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21(1) (2007) 10–41 2007 British Association hyperactivity disorder in adolescents in ISSN 0269-8811 SAGE Publications Ltd,London, Thousand Oaks, adults: recommendations from the British Association for Psychopharmacology D. J. Nutt Psychopharmacology Unit, University of Bristol, Bristol, UK.
K. Fone University of Nottingham, Nottingham UK.
P. Asherson MRC Social Genetic Developmental Psychiatry, Institute of Psychiatry, King’s College London, UK.
D. Bramble Telford & Wrekin PCT, Shrewsbury, UK.
P. Hill London, UK.
K. Matthews University of Dundee, Dundee UK.
K. A. Morris c/o Psychopharmacology Unit, University of Bristol, Bristol, UK.
P. Santosh Institute of Psychiatry, London, UK.
E. Sonuga-Barke University of Southampton, Southampton, UK.
E. Taylor Institute of Psychiatry, London, UK.
M. Weiss University of British Columbia, Vancouver, Canada.
S. Young Bethlem Royal Hospital, Kent, UK. For the Consensus Group (other invited participants at the consensus meeting ‘ADHD in transitionfrom child to adult’ are listed in the Acknowledgements).
Attention-deﬁcit/hyperactivity disorder (ADHD) is an established growing literature on ADHD in older age groups. Much of this initial diagnosis in children, associated with a large body of evidence on the guidance on managing ADHD in adolescents in transition and in adults is beneﬁts of treatment. Adolescents with ADHD are now leaving children’s based on expert opinion derived from childhood evidence. We hope that, services often with no readily identiﬁable adult service to support them, by the time these guidelines are updated, much evidence will be which presents problems as local pharmacy regulations often preclude available to address the many directions for future research that are the prescription of stimulant drugs by general practitioners (GPs). In addition, adults with ADHD symptoms are now starting to present toprimary care and psychiatry services requesting assessment and Keywords
treatment. For these reasons, the British Association for ADHD, hyperkinetic disorders, hyperactivity, impulsivity, Psychopharmacology (BAP) thought it timely to hold a consensus psychostimulants, psychotherapy, co-morbidities conference to review the body of evidence on childhood ADHD and the Corresponding author: Prof. David J. Nutt, Psychopharmacology Unit, Dorothy Hodgkin Building, Whitson St, Bristol BS1 3NY, UK.
ADHD management in adolescents to adults Introduction
quate, or otherwise to flag the area as a direction for futureresearch. A draft of the taped proceedings was drawn up by an In recent years, UK health services have proven inadequate in attending clinician writer and circulated to all speakers and other meeting the needs not only of children with ADHD in transition participants for comment. Key subsequent publications were from children’s services, but also of the growing number of adults added by the writer and speakers at draft stage. All comments newly presenting with ADHD symptoms, often after their child were incorporated as far as possible in the final document, which has been given the diagnosis. Specialist services are now being represents the views of all participants, although the authors take established to manage adolescents in transition and adults with final responsibility for the document.
ADHD. The BAP thought it helpful to act as the vehicle to prepare Categories of evidence for causal relationships, observational a consensus document on best practice in an area that is both con- relationships and strength of recommendations are given in Table 1 and are taken from Shekelle et al. (1999). The strength of The BAP is an association of psychiatrists, psychopharmacolo- recommendation reflects not only the quality of the evidence, but gists and pre-clinical scientists who are interested in the broad also the importance of the area under study. For example, it is pos- field of drugs and the brain. BAP is the largest national organ- sible to have methodologically sound (category I) evidence about ization of its kind worldwide, and publishes the Journal of Psy- an area of practice that is clinically irrelevant, or has such a small chopharmacology. The association started publishing consensus effect that it is of little practical importance and therefore attracts a statements more than a decade ago, and the first BAP guidelines lower strength of recommendation. However, more commonly, it on depression were considered a landmark publication when pub- has been necessary to extrapolate from the available evidence (e.g.
lished in 1993 (Montgomery et al., 1993). That document, which in childhood) leading to weaker levels of recommendation (B, C was updated in 2000 (Anderson et al., 2000), has become the stan- or D) based upon category I evidence statements.
dard of care in many countries because it is considered an accessi-ble consensus to guide practising psychiatrists. The BAP now has a target of publishing one consensus statement per year in theJournal of Psychopharmacology. Recent guidelines have covered Our intention is to present a comprehensive statement to guide cli- management of bipolar disorder (Goodwin, 2003) and drug treat- nicians, who are managing adolescents with ADHD in transition ments for addiction (Lingford-Hughes et al., 2004), with guide- from children’s services, and adults newly presenting with ADHD lines on anxiety published late last year (Baldwin et al., 2005).
symptoms. Although rigorous evidence exists in a few areas, Forthcoming consensus conferences are planned on child psy- overall there is a dearth of evidence that pertains to adolescents chopharmacology, old age psychopharmacology and schizo- and especially adults. Many of the statements in this document are phrenia, all of which will utilize a similar style and process. therefore based on the experience of experts who are currently All guidelines are available via the BAP website treating this adolescent or adult group, with extrapolation from the (http://www.bap.org.uk) and the intention is to update each guide- greater body of rigorous data in children. We anticipate that the situation with regard to research on adult ADHD is likely tochange markedly in the future. Until that time, these guidelines must be considered a first attempt to reach consensus in an areathat continues to attract controversy, and in which we cannot be A consensus conference was held at the Novartis Foundation certain that childhood findings will be confirmed in older age building, London on 24 February 2005. The meeting was spon- groups. We hope that the body of evidence may be considered far sored by unrestricted educational grants from Cephalon, Janssen, more definitive when these guidelines are due for updating.
Lilly, Shire UK and Shire US pharmaceutical companies, which Our consensus on adolescents in transition and adults with had no input into and no responsibility for the meeting and its ADHD is based on the premise that a clinical entity, ADHD, content. Those invited to attend the meeting included BAP exists in childhood and, moreover, that the condition may persist members, representative clinicians from services with a strong in some form in older age groups. The meeting recognized the fact interest in ADHD, and other recognized experts and advocates in that even ADHD in childhood is a controversial diagnosis to make the field, including a representative from Canada who had recently in some quarters of society; thus, a diagnosis in older age groups participated in that country’s consensus statement on adult ADHD might be more controversial in these quarters. The crux of the con- (www.caddra.ca). Observers from the sponsoring companies were troversy seems to be whether the symptoms of ADHD need to be invited to attend but not to participate in the proceedings or in understood as a medical condition or whether the behaviours iden- drafting the guidelines. All attendees completed conflict of interest tified as ADHD are an extreme of the normal spectrum of human statements that are held at the BAP office as per usual BAP policy.
behaviours (e.g. ‘very naughty little boys’). A further dimension is Speakers were asked to present a review of the literature and whether such behaviours necessitate pharmacological treatment or identification of the standard of evidence in their area, with an whether non-pharmacological modifications are sufficient to emphasis on meta-analyses, systematic reviews and randomized controlled trials (RCTs) where available. Each presentation was The consensus of the meeting is that the extreme behaviours followed by a lengthy discussion that aimed to reach consensus characterized under current diagnostic systems represent a clinical where the evidence and/or clinical experience was considered ade- condition in so much as the behaviours cause problems for the ADHD management in adolescents to adults Categories of evidence and strength of recommendations Categories of evidence for causal relationships and treatment Evidence from meta-analysis of randomized controlled trials Evidence from at least one randomized controlled trial Evidence from at least one controlled study without randomization Evidence from at least one other type of quasi-experimental study Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case-control studies Evidence from expert committee reports or opinions and/or clinical experience of respected authorities Categories of evidence for observational relationships Evidence from large, representative population samples Evidence from small, well-designed, but not necessarily representative samples Evidence from non-representative surveys, case reports Evidence from expert committee reports or opinions and/or clinical experience of respected authorities Directly based on category II evidence or extrapolated from category I evidence Directly based on category III evidence or extrapolated from category II evidence Directly based on category IV evidence or extrapolated from category III evidence affected individual, are identified as problematic by others and marked disparities between subgroups. This may indicate that cau- may respond to various forms of clinical treatment or other forms sation is likely to show marked heterogeneity, and/or that tradi- of management, such as environmental restructuring. A diagnosis tional theories on cause and effect in ADHD, that regard ADHD of ADHD is thus warranted to allow affected individuals to access as a homogeneous condition characterized by a single causal appropriate forms of support from health care and other systems.
pathway, are inadequate (Sonuga-Barke, 2003, 2005; Coghill We hope the controversy will be lessened over ADHD in older et al., 2005; Castellanos et al., 2006).
age groups, because in many cases, the affected individual will bethe one to initiate clinical contact. Indeed, it is partly in response to the growing number of such requests that this consensusmeeting was arranged.
