To stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended?

European Neuropsychopharmacology (2011) 21, 584–599

www.elsevier.com/locate/euroneuro

REVIEW

To stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended? Gigi H.H. van de Loo-Neus a , Nanda Rommelse a,b , Jan K. Buitelaar a,c,⁎ a

Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands Department of Psychiatry, Nijmegen Centre for Evidence-Based Practice, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands c Department of Cognitive Neuroscience, Nijmegen Centre for Evidence-Based Practice, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands b

Received 31 May 2010; received in revised form 1 March 2011; accepted 19 March 2011

KEYWORDS Psychostimulants; Atomoxetine; Long-term treatment; ADHD; MTA study; Clinical trials; Side-effects; Safety

Abstract ADHD is a common neuropsychiatric disorder with a strong persistence over time. Medication is frequently used in the clinical management of ADHD. After response, medication is typically prescribed for months to years. It is unclear whether extended medication treatment provides long-term benefits and how long it should be continued. Furthermore, there is concern about the long-term safety of ADHD medication. The aim of this systematic review is to address these issues and provide recommendations about the decision to stop or not to stop ADHD medication. We performed a search in PubMed and focused on medication studies with a treatment longer than 12 weeks in subjects 6–18 years old. Extended placebo-controlled double-blind parallel studies are not available. Placebo-controlled discontinuation studies and prospective long-term observational treatment studies provide evidence that medication management leads to a substantial reduction of ADHD symptoms and less impairment of functioning for a period of about 2 years. There is limited and inconsistent evidence for long-term advantage of medication treatment beyond symptom control, such as improved social functioning, academic achievement, employment status and less adverse psychiatric outcome. In terms of safety, long-term effects of medication on growth, blood pressure and heart rate are limited and the occurrence of suicidal, psychotic and manic symptoms is rare. Animal data about neurotoxic effects of psycho stimulants cannot be directly extrapolated to humans. Therefore, clinical decisions about starting, continuing, and stopping of ADHD medication should be made on an individual basis. Medication free periods should be implemented at regular times to investigate the need for an

⁎ Corresponding author at: Department of Cognitive Neuroscience, Nijmegen Centre for Evidence-Based Practice, Radboud University Nijmegen Medical Centre, P.O. Box 9101 (204), 6500 HB Nijmegen, Netherlands. Tel.: +31 24 3610750. E-mail address: [email protected] (J.K. Buitelaar). 0924-977X/$ - see front matter © 2011 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2011.03.008

To stop or not to stop?

585 ongoing benefit of medication. Unfounded assumptions about continuing benefit of medication use should be abandoned. Careful monitoring of side effects is necessary and must be able to detect early alarming signals. © 2011 Elsevier B.V. and ECNP. All rights reserved.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common behavioral disorders of childhood, characterized by the early onset of age-inappropriate hyperactivity, impulsivity and inattentiveness, and a world-wide pooled population-prevalence of 5.3% (Polanczyk et al., 2007). One of the current psychiatric disease classification system, DSMIV-TR, distinguishes three subtypes: a mainly inattentive, a mainly hyperactive–impulsive and a combined subtype (American Psychiatric Association (APA), 2000). ADHD is a clinically heterogeneous condition, in which symptom overlap or comorbidity with other conditions is the rule rather than the exception. Common comorbidities in children with ADHD include not only oppositional defiant and conduct disorders, anxiety and mood disorders, autistic spectrum disorders but also motor coordination problems, tic disorders, sleep disorders, and specific learning disorders (Biederman and Faraone, 2005; Kadesjo and Gillberg, 2005). Adolescents with ADHD start smoking earlier than their nonADHD peers, are more likely to report binge drinking and present frequent comorbidity with substance use disorders (Wilens, 2004). ADHD is strongly persistent over time. Approximately 15% of the patients still meet full ADHD criteria according to the DSMIV-TR in adulthood, whereas 40–60% remits only partially and has increased symptom counts as adults (Faraone et al., 2006). ADHD in childhood is associated with a range of associated problems, such as academic difficulties, low school grades, increased rates of being expelled from school, poor peer relationships, low self-esteem, family problems and increased burden for family (Coghill et al., 2008). A recent observational study reassessed a UK cohort of 126 school-age children with ADHD five years later in adolescence (Langley et al., 2010). The research team found about 70% of the sample to meet full criteria for ADHD and most of the sample to exhibit high levels of antisocial and criminal behavior and substance use problems in adolescence (Langley et al., 2010). Only 10% of the sample appeared to have functionally and symptomatically recovered, some of whom continued to be prescribed medication. This is comparable with the low levels of functional remission reported in US samples of children with ADHD (Barkley et al., 2004; Biederman et al., 2006). Furthermore, adults with a childhood history of ADHD have higher than expected rates of antisocial and criminal behavior, injuries and accidents, employment and marital difficulties, and health problems and are more likely to have teen pregnancies (Barkley et al., 2004; Biederman et al., 1993, 2006). Given the high burden of ADHD and associated problems on the patient, the family environment and on society as a whole, the need for effective treatment is eminent. Clinical guidelines and practice parameters describe the pivotal role of medication in the clinical management of ADHD (Banaschewski et al., 2006; National Institute for Health & Clinical Excellence (NICE), 2009; Pliszka, 2007; Scottish Intercollegial Network Guidelines (SIGN), 2009; Taylor et al., 2004). These recommendations are based on numerous

clinical trials that have shown both psychostimulant and nonstimulant medications to be highly efficacious in treating ADHD with a percentage of clinical responders around 70% or higher. Therapeutic effects of medication include a reduction of the hyperactivity, impulsivity, and inattention characteristics of patients with ADHD, and improvement of associated behaviors, including on-task behavior, academic performance, and social functioning (Greenhill et al., 2002). The most commonly prescribed medications are the psychostimulants methylphenidate and other amphetamines. Both methylphenidate and amphetamines block presynaptic dopamine and norepinephrine reuptake, whereas amphetamine also increases dopamine release and inhibits monoamine oxidase more potently than methylphenidate. A widely prescribed non-stimulant is atomoxetine, which selectively inhibits norepinephrine reuptake without a direct effect on the dopaminergic neurotransmission. Other medications (agents) not primarily indicated for ADHD, such as alphaadrenergic agonists like clonidine and guanfacine, tricyclic antidepressants, modafinil and bupropion have nevertheless been shown to be more effective than placebo in short term clinical trials (Wilens, 2006). Although head-to-head clinical trials provide the best data to draw conclusions about differences in efficacy between different medications, meta-analyses may serve this purpose as well (Faraone, 2009; Faraone and Buitelaar, 2010). Immediate-release and long-acting psychostimulant medication were found to be equally effective, with effect sizes in the order of 1.0 (Banaschewski et al., 2006). Contrasting the clinical effects of methylphenidate and amphetamines indicates overall larger effect sizes for amphetamines than for methylphenidate (Faraone and Buitelaar, 2010). The nonstimulant atomoxetine is less efficacious than either type of stimulant, with a mean effect size of 0.7 in clinical trials (Michelson et al., 2002; Newcorn et al., 2008).

