherapist Internalising symptoms (anxiety and depression) were measured with an internalising subscale from parent‐ and teacher‐completed SSRS, measured at baseline, 3, 9, and 14 months Children's self‐ratings on the Multidimensional Anxiety Scale for Children (MASC). Assessed at baseline, 3, 9, and 14 months Titration period (Greenhill 2001) Pittsburgh Side Effect Rating Scale (10 adverse events commonly associated with MPH were rated) 3‐year follow‐up (Molina 2007) Substance abuse; substance use was assessed at 24 and 36 months using a child‐reported substance use questionnaire (Molina and Pelham, 2003) adapted for the MTA. The measure included items for lifetime and current (past 6 months) use of licit substances (alcohol, cigarettes, chewing tobacco) and illicit drugs (marijuana and other street drugs). Also included were items for inappropriate or non‐prescribed use of medications, including stimulants Delinquency; assessed by the Self‐Reported Antisocial Behavior Questionnaire through the 24‐month assessment and the Self‐reported delinquency questionnaire at the 36‐month assessment. Delinquency was coded along an ordinal scale based on the most serious act committed during the past 6 months: 0 = no delinquency; 1 = minor delinquency only at home (e.g. theft of less than USD 5 or vandalism); 2 = minor delinquency outside of the home (e.g. vandalism, cheating someone, shoplifting less than USD 5); 3 = moderately serious delinquency (e.g. vandalism, theft of ≥ USD 5, weapon carrying); 4 = serious delinquency (e.g. breaking and entering, drug selling, attacking someone with the intent to seriously hurt or kill, rape); and 5 = engagement in ≥ 2 different level 4 offenses. Because only a small number of MTA children were coded 5 (n = 14 at baseline, n = 4Y5 between 14 and 36 months), we grouped codes 4 and 5 for data analyses, making a 5‐level ordinal scale of 0 to 4 8‐year follow‐up (Molina 2009) Delinquent behaviour coded on a 5‐point ordinal scale using parent and youth report across several measures Number of contact with police and arrests using the Services for Children and Adolescents‐Parent Interview (SCAPI), parent reported Depression rated with the Children's Depression Inventory, self‐rated Anxiety rated with the Multidimensional Anxiety Scale for children, self‐rated Psychiatric hospitalisation by 8 year, parent reported 8‐year follow‐up, substance abuse (Molina 2009) The substance use outcomes were measured at all interviews beginning with the 24‐month assessment Substance use: substance use was assessed with a child/adolescents‐reported questionnaire adapted for the MTA For the analysis of stimulant treatment duration in relation to substance use at the 8‐year follow‐up, the primary outcome was number of substances used in the past 6 months, to ensure that most stimulant treatment received would have preceded substance use. Component variables included the following: 'drunk' once or more or drank alcohol 3 to 4 times or more, ≥ 1 cigarettes/day in the past month (time frame exception specific to tobacco); marijuana ≥ 2 times, and any other illicit drug use or prescription medication misuse. Secondary analyses explored each class of substances separately. Substance Abuse or Dependence (SUD). For the analysis of stimulant treatment exposure over time in relation to substance use at the 8‐year follow‐up, the primary outcome variable was SUD in the past year for any substance (excluding tobacco). Secondary analyses explored alcohol and marijuana/other drug use disorders separately 10‐year follow‐up (Vitello 2012) Blood pressure and heart rate monitoring, measured after participants had been sitting for 5 minutes, adjusted for age and sex Height and weight Hospitalisation measured at each assessment point No symptomatic cardiovascular events leading to medical attention were reported during the period of observation, and no stimulant treatment discontinuation consequent to cardiovascular adverse effects occurred during the 10‐year period Growth (Jensen 2004, Swanson 2007) Height in cm and weight kg, assessed at baseline, 14 months, 24 months, and 36 months
Notes	Sample calculation: yes power analysis, 576 participants were required Ethics approval: yes, approved by both local institutional review boards and the National Institutes of Health Office for Protection From Research Risk Exclusion of MPH non‐responders/children who have previously experienced adverse events on MPH: no Any dropouts due to adverse events: 4 patients were removed during the lead‐in (titration period) because of prohibitive side effects. 1 child with buccal movements, another with skin picking; a third with depression, crying, sleep delay, and appetite loss, and a fourth who was anorexic, listless, and emotionally constricted Comments from the study authors: Main Study (Jensen 1999) Recruitment, screening, and selection procedures aimed to collect a carefully diagnosed sample of impaired children with ADHD and a wide range of comorbid conditions and demographics characteristics representative of patients seen in clinical practice. The design did not include a no‐treatment or placebo group. More than 3/4 of participants given behavioural treatment were successfully maintained without medication throughout the study. Consequently, it should not be concluded that behavioural treatment interventions did not work. Combined treatment and medication management treatments were clinically and statistically superior to behavioural treatment and community care in reducing children's ADHD symptoms. For other areas of function (oppositional/aggressive behaviours, internalising symptoms, social skills, parent‐child relations, and academic achievement), few differences among our treatments were noted, and when found, were generally of smaller magnitude. The significantly lower total daily dose of methylphenidate in the combined treatment arm are noteworthy but not unforeseen. The importance of this finding is unclear, and a rigorous test of the question would likely require a different design Titration period (Greenhill 2001) Its short 28‐day duration also limited its generalisability to long‐term treatment. Rates of response to MPH ran between 70% to 80% within the expected range.The MTA titration study showed a steeper dose‐response curve for younger and lighter ADHD children. When ratings were collected under placebo‐controlled, double‐blind conditions, parents reported more adverse events than did teachers. For this reason, clinicians would be wise to collect MPH side effect ratings from parents in the afternoon and evenings 10‐month follow‐up (Group 2004) At follow‐up, MGT participants' dose levels (in methylphenidate equivalents) were significantly higher than COMB participants. There interesting results suggest the possibility that early COMB interventions might allow reducing overall medication requirements during later periods, consistent with findings that other have reported 3‐year follow‐up (Jensen 2007) By 36 months, none of the randomly assigned treatment groups differed significantly on any of the 5 clinical and functional outcomes. However, despite no significant group differences at the 36‐month assessment, substantial improvement was manifested by all of the groups. Because there were no untreated control groups and because all of the treatment groups were improved in terms of relevant symptomatology at 36 months compared to baseline, it is possible that all of the treatments worked, but at different rates of different time periods. It is interesting that both medication and educational services for 24 to 36 months were markers for poorer outcome at 36 months, suggesting that those who are doing poorly get more treatment yet still do not do as well as those for whom treatment is not considered essential Vitiello 2001 Comorbid anxiety, oppositional defiant disorder, or conduct disorder was not associated with statistically significant differences in MPH dose at end of titration or maintenance, number of medication changes, or time to first change. A short‐term response to placebo occurred in 32 children (of 256 who completed the double‐blind titration) but was maintained in only 3 patients in the long term. Conners 2001 It is clear that the treatment effect in the study depends on the choice of endpoint measure. The results highlight the fact that there is no 'one true outcome' for a randomised clinical trial because different measures may be sensitive to different forms of treatment 8‐year follow‐up (Molina 2008) Across time (to the 8‐year follow‐up) 17.2% of the children were medicated at every assessment beginning with 14‐months reports 10‐year follow‐up, (Vitiello 2012) This clinical trial was not specifically designed to evaluate cardiovascular function. The blood pressure and heart measurements were not conducted under double‐blind conditions, and the measurement methods varied across the clinical sites. Abnormal blood pressure values were not systematically confirmed over 3 separate assessments as required for a diagnosis of prehypertension or hypertension. The time of the day when measurements were made was variable Implications and applications for primary care providers (Jensen 2001) Behavioural treatments may help families actively cope with their child's disorder and make the necessary life accommodations to optimise family functioning, even when such treatments are not as effective as medication in reducing children's ADHD symptoms. Findings suggest that high quality treatments may have considerable impact on restoring AHDH children to normal or near‐normal functioning at home and in the classroom. Because essentially none of the ADHD children met the normal criteria that were met by 88% of comparison children drawn from the same classrooms at the study outset, the notion that ADHD is just normal behaviour labelled by uninformed parents or overwhelmed teachers appears not only implausible, but preposterous Pelham 1999 The 2 major treatment modalities ‐ behavioural and pharmacological ‐ were assessed at different time points relative to the intensive phase of treatment. Specifically, the effects of the pharmacological treatments were assessed at post‐treatment while participants were actively medicated; in contrast, the effects of BEH were assessed following fading of therapist involvement. The intensive period of BEH ended in late December or early January, and endpoint measures were typically taken 4‐6 months later ‐ usually several months after the last planned, face‐to‐face therapeutic contact. This design aspect has numerous implications for interpretation of the findings. For example, we cannot state that the medication (MPH for the vast majority) had long‐term effects. Rather, the results simply demonstrate that effects of MPH given steadily for 14 months are the same at the end of the time as the beginning (indeed the correlations between drug effects at these 2 points of the study are very high). When differences in outcome between these groups (e.g. BEH and MGT) are analysed, it is likely that combined treatment for children whose parents and teachers continued the behavioural