ADHD is highly heritable, with heritability estimates from twin With current science, it is not possible to determine whether studies in the range of 65–90% (Thapar et al., 2001) and average ADHD is an extreme variant of normal behaviour or in a distinct across 20 studies of 76% (Faraone et al., 2005b). Family studies category. However, current science does support the improvement report that both parents and siblings of a child with ADHD are of ADHD symptoms with treatments, particularly but not exclu- around four to five times more likely to have ADHD than the sively pharmacological. It is in this spirit that this consensus docu- general population (Faraone et al., 2000). Although ADHD is ment is presented. The question of who should provide and pay for diagnosed using operational diagnostic criteria, measures of service provision is a matter of health policy and thus beyond the ADHD symptoms are continuously distributed in the general scope of our consensus, although we hope that this consensus will population. Mathematical modelling using De Fries and Fulker (DF) analysis supports the hypothesis that ADHD is the extremeof behaviours that vary genetically throughout the entire popu-lation (Gjone et al., 1996; Levy et al., 1997; Willcutt et al., 2000; Neurodevelopmental background
Price et al., 2001). These data suggest that genetic influences onADHD are distributed throughout the population and correlate The exact cause(s) of ADHD are unknown but the growing liter- with quantitative trait measures of ADHD symptoms. This is ature on genetics, neuroimaging and neuropsychology suggests important since this implies that ADHD is best perceived as a features consistent with a neurodevelopmental condition in which quantitative trait, or series of quantitative traits, rather than a cate- multiple environmental and biological factors, of individually gorical disorder. The implication for clinical practice is that, small effect, interact to produce an abnormal brain condition that similar to other common psychiatric disorders such as anxiety and manifests as cognitive and behavioural deficits (Sonuga-Barke depression, appropriate clinical cut-offs need to be established that et al., 2005). Subsequent bidirectional interactions then occur link ADHD symptoms to significant clinical impairments; given between these deficits and environmental and biological factors to that ADHD is a developmental disorder, this will require estab- modify the phenotype further, resulting in various diagnostic sub- lishment of age- and gender-specific norms. A particular issue for groups under the umbrella term ADHD. Overall, the literature on the diagnosis of ADHD in adults is that the age-appropriate genetic, neurobiological and neuropsychological deficits shows expression of clinical symptoms has yet to be firmly established.
ADHD management in adolescents to adults Genetic influences on ADHD are likely to be the result of mul- tiple genes of small effect size and are expected to interact withenvironmental risk factors (Asherson et al., 2005). Four linkage Detailed coverage of the diverse literature on the influence of scans have been completed and highlight a number of potential environmental factors was beyond the scope of the meeting and chromosomal regions containing genes that increase risk for thus is briefly reviewed in this document. It is noted that environ- ADHD, although there is as yet no clear consensus across the mental factors of significance include pregnancy and birth factors, various data sets, and no genes have been identified that account prematurity, diet, institutional care and other aspects of the for linkage signals (Fisher et al., 2002; Smalley et al., 2002; psychosocial environment (see Biederman, 2005 for a recent Bakker et al., 2003; Ogdie et al., 2003; Arcos-Burgos et al., 2004; review). Several studies also suggest that childhood environmental Ogdie et al., 2004; Hebebrand et al., 2005). Genetic association factors shape the phenotypic expression of ADHD, and co- studies have focused on the analysis of monoamine system genes, morbidity with other behavioural disorders, by acting on genetic due to the marked and rapid response of ADHD symptoms to stim- influences (e.g. Hudziak et al., 2005; Burt et al., 2005; Dick et al., ulants that block the reuptake of dopamine and norepinephrine (see 2005; Jester et al., 2005 I–II). Furthermore, predictors of persist- later). Several genes have been reported to be associated with ence into adulthood include family history of ADHD, psychiatric ADHD in multiple studies, with small but significant effects con- co-morbidity and psychosocial adversity (Biederman, 2005). In firmed by meta-analysis (Asherson et al., 2005; Faraone et al., terms of treatment, various dietary manipulations can improve 2005b, Thapar et al., 2005a). The best evidence for association is ADHD symptoms in at least some children (Egger et al., 1985; with DNA variants of the dopamine D4 (DRD4) and D5 (DRD5) Carter et al., 1993; Boris and Mandel, 1994; Rowe and Rowe, receptors and the dopamine transporter (DAT1), with strong addi- 1994; Schmidt et al., 1997; Dykman and Dykman, 1998; Richard- tional evidence for associations with the serotonin IB receptor son and Puri, 2002 Ib), although the mechanism of these improve- (5-HT ), serotonin transporter (SERT) and synaptosomal associ- ments is unknown. Activities in natural ‘green’ settings have been ated protein-25 (SNAP-25). Gene–environment interactions have linked with symptom improvement in a national sample (Kuo and been reported between DAT1 and maternal use of tobacco (Kahn Taylor, 2004 I). These and other findings (e.g. that brain abnor- et al., 2003) and alcohol (Brookes et al., 2006) during pregnancy malities may not determine phenotype (Castellanos et al., 2002 on the risk of ADHD, and between catechol O-methyltransferase IIa)) could suggest a greater importance of environmental factors and low birth weight on risk for antisocial outcomes among ADHD in some individuals, both in childhood and in older age groups.
cases (Thapar et al., 2005b). Although most studies have focused Environmental restructuring might be particularly important as on children with ADHD, it is interesting to note that the only two part of the management of adults with ADHD, in our experience studies to investigate the DRD4 association in adults with ADHD (see ‘Psychotherapeutic approaches’ below).
were both positive (Muglia et al., 2000; Lynn et al., 2005).
Neuroimaging studies (Bush et al., 2005) have documented significant overall and regional reductions in white matter volumesbetween unmedicated ADHD patients, including those never Neuropsychological research, mainly in children, has documented exposed to relevant medication, and healthy controls (Castellanos various deficits in executive function (especially inhibition), moti- et al., 2002). Medicated patients differ from unmedicated patients, vation and reinforcement, attention, timing, memory and energet- but not from healthy controls, in overall and regional (frontal, ics (covered in detail in ‘Neuropsychological assessment’ below parietal and temporal) white matter volumes. These studies have (Doyle et al., 2005)). This research has clarified that although clearly demonstrated differences in the anatomy and processing of about a third of patients have difficulties with one or another neu- patients with ADHD compared with controls, although these dif- ropsychological test of executive functioning, this is neither uni- ferences do not have the sensitivity or specificity in individuals to versal nor diagnostic. Functional neuroimaging studies have often contribute to differential diagnosis (Seidman et al., 2005).
suggested that brain activation is abnormal during affected tasks Several neuroimaging studies, though not all (van Dyck et al., compared with controls, and specifically is more diffuse than in 2002), have indicated that striatal DAT binding is increased com- controls with failure of inhibitory functions. For example, Tamm pared with controls in ADHD patients (Krause et al., 2000; et al. (2004) have linked a key deficit – abnormal response inhibi- Madras et al., 2002; Spencer et al., 2005a; Volkow et al., 2005) tion on a Go/No Go task – with abnormal activation patterns in including studies in adults (Dougherty et al., 1999; Dresel et al., specific temporal regions compared with controls. This has led to 2000; Krause et al., 2000), suggesting increased density of the the hypothesis that individuals with ADHD may have to use other transporter protein in the striatum. In addition, there is evidence brain regions, when faced with attention demanding tasks, that are from two out of four studies that the DAT1 risk genotype for perhaps less efficient (Bush et al., 2005). Recent evidence also ADHD is associated with increased striatal DAT binding (Heinz et suggests that this is reversible with medication.
al., 2000; Jacobsen et al., 2000; Martinez et al., 2001; Cheon et Various studies are aimed at linking the specific neuropsycho- al., 2003). Moreover, other groups have reported that logical traits (known as endophenotypes – e.g. delay aversion, methylphenidate treatment, which increases extracellular executive motor inhibition, deficit in arousal/activation regulation) dopamine in the human striatum (Volkow et al., 2001), is accom- that may underpin symptoms and behaviours, with neurobiological panied by reductions in DAT binding to control values (Dresel changes (e.g. dysfunction in frontostriatal circuitry, reward et al., 2000; Spencer et al., 2005a; Volkow et al., 2005).
systems and catecholamine function (Waldman, 2005; Willcutt et ADHD management in adolescents to adults al., 2005)). The effects of the identified genetic variants on brain ing the DSM-IV definition of ADHD in partial remission were functioning and resultant phenotypic traits remain unclear, so the included, referring to the persistence of some symptoms associ- possibility remains that such variants could contribute to several ated with significant clinical impairments. Prevalence rates of phenotypes of which one is currently classified as ADHD.