1. Aims ADHD medications are not only efficacious but also proven to be fairly safe in short clinical trials during 6–12 weeks of treatment. However, as ADHD is a rather chronic condition, medication treatment typically will be extended over a long period of time, up to several years. This calls for a critical review of the long-term efficacy and safety of ADHD medication. Are short-term treatment gains maintained in extended treatment? What is the safety outcome of longterm treatment? Does long-term medication treatment contribute to improved long-term outcome? What is the trade-off between potential long-term benefits and safety issues? How long should ADHD medication be continued? The aim of this systematic review is to address these questions and provide clinical recommendations about the clinical decision to stop or not to stop ADHD medication.

586

Table 1

Most important long-term treatment studies. Sample size Design ADHD/Controls

Age (years)

Medication/other treatment

Duration Results treatment (months)

Gillberg et al. (1997)

62 ADHD

RCT relapse prevention

6–11

Methylphenidate (MPH)

15 months

Schachar et al. (1997), Charach et al. (2004) MTA Cooperative Group 1999–2004 Follow-up: Jensen et al. (2007), Molina et al. (2007), Swanson et al. (2007b), Molina et al. (2009)

91 ADHD 79 579 ADHD

RCT follow up

6–12

MPH

RCT Follow up: observational with local normative comparison sample

6–9 10–13 11–13

MedMgt/Beh/ Comb/CC

4 months 5 years 14 months 36 months 36 months 36 months 6–8 years

Michelson et al. (2004); Buitelaar et al. (2007)

416 ADHD 163

RCT relapse prevention RCT relapse prevention following 12 month treatment

6–15

Atomoxetine(ATX)/ placebo (ATX)/placebo

9 months 6 months + 12 months

Klein et al. (2004); Abikoff et al.

103 ADHD

Long term multimodal treatment

7–9

MPH/psychosocial treatment/attention control

24 months 24 months 24 months

485 487/ 272 485 436/ 261

In clinical responders to amphetamine, amphetamine was superior to placebo in maintaining response after 15 months Psychostimulants improve ADHD symptoms for up to 5 years but adverse effects persist Combination treatment (Comb) and medication management (MedMgt)were superior to behavior treatment (Beh) which was superior to community care (CC) The earlier advantaged (14 months) of the medication algorithm was no longer apparent Cause and effect relationships between treatment and delinquency is unclear Self selection bias did not contributed to lack of medication advantage, possibly residual benefits in one class (2) and small current benefits in other class (1) Type of treatment at 14 months does not predict functioning 6–8 years later In patients who responded favorably to ATX, ATX was superior to plac in maintaining response for 9 months Continued treatment associated with superior outcomes compared with placebo, however considerable variability between individuals in magnitude of symptom return after discontinuation Almost 80% of families completed the 2-year study In stimulant-responsive children, there is no support for adding long-term psychosocial intervention to

G.H.H. van de Loo-Neus et al.

Study

Dopfner et al. (2004)

75 ADHD

Barbaresi et al. (2006, 2007)

379 ADHD

So et al. (2008)

90 ADHD

Adaptive multimodal treatment Retrospective birth cohort study

6–10

Randomized group comparison + follow up

7–9.9

Mean 17.2 at follow up

MPH/ 6 months psychoeducation/Beh Stimulants/TCA Mean 41.9 months

MPH versus MPH/Beh 18 months

Biederman et al. (2009) 140 ADHD 120 controls

Case–control observational 22 at Stimulants follow-up study of follow-up 10 years

Unknown

Langley et al. (2010)

Cohort follow up (N = 126)

Unknown

126 ADHD

12–18 at Stimulants follow up

improve ADHD and ODD, benefits from MPH were stable over 2 years In stimulant responsive young children there is no support for academic assistance and psychotherapy to enhance academic achievement or emotional adjustment Both behavior therapy and combined treatment are found effective interventions Treatment effectiveness comparable with treatment efficacy in RCTs, side effects in less than 10%, no continuing treatment throughout adolescence. Claimed longterm beneficial effect on scholastic achievement and grade retention The combination of Beh and low-dose MPH was significantly more effective than MPH-only but at follow up the MPH group caught up in improvement in ADHD symptoms 82 (73%) were previously treated with stimulants. Participants with ADHD who were treated with stimulants were significantly less likely to subsequently develop depressive and anxiety disorders and disruptive behavior and less likely to repeat a grade compared with participants with ADHD who were not treated. Children with ADHD show poor outcome on ADHD and CD despite (drug) treatment, it seemed that greater severity of ADHD led to continued treatment

To stop or not to stop?

(2004); Hechtman et al. (2004)

587

588

2. Methods We performed an internet search of the literature published on PUBMED and this search was repeated in Google Scholar to verify the results. Articles published in the last two decades (1990–2010) were included using the keywords: ADHD, long term treatment, MTA study, relapse prevention, (dex)amphetamine, methylphenidate, clonidine, guanfacine, alpha adrenergic agonists, atomoxetine, bupropion, anti-depressives, and modafinil. We limited our search to papers published in English, in subjects 6–18 years old, with a duration of treatment of 12 weeks or longer, and with a sufficiently large sample size (N=20 subjects). We excluded studies in adult patients and patients with subaverage intelligence. We found 728 hits about the different agents used in ADHD treatment and 485 hits on long-term treatment. Related articles and reference lists were scanned for topics on relapse prevention, long-observational studies and the MTA study. The titles and abstracts of the found papers and references were reviewed for particular relevance and only selected for inclusion when they included information about psychopharmacological treatment of ADHD, long-term treatment, the need for treatment and the safety of treatment. The reference section of each article identified was then closely examined to identify any studies that we may have been missed or that were published before these databases were established. Finally, we selected 53 relevant papers about efficacy, safety and tolerability in long-term treatment, see Table 1 for an overview of the most relevant studies. Most of the papers retrieved were open-label treatment studies. Our search covered all known medications used in the treatment of ADHD, with most papers referring to stimulants and atomoxetine. We found one article on clonidine (Palumbo et al., 2008) and one article about guanfacine studying a sample size N20 subjects and with duration of treatment N=12 weeks (Sallee et al., 2009a).

