hyperactivity disorder: assessing outcomes.

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Pharmacological treatment of attention-deficit/hyperactivity disorder: assessing outcomes Expert Rev. Clin. Pharmacol. 8(4), 383–397 (2015)

Nicoletta Adamo*1, Sarah Seth1,2 and David Coghill1,2 1 National Health Service Tayside, Child and Adolescent Mental Health Service, Dundee, UK 2 Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK *Author for correspondence: Tel.: +44 013 8220 4004 [email protected]

A substantial body of evidence has supported the efficacy and safety of pharmacological treatment available for attention deficit/hyperactivity disorder (ADHD). There is increasing agreement that the important treatment outcomes for ADHD extend beyond improvement in core symptoms and that a more generic (or global) concept of remission is the overarching goal of treatment. However, there is no consensus on the best definition of remission or on how best to conceptualize and measure broader treatment outcomes. In this article, we provide an overview of the various methods and approaches to measuring treatment outcomes for ADHD with respect to symptoms, impairment, quality of life, adverse events and safety as well as cognition. We will describe the ways that they may be used within routine clinical practice and think ahead about the kinds of studies that are required to move the field forward. KEYWORDS: ADHD . adverse events . cognition . functional impairment . quality of life

Excessive inattention, hyperactivity and impulsivity that are present across different settings and have a significant negative impact on a child’s global functioning represent the main features of attention deficit hyperactivity disorder (ADHD), the most common mental health disorders of childhood [1]. Individuals with ADHD have been found to have significantly worse educational, economic and social outcomes, more divorces, higher death and accidents rates, number of psychiatric hospitalizations and incarcerations than non-ADHD individuals [2–5]. Adverse outcomes on driving performance [6] and higher obesity rates have been found among male adults diagnosed with ADHD as children [7]. Reported clinical outcomes in ADHD in prospective longitudinal studies are highly variable, ranging from full remission and absence of functional impairment to relatively poor [8–11]. Increasing evidence has shown that such poor long-term functional outcomes can be prevented, or at least moderated, by appropriate ADHD treatment [4,12–17]. It is now largely accepted that the pharmacological treatment for ADHD is highly effective in reducing symptom severity either alone or in combination with behavioral interventions, has greater

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benefits than behavioral intervention given alone, and that outcomes are improved when a more structured approach to medication management is adopted [18]. The first-line treatment for ADHD is represented by the psychostimulants, methylphenidate, dexamfetamine and the amfetamine pro-drug lisdexamfetamine, each of which reduce symptoms in approximately 70% of patients [19–21]. As shown by recent reviews and a meta-analysis [22,23], strong evidence also supports the efficacy of atomoxetine, a non-stimulant medication, with approximately 45% of individuals responding to treatment. Among the non-stimulants, the a-2-adrenoceptor agonists guanfacine and clonidine have also increasingly been shown to be effective both as standalone [24] and as adjunctive treatments to psychostimulants [25,26]. A large body of research, including systematic reviews and meta-analyses, has corroborated this in children and adolescents, showing medium-to-large effect sizes (0.6–1.0) and low number needed to treat (NNT = 4) for both stimulants and non-stimulants [22,27–29]. Similar to pediatric populations, stimulants have also been shown to be effective in adults with ADHD, although the effect sizes are probably somewhat smaller (~0.6) [30,31].

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Adamo, Seth & Coghill

The primary outcome of these efficacy studies is almost exclusively response to treatment as measured by a change in ADHD symptoms. Although several rating scales and measures are available for the ADHD symptoms, there is evidence that measuring symptomatic reduction or remission following treatment with medication based on one informant’s report only (e.g., parent or teacher) can be somewhat unreliable. Clinical guidance provided by agencies regulating pharmacological trials has therefore required that multiple informants, who could also include the patient, be involved in the outcome assessment. While most available measures are valid and reliable, investigators continue to work on what is the best approach to objectively evaluate the response to pharmacological treatment. Broader functional outcomes were not initially required by the regulators and were therefore not traditionally included in the industry-led studies that make up the bulk of the recent literature [32]. More recent general and ADHD-specific guidance from the regulators has imposed that companies demonstrate evidence for broader efficacy and led to increased interest in the impact of treatment on a range of functional outcomes as well as quality of life (QOL). To a large degree, this has been driven not by a desire to better understand the impact of treatment but to demonstrate value for money and assist setting appropriate levels of price and reimbursement in health care. It is, however, expected that greater symptom reduction will be associated with greater improvements in overall functioning. Accordingly, Buitelaar et al. [33] identified that a symptomatic reduction of at least 50% was generally associated with clinically significant functional improvement. However, it is also the case that the association between symptoms and impairment or between symptoms and QOL is far from perfect. ADHD is not solely about the core symptoms of the disorder but also about the impact these have on the child’s life. Indeed, despite robust reduction in the core ADHD symptoms following pharmacological treatment, a substantial number of patients in community care continue to experience significant ADHD-related impairments [34,35]. As a consequence, when assessing outcomes both in clinical studies and day-to-day clinical practice, it is important to evaluate not only symptoms but also more general functional impairments and QOL consistent with a broader definition of remission. Specifically, Steele et al. [36] have proposed that both investigators and clinicians should aim for a full remission, which would imply: a loss of diagnostic status, minimal or no ADHD symptoms and optimal functioning. In addition to reduced symptoms and functional impairments, it is also essential to monitor safety and treatment-emergent adverse effects (TEAE). Pharmacological trials have at times solely relied on spontaneous reporting of side effects and serious adverse events, potentially taking the risk of missing some TEAE. The introduction of the good clinical practice (GCP) guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use-Good clinical practice (ICH-GCP) has brought more standardized monitoring of both aspects. Yet, there remain questions about methods for measuring and reporting safety and 384

TEAE [37]. Furthermore, there is a relative lack of information about long-term safety of ADHD medications [38]. Within ADHD research, neurocognition is one particular outcome that has been partially neglected and has the potential to impact in both a positive and negative way on the outcome. There is considerable evidence that ADHD medications can improve function across several cognitive domains that are known to be impaired in ADHD [39]. However, there are also concerns that the same medications that help reduce ADHD symptoms may also affect aspects of cognition, such as cognitive flexibility and perseverance [40]. Recent evidence has suggested that there may be a relative dissociation between cognitive and symptomatic aspects of ADHD [41,42]. In part, this may explain why for some individuals with ADHD, symptom reduction alone is not enough to produce a full remission as defined above. Importantly, at a neurocognitive level, ADHD is a highly heterogeneous condition [43–46]. One consequence of this is that cognitive testing is not helpful in making a diagnosis. Yet, different cognitive profiles may predict different treatment responses. For these reasons, we believe that cognitive outcomes are potentially very important and that, in the future it may be possible to use differential cognitive profiling to partition those with ADHD into meaningful subgroups which can be used to allocate treatments in a more evidence based way than is currently possible. In this article, we will provide an overview of the various methods and approaches for measuring treatment outcomes of ADHD treatment with respect to symptoms, impairment, QOL, adverse events, and safety as well as cognition. We will describe how these outcome measures may be utilized within routine clinical practice and think ahead about the kinds of studies that are required to move the field forward. Symptoms

Pharmacological trials on ADHD almost routinely assess efficacy during treatment. In the past, symptoms outcomes were generally measured using parent-report questionnaires, such as the Conners’ Parent Rating Scales [47], the Vanderbilt Assessment Scales [48,49], the ADHD-IV Rating Scale (ADHD-RS; [50]), the Swanson, Nolan, and Pelham, Version IV (SNAP-IV; [51]), and the Home Situations Questionnaires [52]. Each of these instruments has been shown to have acceptable validity and reliability (for a review see [53]). However, using these measures as a parent-rated questionnaire poses a relatively high risk of bias, as it involves the parent providing rates based on their own observation and impressions [54] and might be influenced by various factors including the educational background of the parent or caregiver [55]. To ascertain more objective assessment of symptomatic reduction, recent clinical trials have used clinician ratings based on reports from both patient and parents. Indeed, recent EMA guidelines have required clinician ratings based on multi-source information (parents, teachers and patient when available) as the primary outcomes for the conduct of clinical trials in ADHD, schizophrenia and depression, with similar recommendations in development for autism [56–59]. Specifically, the questionnaire or verbal account Expert Rev. Clin. Pharmacol. 8(4), (2015)