adult ADHD estimated at around 4% have been found in several Finally, neuropsychological deficits neither consistently predict different studies, using DSM-IV criteria, but will vary depending behaviours nor outcome of treatment (e.g. Rhodes et al., 2004, on clinical measures used and the precise way in which the diag- 2005). This could reflect a lack of specificity of the deficit tested nostic criteria are applied (Hill and Schoener, 1996; Gallagher and to the diagnostic group under study or the fact that treatment effi- Blader, 2001; Bloom and Dey, 2004; Faraone and Biederman, cacy is not mediated via those structures and functions involved in 2005; Kooij et al., 2005; Kessler et al., 2006; Faraone et al., While some symptoms (e.g. hyperactivity) tend to diminish or present differently with age, perhaps due to self-medication, adap-tation and neurodevelopment, other symptoms, especially inatten- Several major prospective follow-up studies have documented the tion, (Millstein et al., 1998) are more likely to persist and may natural history of ADHD, especially as patients transit through have a greater impact on adults. Community follow-up of young adolescence into adulthood (Hechtman and Weiss, 1983; Barkley people with untreated ‘hyperactivity’ suggests that impulsiveness et al., 1990; Weiss and Hechtman, 1993; Biederman et al., 1996a; declines in absolute terms, but remains deviant relative to that of Biederman et al., 1996b; Faraone et al., 1996; Biederman et al., age-matched peers (Taylor et al., 1996). These studies have inves- 1998; Mannuzza et al., 1998; Mick et al., 2004; Faraone et al., tigated the frequency of these symptoms in adults but no study to 2006). These studies suggest that a large proportion of child date has evaluated the relative impairment caused by continuation patients show ADHD symptoms that persist to adolescence (esti- of the various symptoms that do remain in the adult population.
mated variously at 50–60%) or adulthood (10–66%; Hill and Attentional difficulties are likely to persist at least in their impact Schoener, 1996; Spencer et al., 1996; Faraone et al., 1996; Bieder- on functioning. Symptoms diminish in frequency and severity as a man et al., 2000; Barkley, 2002; Faraone et al., 2006). A recent consequence of natural developmental processes seen in all chil- meta-analysis of studies that followed children identified with dren and may further diminish, at least in part, due to learned ADHD and matched controls into adulthood has been completed skills, coping strategies and environmental restructuring.
(Faraone et al., 2006). When the definition of ADHD included However, the overall impact may worsen due to the increased only those that met full diagnostic criteria for ADHD, the rate of demands of an adult environment. While the full complement of persistence was approximately 15% at age 25 years. However the diagnostic deficits can often disappear in adulthood, at an age- rate was far higher, approximately 65%, when individuals fulfill- related rate dependent on criteria, impairment persists and may Consensus: ADHD as a neurodevelopmental condition
ADHD is a neurodevelopmental psychiatric condition that most likely results from the interaction of multiple genetic andenvironmental factors, each of small effect, with different patterns creating multiple pathways to symptoms each marked andmediated by different deficit profiles (B).
ADHD is currently understood to be a life-long condition and currently a diagnosis of adult ADHD needs to include childhoodimpairment (either prospectively or retrospectively) (C). The status of disorder of later onset needs to be established.
In the absence of specific markers common to the entire group of ADHD patients, assessment and treatment are guided by phe-notype (symptoms/behaviours/impairments).
Co-morbidity is common in both childhood and adulthood, and may determine outcomes (D). Clinical assessment of ADHDneeds to include careful evaluation for other disorders.
Expression of ADHD and co-morbidities is highly heterogeneous, thus management needs to be individualized (C).
A better aetiological theory is needed that accounts for the causal heterogeneity in the condition (Coghill et al., 2005; Sonuga-Barke, 2005) Is ADHD a categorical difference or the end of spectrum of a population trait? How does phenotype match to genetic, neuropsychological and neuroimaging markers? What are the best ways to subdivide ADHD into subtypes? What underpins the relation between ADHD and environmental factors, such as diet and sleep? How many adults with adult ADHD currently receive alternative diagnoses and treatments within adult psychiatric andprimary care services? Should screening of parents and children of referred patients be considered, and what would be the resource implications ofthis? ADHD management in adolescents to adults worsen in a subset. In such patients, impairment is usually pervasive not considered sufficient to make a diagnosis of ADHD; although or affects more than one domain of activities and may manifest as: the criteria for hyperkinetic disorders better predicts treatment educational, organizational or occupational failures; substance use response than the criteria for ADHD, treatment response varies disorders and other dependent, risky, antisocial or forensic behav- between individuals, while other disorders can respond to current iours; emotional and relationship difficulties and increased medical morbidity (Millstein et al., 1998; Swensen et al., 2000).
The two diagnostic systems have various limitations, not least Co-morbidity is widely considered to be a common finding in the internal tautology that the definition of ADHD or hyperkinetic adolescent and adult ADHD patients, and will affect outcomes disorders rests solely on the criteria that have been established.
(see ‘Comorbid disorders and special situations’). Epidemiological For example, the possibility exists that boys are diagnosed with and clinical studies have shown that more than 80% of adults with ADHD more often than girls because the diagnostic criteria relate ADHD will have another disorder, and the finding that co-morbid- to disruptive behaviours as markers that are more prevalent in ity in adults is similar to that in children, but increases with time, male children. Importantly, these systems do not include associ- raises the question of whether some of this co-morbidity may be ated symptoms, reported by patients which could arguably be the driven by untreated ADHD. Common co-morbid disorders in adulthood include anxiety, depression and antisocial behaviourdisorders, and persisting neurodevelopmental disorders such as dyslexia (Heiligenstein and Keeling, 1995; Biederman et al.,1996b; Marks et al., 2001; Biederman, 2004; McGough et al., Although DSM-IV-TR and ICD-10 have criteria to diagnose 2005; Kessler et al., 2006). The frequency of self-medication and childhood ADHD, these have not been adapted to be appropriate substance use disorders is thought to increase with age but no to adults – e.g. there is no age adjustment to the criteria appropri- studies have confirmed this supposition.
ate to adults. The associated symptoms are similar in the two clas-sifications and full criteria are given in the Appendix.
Diagnosis and assessment
The DSM-IV-TR (APA, 2000) requires all the following criteria for a diagnosis of ADHD: Several issues arise when considering the diagnostic process foradult ADHD. Two major sets of criteria are used worldwide to Either at least six of nine symptoms of inattention or at least diagnose conditions characterized by inattention and/or hyperac- six of nine symptoms of hyperactivity/impulsivity persisting tivity – the Diagnostic and Statistical Manual of Mental for at least 6 months to a maladaptive degree, inconsistent Disorders, fourth edition text revision (DSM-IV-TR, APA, 2000), with developmental level. DSM-IV-TR allows for ADHD ‘in which recognizes ADHD, and the International Classification of partial remission’ that can usefully be applied to adults who Diseases, tenth edition (ICD-10, WHO, 1992), which encom- had ADHD and have persistence of some of the symptoms passes hyperkinetic disorders. Due to differences in criteria, each associated with continued clinical impairments, but who no system identifies different clinical entities with different names – ADHD (APA, 2000) or hyperkinetic disorders (WHO, 1992); the Some symptoms that caused impairment were present before latter generally describes a more restricted and severe subset of DSM-IV combined-type ADHD. We have chosen to use the term Some impairment from symptoms is present in at least two ADHD as shorthand for ADHD and hyperkinetic disorders, except settings (e.g. at home and at school/work).