3. Long-term efficacy Examining the long-term efficacy of ADHD medication by extended placebo-controlled double-blind parallel studies would be ethically impossible since it would require withholding treatments of proven efficacy for a long period of time. Thus, long-term efficacy has been studied using nonrandomized controlled designs in which for example historic controls, alternative treatments, treatment duration and within-subject withdrawal designs have been used (Schachar and Tannock, 1993). Of course, these designs are fundamentally flawed since there is no guarantee for the comparability of the target and control groups before the treatment. Another strategy is to use randomized controlled designs that compare ADHD medication (mostly methylphenidate) to, for example medication plus another active treatment or to another active treatment alone. A review of all non-randomized and randomized extended treatment studies published till 1992 concluded that psychostimulant medication proved to be more effective in ameliorating the core symptoms of ADHD than placebo, nonmedication treatment or no treatment in trials lasting 3–7 months (Schachar and Tannock, 1993). However, few ADHD children became symptom-free, and there was minimal evidence that extended stimulant treatments improved cognitive deficits or reduced associated problems of conduct disorder, academic underachievement, and poor peer-relationships (Schachar and Tannock, 1993). Further, most studies had methodological limitations due to using non-standardized outcome measures and failure to include measures of compliance. Nevertheless, these initial studies provided

G.H.H. van de Loo-Neus et al. the first support for the hypothesis that ADHD medication has a long-term efficacy.

3.1. Randomized placebo-controlled discontinuation designs Later studies used designs with greater methodological rigor. Three studies used a double-blind placebo-controlled discontinuation design that is easier to implement from an ethical point of view since only clearly defined clinical responders will enter the double-blind phase. Patients who relapse drop-out from the trial and can be continued on open-label medication, which safeguards access to effective treatment. One study in 61 children with ADHD showed that amphetamine treatment for up to 15 months was superior to placebo in reducing core symptoms of ADHD and other disruptive behavior problems and tended to lead to improved results on the Wechsler Intelligence Scale for Children— Revised (Gillberg et al., 1997). Another study investigated the long-term efficacy of atomoxetine in 416 children and adolescents with ADHD who responded to an initial 12-week, open-label period of treatment (Michelson et al., 2004). They were randomized to continued atomoxetine treatment or placebo for 9 months under double blind conditions. Atomoxetine was superior to placebo in maintaining response for the ensuing 9 months. In a follow-up study, a second randomization occurred after approximately 1 year of treatment in 163 patients with ADHD who had a stable clinical response (Buitelaar et al., 2007). Patients were rerandomized to an additional 6 months of atomoxetine or placebo. Continuing atomoxetine was associated with superior outcomes compared with placebo substitution. However, there was considerable variability between individuals in the magnitude of symptom return after drug discontinuation. This suggests that some subjects, treated with atomoxetine for a year with good results may consolidate gains made during drug treatment and could benefit from a medication-free trial to assess the need for further continuing ADHD medication.

3.2. Randomized prospective long-duration trials The prospective long-duration dual-site (New York and Montreal) treatment study of children with ADHD randomized 103 clinical responders to (i) methylphenidate treatment alone; (ii) methylphenidate combined with multimodal psychosocial treatment that included parent training and counseling, academic assistance, psychotherapy, and social skills training; or (iii) methylphenidate plus attention control treatment that excluded specific aspects of the psychosocial intervention (Klein et al., 2004). All children relapsed when switched per protocol to single-blind placebo after having been treated with methylphenidate for 12 months, and were restarted with methylphenidate treatment regardless of the prior treatment regime. Compared to methylphenidate treatment alone, combination treatment did not lead to greater reduction of ADHD symptoms, larger advantage on measures of academic achievement or social functioning and did not facilitate methylphenidate discontinuation. Comparable significant improvement occurred across all treatments and continued over the 2 year study period (Abikoff et

To stop or not to stop? al., 2004; Hechtman et al., 2004). The interpretation of the findings however is limited by the lack of an untreated ADHD control group, and by the exclusion of children with ADHD and comorbid conduct disorder. Another prospective study randomized 91 children with ADHD to either 12 months treatment with methylphenidate or placebo with concurrent randomization of the parents to one of two parent interventions (Schachar et al., 1997). Interim results after 4 months of treatment showed that twice-daily methylphenidate improved ADHD symptoms at school but not at home. Children who received the placebo for 4 months however did also show significant clinical improvements in the school setting, which underlines the importance of placebo-controlled designs in examining the effects of extended treatments (Schachar et al., 1997). Frequent crossover from placebo to methylphenidate treatment interfered with the original study plan to evaluate the efficacy of methylphenidate treatment over 12 months. An observation follow-up study over the next 4 years (thus 5 years in total) in 79 subjects indicated that those who adhered to their medication had higher ADHD scores at baseline at school and higher outcome scores at school but also a greater response to treatment at school (Charach et al., 2004). Thus, more severely symptomatic ADHD children were still using medication and were continuing to derive benefits for 5 years. However, the study failed to include an untreated ADHD- or non-ADHD control group, and did not report on outcomes beyond clinical symptoms of ADHD. A German study used an adaptive treatment approach to imitate stepwise clinical decision making (Dopfner et al., 2004a, 2004b). In contrast to efficacy studies which use fixed treatment devices, in an adaptive design treatment may be individually tailored on the basis of clinical needs, similar to a strategy that may be useful in clinical practice. A sample of 75 children with ADHD according to the DSM-III-R or with Hyperkinetic Disorder based on the preliminary ICD-10 research diagnostic criteria was randomized either to medication (methylphenidate) plus psychoeducation (MED + PE) or to behavior therapy including psychotherapy (BT + PE) after a 6-to-8-week baseline period with psychoeducation (PE) alone. In the group starting with behavior therapy 26% of patients received combined treatment in later treatment stages. In most of the cases (82%) with initial medical management, behavior therapy was added. ADHD symptoms, individually defined behavior problems and comorbid symptoms were all significantly reduced after 24 weeks of treatment. In some cases, the investigators prescribed a low dose of methylphenidate only in the morning. Both behavior therapy and combined therapy were proven to be effective interventions, with teacher ratings indicating that combined treatment was more effective than behavior therapy alone. Design aspects such as the small sample size for this kind of study, no fixed treatment devices, open-label medication treatment and relatively low doses of medication prescribed make it difficult to compare this study with other studies. The effectiveness of a combined treatment (methylphenidate plus behavioral treatment) versus methylphenidateonly was tested in 90 Chinese children with ADHD (So et al., 2008). A randomized group comparison design was adopted with two treatment conditions for 6 months with a follow-up assessment at 12 months. The combination of behavior therapy and low-dose of methylphenidate was significantly more effective than methylphenidate-only in reducing ADHD

589 and ODD symptoms at post-treatment. At follow-up the methylphenidate-only group caught up in improvement, while the benefits of the combined group were maintained. This supported the added benefits of behavior therapy on top of medication. Limitations of this study are the open-label medication condition, the lack of a non-ADHD control group, and the increased amount of time and attention invested in the participants in the combined treatment condition, compared to the methylphenidate only group. Furthermore, only about 30% of participants in the combined group returned to the normal range of functioning, which still leaves substantial room for improvement. At follow-up 12 months later, the medication-only group manifested further clinical improvement. No other indicators representing functional outcomes beyond clinical symptoms were used. A 16 week double-blind placebo-controlled trial of 122 children with ADHD has studied the separate and combined effects of clonidine and methylphenidate (Palumbo et al., 2008). Participants were randomly assigned to clonidine, methylphenidate, clonidine in combination with methylphenidate, or placebo according to a 2 × 2 factorial design. Although clonidine was well tolerated, except for frequent sedation, methylphenidate was found to offer the best combination of efficacy and tolerability for ADHD. Overall, these randomized longer duration treatment studies provide evidence for longer term and up to about 2– 5 year beneficial effects on ADHD symptoms, however without evidence of further positive effects beyond symptom control.