Pharmacological treatment of ADHD

is used as the basis for a semi-structured interview and the clinician makes the final rating based on their interpretation of all available information. Do¨pfner et al. [60] confirmed the crosscultural reliability and validity of this method using the ADHD-IV-RS in a European sample. Using this approach for the estimation of symptom severity has the advantage that the clinician can take into account the effects of confounding factors such as 1:1 support in the classroom, balance and summarize parent, child and teacher(s) reports in a single score, and assess whether the ADHD symptoms are pervasive and consistent across settings and result in functional impairments. In clinical practice, the same approach can be used to measure symptom outcomes at the initial stages of treatment (i.e., while titrating ADHD medications up to optimal dose) and during continuing care to monitor longterm effects. This is particularly helpful given recent evidence that routine clinical ADHD care often results in relatively poor outcomes [11] and consistent with the findings from the multimodal treatment of attention deficit hyperactivity disorder (MTA) study that suggest that a well-organized and structured medication protocol is better than routine care (MTA Group, [61],). Accordingly, in light of the results of the MTA and based on our experience with measuring outcome in clinical trials, a model of clinical care, which includes a clinician-rated measure, (i.e., ADHD-RS) has been developed in our clinical service [10], showing a response rate to stimulants comparable to that observed in controlled randomized clinical trials (e.g., [21]). It is important to consider, however, that the use of clinician rating scales only partially overcomes the bias of a single reporter in that it relies on parent and patient’s account of symptoms frequency which might not include an accurate measure of school functioning. Recent efforts indicated that the identification of ADHD cases at the time of diagnosis varies dramatically, depending on whether information is derived from one or two informants (e.g., parent only or parent and teachers; [62,63];). Indeed, to assess ADHD symptoms and treatment-related improvements in symptoms in routine clinical practice, it would be ideal to evaluate teacher ratings, including, for example, the Conner’s Teacher Rating Scale [64], the Vanderbilt Rating Scale–Teacher Version [49], and the Barkley School Situations Questionnaire [52]. Yet, while evaluating teacher ratings is important, it has been difficult to obtain such measures for efficacy studies and the assessment of outcomes in most clinical trials has been mostly performed with the evaluation of parent and child reports. Given some indication that both parent and teacher reports can be biased when aware of ongoing treatment [65], investigators have also studied and compared the efficacy of stimulant medications in a more experimental classroom setting, the Laboratory School Protocol [66,67]. In such a controlled environment, the children’s sustained attention was directly tested by administration of the 10-min Math Test [68], and trained observers could rate the response to treatment using the Swanson, Kotkin, Agler, Mlynnm and Pelham rating scale (SKAMP; [69]). This innovative approach has also proven useful in measuring treatment response throughout informahealthcare.com

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the day when repeated ratings were collected on the same day [67]. The lab school protocol is also potentially helpful in assessing outcomes of non-pharmacological treatment such as parent training and diet interventions where it is difficult to keep parents blind to the study condition. We have found the SKAMP to be very helpful as a teacher rated outcome measure in routine clinical practice [10]. It has a high level of face validity with teachers who are therefore much more likely to complete and return the questionnaires. While the focus of this article is on the management of the core symptoms of ADHD and related functional impairments, it is important to acknowledge that ADHD is often comorbid with other disorders. There is, for example, evidence to suggest that the presence of coexisting disruptive behaviors alongside ADHD has an impact on ADHD outcomes [70]. We strongly support that a full range of possible comorbid psychiatric and developmental disorders are considered during the assessment process and that in depth assessments are conducted as indicated. Furthermore, as the presence of disruptive behaviors, emotional problems and other symptoms or difficulties might impact on the clinician’s judgment of the response to treatment [71], monitoring the severity of comorbid symptoms during the ADHD treatment at follow-up visits is an important part of the assessment. While there are occasions (e.g., severe depression or psychosis) where the treatment of a comorbid disorder will precede the treatment of ADHD, it is also common to start treatment for ADHD in the presence of another disorder. In such cases, it is clearly necessary to also monitor the progression and outcomes for that disorder. In general, we would support the use of specific scales relevant to the coexisting disorder in the same way as one would when treating that disorder in isolation. A full discussion of the appropriate scales is beyond the scope of this article; however, we would point out that in addition to the inattentive and hyperactive/ impulsive subscales, the SNAP-IV [51] allows for measuring changes in DSM-based symptoms of oppositional defiant disorder (ODD). Also, the ODD symptom reduction has been measured with parent and teacher versions of the Day Profile of ADHD Symptoms rating scale [72], which has shown good validity also for rating over weekly compared with daily periods of observation. Improvements in the emotional lability (EL) often associated with ADHD have also been associated with treatment with stimulants. Using the EL subscale of the Conners’ Parent Rating Scale, a large study demonstrated the effects of lisdexamfetamine on EL [73]. Recently, the10-item parent Emotional Dysregulation Scale and the self-report, six-item Emotional Lability Scale have been developed [74]. Similarly, the freely available Affective Reactivity Index scale [75] is likely to facilitate a shorter, yet reliable measure of EL. Following a plea for more objective measures, the use of actigraphy has been increasingly proposed as a potential approach to assessing ADHD treatment outcomes with regard to behavioral activity levels [76]. Along the same lines, more wearable technologies are being developed and these approaches might grow over the next few years offering clinicians the 385


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opportunity to monitor ADHD symptoms and treatment response remotely with the aid of mobile phones (for further details see the Mind Tech programme at http://www.mindtech. org.uk/projects.html). Emerging technologies with potential to assist in the assessment of outcomes also include the Qbtech test (e.g., [77]), which administers a computerized task to the individual while measuring his attention, impulsivity and movement while doing this task (https://www.qbtech.com/ qbtest.html; also see below in ‘Cognition’). While it is generally agreed that a more categorical outcome (i.e., remission) would help assess the response to ADHD treatment, as yet there is no accepted definition of remission. In many ADHD pharmacological trials, the clinical response has been defined as symptom remission by measuring the reduction from baseline on one of the symptomatic rating scales, such as the ADHD-RS (e.g., total score £18) or the SNAP-IV (e.g., endpoint mean per item score of £1) [78]. However, while informative, changes in mean rating-scale scores cannot describe the degree of symptom improvement experienced at an individual level. Therefore, investigators have started looking at the number of ‘responders’ to the specific pharmacological treatment, with the responders being defined as those individuals with a pre-determined percentage of symptom reduction in the rating scales (e.g., ADHD-RS). Thus, by changing the focus of outcome from the statistically significant to the clinically significant change [79], the responder analysis approach is based on an individual rather than a group response. Specifically, the approach applies the Jacobson and Truax methods [79], in which the degree of change at the level of the individual is measured in the context of observed changes for the whole sample by dividing it for the standard error of the pre-/posttreatment change. This has facilitated comparisons of the efficacy between atomoxetine and lisdexamfetamine [80], lisdexamfetamine and extended-release methylphenidate [81] and atomoxetine and guanfacine [82], independent of the mean changes in ADHD-RS. The adoption of the responder analysis method is allowing us to start moving toward a more empirical and standard method of defining response in more basic science studies. However, it is still necessary for investigators to agree on a standard definition of response and our vote would go to the adoption of the Jacobson and Truax approach [79,83]. This approach, originally designed for use in psychotherapy outcome trials, facilitates the empirical calculation of two complementary metrics; the Reliable Change Index, which is the minimum change from baseline that signifies a real and reliable change, and the Clinically Significant Change, which is the cut-off between the ‘clinical’ and the ‘healthy’ populations. Guidelines on drug development in ADHD also now insist that there is evidence of relapse prevention before a drug is awarded a license [56]. Specifically, this entails defining criteria for relapse and then measuring the rate of relapse following a blinded placebo–controlled, randomized-withdrawal of an active treatment from subjects who have demonstrated a good response to this treatment. Using such a design, investigators have provided evidence of high relapse rates following blinded 386

withdrawal from long-term treatment with lisdexamfetamine [84] as well as short-term treatment with methylphenidate [85]. Rates of relapse following withdrawal with atomoxetine differed between children who were randomized to placebo after an initial trial with medication and those who continued to receive active treatment and were much lower than anticipated [86,87]. Impairment & quality of life Functional impairment

Symptom reduction and clinical response based on symptom levels have initially been frequently used outcome measures. More recently, definitions of clinical response that go beyond the symptom relief and that include a combination of symptom rating scales and more generic measures of outcome have been proposed [36]. Both previous (DSM-IV) and currently available (DSM-5 and ICD-10) classification systems for psychiatric disorders emphasize that in addition to meeting the symptom criteria, it is important for there to be significant impairment in one or more areas of functioning to make the diagnosis of ADHD. Therefore, when measuring ADHD treatment outcomes, it would seem important to also monitor functional impairments [88]. While treatment-related changes in impairment were often not included in past studies, this is now becoming the norm. Specifically, the recent drug development regulations mentioned above require functional measures as a part of the regulatory process [89]. This was driven by the need to justify not only clinical effectiveness but also cost–effectiveness of a treatment and provide evidence to support discussions about price and reimbursement for healthcare providers. In the research context, investigators typically complete an evaluation of functional impairment as part of the general assessment of diagnostic criteria and inclusion into a trial through the use of standardized assessment tools, such as the Schedule of Affective Disorders and Schizophrenia for Children-Present and Lifetime Version (K-SADS-PL; [90];). However, the K-SADS and other diagnostic interviews are not well suited for use as outcome measures as they do not allow for a dimensional rating that can measure change as a continuous variable. Several scales have been validated for the assessment of functioning impairment based on the clinicians’, parent, child or teacher reports, some of which are generic and assess the overall severity of impairment and some of which are disorder specific and focus on ADHD-related impairments. Together with symptomatic remission, reduction in the impact of ADHD into the daily functioning, or syndromal remission, has often been assessed using the Clinical Global Impression of Severity of Illness for the ADHD diagnosis (CGI-S; e.g., a post-treatment score £2). In addition, a change in score on the Clinical Global Impression Improvement (CGI-I; post-treatment >2) with regard to the ADHD condition is commonly used as primary outcome measure in clinical trials and appears as a common measure in systematic reviews and meta-analyses [23,24]. Both scales have also been demonstrated to be valid and reliable in clinical settings [91]. Another commonly used generic clinician-based scale in pharmacological Expert Rev. Clin. Pharmacol. 8(4), (2015)