Clear evidence of clinically significant impairment in social, In the absence of any definitive and objective test (e.g. genetic academic or occupational functioning.
or neuropsychological), the purpose of the diagnostic process Symptoms do not occur exclusively during a pervasive needs consideration. Currently, diagnosis is a process of identify- developmental disorder or psychotic disorder and are not ing extreme behaviour that requires and is amenable to profes- better accounted for by another mental health disorder.
sional help. However, this process can be used to validateobservers’ views of extreme behaviour rather than to identify DSM-IV-TR distinguishes three subtypes of ADHD on the basis markers of an underlying pathological process, with manifesta- of clinical symptoms: (a) predominantly inattentive type, (b) pre- tions that map to the label of ADHD. As in most areas of medi- dominantly hyperactive/impulsive type or (c) combined type cine, ADHD is diagnosed clinically. The only valid ‘test’ for (presence of inattention and hyperactivity/impulsivity). These sub- ADHD is the use of rating scales that have been normed on large types are defined by the absence of a six of nine symptom cut-off populations, and can identify whether the child is affected by this in any one of the domains, although the patient may still have disorder, other disorders and functional impairment compared significant symptoms (five of nine), impairment, or be markedly with age- and gender-matched peers. The use of rating scales com- discrepant for age and gender norms in the area in which they fail bined with a developmental history, observation, family and other risk factors, and impairments consistent with the disorder allows ahigh level of diagnostic certainty between clinicians and predict- ICD-10
Two types of WHO criteria exist (WHO, 1992) – the ing response to treatment (Barkley, 2006). Treatment response is general criteria and the diagnostic criteria for research (DCR), ADHD management in adolescents to adults which are more specific than the general criteria and closer to theDSM-IV-TR criteria. The diagnostic basis of ICD-10 hyperkinetic Proposed BAP extended adult symptom checklist
disorders is the existence of both impaired attention and overactiv- Lack of attention to detail or carelessness ity evident in more than one situation (e.g. home, educational set- Inattention in tasks or activities the patient finds tedious tings, clinic). The presence or absence of conduct disorder constitutes the basis for the main subdivision of hyperkinetic dis- orders – disturbance of activity and attention versus hyperkinetic Starting many tasks while having difficulty finishing For the general ICD-10 diagnosis, behavioural problems should be longstanding and have started before age 6 years. The Avoidance of, dislike of, or inability to expend sus- caveat is made that due to wide normal variation in activity, only extreme degrees of hyperactivity should lead to a diagnosis in pre- school children. Associated features are not necessary or sufficient for the diagnosis but help sustain the disorder, including; disinhi- bition in social relationships, recklessness in situations involving some danger, and impulsive flouting of social rules (as shown by Restlessness or an inability to sit still in low-stimulation intruding on or interrupting others’ activities, prematurely answer- ing questions before they have been completed or difficulty in Inappropriate or excessive activity or an internal feeling Difficulty keeping quiet; talking out of turn The ICD-10 DCR recognizes seven criteria: Unfocused mental activity; difficulty turning thoughtsoff Demonstrable abnormalities at home: at least three of five Blurting out responses; poor social timing in dialogue problems of inattention, at least three of five problems of Trouble waiting if there is nothing to do hyperactivity, at least one of three problems of hyperactivity.
Demonstrable abnormalities at school or nursery: at least two of four attentional problems and at least three of five activity Directly observed abnormality of attention or inactivity.
Does not meet criteria for pervasive developmental disorders,mania, depressive or anxiety disorder.
purposes but may be useful in conjunction with a formal clinical evaluation, or serially to evaluate symptom changes. Several dif- ferent types of scales may be helpful: screens for adult ADHDsymptoms, screen for co-morbidity (Gadow et al., 1999), and Thus the DSM-IV-TR criteria identify a broader group of patients examination of impact of ADHD on functional impairment (Weiss than the ICD-10 (Tripp et al., 1999). No definitive system exists to and Weiss, 2004). Generic functioning scales have shown poor diagnose adult ADHD, while use of these childhood diagnostic correlation with ADHD symptoms, making it clear that ADHD systems in adults raises various difficulties, not least the alteration of specific functional scales are needed (Gordon et al., 2006).
symptoms in adulthood. Thus, the consensus group thought it would Two shorter scales have been developed to allow a rapid initial be helpful to present an extended checklist of adult symptoms in this screen in various clinical settings, and are based on the 18 symp- document, based on childhood diagnostic symptoms plus additional toms listed in both the DSM-IV-TR and the ICD-10 DCR criteria.
adult symptoms (APA, 2000; WHO, 1992; Wender, 1995).
The six-item Adult ADHD Self-Report Scale screener (ASRS-v1.1, Adler et al., 2004; Kessler et al., 2005) is patient-rated while Rating scales
Various rating scales have been developed to help the ADHD Rating Scale (ADHDRS-IV-Inv, Adler et al., 2005b) is diagnose adult ADHD, including three self-report scales. The 61- clinician administered with good reliability and moderate item Wender Utah Rating Scale focuses on retrospective symp- agreement between raters. The ASRS (available at www.med.
toms in childhood plus current hyperactivity, inattention and other nyu.edu/psych/assets/adhdscreen18.pdf) and the Canadian Con- symptoms. It relies on retrospective recall by the individual but sensus screening checklist (www.caddra.ca) are given in the has been validated against parent report and found to be reliable Appendix. Other scales can be downloaded from www.caddra.ca (Ward et al., 1993). Others include the Adult Self Report Scale (Adler et al., 2004; Kessler et al., 2005), Conners Adult ADHDRating Scale (Conners et al., 1998), the 40-item Brown Adult Attention Deficit Disorder Scale (Brown, 1996) and the BarkleySelf, Other and Past ADHD symptom checklists (Barkley and Many studies in children but few in adolescents have documented Murphy, 2006). None of these scales is sufficient for diagnostic various deficits of neuropsychological testing. The limited liter- ADHD management in adolescents to adults Summary of evidence on neuropsychological assessment Quality: quantitative review (A); qualitative review (B); no review (C); no studies (D)Quantity: more than ten studies (A); ﬁve to ten studies (B); two to four studies (C); one study (D); no studies (E)Strength: I = no effect d < 0.2; II = small effect d 0.2–0.4; III = moderate d 0.4–0.7; IV = large d 0.7–1.0; V = very large d > 1.0Tests are: Continuous Performance Test commission errors; Continuous Performance Test ommission errors; Stop Signal Reaction Times; Spatial workingmemory; Verbal working memory; Tower of London/Hanoi; Trials-B; Stroop interference; Wisconsin card sorting task; Time discrimination; Timereproduction; Interstimulus interval effects; responses to reward, punishment; Choice for delayed rewards ature in adults reports similar patterns, although marked hetero- 2003, 2005; Coghill et al., 2005). Alternate theories include a geneity exists (Schoeclin and Engel, 2005; Frazier et al., 2004; failure of specific response-inhibition mechanisms (Willcutt et al., Harvey et al., 2004; Seidman et al., 2004; Nigg, 2005).
2005), altered reward or motivational pathways (Luman et al., Commonly reported impairments are found in tasks involving 2005), abnormal processing of time-related cues (Toplak and executive functions, selective and sustained attention, response Tannock, in submission), non-working memory (Rhodes et al., inhibition, working memory and reward-related motivation. Find- 2004, 2005) and diffuse abnormalities in energetics (Seargant, ings on specific tests in various domains are shown in Table 2.
2005). Current thinking is that these impairments may reflect dys- However as suggested above, the traditional neuropsychologi- regulation in distinct underlying neural circuitries, that is: frontal, cal model of ADHD, which holds that symptoms are the product (dorsolateral prefrontal cortex), dorsal and medial striatal function of a common core deficit expressed by all affected individuals, is reflecting executive function deficits; cerebellum and its outputs now contentious (Sonuga-Barke, 2002, 2003, 2005; Castellanos et affecting timing (with modulation by norepinephrine); ventro-stri- al., 2006). The emerging consensus is that ADHD is a neuropsy- atal-prefrontal (orbito-frontal) circuitry affecting reward and pun- chologically heterogeneous disorder, with different patterns of ishment processing, motivation and delay aversion (with impairments seen in different individuals (Sonuga-Barke, 2002, modulation by dopamine); temporal and amygdalo-hippocampal ADHD management in adolescents to adults circuitry affecting non-working memory; and distributed circuitry individual, which can then be explored further with rating scales, implicated in abnormal cognitive energetics.
and where indicated neuropsychology. Treatment response is not While little is known about the value of neuropsychological thought to be sufficiently specific to form part of the diagnostic assessment in differential diagnosis in adults and adolescents (Lovejoy et al., 1999) most studies in children reveal that tests ofexecutive function and attention show good positive predictive Diagnostic difﬁculties in adults
power but poor negative predictive power (Barkley et al., 1992; may be made under several circumstances. The most straight- Sharma et al., 1991; Grodzinsky and Barkley, 1999; Rielly et al., forward scenario is the persistence of symptoms or problem 1999; Doyle et al., 2000; Dickerson Mayes et al., 2001; Berlin et behaviours in individuals in transition from child and adolescent al., 2004). Thus, use of such tests alone will lead to false-negative mental health services. Individuals that present in adulthood may diagnoses (children without neuropsychological executive impair- self-report symptoms of ADHD or observations of others. ADHD ment will still have the condition), which is unsurprising given the might also be identified through presentation with a co-morbid heterogeneity of neuropsychological findings.
diagnosis such as substance use disorders or a difficulty in a The effect of co-morbidities on such tests is not well domain of functioning (e.g. referral from occupational health serv- researched. General intelligence testing can be useful to relate IQ ices). The availability of management strategies suggests the pos- to the level of academic and occupational achievement and to sibility of screening – either in the parents or siblings of those investigate or exclude learning disabilities. However, it raises the identified with ADHD or in children and adults with problem issue of labelling based on IQ testing alone. This is particularly behaviours. This latter strategy might present a potential source of important for individuals with ADHD since it is possible that IQ gender bias since a focus on conduct disorder and related behav- testing results will show increased variation in this group and are iours might be one explanation of the high male: female ratio likely to be affected by the attention and motivation of individuals among children diagnosed with ADHD (Pineda et al., 1999; and/or by underachievement in education. For example, a recent Jackson and King, 2004). Some evidence suggests that equal study of the WISC-IV in 118 children showed the working numbers of women and men are affected with ADHD as adults memory tests to be the lowest score in all 118 children, thus low- (Murphy and Barkley, 1996; Rowland et al., 2002), which raises ering the overall IQ score secondary to a deficit considered spe- the possibility that girls with ADHD are underdiagnosed.
cific to ADHD (Mayes and Calhoun, 2006).