3.3. Non-randomized observational studies There are a large number of non-randomized observational studies of longer term treatment of ADHD. Many of these studies are open-label extension studies of clinical responders identified in short-term randomized clinical trials. The tolerability and effectiveness of once-daily extended release methylphenidate (OROS®) after 12 months in 407 children diagnosed with ADHD have been reported (Wilens et al., 2003). Of these subjects 289/407 (71%) completed 12 months of treatment. The average daily dose was increased throughout those 12 months. Effectiveness was maintained for up to 12 months and this treatment appears to be relatively well tolerated. Similar results were seen with once-daily mixed amphetamine salts (MAS XR) (McGough et al., 2005). This was a 24-month open-label study with 568 subjects. MAS XR was well tolerated and significant behavioral improvements were consistently maintaining during 24 months of treatment. Of the 568 children enrolled in the study, 273 (48%) completed 24 months of treatment. The number of subjects that discontinued due to adverse events in this study was higher than in the study of Wilens et al. (resp. 15% and 6.9%). Several clinical studies demonstrated the benefit of atomoxetine maintenance therapy in open-label extension and relapse prevention studies (Buitelaar et al., 2007; Hazell et al., 2006; Michelson et al., 2004; Newcorn et al., 2006; Wilens et al., 2006). A study compared two different atomoxetine maintenance doses (0.8 and 1.4 mg/kg/day) in 178 adolescents with ADHD in a 40 week study after a titration period of 8 weeks

590 (Wietecha et al., 2009). Both doses were equally well tolerated. The largest part of the clinical improvement was achieved during the acute treatment phase. Treatment benefit at 8 weeks was better maintained long-term with the 1.4 mg/kg/ day than with the 0.8 mg/kg/day dose. In both groups only 37% of the subjects did complete the maintenance treatment. Most patients discontinued the maintenance treatment because of adverse events. Two studies have investigated the effects of longer term treatment on executive functioning and on academic grades. In a 12 week open-label atomoxetine treatment trial among 30 drug-naïve male patients with ADHD the effect on executive functions was studied (Gau and Shang, 2010). A significant improvement in various non-verbal executive functions was achieved in addition to a significant reduction of ADHD-related symptom. Again, no placebo-control group was included and changes in performance may be due to practice effects. A 16week open-label study in 19 school-aged, Taiwanese children with ADHD reported a rapid improvement in academic grades after treatment with methylphenidate, despite a relatively low dosage (Yang et al., 2004). Because of the small sample size and a lack of placebo control group these results should be interpreted with caution. There is no information available on the long-term efficacy and safety of clonidine. However, the long-term efficacy and safety of another alpha adrenergic agonist, guanfacine extended release (GXR), have been investigated in 262 children and adolescents with ADHD in a 2-year open label extension study of antecedent trials (Sallee et al., 2009b). Subjects were titrated to 1, 2, 3, or 4 mg/day of GXR alone or in combination with a psychostimulant. The effects of GXR were early apparent and long lasting. Improvement scores at baseline were sustained throughout the study through end point. The majority of adverse events were mild to moderate. Early discontinuation occurred in 171 of 208 (82%) subjects in the monotherapy GXR subgroup and 31 of 54 subjects (57%) receiving a co-administered psychostimulant. Withdrawal of consent was the most frequent reason for discontinuation in both subgroups. This suggests that discontinuation is primarily due to the burden of participating in a clinical study with the associated investments in time for visits and completion of instruments, although this may be confounded by other reasons as lack of efficacy or safety issues. Again, these non-randomized observational studies of longer duration provide evidence for maintenance of early medication effects on ADHD symptom control over periods of 1–2 years. Positive effects on academic achievement and executive functions have been reported for periods around three to four months, but it is unclear to what extent these aspects improve in the long term.

3.4. Cohort studies Some cohort studies may provide useful information on the long-term effects of medication on ADHD and related disorders. In the UK cohort study described earlier (Langley et al., 2010), 63% of the sample reported being prescribed stimulant medication at the follow-up in adolescence. Those prescribed stimulant medication had significantly more ADHD symptoms and higher rates of ADHD diagnoses than those no longer using medication. This may be due to confound by indication in that children with more severe

G.H.H. van de Loo-Neus et al. ADHD may be prescribed medication more often than those with less severe ADHD. Medication use was not significantly associated with follow-up conduct disorder diagnosis or conduct disorder symptoms, binge drinking, cigarette or cannabis use. A retrospective study described stimulant medication treatment provided throughout childhood to 379 children with research-identified ADHD in the 1976–1982 Rochester, MN, birth cohort. Subjects were retrospectively followed from birth until a mean of 17.2 years of age. The complete medical record of each subject was reviewed, and school records were retrieved to obtain information about reading achievement, grade retention and school dropout (Barbaresi et al., 2006, 2007). The history and results of each episode of stimulant treatment were compared by gender, DSM-IV subtype of ADHD, and type of stimulant medication. Overall, 78% of subjects were treated with stimulants. The authors claimed stimulant treatment to be associated with improved reading achievement and less grade retention, but the average reading score at the time of the last assessment was similar between the group of cases that were treated versus not treated with stimulants. Further, the proportion of school dropout was similar between treated and untreated cases (Barbaresi et al., 2007). Thus, these cohort studies do not support statements that medication treatment of ADHD leads to improved longterm outcomes.

3.5. Case–control studies A case–control 10-year prospective follow-up study into young-adult years of children and adolescents with ADHD examined the effects of medication treatment on long-term outcomes (Biederman et al., 2009). At baseline, the study included 140 consecutively referred white children with ADHD and 120 non-ADHD matched controls, aged 6 to 18 years. At the 10-year follow-up, 112 (80%) and 105 (88%) of the children in the ADHD and control groups, respectively, were reassessed (mean age: 22 years). Of the 112 participants with ADHD, 82 (73%) were previously treated with stimulants. Participants with ADHD who were treated with stimulants were significantly less likely to subsequently develop depressive and anxiety disorders and disruptive behavior and less likely to repeat a grade compared with participants with ADHD who were not treated (Biederman et al., 2009). The strengths of the study are the case–control design and the long follow-up period, whereas limitations are that information on the treatments received and the onset of comorbid disorders was collected retrospectively. The results confirm the finding of an earlier small retrospective study in 75 children with ADHD that medication treatment of ADHD may protect for the onset of later depression (Daviss et al., 2008). Further, the results are somewhat in accordance with another prospective study on the relationship of childhood stimulant treatment to academic functioning during adolescence (Powers et al., 2008). A sample of 90 children with ADHD diagnosed when they were 7–11 years old, was reevaluated on average 9 years later. ADHD patients who did and did not receive treatment with stimulant medication were compared to each other and to a neverADHD comparison group (n = 80) on three subtests from the

To stop or not to stop? Wechsler Individual Achievement Test-II (WIAT-II), as well as high school grade point average (GPA) and number of retentions in school as derived from school records. ADHD patients treated with psychostimulant medication achieved better academic outcomes, as measured by WIAT-II subtests and school GPA, than those not treated with psychostimulants. There was no significant medication effect on the repetition of school grades. Overall, however, treated patients with ADHD did not fare as well as the never-ADHD comparison group. Nonetheless, these studies suggest that stimulant treatment is associated with long-term beneficial outcomes outside the domain of ADHD symptoms, which is at variance with the conclusions to be drawn from the MTA study to be discussed below.