trials for ADHD and increasingly in clinical practice is also the Children’s Global Assessment of Functioning (CGAS; [92,93]). Other well-validated scales that are used less commonly include the Columbia Impairment Rating scale [94,95] and the Child and Adolescent Functional Assessment Scale [96]. Recently, several measures have been developed with better specificity for ADHD-related impairments than these generic scales. Of these, the Weiss Functional Impairment Rating ScaleParent Report (WFIRS-P) is the best known. The WFIRS-P is a free publicly available ADHD-specific instrument that measures typical day-to-day problems associated with ADHD symptoms [97,98]. It covers several aspects of everyday functioning, such as family, school, life skills, child’s self-concept, social activities and risky activities. The WFIRS-P has demonstrated internal consistency, sensitivity to change and convergent validity with the more generic Columbia Impairment Scale and the Global Assessment of Functioning [99]. However, despite communications of promising initial psychometric properties [88], the use of the WFIRS-P is currently supported by only a few published psychometric studies and limited normative or reference population data. More importantly, while a value of 0.5 standard deviation has been used as a meaningful group difference between ADHD and comparison at baseline [100], it remains to be confirmed what minimum score change in the WFIRS-P after ADHD treatment reflects clinically relevant improvements in functional impairment. Recent functional outcome findings on response to treatment with stimulants reported mean WFIRS-P total scores for untreated ADHD (i.e., at baseline) of around 1 (based on a 0–3 Likert scale where 0 is best and 3 worst), and showed that even those children with severe ADHD only scored positively on a small number of items on each of the 10 subscales [101]. Although the scale’s psychometric properties appear to be acceptable when used for differentiating large groups of children with ADHD from typically developing children or measuring treatment-related changes in clinical trials, the WFIRS-P scores may not reliably measure functional impairment at the individual level and therefore may not be helpful when used in clinical practice. The parent-report ADHD Impact Module (AIM) was also developed to assess the specific effects of ADHD symptoms on the person’s role, their emotional and social well being with the additional focus on the impairment within the family [102]. The AIM has demonstrated both baseline function impairment and significant improvements in functioning following stimulant treatment in a number of studies on adults with ADHD [103]. However, we are unaware of any published findings of treatment response data on the AIM indices in children and adolescents and its use has been limited possibly related to its high cost. A similar, freely available tool is the Family Strain Index, a short (6-items) and reliable questionnaire designed to measure the burden experienced by parents and families with children with ADHD [104]. Using the Life Participation ScaleChild Version (LPS; [105,106];), which was designed and validated to measure changes in ADHD-related adaptive functioning and QOL, Buitelaar et al. [33] further demonstrated the informahealthcare.com

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importance of assessing the impact of symptoms on the global functioning. Specifically, the ADHD treatment appeared to result in a measurable functional improvement when children presented with a sound symptom reduction in the ADHD. Several guidelines stress the importance of taking the child’s or young person’s view into account when determining the clinical significance of ADHD-related impairments (NICE clinical guidelines for ADHD, http://www.nice.org.uk/guidance/cg72). However, it has been shown that children and adolescents are less likely to acknowledge the full impact of ADHD on their overall functioning and that they tend to overestimate their abilities and skills in specific functional domains, including, for example, academic and social performance [107]. Furthermore, child reports have been identified as having a relatively low reliability [108]. Therefore, the use of child report alone in the assessment of functional impairment assessment is probably not wise. Quality of life

In addition to reductions in symptoms, improvement in functional impairment and remission, an improvement in the health-related QOL is increasingly identified as a key goal of ADHD treatments [109]. QOL has been defined by the WHO as “the individual’s perception of their position in life, in the context of culture and value systems in which they live, and in relation to their goals, expectations, standards, and concerns” [110], with health-related QOL being the impact of illhealth on QOL. Similar to the functional impairment outcomes, demonstrating improvements in QOL has also been included as a requirement for the development of clinical programs by the EMA in their guidance for ADHD [89]. A broad range of generic measures has been used to assess QOL in ADHD populations. The Child Health Questionnaire, the Pediatric Quality of Life Inventory 4.0 (PedsQL), and the Child Health and Illness Profile (CHIP) all have both child- and parent-rated versions and have shown acceptable reliability and validity [111–113]. These generic scales explore a variety of nonADHD-related difficulties in areas ranging from physical health to psychosocial components, such as emotional well-being, integration, and functioning in social and school domains. While it is generally accepted that QOL is best thought of as a multidimensional construct and that it is not usually adequate to give a single score outcome, there is, as yet, no real agreement on how best to define the various domains of QOL and the various measures classify different components in different ways. ADHD has significant impact on QOL with scores on the various domains and subdomains often around two standard deviations below the norm. This impact of ADHD on QOL appears to be at least, if not more, as great as that associated with physical conditions, such as asthma [114] and diabetes [115]. Using the parent version of the CHIP, several studies have reported very similar ratings for impaired QOL in independent samples of children with untreated ADHD [33,101,115,116]. Similar to what has been reported for functional outcomes, the children and adolescents with psychiatric disorders do not perceive their own QOL to be as impaired as it is rated by their caregivers [109,117]. 387


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This is in agreement with several reports of only partial convergence between child and parent proxy-reports of QOL and psychosocial functioning [118,119]. The risk is that some domains, like the family relationship, might not be divergent from functional impairment measured by the family functioning scales, such as in the parent-rated LPS described above [33]. In addition, it is important to consider the possibility of bias due to the impact of the child’s ADHD onto the parents’ emotional distress and QOL [120–122]. Although there is emerging evidence for more convergence between child and parent ratings of the poorer QOL in ADHD, the degree of convergence seems to be dependent to some degree on which scale is used [115,123]. Based on current understanding, it is recommended that information from multiple reporters should be collected and that the child-report versions should be considered as the first informant of his/her health-related QOL. Available evidence suggests an association between higher levels of symptoms predict poorer health-related QOL. However, while these associations are statistically significant, they tend to be small to moderate in strength, indicating that QOL and symptom scales are tapping into relatively independent domains [109,115]. The use of QOL measures in ADHD treatment trials is a relatively recent phenomenon. There are now several published studies that have used QOL measures to assess outcomes in clinical trials of ADHD medications. Initially, the focus was on the impact of non-stimulants, specifically atomoxetine [32,124] but more recently, growing evidence has supported positive effects on QOL for lisdexamfetamine [101,125,126] and methylphenidate [127–129]. The majority of these trials have captured parent rather than child ratings. Thus far, the ADHD treatment improvements in QOL have not been yet assessed with any ADHD-specific QOL scales in children and adolescents. In contrast, self-rated ADHD-specific measures of QOL have been used in one trial in adult ADHD using the Adult ADHD QOL scale [130]. Adverse events & safety

The pharmacological treatment for ADHD has been mostly associated with the emergence of common but temporary side effects of mild severity, while serious TEAEs are reported in only a minority of patients [38]. There is ongoing debate on the clinical importance of common effects of both stimulants and nonstimulants, such as slower weight gain and reduced growth [131], and cardiovascular effects, such as raised blood pressure (BP) and tachycardia, particularly with respect to those associated with long-term use [38]. While a recent Danish study (n = 714,258) concluded that the use of stimulants in ADHD was associated with increased risk of adverse cardiovascular event (adjusted hazard ratio = 1.83), these data are hard to interpret because the event category included a very wide range of events, such as hypertension and rheumatic fever and a category named ‘cardiovascular disease not otherwise specified’ which accounted for 40% of cases [132]. In contrast, an American study (n = 1,200,438) did not find any indication for an increase in the risk for serious cardiovascular events in children and young 388

adults taking ADHD medications [133]. The European ADHD Guidelines Group has made recommendations for the management of cardiovascular risk [134] and we would agree that in all stimulant-treated patients, BP should be monitored during treatment; for patients with pre-existing cardiac conditions, stimulants should be used cautiously and only after consultation with a cardiologist, with BP monitored during treatment. Most studies on the effects of pharmacological treatment for ADHD do report the emergence of TEAEs. The methods used for collection of TEAEs varied from collection of spontaneous reporting of common side effects, to the emergence of serious AEs, to the use of standardized scales and clinical investigations. Several studies have included in their safety measures clinical laboratory parameters, including hematology and clinical chemistry, and cardiac safety parameters, BP and pulse as well as 12-lead ECG or 24-h Holter monitoring. The percentage of TEAEs leading to discontinuation has also been reported within the adverse events outcomes. While repeated investigations are recommended procedures in clinical trials, weekly or monthly clinical laboratory tests and physiological tests are not clinically necessary, feasible or cost-effective in day-to-day practice. In contrast, the use of conventional or standardized measures to assess treatment-emergent side effects can be easily implemented in both inpatient and outpatient units. In clinical routine practice, it is common that clinicians record BP and pulse rate measurements during routine reviews. Yet, it is also important to plot these measurements against standard data that are age and sex appropriate as this might help detect children with elevated BP or tachycardia [135]. Indeed, while pharmacological ADHD treatment does not routinely cause changes in BP and HR, up to 5–15% of patients present with heightened BP and pulse above the 95th percentile, which persists for the duration of the treatment [136]. To facilitate the evaluation of parameters in our clinical service, clinicians have been provided with standardized BP charts that are also available online for public use at http://www.healthcareimprovementscotland. org/our_work/mental_health/adhd_services_over_scotland/stage_3_ adhd_final_report.aspx. Initially, in clinical trials, TEAEs were generally measured by spontaneous reporting. Later requirements encouraged the assessment of tolerability and safety with the Medical Dictionary for Regulatory Activities available at http://www.meddra. org/ [137]. This generic measure can create confusion with similar AEs being coded differently depending on the free text entered by the clinician. For example, the entry ‘abdominal pain’ does not clarify whether the AE relates to ‘upper abdominal pain’ and the term ‘anorexia’ for loss of appetite can be potentially confused with ‘anorexia nervosa.’ Greenhill et al. [37] recently summarized the available tools for TEAEs reporting, and acknowledged that there is no agreement on what is the most appropriate way to elicit and record side effects. More recently, in an attempt to make the recording and reporting of TEAEs more consistent, investigators have started using structured tools. Long-term safety and tolerability studies have used the Brief Psychiatric Rating Scale [138,139] and the Expert Rev. Clin. Pharmacol. 8(4), (2015)