Diagnosis of ADHD in adults raises other issues in addition to Until the heterogeneity of ADHD is better characterized and an those already identified. The importance of making a diagnosis in optimal battery of tests in multiple domains is compiled, the prac- adults is the identification of impairments that are amenable to tical value of experimental neuropsychological assessment may lie treatment. Moreover, being given a diagnosis of adult ADHD may in profiling areas of particular deficits in individual cases, which help individuals understand why their attainment has failed to cor- may then help to indicate specific solutions to task-related impair- relate with that expected of them, but can also reduce self-esteem, ments, and then to monitor outcomes. Further, neuropsychological which may itself have an adverse impact on functioning. The diag- subtyping of patterns of deficits might shed more light on the nostic and assessment process is further complicated by differ- underlying pathological processes and potentially help tailor treat- ences in co-morbidities, which may be a more important focus for To make a diagnosis of ADHD in adults, current diagnostic systems require the presence of ADHD symptoms from childhood.
Assessment and differential diagnosis Whilst this is unlikely to be a problem for individuals in transition The importance of a full clinical assessment needs to be emphas- from children’s services, presentation for the first time in adult- ized, including neurodevelopmental history (Weiss and Murray, hood raises the question of whether ADHD is always a continuum 2003, 2004; Biederman, 2005; Asherson, 2005). It may be worth from childhood deficits or whether adult-onset ADHD can occur.
setting aside any preconceptions of an individual’s diagnosis from A view shared by many clinicians is that whilst symptoms are previous contacts with health services and starting from first prin- likely to have been present throughout development, there are ciples, using standard assessment techniques available in psychi- groups for whom these symptoms only become impairing at atric services. The presence of ADHD symptoms needs to be particular stages of development, often around significant trans- elicited plus symptoms of differential and co-morbid disorders itions, e.g. from primary to secondary school or from school to (see also ‘Co-morbid disorders and special situations’), and their college or to work. Whilst the current diagnostic frameworks impact on various domains of functioning needs to be assessed.
would not formally recognize these cases as late-onset ADHD, The differential diagnosis of ADHD includes neurodevelopmental they will meet all criteria for diagnosis excepting that for onset of disorders (learning disability, autistic spectrum disorders, commu- nication difficulties, etc.), anxiety, depression, bipolar disorder, Another requirement for diagnosis is the number of symptoms substance use disorders and personality disorders. Some clinicians reported but, given the natural history of the disorder and other also advocate a full examination including neurology, since subtle sources of heterogeneity, many adults may not reach full diagnos- deficits like gaze instability and word-finding defects have been tic criteria. Furthermore, adults have a greater ability to adapt to reported (Weiss and Murray, 2004 IV). The clinical assessment their environment and the demands that this places on them, which may generate hypotheses about specific disorders or deficits in an may alter the ways in which symptoms are expressed. However, ADHD management in adolescents to adults Recommendations – diagnosis and assessment
Diagnosis in adulthood requires specialist skills – i.e. those used by psychiatrists – but should involve primary care practitioners,
who should be trained to be aware of the diagnosis (D). Assessment includes symptoms (past and present), impairments in different
contexts, influence of changing demands through life, exclusion of differentials, and application of clinical examination, rating
scales and other tools as indicated.
Diagnosis has a major impacts, so the purpose of diagnosis is to identify those who are likely to benefit from treatment optionswhere these are available (D).
Preferable diagnostic and assessment criteria are an extended checklist based on DSM-IV-TR and ICD-10 and adult symptoms(D) (see panel and Appendix).
Assessment needs to confirm impairment in different scenarios: (a) a history of childhood ADHD or suggestive symptoms(impairments/failure of attainment/demands and co-morbidity), (b) current evidence of symptoms leading to pervasive impair-ment in more than one domain (given context demands and skills) (D).
Multiple informants need to be used where possible (at least one contemporary and one developmental) with consent, espe-cially for younger patients (D).
Current neuropsychological tests based solely on executive function are likely to be of limited diagnostic value, though testbatteries that assess multiple domains of neuropsychological performance may be useful to determine individual deficits and tosuggest tailored management strategies (D).
Sensitive use of general intelligence tests can be useful to ascertain potential attainment, and to diagnose co-morbid learningdisabilities (D). Interest, reward and educational achievement are important complicating factors (D).
Clinicians need to be aware of the impact of diagnosis and testing on the individual, particularly on self-esteem (D).
Treatment response cannot be used to make a diagnosis of ADHD (D).
What criteria and checklists are required to incorporate better subjective adult symptomatology, to highlight possible neuropsy-chological deficits and to map treatment responses? What will be the impact of extending the symptom checklists on sensitivity and specificity of diagnosis? How can the diagnostic process avoid gender and other biases and match to an underlying pathological process reflected insymptoms rather than to external complaints? What is the practical place of neuropsychology (who to test, with what, and when with what value)? What can neuropsychological subtyping tell us about different neuropsychological traits (endophenotypes) within ADHD andtheir relationship with causation, behaviours, co-morbidity and treatment responses? What are the natural history or neurodevelopmental milestones in different domains of neuropsychological functioning espe-cially in relation to transitions between childhood/adolescence and adulthood? Can a diagnostically useful battery of tests that measures across domains of functioning, be compiled to improve diagnosis? What are the useful thresholds regarding diagnosis to determine whether symptoms will or will not be amenable to treatment? Since the current subtypes are based on male child norms that are problematic, what further research is needed on subtypes? Ofnote, the inattentive subtype includes patients who have never had problems with hyperactivity, but also those who have sub-threshold hyperactivity and impulsive symptoms that are representative of the combined type. There are very few patients whoare just hyperactive and no research to indicate that these people are impaired or simply not reporting problems with attention.
some will still have substantial impairments amenable to treat- thus narrowing diagnostic criteria to those who are actually having ment, which will not be highlighted by use of diagnostic systems but rather through a detailed assessment of associated impairments Use of the current childhood diagnostic systems (APA, 2000; (Weiss and Murray, 2004). Epidemiological data support the WHO, 1992) in adults requires validation of ADHD symptomatol- validity of applying a lower threshold in adults (e.g. four or five ogy from observers since self-reported symptoms are not included.
out of nine criteria), as this lower threshold correlates significantly However, individuals who present in adulthood with ADHD with impairment (Kooij et al., 2005). The emphasis on functional report their symptoms but may also lack insight into their current impairment has several effects. First, it permits recognition of the symptoms (Magnusson et al., 2006). In addition, the need to need for treatment in those patients who are impaired but subsyn- collect data on possible impairments as a child raises the possibil- dromal. Second, it raises questions about the value of treatments in ity of recall bias in the individual, especially for symptoms such as patients with symptoms and no evidence of current impairment, impulsivity and their impact. Use of informants, if available, to ADHD management in adolescents to adults report on current and childhood behaviour requires consent and meta-analysis. Qualitative assessment suggests that all agents are could be unreliable depending on the nature of the informant and more effective than placebo and have similar efficacy, although their relationship to the individual (e.g. partner, parent, employer, there have been few head-to-head comparisons. Cost-effectiveness modelling indicates that use of all three agents sequentially is ben-eficial, and although the order of sequential prescribing is not clearon a clinical basis, dexamfetamine would be first line on the basis Treatment
of cost alone. However, these agents are not equivalent in terms ofside effects (for example, dexamfetamine is considered by many Physicians identify and treat patients based on symptoms.