3.6. Multimodal treatment study of ADHD (MTA) The most comprehensive study of the long-term effects of ADHD medication has been the Multimodal Treatment Study of ADHD (MTA) (The MTA Cooperative Group, 1999). The MTA study randomized 579 children with ADHD 7–10 years old to 4 conditions: (i) intensive intervention with medication management (MedMgt), (ii) intensive behavior modification therapy (Beh), (iii) the combination of these two (Comb) and (iv) treatment by their local clinician in the community (community comparison (CC)). The most important finding after 14 months was the superiority of both intensive medication groups (MedMgt and Comb) over the Beh and CC conditions (The MTA Cooperative Group, 1999). There were modest additional benefits of the combination treatment over medication alone. After the first 14 months the intensive protocolized treatments were abandoned and a naturalistic, prospective follow-up of the sample was conducted, where patients could be treated according to their clinical need and preferences. In the intention-to-treat analysis of the originally randomly assigned treatments at the 24 months follow-up, the MTA medication strategy showed persisting significant superiority over Beh and CC for ADHD and oppositional-defiant symptoms although not as great as at 14 months. Significant additional benefits of Comb over MedMgt and of Beh over CC were not found. Continuing medication use partly mediated the persisting superiority of Comb and MedMgt (The MTA Cooperative Group, 2004a, 2004b). At the 36 months follow-up, data were available of 84% of the original sample which was then 10 to 13 years old (Jensen et al., 2007). The originally assigned treatment conditions did not differ significantly on any outcome measure at 36 months. The percentage of children taking regular medication changed between 14 and 36 months across the initial treatment groups: Beh significantly increased (14% to 45%), MedMgt and Comb significantly decreased (91% to 71%), and CC remained constant (60%–62%). According to the MTA study protocol, the randomized treatment design was stopped at 14 months, and all children received community care after month 14. Regardless of their changes in treatment use, all of the groups showed symptom improvement over baseline. However, when compared to a local comparison group without ADHD, MTA children had at 36 months significantly higher rates of delinquency and substance use (Molina et al., 2007). The data indicated that children randomized to intensive behavior therapy had less 24-month substance use than other MTA

591 children, whereas more days of prescribed medication were associated with more serious delinquency but not substance use. Given the observational design, cause-and-effect relationships between medication treatment and delinquency are unclear. An important secondary analysis of the trajectory of ADHD symptoms in the first 3 years identified three classes: class 1 (34% of the MTA sample) with initial small improvement after 14 months followed by further gradual improvement over the years 2 and 3; class 2 (52%) with initial large improvement at 14 months that was maintained for 3 years; and class 3 (14%) with initial large improvement at 14 months followed by deterioration to pre-treatment level of symptoms (Swanson et al., 2007b). Class 2, when compared to classes 1 and 3, appeared to be less severely impaired at baseline, as reflected by higher IQ, higher birth weight, lower symptom scores and better prosocial skills. Furthermore, family characteristics differentiated between the classes, with class 2 having a lower rate of separation or divorce, and a higher family income. The consistent use of medication over 3 years made a significant contribution to the outcome in class 1 only, whereas the effect of medication status was not significant in classes 2 and 3. About 75% of the original MTA subjects did participate in a further follow-up 6 and 8 years after enrolment. The originally randomized treatment groups did not differ significantly on any clinically relevant outcome, including symptom scores of ADHD and other disruptive disorders, grades earned in school, arrests, psychiatric hospitalizations, and substance use (Molina et al., 2009). After the 14-month controlled trial 257 children of the total MTA sample used medication. Of this group 62% had stopped using medication at some point in time and were not medicated at the 8-year follow-up. But adjusting for this did not change the results. The only exception was that math achievement at 36 months and 6 and 8 years appeared to be related strongly to continuous medication treatment (Molina et al., 2009). The MTA participants fared worse than the local comparison group without ADHD on almost all of the variables tested. Thus, type or intensity of 14 months of treatment for ADHD in childhood or later treatments received did not predict functioning 6 to 8 years later. What did predict 55% of the outcomes at 8 year however was the trajectory of the ADHD symptoms in the first 3 years of the study, regardless of treatments received. That is, an initially strong improvement after 14 months that was maintained in the next 2 years (class 2 from Swanson's 2007 analysis) was related to a better outcome at 6 and 8 years later. The interpretation of the MTA findings is complicated by the switch in design after 14 months from a randomized trial to an observational study, and the lack of an untreated ADHD comparison group. As a group, all MTA participants did better in terms of symptom severity and impairment of functioning at 6 and 8 years than at baseline, but at the same time, they did not bridge the gap that separated them from the normative comparison group. The washout of the initial effect of the early intensive medication algorithm may be due to age-related decline in ADHD symptoms, changes in medication management intensity, starting or stopping medications altogether, or other yet unknown factors. The early ADHD symptom trajectory regardless of treatment type is prognostic, and children with behavioral and sociodemographic advantage, with the best response to any treatment, will have the best long-term

592 prognosis. It is unclear to which extent the limited effects of medication in the MTA study are due to poor adherence (Pappadopulos et al., 2009).

3.7. ADHD in adults So far, we reviewed long-term efficacy of medication in children and adolescents with ADHD. However, there is massive evidence that ADHD is an important and valid condition as well in adults, for review see Antshel et al. (2008), Barkley (2009), and Fayyad et al. (2007). Adults with ADHD may have been diagnosed in childhood or adolescence, and continuously using their medication from then onward. This medication use in Europe is covered by the childhood ADHD label. Alternatively, adults may have been clinically referred or self-referred and diagnosed with having ADHD after age 18, and been started on ADHD medication at adult age. In at least most of Europe at present only atomoxetine has a license for use in adults if previously prescribed in childhood. Further use is formally off-label in Europe. Numerous controlled and well-performed short-term medication trials have shown both stimulant and nonstimulant medication to be effective in controlling ADHD symptoms in adults, e.g. (Medori et al. (2008) and Michelson et al. (2003). The short-term efficacy of ADHD medication in adults is further supported by recent meta-analyses (Faraone and Glatt, 2010; Meszaros et al., 2009). However, similarly as for children and adolescents, the question for adults with ADHD is how long medication treatment should be extended. Aside from observational studies, no other long-term controlled or randomized treatment studies in adults have been performed. Thus, unfortunately, this question cannot be answered on empirical grounds.