psychiatric adverse events rating scale of the US FDA for psychiatric adverse events. Indeed, tics, symptoms of anxiety, irritability, sadness, crying, withdrawal, psychosis and mania have also been associated with initiation of stimulant and non-stimulant medications. The exact prevalence of these is yet not well described; however, current studies underway in Europe (e.g., ADDUCE, http://adhd-adduce.org and SPD489-404, https://clinicaltrials. gov/ct2/show/NCT01328756) will provide more accurate data for methylphenidate and lisdexamfetamine. For further discussion on the occurrence, monitoring and management of such TEAE in the ADHD treatment, we direct the readers’ attention to a recent practitioner review [134]. A few studies have also used the SAFTEE [140], systematic assessment of side effects in clinical trials which is, however, extremely long, as it includes nearly 80 items, and less suitable for routine care. Several of these initiatives are a response to the changes in EMA regulations that require data on long-term effects of stimulants on growth and puberty, as well as psychiatric, neurological, cardiovascular outcomes in children, adolescents and young adults (for an example, see the ADDUCE project at http://adhd-adduce.org). It is suggested that clinicians routinely ask about the emergence of these symptoms in clinical practice. A shorter version of the 17-item Barkley Stimulant Side Effect Rating Scale (BSSERS; [141];) can be used to routinely assess the most commonly reported AEs thought to be associated with drug treatments for ADHD, including insomnia, appetite, physical symptoms, such as head and stomach aches, and emotionality and irritability. An example of an adapted version of this scale is available in the supplementary files in Coghill et al. [10]. The focus is on the level of impairment caused by the specific side effect that in the BSSERS is rated on a 0–9-point scale (0 = no adverse event; 9 = very serious or frequent adverse event). Others have suggested that simplified ratings may be more user friendly without a loss of important information [10]. Systematic collection of adverse events reports at baseline and then throughout treatment helps to understand which symptoms are related to the disorder and which have arisen as a consequence of treatment [142]. This is particularly relevant in ADHD where many of the potential AEs are common in untreated ADHD (and may actually improve with treatment). In addition, following a structured protocol that includes the same structured data collection instruments and standardized assessment tools during the beginning of the treatment and in continuing care clinics allows consistency between professionals from different disciplines, with different levels of experience, and over time. Cognition

An increasing number of pharmacological trials have investigated the effects of stimulants and non-stimulants on the cognition deficits typically observed in ADHD. Indeed, cognitive outcome measures can be relevant both to treatment-related improvement and adverse effects. Increasing evidence supports the association between ADHD and lower overall cognitive level as indexed by the intellectual informahealthcare.com

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coefficient. In a meta-analytic review, regardless of age and ADHD subtype, individuals with ADHD performed lower than the control groups in their Full Scale Intelligence Quotient (FSIQ; [143]). Surprisingly, baseline IQ estimates appear to be unrelated to parent and teacher reports of symptoms severity [144]. Yet, based on the hypothesis that ADHD-related behaviors during completion of intellectual testing impact on performance, some studies have included IQ estimates as outcomes of the pharmacological ADHD treatment. Specifically, small but significant increases in IQ scores have been reported following both short- and long-term treatment with stimulants [145–147]. To date, it remains unclear whether posttreatment IQ improvements may reflect the extent to which ADHD symptoms impact cognitive assessments, indicating that IQ measures might rather capture symptom reduction when assessing treatment outcomes. Furthermore, while the mean impact of ADHD on IQ is suggested to be 2 FSIQ points [144], there is no conclusive evidence that would define a clinically meaningful minimum change score after treatment with medications. Deficits across a broad range of higher order cognitive domains have been found in children and adolescents with ADHD (e.g., [43,44],) and have been proposed as predictors of persisting ADHD diagnosis or symptoms in adulthood [148]. Furthermore, cognitive dysfunctions have been indicated as predictors of poor long-term functional outcomes, such as grade retention and academic underachievement in individuals with ADHD in some, but not all, studies [149]. ADHD has been most consistently associated with deficits in executive and nonexecutive functions, including response inhibition, executive and non-executive aspects of working memory, set-shifting, planning, reaction times, and reaction time variability. It is now generally accepted that ADHD is a heterogeneous condition at a cognitive level, in that only a proportion of children with ADHD present with problems in any one cognitive function and it is not uncommon to observe children with ADHD who do not seem to exhibit deficits in any of these domains [43–45,150]. Therefore, it is not yet possible to use cognitive dysfunctions to support a diagnosis nor is it helpful to use them to monitor treatment outcomes in clinical practice. In the future, however, these measures may be useful to partition subjects and allocate children with specific deficits to the most appropriate treatments, including also combined pharmacological treatment with non-pharmacological interventions, such as working memory training, organizational skills training, and neuro-feedback. Another problem arises from recent understanding about the relation between cognition and symptoms. It has been traditionally believed that there is a linear relation between cognition and symptoms whereby cognitive deficits are directly and causally related to symptoms, which in turn result in the observed impairment. However, few studies have directly tested this hypothesis and recent reports cast some doubt on the model. ADHD medications do appear to have a positive impact on many of the cognitive domains associated with ADHD. A recent meta-analysis testing the effects of 389


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methylphenidate on cognition indicated improvements in all of the cognitive domains assessed, albeit with small-to-moderate effect sizes [39]. Other studies have, however, suggested that, despite optimizing clinical response, ADHD medications have not consistently demonstrated efficacy in improving measures of cognition [151]. Direct examinations of these relations found that while methylphenidate improved several aspects of cognition as well as symptoms, the changes across the two domains were not correlated (i.e., those that improved symptomatically did not necessarily improve cognitively) [83,152]. Intriguingly, recent evidence on longitudinal data has shown that ADHD remitters do not improve on neurocognitive functions compared with individuals with persistent ADHD [148]. Altogether, these findings have lead us to propose that the relation between symptoms and cognition, at least as measured by formal cognitive tasks, may be more in parallel than in series [42]. The implications of these results on treatment outcome assessment are complex. While an ADHD treatment may result in remission with respect to core symptoms, cognitive deficits and overall impairment may not necessarily improve to the same extent. The opposite case, with treatment producing improvement in cognition but not symptoms, is also possible [153]. It may be that in the future, we will be recommending the measurement of both symptoms and cognition as routine but further research is required before we can be clear about these sorts of clinical recommendations. Commercial tests and packages marketed as potential aids to measuring treatment response are starting to appear. Unfortunately, there are not yet enough data in the peer reviewed literature to make a judgment on their psychometric properties or their validity and reliability. In our view, it is therefore too early to say whether or not they will be of general benefit in routine clinical practice either for the early prediction of treatment response or as an aid to optimizing treatment. The results and findings discussed above relate to studies where cognition is measured by specific cognitive tasks and batteries such as the Cambridge Neuropsychological Test Automated Battery [154]. An alternative approach to measuring cognitive functioning is via questionnaire measures, such as the Behavior Rating Inventory of Executive Function (BRIEF; [155];). The BRIEF has been proposed as a valid indirect measure of response to treatment on cognition. Adult ADHD research has more frequently used this scale than for children and showed positive effects. However, the correlations between tasks and questionnaire-based measures of cognition have been found to be rather low, suggesting that they are actually measuring very different aspects of functioning. Indeed, the correlations between cognitive functions scales and symptoms are considerably higher than those between cognitive tasks results and symptoms [156,157]. It is therefore possible that the BRIEF might be more a proxy measure for the impact of symptoms and for impairment rather than a true cognitive measure. Outcomes of pharmacological treatment can also include cognitive adverse effects. Indeed, while, most commonly, the administration of stimulants has been associated with 390

improvement on an individual’s persistence on task and motivation [158,159], it has been also reported that these medications might impair cognitive flexibility (i.e., excessively enhance perseverance) and cause cognitive overfocusing [40], reward desensitization [160], and impaired memory [161]. Other evidence suggests that methylphenidate-related worsening in cognitive flexibility is temporary [162] and adaptation and creativity do not appear to be impaired when impulsivity is controlled by treatment [163]. Further study on this aspect of treatment response is ongoing. Expert commentary & recommendations for clinical practice