to have greater abuse potential than methylphenidate), and the However, patients come to clinical practice with the hope of func- response to different agents varies both between individuals and at tional change, which is the key goal of management. Change in psychological functioning and functioning in other domains is The effects of drug treatment require careful monitoring and essential since ‘pills don’t build skills’ and treatment of inattention dose adjustment. Scales such as the Clinical Global Adjustment and other core symptoms is not beneficial if patients have nothing Scale (Shaffer et al., 1983), the ADHD checklists (Adler et al., to do. A package of care needs to be developed from available 2005; Barkley, 2006) and Conners’ scales (Conners et al., 1998) options on an individual basis after a thorough assessment (Weiss are useful tools for disease monitoring and service audit. Patients and Murray, 2004; Asherson, 2005, IV).
and parents should be questioned for concordance over reportedeffects, as well as compliance. Any history of tolerance or diurnal changes in symptom control should be specifically elicited. Ado-lescents need to be advised of the potential interaction with recre- Drug treatment for children with ADHD has substantially ational drugs, including possibly cannabis, although strong increased in the past decade, in part due to increased recognition warnings against substance use might need to be balanced against of the disorder and perhaps also due to changing views on the the need to engage the patient with treatment. Substance use or impairment thresholds for drug treatment. In the UK, GP prescrib- dependence might need to be addressed prior to being able to ing of methylphenidate has increased sixfold (PPA data www.
publications.doh.gov.uk/prescriptionstatistics/index.htm), although Various questions remain open over prescribing in childhood, rates remain about 20 times lower than in the USA for both pre- and would benefit from future research. Comparable data on cost scribing and treatment. Therapeutic agents licensed in the UK and effectiveness of different drugs are lacking, as are data on long- comparative costs are listed in Table 3, and are all used in primary term effects, including adverse events and effects on different care. These agents plus mixed amfetamine salts (Adderall) are symptom domains, including broader areas of functioning such as generally available elsewhere. Safety alerts have been issued over social adjustment. Data are also lacking regarding the effects of atomoxetine use in childhood, concerning rare hepatotoxicity (one longer acting preparations on phenomena such as tolerance and possible case, one probable case in 3.8 million) and, recently, sensitization. The mechanisms of diurnal and long-term changes increased suicidal thoughts (five cases out of 1357 cases) or in symptoms per se are not well understood nor is the basis of behaviour (one case). All of these rare events are below the preva- variation in effective medication dosages, though increasing dose lence of similar events in the general population.
with increasing body size is well recognized. Better outcome An appraisal for the National Institute for Clinical Excellence measures are required to assess broader effects, including quality (NICE, 2006 Ia) has identified 65 acceptable trial reports on the of life measures because the QALY is inadequate in this scenario.
first-line agents, although most are of low quality, and the hetero-geneity of measures, methods and participants has precluded a Drug treatment of adults with ADHD is relatively new, having Agents licensed in children (data from the British National been prompted by the entry into adult services of people previ- ously treated in children’s services. However, clinical experience in specialist adult ADHD clinics suggests that the majority ofadult patients are diagnosed as adults, while most adolescent patients stop or are taken off medication. While it is not known whether all findings in children can be extrapolated to adults, psy- chostimulants have comparable effects in adults as in children and adolescents (Faraone et al., 2004; Kooij et al., 2004; Spencer et al., 2005b 1a). Global functioning and adult symptoms such as unstable mood and ceaseless mental activity are thought to respond as well to psychostimulants as do other core symptoms(Asherson, 2005).
Note – prices may change and the dosages given are not necessarily Prescribing and monitoring strategies are no more complex than those used in the management of children, and can be based ADHD management in adolescents to adults on usual approaches utilized in adult services. However, a rigor- than DAT, (Thomason and Michelson, 2004; Gehlert et al., 1995).
ous approach to diagnosis is warranted since adult patients are per- Neuroimaging studies in humans have failed to clarify the relative ceived to present commonly with and be treated for anxiety and therapeutic benefit resulting from targeting DAT or NET inde- depression either as the primary disorder or as part of a personality pendently. In particular, no high-affinity ligands exist to visualize disorder. It is important that such patients are correctly diagnosed the norepinephrine transporter in the human brain making it diffi- and treated within adult psychiatric services, since symptoms can cult to establish the therapeutic importance of NET inhibition.
respond to treatment. Moreover, specialist services are able to Nonetheless, imaging studies indicate that methylphenidate binds monitor treated patients in a similar manner to those with other strongly to DAT and indirect evidence suggests that this elevates conditions, for compliance, response and potential adverse effects, dopamine levels within an hour when given in therapeutic doses including physical side effects like hypertension and weight loss, by oral administration (Volkow et al., 1998; Krause et al., 2000).
and effects on co-morbid symptoms. The best outcomes for moni- These changes are accompanied by an increase in synaptic toring response within trials and for individuals are not known but dopamine that is dependent on cell-firing rates. Thus, following may include ratings of core and co-morbid symptoms and effects methylphenidate administration, a salient stimulus is found to on various domains of functioning. In general, compliance may be elicit greater synaptic dopamine levels than a neutral stimulus better in adults than in children, although the reverse may also be true. Patients may discontinue treatment due to disorganization, Animal studies show that psychostimulants induce an increase difficulty with persistence, negative and uninformed media in cFos-like immunoreactivity consistent with it causing neuronal (leading for example to employer prejudice), fears over activation in the striatum, including the caudate, and in the dependency, mistaking the treatment as the cause of the stigma of mediofrontal cortex (Lin et al., 1996). However, microdialysis in the disorder, and lack of knowledge on other long-term effects.
rats shows that intraperitoneal methylphenidate increases the Atomoxetine is licensed in the USA for the treatment of adult synaptic overflow of hippocampal norepinephrine and striatal ADHD and in the UK for the treatment of adults who have previ- dopamine efflux to a similar magnitude (Kuczenski and Segal, ously been treated for ADHD as children. No agent is currently 2001). Furthermore, with oral methylphenidate, hippocampal nor- licensed in the UK for adults newly diagnosed with ADHD so pre- epinephrine efflux is evoked by lower doses than are required to scribing is off-label. The drugs of first choice for the treatment of elicit nucleus accumbens dopamine efflux (Kuczenski and Segal, adult ADHD are classified as either psychostimulants (e.g.
2002). In contrast, atomoxetine causes a selective increase in cFos methylphenidate, amfetamines (Maidment, 2003a)) or non-stimu- within the prefrontal cortex without increasing expression within lant (e.g. atomoxetine (Thomason and Michelson, 2004)) (see Table the nucleus accumbens or striatum, consistent with it being a 3). Other non-stimulant agents reported to have some efficacy selective inhibitor of NET as indicated from in vitro data (Bymas- include alpha2 adrenoceptor agonists (clonidine and guanfacine), ter et al., 2002). Yet, systemic atomoxetine administration tricyclic antidepressants, bupropion, modafinil and venlafaxine produced an equivalent threefold increase in prefrontal norepi- (Maidment, 2003b). No efficacy has been found for selective sero- nephrine and dopamine efflux measured by microdialysis (Bymas- tonin-reuptake inhibitors, which may be because effective agents ter et al., 2002), whereas extracellular norepinephrine but not generally act via dopamine and/or norepinephrine as discussed next.
dopamine is increased in other brain regions, including the hip- In general, core symptoms are thought to respond better to psychos- pocampus (Swanson et al., 2006). The prefrontal cortex contains timulants and atomoxetine than to antidepressants, although no very low levels of DAT but dopamine and norepinephrine have head-to-head studies have been done (Biederman and Spencer, very similar affinity for NET, so it is possible that dopamine reup- 2001; Maidment, 2003a; Maidment, 2003b).
take may occur via NET in this brain area. Furthermore, adreno-ceptor agonists (guanfacine and clonidine), which are thought to Mechanisms of drug action
activate prefrontal cortex postsynaptic alpha2 adrenoceptors, have fied act on dopamine and/or norepinephrine neurotransmission, been shown to improve performance of non-human primates in a either as agonists or as reuptake inhibitors with the exception of spatial working memory task (Avery et al., 2000).
modafinil, whose mechanism of action remains unclear (Fone andNutt, 2005). Methylphenidate is a potent inhibitor of dopamine Clinical efﬁcacy
Discussions on clinical efficacy are limited by reuptake (Andersen, 1989; Thomason and Michelson, 2004), by the lack of head-to-head studies with adequate and unbiased binding to the cocaine-binding site on the DAT, but in vitro data methodology. In general, all agents with evidence of efficacy in on reuptake inhibition suggest that it also has a very high affinity adults can reduce core symptoms, although effects on different for the norepinephrine transporter (NET). The primary action of symptoms and global functioning may vary between agents and dexamfetamine is inhibition of dopamine reuptake but in addition, individuals. In the absence of any obvious prescribing hierarchy, amfetamines can cross the cell membrane by a mechanism choice of agent may depend on pharmacological factors other than independent of the transporter, and interact with the vesicular efficacy (particularly abuse potential, side-effect profile and toxic- monoamine transporter 2 (VMAT2), thereby displacing vesicular ity in overdose), as well as individual factors (such as patient dopamine and causing the release of newly synthesized intraneu- choice and co-morbidity). The effect of genotype on treatment ronal monoamine (Ferris and Tang, 1979; Fleckenstein and response is unclear, although a poor response to methylphenidate Hanson, 2003). Atomoxetine is a relatively selective NET has been reported in children homozygous for the less common inhibitor, having approximately a 300-fold higher affinity for NET nine-repeat DAT1 genotype (Stein et al., 2005).