interventions they had been taught will have an outcome superior to MGT, while combined treatment, for those whose parents and teachers did not continue BEH will be equivalent to MGT alone (which would not be surprising, as functionally that would be what they were receiving) Growth 24‐month outcomes (Jensen 2004) The growth suppression effects could be related to a medication effect, with the continuously treated subgroup having slower growth than the untreated subgroup. Alternatively, the 'continuously treated subgroup', defined by unknown self‐selection factors, could have had a slower growth rate before the start of the study, which continued during the treatment and follow‐up phases on the MTA. Our data cannot make a determination of the validity of these alternative interpretations. At this first follow‐up, our observations were of the children in the MTA when they were between the ages of 9 and 11 years, which is before expected phase of accelerated growth in adolescence and before the expected age when growth slows and final height is approximated. The rate of growth as well as the length of the growth phase together determines ultimate (adult) height, and it is possible that the consistent treatment with medication may reduce the rate but lengthen the duration of growth, so final height would be delayed but not reduced. It is possible that the never‐medicated group was pared down to good responders and the medicated groups enriched with poor behavioural responders. In the analysis of 14‐ to 24‐month change scores, the 'Medication status' was significant for both height (Chi2 = 16.16, P < 0.001) and weight (Chi2 = 13.32, P < 0.004) Growth 36 months assessment (Swanson 2007) We did not document a decrease in relative size in the group of participants with a history of treatment before entry into the MTA protocol during subsequent treatment with stimulant medication over 3 years. However, this group (the consistently medicated naturalistic subgroup) was smaller than the stimulant‐naïve group (the newly medicated naturalistic subgroup at entry, suggesting that early treatment of children (before the ages of 7‐9 years) with stimulant medication may have produced a reduction of growth rate before entry into the MTA protocol Key conclusions of the study authors: Main study (Jensen 1999) For ADHD symptoms, our carefully crafted medication management was superior to behavioural treatment and to routine community care that included medication. Our combined treatment did not yield significantly greater benefits than medications management for core ADHD symptoms but may have provided modest advantages for non‐ADHD symptom and positive functioning outcomes Vitiello 2001 For most children, initial titration found a dose of MPH in the general range of the effective maintenance dose but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are needed Titration period (Greenhill 2001) The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10‐50 mg/day) across participants, effect sizes on impairment and deportment, as well as dose‐related adverse events. With 3 times daily dosing, the MTA titration trial showed that significant stimulant medication effects on ADHD symptom reduction and drug‐related adverse events could be detected by parents and teachers using daily ratings under controlled conditions 10‐month follow‐up (MTA Group 2004) The benefits of intensive medical intervention for ADHD extend 10 months beyond the intensive treatment phase only in symptom domains and diminish over time. 3‐year follow‐up (Jensen 2007) By 36 months the earlier advantage of having had 14 months of the medication algorithm was no longer apparent, possibly due to age‐related decline in ADHD symptoms, changes in medication management intensity, starting or stopping medications altogether, or other factors not yet evaluated. 24‐ and 36‐month assessment of delinquency and substance abuse (Molina 2007) Cause‐and‐effect relationships between medication treatment and delinquency are unclear; the absence of associations between medication treatment and substance use need to be re‐evaluated at older ages. Findings underscore the need for continuous monitoring of these outcomes as children with attention deficit/hyperactivity disorder enter adolescence. There were no statistically significant effects at the P < 0.05 level of randomly assigned treatment on individuals rate of change in delinquency between baseline and 36 months. Result suggests the possibility that increasing delinquency between 24 and 36 months was associated with an increase in substance use in the same time period. We did not find evidence of protective or adverse effects of medication treatment for ADHD in either study. 8‐year follow‐up (Molina 2009) Type or intensity of 14 months of treatment for ADHD in childhood (at age 7‐9.9 years) does not predict functioning 6 to 8 years later. Rather, early ADHD symptom trajectory regardless of treatment type is prognostic. This finding implies that children with behavioural and sociodemographic advantage, with the best response to any treatment, will have the best long‐term prognosis. As a group, however, despite initial symptom improvement during treatment that is largely maintained after treatment, children with combined‐type ADHD exhibit significant impairment in adolescence. Innovative treatment approaches targeting specific areas of adolescent impairment are needed 10‐year follow‐up blood pressure (Vitiello 2012) Stimulant treatment did not increase the risk for prehypertension or hypertension over the 10‐year period