Converging evidence has shown that symptom ratings and their changes after ADHD treatment may be incomplete when based on one informant only, such as parent rating scales. It is therefore increasingly being recommended that clinicians not only make use of high quality multisource information when assessing outcomes but also include measures of impairment and QOL. Having reviewed the available evidence, we suggest that, at the very least, the clinician should seek to take account of symptoms severity both during the diagnostic process and at all stages of treatment using a DSM-based rating scale such as the ADHD-RS or the SNAP-IV scored by the clinician but based on all available information. For those children who presented with one or more psychiatric comorbidities before treatment, clinicians should also monitor the persistence and severity of the associated symptoms and evaluate their impact on the overall clinical impression of the response to the ADHD treatment. Even though the structured assessment of more general functioning and functional outcomes is not imperative, it can provide very valuable additional information and inform treatment decisions. In routine clinical practice, this can be very easily attained with little extra effort using generic measures, such as the CGI and C-GAS. For the CGI, a useful approach is to make a note of three areas of particular concern at baseline before starting on treatment that can then be used as a reference point for assessing subsequent change. More specific scales of condition-specific impairment, such as the WFIRS-P have been developed. Unfortunately, the lack of standardized and normative data and, maybe more importantly, the rather restricted range of scores in even untreated patients rather limits the use of WFIRS as a measure of change in individual patients in day-to-day practice. In contrast, assessment of QOL using instruments such as the CHIP-CE and the pediatric quality of life inventory 4.0 (PedsQL) would seem to be more feasible. These scales have consistently been demonstrated to be able to identify ADHDrelated problems in QOL and, in clinical trials, are reliable measures of change. It is possible that changes in QOL take longer to develop than changes in symptoms; therefore, while we would recommend measuring symptoms and impairment at every visit, once treatment is stabilized, it is probably sufficient to restrict measurement of QOL to once a year. There is currently no consensus on how best to assess safety and tolerability outcomes. We would, however, recommend Expert Rev. Clin. Pharmacol. 8(4), (2015)



that, as with symptoms, potential AEs should be systematically assessed at every visit. Specifically, it is advisable that physiological parameters are plotted on to charts standardized for age and sex and AEs reports are solicited with the aid of semistructured rating scales both at baseline and during follow-up appointments (see for an example the scale available in the supplement materials of [10]). From a clinical perspective, it is likely that cognitive testing will become increasingly important in the future. However, at the moment, it is not clear for which children they should be used and when, what the best measures and approach will be or how to interpret the results obtained. We need a better understanding of the relevance of cognitive profile to treatment response and better define the explicit relations (positive and negative) among symptoms, cognition, impairment and QOL. Five-year view

While clinical research has used tools to assess several aspects of treatment outcomes, including impairment and QOL, this has not translated into routine clinical practice. An increasing number of instruments are available but there is the need for completing the development of psychometrically validated instruments to measure treatment response beyond symptom reduction. In addition, more effort should be made to evaluate whether ADHD treatment outcomes in routine clinical practice are comparable with those seen in clinical trials. Research trials that focus more on an individualized assessment of treatment response (e.g., Jacboson & Truax approach) and adverse outcomes (e.g., increases in BP) will also be essential. Overall, there is increasing need for objective measures of response to the treatment for ADHD; the development of reliable instruments that

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take advantage of wearable technology will be key to assess more objectively symptom changes in response to treatment. With regards to TEAEs, clinical trials are underway, which will provide further evidence on psychiatric adverse effects of medications for ADHD. Finally, future research will need to investigate to what extent neurocognitive profiles are helpful both in monitoring the severity of the ADHD-related impairments, and whether stratifying and partitioning those with ADHD with respect their cognitive profile can identify more homogeneous sub-populations with differential response profiles. If successful, this approach would mark a major step toward individualized approach to the treatment of those with ADHD. Financial & competing interests disclosure

S Seth has received compensation for serving as a consultant or speaker, and she or the institution she works for have received research support or royalties from the following companies or organizations: Lilly, Shire Jansen-Cilag, and Oxford University Press. The present work is unrelated to the aforementioned support and relationships, and none of the companies listed had any involvement in the preparation of the manuscript. D Coghill has received compensation for serving as a consultant or speaker, and he or the institution he works for have received research support or royalties from the following companies or organizations: Flynn, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, Vifor Pharma. The present work is unrelated to the aforementioned support and relationships, and none of the companies listed had any involvement in the preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues .

There is compelling evidence that treatment with medications is effective and prevents, at least, in part, the poor long-term outcomes associated with ADHD.

.

In measuring outcomes of ADHD treatment, clinical trials have mostly focused on efficacy of medications in reducing ADHD symptoms and on safety and tolerability of the administration of the compounds, with increasing interest also on functional and QOL outcomes. Furthermore, pharmacology regulators have required that these aspects are included in clinical trials.

.

Clinicians should seek to measure ADHD treatment response based on a more global concept of remission that includes a range of outcomes from symptoms to impairment and QOL, to persistence and severity of the associated symptoms when comorbid disorders are present.

.

It is important that symptomatic reduction is measured with clinician-rated DSM-based rating scales like the ADHD-RS or the SNAP-IV based on all available information at diagnosis and at all stages of treatment.

.

Measuring functional outcomes with generic measures of functioning like the CGI and C-GAS adds little time to the assessment, can inform treatment decisions and should be part of routine visits.

.

Assessment of adverse events and safety is advisable at baseline and at all stages of treatment and best obtained with structured measures and comparison of physiological parameters with normative data.

.

In clinical practice, it would also be advisable to periodically (i.e., yearly) measure quality of life through child report once treatment is stable.

.

While cognition does not currently represent a helpful measure of treatment outcome, there is potential for further development in this area.


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ADHD clinical care pathway. Child and Adolesc Psychiatry Mental Health; in press

References Papers of special note have been highlighted as: . of interest .. of considerable interest 1.


2.

3.

4.

5.

6.

7.

8.

.

9.

10.

Polanczyk G, de Lima MS, Horta BL, et al. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiat 2007;164(6):942-8 Swensen A, Birnbaum HG, Ben Hamadi R, et al. Incidence and costs of accidents among attention-deficit/hyperactivity disorder patients. J Adoles Health 2004; 35(4):346.e1-9 Barkley RA, Fischer M. The unique contribution of emotional impulsiveness to impairment in major life activities in hyperactive children as adults. J Am Acad Child Adoles Psych 2010;49(5):503-13 Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the united states: results from the national comorbidity survey replication. Am J Psychiat 2006;163(4):716-23 Dalsgaard S, Ostergaard SD, Leckman JF, et al. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015. [Epub ahead of print] Fischer M, Barkley RA, Smallish L, Fletcher K. Hyperactive children as young adults: driving abilities, safe driving behavior, and adverse driving outcomes. Accid Anal Prev 2007;39(1):94-105 Cortese S, Ramos Olazagasti MA, Klein RG, et al. Obesity in men with childhood ADHD: a 33-year controlled, prospective, follow-up study. Pediatrics 2013;131(6): e1731-8 Klein RG, Mannuzza S, Olazagasti MA, et al. Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later. Arch Gen Psychiatry 2012;69(12):1295-303 Rigorously conducted longitudinal study examining the impact of attention deficit/ hyperactivity disorder (ADHD) on long-term clinical and functional outcomes for individuals diagnosed with ADHD in childhood. Ramos Olazagasti MA, Klein RG, Mannuzza S, et al. Does childhood attention-deficit/hyperactivity disorder predict risk-taking and medical illnesses in adulthood? J Am Acad Child Adolesc Psychiatry 2013;52(2):153-162.e4 Coghill D, Markarian M, Seth S. Effective management of attention-deficit/ hyperactivity disorder (ADHD) through structured re-assessment: the Dundee

392

.

A clear description of an evidence-based approach to measuring outcomes in routine clinical practice and the clinical benefits of this approach.

11.

Langley K, Fowler T, Ford T, et al. Adolescent clinical outcomes for young people with attention-deficit hyperactivity disorder. Br J Psychiatry 2010;196(3): 235-40

12.

Fredriksen M, Halmoy A, Faraone SV, Haavik J. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies. Eur Neuropsychopharmacol 2013;23(6):508-27

.

Review of the long-term beneficial effects and tolerability of stimulant medications for ADHD.

13.

Bihlar Muld B, Jokinen J, Bolte S, Hirvikoski T. Long-term outcomes of pharmacologically treated versus non-treated adults with ADHD and substance use disorder: a naturalistic study. J Subst Abuse Treat 2015;51:82-90

14.

Lichtenstein P, Halldner L, Zetterqvist J, et al. Medication for attention deficit-hyperactivity disorder and criminality. N Eng J Med 2012;367(21): 2006-14

20.

Wilens TE. Effects of methylphenidate on the catecholaminergic system in attentiondeficit/hyperactivity disorder. J Clin Psychopharmacol 2008;28(3):S46-53

21.

Coghill D, Banaschewski T, Lecendreux M, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/ hyperactivity disorder. Eur Neuropsychopharmacol 2013;23(10): 1208-18

22.

Schwartz S, Correll CU. Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. J Am Acad Child Adolesc Psychiatry 2014;53(2):174-87

23.

Savill NC, Buitelaar JK, Anand E, et al. The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research. CNS Drugs 2015;29(2): 131-51

24.

Ruggiero S, Clavenna A, Reale L, et al. Guanfacine for attention deficit and hyperactivity disorder in pediatrics: a systematic review and meta-analysis. Eur Neuropsychopharmacol 2014;24(10): 1578-90

25.

Kollins SH, Jain R, Brams M, et al. Clonidine extended-release tablets as add-on therapy to psychostimulants in children and adolescents with pediatrics. ADHD 2011; 127(6):e1406-13

26.

Childress AC. Guanfacine extended release as adjunctive therapy to psychostimulants in children and adolescents with attentiondeficit/hyperactivity disorder. Adv Ther 2012;29(5):385-400

27.

Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. Eur Child Adolesc Psychiatry 2010;19(4): 353-64

15.

Man KK, Chan EW, Coghill D, et al. Methylphenidate and the risk of trauma. Pediatrics 2015;135(1):40-8

16.

Raman SR, Marshall SW, Haynes K, et al. Stimulant treatment and injury among children with attention deficit hyperactivity disorder: an application of the self-controlled case series study design. Inj Prev 2013;19(3):164-70

17.