ADHD management in adolescents to adults In children and adolescents, over 200 trial reports indicate in adults (Michelson et al., 2003; Faraone et al., 2005a Ib).
around a 70% short-term response rate with methylphenidate treat- However, effects on overall functioning are debated, while no ment (Smith et al., 2000 Ib; Schachter et al., 2001). A recent long-term efficacy trials have yet been reported, although an meta-analysis of several adult trials of methylphenidate indicates interim analysis in adults has been reported (Adler et al., 2005a).
that response rates and effect size of treatment in adults is compa- Thus, its place in clinical practice is not yet fully defined. Other rable with, although somewhat lower than, those in children norepinephrine uptake blocking agents such as desipramine (Faraone et al., 2004 Ia). Notably, greater response rates were (Wilens et al., 1996 Ib) have similar effects in trials while open identified by physician ratings compared with self-report, and in studies on venlafaxine report comparable responses (Adler et al., global functioning rather than core symptomatology. Long-acting 1995; Hedges et al., 1995; Findling et al., 1996 IIb). It is not preparations are reported to have similar response rates and effect known whether other noradrenergic agents like reboxetine, dulox- sizes to standard methylphenidate (Santosh and Taylor, 2000 Ib).
etine and lofepramine have any efficacy in ADHD. Guanfacine is It should be noted, however, that the long-acting preparations may reported in one small trial to have similar efficacy to dexamfeta- improve compliance, minimise abuse, diminish rebound symp- mine (Taylor and Russo, 2001 Ib), as is the non-stimulant wake- toms and address impairment later in the day, which has been fulness-promoting agent modafinil (Taylor and Russo, 2001 Ib) shown to lead to preferential effectiveness in children (Steele et al., 2006).
Monitoring and adverse effects
The meta-analysis found response rates varied between trials ments, patients should be specifically questioned about efficacy on (25–78%); this report and a subsequent trial (76%) indicate that core symptoms and in various domains of functioning, as well as greater responses are found with higher dosing regimes (1 mg/kg) effects on co-morbid symptoms and side effects noted. The find- that are comparable with those effective in children (Faraone et ings of the MTA study strongly suggest that active and fairly al., 2004; Spencer et al., 2005b Ia). Other factors found to corre- intensive monitoring of drug treatments improves effectiveness late with response include reduced level of functioning (psychi- (MTA Cooperative Group, 1999). Patients do not always report atric outpatients versus high functioning academic underachievers) psychiatric effects, which they may not realize can be induced by and psychiatric co-morbidity, although the latter was not con- medication. Therefore, direct questioning about changes in affect, firmed in the latest trial (Spencer et al., 2005b).
anger or personality should be part of the follow-up interview. The Similar but more limited findings are reported for dexamfeta- physician also needs to ask directly about difficulty with com- mine (dextro- or D-amfetamine) (Arnold et al., 1989; Paterson et pliance, since this is often problematic in ADHD and may not be al., 1999; Taylor and Russo, 2000, 2001 Ib), Adderall mixed reported spontaneously. Diurnal changes in effects should also be amfetamine salts (Spencer et al., 2001; Biederman et al., 2005 Ib), sought, since these may be ameliorated by adjustment of dose the psychostimulant pemoline (Wilens et al., 1999b Ib), and the timing or with longer-acting preparations. In addition, long-term dopaminergic agent bupropion (Wender and Reimherr, 1990; monitoring of blood pressure, pulse and weight is indicated. All Wilens et al., 2001 Ib). However, pemoline is associated with the treatments for ADHD are associated with mild statistical hepatotoxicity (Marotta and Roberts, 1998 III) and has been with- increases in blood pressure and pulse which may not be problem- atic in children, but could be problematic in those with antecedent Several randomized, double-blind placebo-controlled trials cardiac disease, hypertension or those who engage in extreme have confirmed the efficacy of atomoxetine in children and adoles- sports. Treatment adjustment should be guided by report of symp- cents (Thomason and Michelson, 2004 Ib), and similar findings toms and functioning in various domains as well as rating scores.
with an effect size of 0.35–0.4 have been reported from two trials Optimal outcome is the dose which leads to best functional Guidance on prescribing
Off-label. Prescribing for adult ADHD is necessarily off-label since no agent is licensed for this indication – although atomoxetine is
licensed for use in adults but only when ADHD treatment was initiated in childhood. The BNF (Joint Formulary Committee, 2005)
states: ‘Unlicensed use of medicines becomes necessary if the clinical need cannot be met by licensed medicines; such use should be
supported by appropriate evidence and experience.’ However, the BNF also states that prescribing medicines outside the recommenda-
tions of marketing authorization alters (and probably increases) the doctor’s professional responsibility. This latter statement might
explain a reluctance to prescribe beyond marketing authorization by clinicians, particularly in primary care. Although controlled evid-
ence for prescribing in adults is not extensive, this consensus statement can be considered to meet the criteria for adequate evidence and
experience in prescribing standard medications to adults with ADHD, when done in the context or with support of specialist psychiatric
services. However, it is noted that supplementary prescribers are not contracted for unlicensed prescribing.
Controlled drugs. Prescriptions for psychostimulants (CD) are subject to prescription requirements, which might be altered in the
future, notably for computer prescribing. Currently in the UK, prescriptions must be indelible, signed and dated by the prescriber
with their address, and must always state in the prescriber’s own handwriting: name and address of patient; the form and strength of
a preparation (e.g. 10 mg tablets); total quantity or number of dose units in words and figures (e.g. 900 mg = nine hundred milligrams
OR Ϫ90 = ninety doses); the dose (e.g. 10 mg tds).
ADHD management in adolescents to adults outcome, balancing adverse effects against benefits for that indi- Diversion of psychostimulants is reported, in particular for short-acting preparations. Very few clinical studies have evaluated Various concerns have been raised over long-term treatment the risk/benefit ratio of long-term stimulant medication at thera- effects, including the potential for tolerance over time, and peutic doses on human brain and behaviour (Volkow and Insel, adverse effects of psychostimulants such as psychosis, sensitiza- 2003) – imaging studies indicate that cocaine induces a similar tion, dependency and withdrawal reactions (Ashton et al., 2006).
blockade of striatal DAT to that seen with methylphenidate Few data exist to guide clinicians since no long-term treatment (Volkow et al., 1999). Circumstantial evidence exists for sensiti- trials have been conducted in adults with ADHD. The long-term zation and tolerance, which can be precursors to dependency; in effects were reviewed in an analysis of existing short- and long- particular, from baseline data of COMACs (Swanson et al., 2004; term follow-up studies of stimulants in children with ADHD Sonuga-Barke et al., 2005) and from the titration phase of the (Hechtman and Greenfield, 2003). The conclusions were that chil- MTA (Galanter et al., 2003), in which possible rebound was seen dren with ADHD treated with stimulants for as long as 2 years that might be due to tolerance (Sonuga-Barke et al., 2004).
continue to benefit from the treatment, with improvements Co-morbid substance use is common in untreated ADHD (see observed in ADHD symptoms, co-morbid oppositional defiant dis- also ‘Substance use disorders’ below). Treatment in children has order and academic and social functioning, with no significant been repeatedly shown to be linked to a reduction in acquiring problems of tolerance or adverse effects. Long-term, prospective substance misuse, but the effect of treatment at other ages is not follow-up studies into adulthood show that stimulant treatment known. A meta-analysis of six trials in children found a 1.9-fold in childhood has slight benefits regarding social skills and reduction in incidence of substance use in medicated comparedself-esteem. Long-term adverse effects from stimulant treatment in with unmedicated patients (Wilens et al., 2003 Ia). Notably, childhood regarding adult height or future substance abuse have studies of methylphenidate-treated rats have found that treatment not been supported by existing studies.
during the equivalent age to human childhood reduces the reward- Substance use is a particular concern, both surrounding the related effects of cocaine (Carlezon et al., 2003), while treatment abuse potential of psychostimulants and the effect of treatment on during the equivalent age to adulthood enhances cocaine reward co-morbid substance use disorders. Abuse potential is related to (Brandon et al., 2001). However, clinical experience suggests the route of administration and the rate of absorption/bioavailabil- probable lower use of recreational drugs in medicated adults, ity of the drug, and may relate to the resultant rate of dopamine although adolescence might carry a differing vulnerability. Thus, release, which is higher for dopamine releasers than pure reuptake rigorous studies are needed to determine the long-term effects of inhibitors (Kollins, 2003). Slow-release preparations have less pharmacotherapy in different age groups, particularly on co- abuse potential and are less amenable to use through abused routes morbid recreational substance use. Research is also needed to such as snorting. They are to be preferred for patients with a determine whether treatment of ADHD in patients currently using history of, or risk factors for, drug misuse.
cannabis and/or alcohol on a daily basis is effective.