4. Role of comorbid disorders It is the rule rather than the exception that ADHD is comorbid with other conditions, such as oppositional defiant disorder, conduct disorder, mood and anxiety disorder, tic disorder or learning problems. In case of comorbid ADHD more often a combination of treatment modalities will be indicated (Taylor et al., 2004). This may influence the need for longterm treatment with medication. However, extensive analysis of the MTA data failed to show a direct and decisive impact of the presence of comorbid conditions on the link between long-term efficacy of medication and long-term outcome (Molina et al., 2009).

4.1. Tic disorders A number of studies investigated the long-term efficacy and safety of medication in children with ADHD and comorbid tic disorders. A 2-year follow-up study evaluated long-term methylphenidate therapy in thirty-four prepubertal children with comorbid ADHD and chronic multiple tic disorder (Gadow et al., 1999). The treatment with methylphenidate seemed to be safe and effective for the management of ADHD in many but not all children. At the group level, there was no evidence that motor tics or vocal tics changed in frequency or severity during maintenance therapy compared with diagnostic or initial double-blind placebo evaluations.

G.H.H. van de Loo-Neus et al. The possibility of tic exacerbation in individual cases however could not be ruled out. A study randomized 136 children over four treatment groups with clonidine, methylphenidate and placebo for 16 weeks. Methylphenidate and clonidine (particularly in combination) were found effective for ADHD in children with comorbid tics (Tourette's Syndrome Study Group, 2002). Recommendations to avoid methylphenidate because of concerns of worsening tics were not supported by this trial. The efficacy and safety of atomoxetine were investigated in children with ADHD and comorbid tic disorders (N = 148) (Allen et al., 2005). Patients were randomly assigned to double-blind treatment with placebo or atomoxetine (0.5 to 1.5 mg/kg/day) for up to 18 weeks. Overall, treatment with atomoxetine was associated with both significant reduction of ADHD symptoms and of tic severity, compared to placebo. Atomoxetine did worsen tics only in 14% of the subjects whereas placebo worsened tics in 30% of the subjects. These results of the effects of atomoxetine in ADHD and tic disorders are very similar to those of a later report (Spencer et al., 2008). These results show that atomoxetine is efficacious for treatment of ADHD and well tolerated in children with comorbid tic disorders.

4.2. Autism spectrum disorders A common comorbidity of ADHD which so far has not been studied thoroughly and also was not addressed in the MTA study is the combination of ADHD and Autism Spectrum Disorders (ASD). Proportionally more children with ADHD and ASD are being treated with medication (3–75%) compared to children having only ASD (3–34%) (Gadow et al., 2006). This suggests that in clinical practice the need for a specific treatment approach for children with both disorders is recognized. Similarly, children with the combined diagnosis are more often hospitalized and receive special education compared to children with ADHD-only (Gadow et al., 2009), which is probably associated with their more severe and more varied symptomatology. However, the number of studies comparing treatment effectiveness in children with a combined ADHD–ASD diagnosis versus children with one or the other disorder is scarce, and often underpowered or suffering from methodological shortcomings (like being uncontrolled studies, not being double-blind evaluations, et cetera). It does appear, though, that similar to studies in ADHD-only patients, psychostimulants and noradrenergic reuptake inhibitors are effective in the treatment of inattention, overactivity and impulsiveness in patients with a combined diagnosis of ADHD and ASD (Aman et al., 2008; Handen et al., 2000; Posey et al., 2006; Santosh et al., 2006; Troost et al., 2006). Importantly, tics or repetitive behaviors appear not to be worsened by the use of psychostimulants in these children (Santosh et al., 2006). Antipsychotics, and alpha adrenergic agonists also appear to be effective, in contrast to newer antidepressants, anxiolytics and mood stabilizers (Aman et al., 2008). The magnitude of the effect of psychostimulants on ADHD symptoms appears smaller in ADHD plus ASD patients compared to ADHD-only patients and side effects may be more profound (Reiersen and Todd, 2008; Research Units on Pediatric Psychopharmacology (RUPP), 2005). Children with a ADHD plus ASD diagnosis seem to be in need of additional classes of pharmacologic

To stop or not to stop? agents (such as alpha-agonists, selective serotonin reuptake inhibitors and neuroleptics) (Reiersen and Todd, 2008). Data about the long-term efficacy of medication in complex cases of ADHD plus ASD however are lacking so far.

4.3. Other comorbidities The presence of comorbid anxiety did not appear to influence the clinical response to a standard dose of methylphenidate or the development of side effects in a 4month randomized trial (Diamond et al., 1999). Effects on anxiety symptoms were not measured. Atomoxetine was efficacious in reducing ADHD symptoms in a 12 week randomized trial in patients who have ADHD with comorbid anxiety and was well tolerated (Geller et al., 2007). There was also a significant reduction in independently assessed anxiety symptoms. In a 42 week continuation study, comorbid ODD did not influenced the rate of relapse of patients with ADHD during longer-term treatment with atomoxetine (Hazell et al., 2006).

5. Long-term safety Common short-term side effects of psychostimulant medication are insomnia, loss of appetite, irritability, gastrointestinal problems, and headaches (Greenhill et al., 2002), and those on atomoxetine decreased appetite, vomiting, nausea, dyspepsia and somnolence (Michelson et al., 2001). Most of the side effects, like headache, irritability, proneness to cry or gastro-intestinal problems tend to subside over time or can possibly be avoided or diminished with lowering the dose. Even sleep problems, which frequently occur in stimulant users can improve most of the time with another timing of the dose or trying medication of another class (Graham et al., 2011). Relevant for the questions addressed in this paper however are side effects that are not immediately apparent, but appear after months or years of use of stimulants, atomoxetine or other medication and/or may consist of cumulative effects on the physiology of the body or on the neurobiology of the brain of patients with ADHD. We will briefly review the evidence for such long-term safety problems, for a more extensive review see Graham et al. (2011).