Dalsgaard S, Nielsen HS, Simonsen M. Consequences of ADHD medication use for children’s outcomes. J Health Econ 2014;37:137-51

18.

MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA cooperative group. multimodal treatment study of children with ADHD. Arch Gen Psychiatry 1999; 56(12):1073-86

28.

Hirota T, Schwartz S, Correll CU. Alpha-2 agonists for attention-deficit/ hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. J Am Acad Child Adolesc Psychiatry 2014; 53(2):153-73

19.

Hanwella R, Senanayake M, de Silva V. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry 2011;11:176

29.

Banaschewski T, Coghill D, Santosh P, et al. Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry 2006;15(8):476-95

30.

Castells X, Ramos-Quiroga JA, Rigau D, et al. Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder:

Expert Rev. Clin. Pharmacol. 8(4), (2015)


a meta-regression analysis. CNS Drugs 2011;25(2):157-69 31.


32.

33.

34.

35.

36.

Faraone SV, Spencer T, Aleardi M, et al. Meta-analysis of the efficacy of methylphenidate for treating adult attentiondeficit/hyperactivity disorder. J Clin Psychopharmacol 2004;24(1):24-9 Coghill D. The impact of medications on quality of life in attention-deficit hyperactivity disorder: a systematic review. CNS Drugs 2010;24(10):843-66 Buitelaar JK, Wilens TE, Zhang S, et al. Comparison of symptomatic versus functional changes in children and adolescents with ADHD during randomized, double-blind treatment with psychostimulants, atomoxetine, or placebo. J Child Psychol Psychiatry 2009;50(3): 335-42 O’Connor BC, Garner AA, Peugh JL, et al. Improved but still impaired: symptom-impairment correspondence among youth with attention-deficit hyperactivity disorder receiving community-based care. J Dev Behav Pediatr 2015;36(2):106-14 Epstein JN, Langberg JM, Lichtenstein PK, et al. Attention-deficit/hyperactivity disorder outcomes for children treated in community-based pediatric settings. Arch Pediatr Adolesc Med 2010;164(2):160-5 Steele M, Jensen PS, Quinn DM. Remission versus response as the goal of therapy in ADHD: a new standard for the field? Clin Therapeut 2006;28(11): 1892-908

37.

Greenhill LL, Shockey E, Davies M, et al. Review of safety assessment methods used in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry 2003;42(6):627-33

38.

Graham J, Coghill D. Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs 2008;22(3):213-37

39.

..

40.

Coghill DR, Seth S, Pedroso S, et al. Effects of methylphenidate on cognitive functions in children and adolescents with attention-deficit/hyperactivity disorder: evidence from a systematic review and a meta-analysis. Biol Psychiatry 2014;76(8): 603-15 Review of the evidence supporting the effects of stimulants on the neurocognitive deficits observed in ADHD. Advokat C. What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity


51.

Swanson JM, Nolan W, Pelham WE. The SNAP-IV rating scale. 1992. Available from: http://www.adhd.net

52.

DuPaul GJ, Barkley RA. Situational variability of attention problems: psychometric properties of the revised home and school situations questionnaires. J Clin Child Psychol 1992;21(2):178-88

53.

Collett BR, Ohan JL, Myers KM. Ten-year review of rating scales. V: scales assessing attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2003;42(9): 1015-37

.

Review of available instruments for measuring the effects of ADHD medications on symptoms.

54.

Pelham WE Jr, Fabiano GA, Massetti GM. Evidence-based assessment of attention deficit hyperactivity disorder in children and adolescents. J Clin Child Adolesc Psychol 2005;34(3):449-76

55.

Weckerly J, Aarons GA, Leslie LK, et al. Attention on inattention: the differential effect of caregiver education on endorsement of ADHD symptoms. J Dev Behav Pediatr 2005;26(3):201-8

56.

European Medicines Agency (EMA). C.f.M. P.f.H.U.C. Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD). 2009

57.

European Medicines Agency (EMA). C.f.M. P.f.H.U.C, Guideline on clinical investigation of medicinal products, including depot preparations, in the treatment of schizophrenia. 2012

58.

European Medicines Agency (EMA). C.f.M. P.f.H.U.C, Guideline on clinical investigation of medicinal products in the treatment of depression. 2013

59.

Wolraich ML, Lambert W, Doffing MA, et al. Psychometric properties of the Vanderbilt ADHD diagnostic parent rating scale in a referred population. J Pediatr Psychol 2003;28(8):559-67

European Medicines Agency (EMA). C.f.M. P.f.H.U.C, Draft concept paper on the development of medicinal products for the treatment of autism spectrum disorder. 2013

60.

Wolraich ML, Feurer ID, Hannah JN, et al. Obtaining systematic teacher reports of disruptive behavior disorders utilizing DSM-IV. J Abnorm Child Psychol 1998; 26(2):141-52

Do¨pfner M, Steinhausen HC, Coghill D, et al. Cross-cultural reliability and validity of ADHD assessed by the ADHD Rating Scale in a pan-European study. Eur Child Adolesc Psychiatry 2006;15(1):i46-55

61.

Group, MC. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA cooperative group. multimodal treatment study of children with ADHD. Arch Gen Psychiatry 1999;56(12):1073-86

62.

Valo S, Tannock R. Diagnostic instability of DSM–IV ADHD subtypes: effects of informant source, instrumentation, and

disorder (ADHD). Neurosci Biobehav Rev 2010;34(8):1256-66 41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

Review

Coghill D. Editorial: Acknowledging complexity and heterogeneity in causality– implications of recent insights into neuropsychology of childhood disorders for clinical practice. J Child Psychol Psychiatry 2014;55(7):737-40 Coghill DR, Hayward D, Rhodes SM, et al. A longitudinal examination of neuropsychological and clinical functioning in boys with attention deficit hyperactivity disorder (ADHD): improvements in executive functioning do not explain clinical improvement. Psychol Med 2014;44(5): 1087-99 Coghill DR, Seth S, Matthews K. A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models. Psychol Med 2014; 44(9):1989-2001 Nigg JT, Willcutt EG, Doyle AE, Sonuga-Barke EJ. Causal heterogeneity in attention-deficit/hyperactivity disorder: do we need neuropsychologically impaired subtypes? Biol Psychiatry 2005;57(11): 1224-30 Willcutt EG, Doyle AE, Nigg JT, et al. Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 2005;57(11):1336-46 Sonuga-Barke E, Bitsakou P, Thompson M. Beyond the dual pathway model: evidence for the dissociation of timing, inhibitory, and delay-related impairments in attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010;49(4):345-55 Conners CK. Conners’ rating scales-revised user’s manual. Multi-Health Systems. Multi-Health Systems, Inc., North Tonawanda, NY; 1997

DuPaul GJ. ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretation. 1998: Guilford Press

393

Review



methods for combining symptom reports. J Clin Child Adolesc Psychol 2010;39(6): 749-60 63.

Shemmassian SK, Lee SS. Comparing four methods of integrating parent and teacher symptom ratings of attention-deficit/ hyperactivity disorder (ADHD). J Psychopathol Behav Assess 2012;34(1): 1-10

64.

Conners CK. Rating scales in attentiondeficit/hyperactivity disorder: use in assessment and treatment monitoring. J Clin Psychiatry 1998;59(7):24-30

65.

66.

67.

68.

Waschbusch DA, Pelham WE Jr, Waxmonsky J, Johnston C. Are there placebo effects in the medication treatment of children with attention-deficit hyperactivity disorder? J Dev Behav Pediatr 2009;30(2):158-68 Pelham WE, Waxmonsky JG, Schentag J, et al. Efficacy of a methylphenidate transdermal system versus t.i.d. methylphenidate in a laboratory setting. J Atten Disord 2011;15(1):28-35 Swanson JM, Lerner M, Wigal T, et al. The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications. J Atten Disord 2002; 6(Suppl 1):S73-88 Swanson J, Wigal S, Greenhill L, et al. Objective and subjective measures of the pharmacodynamic effects of Adderall in the treatment of children with ADHD in a controlled laboratory classroom setting. Psychopharmacol Bull 1998;34(1):55-60

69.

Wigal SB, Gupta S, Guinta D, Swanson JM. Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacol Bull 1998;34(1):47-53

70.

Dalsgaard S, Mortensen PB, Frydenberg M, Thomsen PH. Conduct problems, gender and adult psychiatric outcome of children with attention-deficit hyperactivity disorder. Br J Psychiatry 2002;181:416-21

71.

72.

73.

12 years of age with ADHD in a double-blind placebo-controlled trial. J Atten Disord 2014;18(2):123-32 74.

Rosler M, Retz W, Fischer R, et al. Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD. World J Biol Psychiatry 2010;11(5):709-18

75.

Stringaris A, Goodman R, Ferdinando S, et al. The Affective Reactivity Index: a concise irritability scale for clinical and research settings. J Child Psychol Psychiatry 2012;53(11):1109-17

84.

Coghill DR, Banaschewski T, Lecendreux M, et al. Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attentiondeficit/hyperactivity disorder: randomized-withdrawal study design. J Am Acad Child Adolesc Psychiatry 2014;53(6): 647-657 e1

85.

Arnold LE, Lindsay RL, Conners CK, et al. A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2004;14(4): 542-54

76.

De Crescenzo F, Armando M, Mazzone L, et al. The use of actigraphy in the monitoring of methylphenidate versus placebo in ADHD: a meta-analysis. Atten Defic Hyperact Disord 2014;6(1):49-58

86.

77.