of observation. However, stimulant had a persistent adrenergic effect on heart rate during treatment Growth studies, 24‐month follow‐up (Jensen 2004) In the MTA follow‐up, exploratory naturalistic analyses suggest that consistent use of stimulant medication was associated with maintenance of effectiveness but continued mild growth suppression Growth studies, 3‐year follow‐up (Swanson 2007) Children with combined type attention‐deficit/hyperactivity disorder were, as a group, larger than expected from norms before treatment but showed stimulant‐related decreases in growth rates after initiation of treatment, which appeared symptomatic within 3 years without evidence of growth rebound Pelham 1999 Active medication for ADHD is better than withdrawn BT (on some but not most measures). Combined treatment adds modestly to active medication but is superior to behaviour management alone. Study treatments that include active medication are better than community treatments that include medication, while BT is comparable to medication as delivered in the community. Concurrent BT results in ≥ 20% lower and non‐increasing medication dosages relative to treatment with medication alone. Comorbidity (Jensen 2001) Our findings suggest that ADHD children with and without ODD/CD and ANX differed on many baseline characteristics, outcomes, and response to treatment. Children with ANX tended to be more treatment‐responsive than ADHD + ODD/CD and even ADHD‐only participants Anxiety (March 2000) Contravening earlier studies, no adverse effects of anxiety on medication response for core ADHD or other outcomes in anxious or non‐anxious ADHD children was demonstrated. When treating ADHD, it is important to search for comorbid anxiety and negative affectivity and to adjust treatment strategies accordingly Swanson 2007 Long‐term benefits from consistent treatment were not documented; selection bias was not shown to account for the loss of relative superiority of medication over time; there was no evidence for 'catch‐up' growth; early treatment with medication did not protect against later adverse outcomes. We expect that these challenges to the field's views will contribute to future controversies about the long‐term outcomes in the MTA Substance use (Molina 2012) Our findings did not provide any evidence that ADHD medication protects from, or increases risk for, adolescent substance use or SUD. This finding held for recent medication and for days cumulatively treated with stimulants. Unmeasured confounders may have been operating because of the naturalistic follow‐up study design and we did not statistically control for psychopathology and functioning at the follow‐up assessment. The observed lack of associations between stimulant exposure over time and adolescent substance use/SUD do not discount the possibility that brain‐based changes in neural mechanisms underlying addiction vulnerability are occurring as a function of prolonged stimulant treatment. The substance use/SUD outcomes for the MTA should be considered in the context of several unique study features and limitations. All of the children in the MTA were diagnosed with the combined type of DSM‐IV ADHD, and generalisation of study results should generally not extend beyond this subtype. Our follow‐up assessments, which relied on self‐report and often with 2‐year windows, may have missed episodes of substance use, and rates may be underestimated Pelham 2000 75% of the children in the behavioural treatment group were maintained without medication for 14 months, and 64% did not meet diagnostic criteria for ADHD at 14 months based on the DISC interview (MTA Cooperative Group, 1999a, 1999b). Such findings highlight the fact that intensive behavioural treatments are a viable alternative to medication in treatment of ADHD Comments from the review authors: The authors from the MTA study have written more than 70 articles describing different outcomes and challenges of the study. We have only included those found in our comprehensive literature search or others we found relevant to include looking through the articles reference lists. We have discussed whether to include the MTA study or not since not all of the patients randomised to medication (COMB + MGT group) received MPH. Those who did not have an adequate response to MPH were given other medication (e.g. dextroamphetamine, pemoline, imipramine, or no medication). Furthermore, some of the participants in the BEH group were also medicated during the 14‐month randomisation phase. For all other studies in the review, we have only included those with pure MPH receivers. Furthermore lots of the participants did not have an ADHD diagnosis at the follow‐up assessment. At 8‐year follow‐up only 30% of the remaining participants still had a diagnosis of ADHD. However, we have chosen to use the data from MTA since it is such a large and well‐known study. All of the MTA analyses will be part of the review as sensitivity analyses Regarding Molina 2012 (substance use): we have included/asked for additional data for this article, even though that the group that were medicated in the more group were only medicated for mean 2071.10 (SD 728.87) days out of the 8 years the follow‐up took place. The following articles from the MTA study have only been assessed by one review author: Pelham 2000, Carey 2000, Swanson and Hinshaw 2007, Galanter 2003, Hinshaw 1999, Molina 2013 We sent several emails to the MTA group in order to get additional information and furthermore spoke orally to some of the authors. We did not get additional data