5.1. Growth Reduced caloric intake or inadequate nutrition due to decrease in appetite, a side-effect of stimulants, may affect growth. Longitudinal growth data of children with ADHD treated with stimulants indicate a reduction in both height and weight gain, with a reduction in height of about 1 cm/year during the first 1–3 years of treatment (Faraone et al., 2008; Poulton, 2005; Swanson et al., 2007a). The reduction in weight gain appeared to be somewhat more pronounced than that for height. After the third year of treatment in the MTA study, the reduction of gain of weight (2.7 kg less than predicted) and height (2.0 cm less than predicted) leveled off and was maintained (Swanson et al., 2007a), but another study described reductions in expected height after several years of exposure (Charach et al., 2006). Data from this same study

593 suggest that stimulant effects on growth may be dosedependent, with greater growth deficits at higher doses of stimulants. Studies among preschoolers further indicate that children between 3 and 5 years of age using stimulants seem to be more vulnerable to growth problems than older children (Greenhill et al., 2006; Swanson et al., 2006). Periods of discontinuation of medication (drug holidays) may lead to rebound growth in children with medication-induced growth deficits (Pliszka et al., 2006). Thus, drug holidays should be considered in children with a growth of height or weight which significantly and negatively deviates from the child's percentile lines. Also switching to a non-stimulant could be considered. Older studies report that final adult height of children with ADHD who have been treated with stimulants for a long period of time, is not affected when compared against estimates of their predict height (Klein et al., 1988). Small effects on growth were also observed in children treated with atomoxetine during the first 2 years, but these effects washedout after prolonged treatment (Spencer et al., 2005, 2007). Overall, there is an enormous individual variability in the effects of ADHD medication on growth (Berman et al., 2008). Clinically, this translates into the need for careful and periodic monitoring of height and weight during medication treatment for ADHD.

5.2. Psychotic and manic symptoms It is known for a long time that stimulants have the potential to induce psychosis-like or manic-like symptoms in children, although this occurs very rarely (Lucas and Weiss, 1971). At high doses of psychostimulants, and in abusers of methamphetamine, a more potent psychostimulant, more circumscribed psychotic conditions can be induced. A recent systematic review of the United States Food and Drugs Administration (FDA) included 49 randomized controlled trials of ADHD medication and found a total of 11 psychosis/mania events during 743 person years of exposure with ADHD drug treatment compared to no psychosis events reported with placebo (Mosholder et al., 2009). There are no predictors for this alarming side effect (Ross, 2006). The majority of these reactions present no immediate danger but suicidal ideation, command hallucinations, increased aggressive urges and impaired judgement must be identified. Discontinuation of the stimulant is recommended and these psychotic or manic symptoms resolve generally in 24– 48 h. There is no strong evidence that psychotic reactions to stimulants predict later risk of bipolar or schizophrenic illnesses.

5.3. Suicidality The FDA added in 2005 a ‘black box’ warning to the product labeling of atomoxetine on the basis of a signal from the atomoxetine clinical trials database for a small but statistically significant increased risk of suicidal thoughts among atomoxetine-treated children and adolescents compared with patients in those trials taking placebo. A meta-analysis showed that suicidal ideation was more frequently observed in clinical trials among children and adolescents treated with atomoxetine (5/ 1357) compared to those treated with placebo (0/851) (Bangs et al., 2008). There was one suicide attempt in the atomoxetine treated group and no completed suicide occurred during the trials. There is unfortunately no systematic data in the public

594 domain about the occurrence of suicidal ideation and events associated with psychostimulant treatment. One should recognize that ADHD on itself, regardless of its treatment, is a risk factor for suicidal attempts (Young, 2008). Further, selfreported suicide-related events are common in children and particular adolescents who have neither been diagnosed with, nor treated for, ADHD. There is no evidence that the observed event rate of suicide-related events in children treated with ADHD drugs is greater than the expected rate in the general population.

5.4. Cardiovascular effects Recent reports of sudden cardiac deaths of patients taking both stimulant and non-stimulant ADHD drugs have alarmed clinicians, families and regulatory bodies. Sudden death is very rare in the general pediatric population (Nissen, 2006). Although sudden death, increased heart rate and QTc prolongation (prolongation of the total time for ventricular depolarization and repolarization) have been reported with methylphenidate, dexamphetamine and atomoxetine, overall insufficient data exists to truly demonstrate an increased sudden death risk with these medications (Warren et al., 2009). A recent retrospective study concluded that exposure to methylphenidate and amphetamine salts showed similar risk for cardiac emergency department visits (Winterstein et al., 2009). All stimulant medications for the treatment of ADHD are reported to cause on average small elevations in blood pressure and heart rate (Wilens et al., 2004). In some individual patients, this rise in heart rate and blood pressure may be more significant and move them into the range of having clinically relevant tachycardia and hypertension. Although in theory small but persistent changes of heart rate and blood pressure could by a cumulative effect over time contribute to intimal plaque formation, left ventricular hypertrophy and increased incidence of cerebrovascular disease in adults (Lewington et al., 2002), they are unlikely to be a risk factor for serious cardiac pathology. Systematic data to quantify this risk are not yet available. Therefore, the clinical message is to perform a pre-treatment evaluation into individual risk factors, and to acquire an ECG in children with higher risks. Further, to monitor heart rate and blood pressure regularly during medication treatment and adapt the medication regime when increases of heart rate or blood pressure move them into the clinical range, even more so when the patient has other risk factors for cardiovascular disease such as obesity, unhealthy lifestyle and familial vulnerability.

5.5. Effects on the brain Psychostimulants exert powerful effects on the brain's neurotransmitter systems, in particular on the dopaminergic system. Prolonged exposure of experimental animals to acute high and parenterally administered doses of amphetamine or the more potent amphetamines has shown to induce neurotoxic effects on the dopaminergic nerve terminals, which were found to persist for years after the drug exposure had been terminated (for a recent review, see Berman et al., 2009). These deficits were not accompanied by damage of the dopamine-containing cell bodies in the substantia nigra. There are marked species differences in

G.H.H. van de Loo-Neus et al. vulnerability to the neurotoxic effects of stimulants (Advokat, 2007). Therefore, the relevance of these data to the consequences of the prescription of low dose orally administered methylphenidate or amphetamines in humans is unclear. Structural MRI studies found that unmedicated ADHD children had smaller brain white matter volumes than stimulant-treated children with ADHD or children without ADHD (Castellanos et al., 2002). Further, no differences in the initial cortical thickness or the course of cortical thickness development has been found between medication naive children with ADHD and medicated children with ADHD (Shaw et al., 2009). The interpretation of these studies is limited by their observational designs and lack of randomization of treatment. However, the data suggest at least that early stimulant treatment may normalize brain white matter volume and does not interfere with changes of cortical thickness over age in ADHD. Systematic prospective large scale neuroimaging studies into the possibility that chronic stimulant treatment is associated with enduring functional changes of the setpoint, activation pattern or efficiency of the dopaminergic or other transmitter systems of ADHD patients are lacking but very needed.