Tabori-Kraft J, Sorensen MJ, Kaergaard M, et al. Is OPTAx useful for monitoring the effect of stimulants on hyperactivity and inattention? A brief report. Eur Child Adolesc Psychiatry 2007;16(5):347-51

Buitelaar JK, Michelson D, Danckaerts M, et al. A randomized, double-blind study of continuation treatment for attention-deficit/ hyperactivity disorder after 1 year. Biol Psychiatry 2007;61(5):694-9

87.

78.

Ramos-Quiroga JA, Casas M. Achieving remission as a routine goal of pharmacotherapy in attention-deficit hyperactivity disorder. CNS Drugs 2011; 25(1):17-36

Michelson D, Buitelaar JK, Danckaerts M, et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004;43(7):896-904

79.

Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Cons Clin Psychol 1991;59(1):12-19

88.

..

Use of the responder analysis approach, which is based on an individual rather than a group response.

Epstein JN, Weiss MD. Assessing treatment outcomes in attention-deficit/hyperactivity disorder: a narrative review. Prim Care Companion CNS Disord 2012;14(6): 11r01336

..

Review and expert-based guidance on the instruments available for the assessment of the ADHD treatment outcomes from the symptom reduction to the ADHD-related impairment and the quality of life.

89.

European Medicines Agency (EMA). C.f.M. P.f.H.u.C. Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD). 2010. Available from: www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2010/ 08/WC500095686.pdf

90.

Kaufman J, Birmaher B, Brent D, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997;36(7):980-8

91.

Berk M, Ng F, Dodd S, et al. The validity of the CGI severity and improvement scales as measures of clinical effectiveness suitable for routine clinical use. J Eval Clin Pract 2008;14(6):979-83

80.

81.

Coghill D, Spiel G, Baldursson G, et al. Which factors impact on clinician-rated impairment in children with ADHD? Eur Child Adolesc Psychiatry 2006;15(1):I30-7 Breuer D, Gortz-Dorten A, Rothenberger A, Dopfner M. Assessment of daily profiles of ADHD and ODD symptoms, and symptomatology related to ADHD medication, by parent and teacher ratings. Eur Child Adolesc Psychiatry 2011; 20(Suppl 2):S289-96

82.

Childress AC, Arnold V, Adeyi B, et al. The effects of lisdexamfetamine dimesylate on emotional lability in children 6 to

83.

394

attention-deficit/hyperactivity disorder. Biol Psychiatry 2007;62(9):954-62

Dittmann RW, Cardo E, Nagy P, et al. Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder. CNS Drugs 2014;28(11):1059-69 Soutullo C, Banaschewski T, Lecendreux M, et al. A post hoc comparison of the effects of lisdexamfetamine dimesylate and osmotic-release oral system methylphenidate on symptoms of attention-deficit hyperactivity disorder in children and adolescents. CNS Drugs 2013;27(9):743-51 Erder MH, Xie J, Signorovitch JE, et al. Cost effectiveness of guanfacine extended-release versus atomoxetine for the treatment of attention-deficit/hyperactivity disorder: application of a matching-adjusted indirect comparison. Appl Health Econ Health Policy 2012;10(6):381-95 Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with




92.

Shaffer D, Gould MS, Brasic J, et al. A children’s global assessment scale (CGAS). Arch Gen Psychiatry 1983;40(11):1228-31

93.

Bird HR, Canino G, Rubio-Stipec M, Ribera JC. Further measures of the psychometric properties of the children’s global assessment scale. Arch Gen Psychiatry 1987;44(9):821-4

94.

Bird HR, Shaffer D, Fisher P, et al. The Columbia Impairmenr Scale (CIS): pilot findings on a measure of global impairment for children and adolescents. J Method Psychiatr Res 1993;3:167-76

95.

Bird HR, Andrews H, Schwab-Stone M, et al. Global measures of impairment for epidemiologic and clinical use with children and adolescents. J Method Psychiatr Res 1996;6:295-307

96.

97.

98.

99.

100.

101.

102.

103.

Hodges K, Doucette-Gates A, Liao Q. The relationship between the child and adolescent functional assessment scale (CAFAS) and indicators of functioning. J Child Family Stud 1999;8:108-22 Maziade M, Rouleau N, Lee B, et al. Atomoxetine and neuropsychological function in children with attention-deficit/ hyperactivity disorder: results of a pilot study. J Child Adolesc Psychopharmacol 2009;19(6):709-18 Stein MA, Waldman ID, Charney E, et al. Dose effects and comparative effectiveness of extended release dexmethylphenidate and mixed amphetamine salts. J Child Adolesc Psychopharmacol 2011;21(6):581-8

A review of the literature. Eur Neuropsychopharmacol 2013;23(6):528-33 104.

105.

106.

107.

108.

109.

(CADDRA), C.A.D.H.D.R.A. Canadian ADHD Practice Guidelines. 3rd editon, ed. CADDRA, Toronto; 2011 Fuentes J, Danckaerts M, Cardo E, et al. Long-term quality-of-life and functioning comparison of atomoxetine versus other standard treatment in pediatric attentiondeficit/hyperactivity disorder. J Clin Psychopharmacol 2013;33(6):766-74

..

110.

Banaschewski T, Soutullo C, Lecendreux M, et al. Health-related quality of life and functional outcomes from a randomized, controlled study of lisdexamfetamine dimesylate in children and adolescents with attention deficit hyperactivity disorder. CNS Drugs 2013;27(10):829-40

111.

Landgraf JM, Rich M, Rappaport L. Measuring quality of life in children with attention-deficit/hyperactivity disorder and their families: development and evaluation of a new tool. Arch Pediatr Adolesc Med 2002;156(4):384-91

112.

Surman CB, Hammerness PG, Pion K, Faraone SV. Do stimulants improve functioning in adults with ADHD?


Riley AW, Lyman LM, Spiel G, et al. The family strain index (FSI). Reliability, validity, and factor structure of a brief questionnaire for families of children with ADHD. Eur Child Adolesc Psychiatry 2006;15(Suppl 1):I72-8 Saylor K, Buermeyer C, Sutton V, et al. The life participation scale for attentiondeficit/hyperactivity disorder–child version: psychometric properties of an adaptive change instrument. J Child Adolesc Psychopharmacol 2007;17(6):831-42 Kelsey DK, Sumner CR, Casat CD, et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics 2004; 114(1):e1-8 Hoza B, Pelham WE Jr, Dobbs J, et al. Do boys with attention-deficit/hyperactivity disorder have positive illusory self-concepts? J Abnorm Psychol 2002;111(2):268-78 Shaffer D, Fisher P, Lucas CP, et al. NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 2000;39(1):28-38 Danckaerts M, Sonuga-Barke EJ, Banaschewski T, et al. The quality of life of children with attention deficit/hyperactivity disorder: a systematic review. Eur Child Adolesc Psychiatry 2010;19(2):83-105 Review of the impact of ADHD on the quality of life and the available instruments to measure quality of life and its changes during the ADHD treatment. WHO. The world health organization quality of life assessment (WHOQOL): position paper from the world health organization. Soc Sci Med 1995;41(10): 1403-9 Rentz AM, Matza LS, Secnik K, et al. Psychometric validation of the child health questionnaire (CHQ) in a sample of children and adolescents with attentiondeficit/hyperactivity disorder. Qual Life Res 2005;14(3):719-34 Varni JW, Burwinkle TM. The PedsQL as a patient-reported outcome in children and adolescents with Attention-Deficit/ Hyperactivity Disorder: a population-based study. Health Qual Life Outcomes 2006;4:26

Review

113.

Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001;39(8): 800-12

114.

Escobar R, Soutullo CA, Hervas A, et al. Worse quality of life for children with newly diagnosed attention-deficit/ hyperactivity disorder, compared with asthmatic and healthy children. Pediatrics 2005;116(3):e364-9

115.

Coghill D, Hodgkins P. Health-related quality of life of children with attentiondeficit/hyperactivity disorder versus children with diabetes and healthy controls. Eur Child Adolesc Psychiatry 2009; in press

.

Article demonstrating comparable and higher impact of ADHD on the individuals’ quality of life than that of a chronic medical condition with the use of the Child Health and Illness Profile scale for the assessment of quality of life.

116.

Riley AW, Coghill D, Forrest CB, et al. Validity of the health-related quality of life assessment in the ADORE study: parent report form of the CHIP-Child Edition. Eur Child Adolesc Psychiatry 2006; 15(Suppl 1):I63-71

117.

Kamp-Becker I, Schroder J, Muehlan H, et al. Health-related quality of life in children and adolescents with autism spectrum disorder. Z Kinder Jugendpsychiatr Psychother 2011;39(2): 123-31

118.

Cavanna AE, David K, Bandera V, et al. Health-related quality of life in Gilles de la Tourette syndrome: a decade of research. Behav Neurol 2013;27(1):83-93

119.

Jardine J, Glinianaia SV, McConachie H, et al. Self-reported quality of life of young children with conditions from early infancy: a systematic review. Pediatrics 2014;134(4): e1129-48

120.

Lin YF, Chung HH. Parenting stress and parents’ willingness to accept treatment in relation to behavioral problems of children with attention-deficit hyperactive disorder. J Nurs Res 2002;10(1):43-56

121.

Xiang YT, Luk ES, Lai KY. Health-related quality of life in children and adolescents with autism spectrum disorder. Z Kinder Jugendpsychiatr Psychother 2011;43(8): 731-8

122.

Riley AW, Spiel G, Coghill D, et al. Factors related to health-related quality of life (HRQoL) among children with ADHD in Europe at entry into treatment. Eur Child Adolesc Psychiatry 2006;15(1):I38-45

395

Review


123.