6. Conclusions and recommendations ADHD medications have shown to lead to powerful short-term effects in reducing the key symptoms of ADHD in numerous wellcontrolled clinical trials. These effects however seemed to be short-lived, and disappear when medication is discontinued. The data from the atomoxetine discontinuation study suggests however that at least for some patients the effects of atomoxetine do not always fade away when medication is stopped (Buitelaar et al., 2007). Since ADHD is a chronic condition with a strong persistence over time, we might hypothesize long during symptom control by extended use of medication nonetheless to provide long-term benefits in several ways. First, long during and stable symptom control might facilitate the acceptance of, and compliance with, nonpharmacological interventions or even augment their effects. Second, the yield of longstanding symptom control might be translated and capitalized into long-term improvement of social functioning, academic achievement, employment status and into lowering the risk for secondary complications as substance use, and antisocial and delinquent activities. Third, medication induced symptom control might help the child with ADHD to bridge and survive a difficult developmental period until agerelated decline of symptoms would lead to a developmental normalization. The current data however do overall not provide support for this hypothesis. The data indicate that intensive medication management provides for a strong reduction of ADHD symptoms, and also less impairment of functioning for at least 2–5 years or so. There is limited and inconsistent evidence for long-term effects of stimulant medication on reducing the development of comorbid disorders and school grade retention (Biederman et al., 2009). For the majority of children with ADHD, long-term follow-up data fail to provide support for long-term advantages of medication treatment in addition to the effect of ADHD symptom control. The analyses of the MTA study (Molina et al., 2009; Swanson et al., 2007b) and placebo-controlled discontinuation design

To stop or not to stop? studies with atomoxetine (Buitelaar et al., 2007) suggest that quite a subsample of children with ADHD show a strong positive response to medication in the first 2 years of treatment, may consolidate their treatment benefits thereafter and stay rather stable when medication would be withdrawn. For another group of patients, continuous use of medication over months and years appears to lead to gradual further improvements of symptom control and lesser impairment. The suggestion that this might lead to further improved functional outcomes until after 3 years however is not supported by the MTA follow-up at 6 and 8 years. There is the possibility that for yet another group of patients, class 3 in Swanson et al. (2007a, 2007b) analysis, an intensive medication treatment protocol should be provided for a longer period than just the first 14 months in order to avoid relapse to pre-treatment level of symptoms. The outcome of long-term treatment studies challenges the theoretical models outlined above about how short-term symptom control could be translated into long-term benefits. There is no evidence for superiority of combination treatment of medication and intensive behavioral therapy at the long-term, inconsistent evidence for strong secondary spin-off effects on social development, achievement status, and comorbidity, and no evidence that children with ADHD will catch-up and normalize in adolescence or young adulthood after having been medically guided through a difficult period of development. There are growing concerns over the long-term safety of ADHD medication. However, evidence suggests that longterm risks for delay of growth, induction of psychotic or manic symptoms or suicidality, cardiovascular disease and death, and neurotoxicity seem to be very minor. Further, the overall balance between these potential long-term risks and the documented benefits of symptom control is on the positive side. Careful and systematic monitoring of side effects during long-term treatment is necessary and should be able to detect early alarming signals. Nevertheless, longterm safety of the ADHD medication is not fully known, and further research into several areas, such as long-term effects on the brain, growth, suicidality and adverse psychiatric outcomes is needed. A recently EU 7th Framework funded program (ADDUCE–ADHD Drug Use Chronic Effects) will have a closer look at several of these issues. Current treatment studies, including the MTA, unfortunately lack any information about the genetic make-up of the patients, their pattern of cognitive strengths and weaknesses, and measures of structure and function of their brains. Recent data suggest these to be potentially important by showing that the pattern of cortical thickness in childhood is related to outcome in adolescence (Shaw et al., 2006, 2007). Thus, we are yet unable to profile the patients in terms of genetic, cognitive and neural characteristics and add a neuroscience level to the prediction of long-term effects of treatment and outcome. The same applies to our lack of knowledge about individual characteristics that determine the risk for long-term safety concerns. It is also unknown what the psychological impact is of longterm medication use on the self image of children with ADHD. To which extent do they perceive the medication as helpful, and to which do they feel stigmatized? Many children with ADHD discontinue their medication in adolescence, and the reasons for discontinuation are poorly understood. Even when children are

595 using medication for a long period of time, clinicians should be attentive to offer additional treatment modalities that might be useful, such as behavior therapy, social skills training, family support, and coaching. There is further definitely a need to enlarge the evidence for the short-term and long-term effects of non-medication treatments, such as the restricted elimination diet (Pelsser et al., 2011), cognitive training (Klingberg et al., 2005), and neurofeedback (Arns et al., 2009). The results of this review mean that clinical decisions about starting, continuing, and stopping ADHD medication have to be made on an individual basis. As previously mentioned sideeffects will be a reason to stop taking medication in only a small number of cases. Most side-effects can be dealt with in a satisfactory way by an adjustment of the dose. Comorbidity in general does not change the clinical decisions in choosing medication. Most comorbidities do not negatively influence the effect of medication on ADHD symptoms, except possibly for autism spectrum disorders. There is some evidence that tics or anxiety will improve through the use of atomoxetine, but both atomoxetine and stimulants will not exacerbate tics or anxiety. It is still unproven that disruptive behavior or substance use will diminish by treating ADHD with medication, despite positive claims on the basis of observational case–control studies (Biederman et al., 2009). On the contrary, disruptive disorders seem to persist and evolve despite medication (Langley et al., 2010). Long-term guidance remains necessary for this group. Overall, when medication is prescribed, it should be offered in a systematic and protocolized way, with regular visits and with a clinician's keen eye to look for room for further improvement and with systematic strategies to optimize adherence, in particular in adolescents with ADHD, as has been shown by the lessons from the MTA study. We can neither recommend that all children and adolescents with ADHD should be medicated for years and years, nor that medication should be stopped after at most 2 years of treatment. Clinical experience shows that a substantial subsample of children with ADHD continue benefitting from long-term medical treatment in terms of ADHD symptom control, while other children with ADHD fail to show beneficial effects of medication after 1 or 2 years. We cannot make predictions about the length of medication treatment needed just at its start. Rather, it seems reasonable and in accordance with expert opinion that we should implement periodic, probably annually, medication free periods, also in adults with ADHD. This should be implemented to check for the need for, and ongoing benefits of, medication. The task of the clinician is to decide when it is needed and how to execute this. To prevent that the rebound effect is confounded by emerging ADHD symptoms, a medication free period should last several days to one week or longer. Some colleagues would prefer to use an N-of-1 trial which turns out to be an effective method to identify optimal treatment in patients in whom disease management is uncertain (Nikles et al., 2006; Scuffham et al., 2010). Unfounded assumptions about continuing benefits of medication use should be abandoned.

Role of the funding source None.

596

Contributors All authors performed literature searches and contributed equally to the writing of the manuscript.

Conflict of interest Jan K Buitelaar has been, in the past 3 years, a consultant to / member of advisory board of / and/or speaker for Janssen Cilag BV, Eli Lilly, Organon/Shering Plough, UCB, Shire, Medice, and Servier. He is not an employee or a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. Gigi HH van de Loo-Neus has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Janssen Cilag BV, Eli Lilly, UCB, Shire and Medice. She is not an employee or a stock shareholder of any of these companies. She has no other financial or material support, including expert testimony, patents, and royalties.

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