Marques JC, Oliveira JA, Goulardins JB, et al. Comparison of child self-reports and parent proxy-reports on quality of life of children with attention deficit hyperactivity disorder. Health Qual Life Outcomes 2013;11:186

124.

Coghill D. Pragmatic measures in paediatric psychopharmacology-are we getting it right? Eur Neuropsychopharmacol 2011;21(8): 571-83

125.

Banaschewski T, Johnson M, Lecendreux M, et al. Health-related quality of life and functional outcomes from a randomized-withdrawal study of long-term lisdexamfetamine dimesylate treatment in children and adolescents with attentiondeficit/hyperactivity disorder. CNS Drugs 2014;28(12):1191-203

126.

127.

128.

129.

130.

131.

132.

Childress AC, Cutler AJ, Saylor K, et al. Participant-perceived quality of life in a long-term, open-label trial of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2014; 24(4):210-17 Altin M, El-Shafei AA, Yu M, et al. Pharmacological treatment for attention deficit hyperactivity disorder: functional outcomes in children and adolescents from non-Western countries. Drugs Context 2013;2013:212260 Ghanizadeh A, Sayyari Z, Mohammadi MR. Effect of methylphenidate and folic Acid on ADHD symptoms and quality of life and aggression: a randomized double blind placebo controlled clinical trial. Iran J Psychiatry 2013;8(3):108-12 Haertling F, Mueller BO. Bilke-hentsch, effectiveness and safety of a long-acting, once-daily, two-phase release formulation of methylphenidate (Ritalin LA) in school children under daily practice conditions. Atten Defic Hyperact Disord 2014. [Epub ahead of print] Brod M, Adler LA, Lipsius S, et al. Validation of the adult attention-deficit/ hyperactivity disorder quality-of-life scale in European patients: comparison with patients from the USA. Atten Defic Hyperact Disord 2015 [Epub ahead of print] Faraone SV, Biederman J, Morley CP, Spencer TJ. Effect of stimulants on height and weight: a review of the literature. J Am Acad Child Adolesc Psychiatry 2008;47(9): 994-1009 Dalsgaard S, Kvist AP, Leckman JF, et al. Cardiovascular safety of stimulants in children with Attention-Deficit/ Hyperactivity Disorder: A nationwide

396

prospective cohort study. J Child Adolesc Psychopharmacol 2014;24(6):302-10 133.

Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Eng J Med 2011;365(20):1896-904

134.

Cortese S, Holtmann M, Banaschewski T, et al. European ADHD Guidelines Group, Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry 2013;54(3):227-46

..

Review of the recent evidence and expert opinion on the management of adverse events associated with medications for ADHD.

135.

Graham J, Banaschewski T, Buitelaar J, et al. European guidelines on managing adverse effects of medication for ADHD. Eur Child Adolesc Psychiatry 2011;20(1): 17-37

136.

Hammerness PG, Perrin JM, Shelley-Abrahamson R, Wilens TE. Cardiovascular risk of stimulant treatment in pediatric attention-deficit/hyperactivity disorder: update and clinical recommendations. J Am Acad Child Adolesc Psychiatry 2011;50(10):978-90

137.

Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf 1999;20(2):109-17

138.

Mullins D, Pfefferbaum B, Schultz H, Overall JE. Brief psychiatric rating scale for children: quantitative scoring of medical records. Psychiatry Res 1986;19(1):43-9

139.

Overall JE, Gorham DR. The brief psychiatric rating scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacol Bull 1988;24:97-9

140.

Levine J, Schooler NR. SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacol Bull 1986;22(2):343-81

141.

Barkley RA, McMurray MB, Edelbrock CS, Robbins K. Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics 1990;86(2):184-92

142.

Sonuga-Barke EJ, Coghill D, Wigal T, et al. Adverse reactions to methylphenidate treatment for attention-deficit/hyperactivity disorder: structure and associations with clinical characteristics and symptom control. J Child Adolesc Psychopharmacol 2009; 19(6):683-90

143.

Frazier TW, Demaree HA, Youngstrom EA. Meta-analysis of intellectual and neuropsychological test performance in attention-deficit/hyperactivity disorder. Neuropsychology 2004;18(3):543-55

144.

Jepsen JR, Fagerlund B, Mortensen EL. Do attention deficits influence IQ assessment in children and adolescents with ADHD? J Atten Disord 2009;12(6):551-62

145.

Gimpel GA, Collett BR, Veeder MA, et al. Effects of stimulant medication on cognitive performance of children with ADHD. Clin Pediatr 2005;44(5):405-11

146.

Gillberg C, Melander H, von Knorring AL, et al. Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997;54(9):857-64

147.

Tsai CS, Huang YS, Wu CL, et al. Long-term effects of stimulants on neurocognitive performance of Taiwanese children with attention-deficit/hyperactivity disorder. BMC Psychiatry 2013;13:330

148.

van Lieshout M, Luman M, Buitelaar J, et al. Does neurocognitive functioning predict future or persistence of ADHD? A systematic review. Clin Psychol Rev 2013; 33(4):539-60

149.

Biederman J, Monuteaux MC, Doyle AE, et al. Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children. J Cons Clin Psychol 2004;72(5): 757-66

150.

Wahlstedt C, Thorell LB, Bohlin G. Heterogeneity in ADHD: neuropsychological pathways, comorbidity and symptom domains. J Abnorm Child Psychol 2009;37(4):551-64

151.

Gualtieri C.T, Johnson LG. Medications do not necessarily normalize cognition in ADHD patients. J Atten Disord 2008; 11(4):459-69

152.

Bedard AC, Stein MA, Halperin JM, et al. Differential impact of methylphenidate and atomoxetine on sustained attention in youth with attention-deficit/hyperactivity disorder. J Child Psychol Psychiatry 2015;56(1):40-8

.

Comparison of the effects two ADHD medications on several measures of neurocognition and differential effects of the drugs on the cognitive deficits and symptom reduction.

153.

Cortese S, Ferrin M, Brandeis D, et al. Cognitive training for attention-deficit/ hyperactivity disorder: meta-analysis of clinical and neuropsychological outcomes from randomized controlled trials. J Am



Acad Child Adolesc Psychiatry 2015;54(3): 164-74 154.


155.

156.

Morris RC, Evendon JL, Sahakian BJ, Robbins TW. In cognitive neurochemistry. In: Stahl SM, Iverson SD, Goodman EC, Computer-aided assessment of dementia: comparative studies of neuropsychological deficits in Alzheimer-type dementia and Parkinson’s disease. Oxford University Press, Oxford; 1987. pp 21-36 Gioia GA, Isquith PK, Guy SC, et al. BRIEF: behavior rating inventory of executive function: professional manual. Psychol Assess Res 2000 Brown TE, Landgraf JM. Improvements in executive function correlate with enhanced performance and functioning and health-related quality of life: evidence from 2 large, double-blind, randomized, placebo-controlled trials in ADHD. Postgrad Med 2010;122(5):42-51


157.

158.

Findling RL, Adeyi B, Dirks B, et al. Parent-reported executive function behaviors and clinician ratings of attention-deficit/ hyperactivity disorder symptoms in children treated with lisdexamfetamine dimesylate. J Child Adolesc Psychopharmacol 2013; 23(1):28-35 Volkow ND, Wang GJ, Fowler JS, et al. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry 2004;161(7):1173-80

159.

Douglas VI, Barr RG, Desilets J, Sherman E. Do high doses of stimulants impair flexible thinking in attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 1995;34(7):877-85

160.

Andersen SL, Napierata L, Brenhouse HC, Sonntag KC. Juvenile methylphenidate modulates reward-related behaviors and cerebral blood flow by decreasing cortical

Review

D3 receptors. Eur J Neurosci 2008;27(11): 2962-72 161.

Sprague RL, Sleator EK. Methylphenidate in hyperkinetic children: differences in dose effects on learning and social behavior. Science 1977;198(4323):1274-6

162.

Tannock R, Schachar R. Methylphenidate and cognitive perseveration in hyperactive children. J Child Psychol Psychiatry 1992; 33(7):1217-28

163.

Funk JB, Chessare JB, Weaver MT, Exley AR. Attention deficit hyperactivity disorder, creativity, and the effects of methylphenidate. Pediatrics 1993;91(4): 816-19

397

Hyperactivity Disorder.

Assessing sensory processing problems in children with and without attention deficit hyperactivity disorder.

hyperactivity disorder.

hyperactivity disorder Under Treatment Outcomes Research (AUTOR): a European observational study in pediatric subjects.

hyperactivity disorder: a systematic review.

Hyperactivity Disorder: MTA Results.

hyperactivity disorder (ADHD).

hyperactivity disorder.

hyperactivity disorder.

Hyperactivity Disorder: 2 Case Reports.

or bipolar disorder?].

Comorbidity of attention-deficit hyperactivity disorder and overanxious disorder.

Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Hyperactivity Disorder.

Proprioceptive diagnostics in attention deficit hyperactivity disorder.

[Neurobiology of attention deficit hyperactivity disorder].

hyperactivity disorder treatment.

hyperactivity disorder.

Emotion dysregulation in attention deficit hyperactivity disorder.

The misnomer of attention-deficit hyperactivity disorder.

Adult Attention Deficit Hyperactivity Disorder and comorbidity.

Treating children with attention-deficit hyperactivity disorder.

hyperactivity disorder in postsecondary students.

Driving and attention deficit hyperactivity disorder.