Recommendations – drug treatments
Proven drug treatments in children include psychostimulants (A) and atomoxetine (A) as first-line treatments, with imipramine,which is metabolized to desipramine, (B) and bupropion (B) as second-line treatments and clonidine and guanfacine as pos-sible adjunctive treatment (D).
Adult patients with ADHD are most likely to present to primary care, but drug treatment is best initiated and optimized by sec-ondary/specialist services (D).
Drug treatment needs to be chosen and adapted to best fit the individual, including the patient’s preferences and concerns (D).
Meta-analysis of methlyphenidate in adults demonstrates similar drug response effect sizes to that seen in children (A).
The limited evidence in adults suggests that agents that enhance synaptic dopamine have far better efficacy than other treat-ments for core symptoms – amfetamines, methylphenidate and atomoxetine are all effective but not equivalent, since they havedifferent actions and hazards (A).
Drug prescribing in adults is usually off-label but clinicians are supported in prescribing by these BAP guidelines (D).
Drug treatment requires regular, preferably structured, monitoring and review (e.g. for dose adjustment). For uncomplicatedcases this should be every 6–12 months.
Clinicians need regularly to assess patients on medication for ADHD and other symptoms, global and specific functioning,adverse effects, concordance of effects (e.g. between patient, doctor, informants), psychiatric side effects, cardiovasculareffects, compliance and tolerance (daily and long term) (D, S).
Drug treatment should NOT be initiated if the diagnosis is uncertain or benefit is unlikely (D).
Abuse potential is related to drug action and formulation – abuse by patients seems low, but diversion can occur with stimu-lants for performance enhancement or weight loss (D). Slow-release preparations of these agents or atomoxetine are to be pre-ferred for patients with a history or who are at risk of drug misuse (D). Controlled studies are required to confirm theseobservations.
ADHD management in adolescents to adults Key uncertainties
Can we extrapolate from treatment studies in children? Can drug treatment be continued and monitored in primary care with training and support? With such an arrangement, whatwould the workload and resources implications be for both primary and secondary care? How is individual outcome of drug treatment best assessed? How do classes of drugs compare with each other in head-to-head comparisons and with psychotherapeutic approaches inadults? What factors underlie individual differences in drug response, tolerance and other side effects and how is treatment bestmatched to individuals and types of impairments? What is the effectiveness of various drug treatments beyond clinical ADHD trials? Do different drug treatments have differential effects on different underlying deficits (endophenotypes)? What are the effects of different drug treatments on symptoms beyond ADHD core (e.g. functioning/impairment), risk–benefitanalysis and tolerance? What are effects of long-term drug treatment and how feasible are long-term follow-up studies given likely high dropout rates? What are better measures of effectiveness and cost effectiveness for drug trials? What are the important interactions with other prescribed psychoactive medications (e.g. SSRIs) and with recreational drugs? When are drug treatments best avoided (e.g. women of child-bearing age, certain age groups, patients with nothing to do)? chotherapeutic approach led to decreased self-esteem andincreased frustration. In a review of 36 patients improved but not The Multimodal Treatment Study in ADHD (MTA Cooperative remitted on medication, 85% of those who also had co-morbidity Group, 1999) has provided definitive evidence on the role of psy- found benefits of adapted cognitive–behavioural therapy on chotherapy in childhood, with the conclusion that psychotherapy anxiety, depression and functioning (Wilens et al., 1999a III).
provides a small additional benefit when added to drug treatment.
Two controlled, non-randomized studies are reported. Seventeen Compared with children, adults are mostly self-referred and thus patients given psycho-education and organizational skills teaching are self-selected and generally more motivated. However, adults versus no treatment found improvements in organization, attention have usually left the education system where skills are taught and and emotional stability but a reduction in self-esteem (Wiggins may also be affected by lifetime failures and effects of co-morbidity.
et al., 1999 IIa). In 15 patients, dialectical behaviour therapy Good evidence of the effects of psychotherapy in adulthood is showed improvements in ADHD symptoms, depression and func- sparse. Moreover, the usefulness of published studies is limited tioning compared to control treatment (Hesslinger et al., 2002 IIa).
due to small numbers, lack of evidence on long-term unmedicated Three RCTs are published, with some good effect sizes patients, failure to consistently rate effects beyond core and co- reported in terms of core symptoms, and providing some insights morbid symptoms, exclusion of patients with extreme symptoms into the interaction of psychotherapy with medication. A cognitive or co-morbidity, and analysis of completers only.
remediation programme using a brain injury model in 44 patients Clinical experience indicates that general psychotherapeutic versus waiting list controls showed moderate effects on core support and psycho-education around the time of adult diagnosis, symptoms and organization with minimal improvement of self- treatment initiation and review seems helpful. Aims of psycho- esteem and anger (Stevenson et al., 2002 Ib). Notably, effects on education are to inform on the condition, natural history and prog- core symptoms and organizational skills were maintained at 1 year nosis, to prevent further negative effects on self-esteem or while effects on anger were not. A retrospective examination of unrealistic expectations of treatment and to give perspective to the effects of cognitive remediation found no difference between individual neurodevelopmental history. Advice to and screening of medicated and unmedicated patients but numbers were small family members may also be initiated at this time. A review of the psychosocial environment is essential to assess specific limitations Weiss and the ADHD Research Group have examined the in various domains, the level of executive demands and coping effects of individualized problem-focused therapy in 33 patients skills already acquired. Assistance with improving coping skills on dexamfetamine versus those on placebo (unpublished data Ib).
and efforts at environmental restructuring may have a powerful Problem-focused therapy was found to be more effective in redu- impact on the functioning of adults with ADHD. Group therapy, cing core symptoms and improving functioning in medicated where available, may help with social isolation, especially around patients than controls. Modified cognitive–behavioural therapy the critical period where treatment initiation can enhance plus medication demonstrated greater benefits than psychotherapy experience of failure and lead to loss of self-esteem, depression or medication alone particularly on ADHD symptoms, with lesser and substance use (Safren et al., 2005a).
effects on anxiety and depression in 32 patients (Safren et al., In terms of psychotherapy, an initial retrospective notes review conducted by Ratey et al. (1992 III) found that a dynamic psy- ADHD management in adolescents to adults Recommendations – psychotherapeutic approaches
General psychotherapeutic support to the individual, family and others around time of diagnosis and treatment initiation ishelpful to inform on the condition and prognosis, to prevent negative effects on self-esteem or unrealistic expectations of treat-ment, to adapt positive and negative coping strategies and to give perspective to individual neurodevelopmental history (D).
Structured, adapted psychotherapies may be useful to build confidence, develop executive skills, address anxiety and depres-sion and improve functioning (B), while group therapy may help for social isolation (C/D).
Evidence in childhood suggests that psychotherapies are beneficial for co-morbid anxiety and for functional outcomes beyondthe core symptoms, when added to drug treatment (B). Since adults are self-referred, may no longer have access to school orskills development and are motivated once symptoms improve, there is reason to suggest that non-pharmacological treatmentsmay be useful in augmenting the functional outcomes of medication alone (D).
Involvement of educational/occupational psychologists and other relevant personnel for environmental restructuring can maxi-mize functioning at college/work (D).
Whether and what types of therapy might best work for the different aspects of ADHD (different core symptoms, global func-tioning) and for different co-morbidities? How best to combine drug treatments, psycho-education, psychotherapeutic approaches, and environmental restructuring? Can psychotherapy be used with good effect in adults unable to take, or who do not respond to, medication? What is the natural history of the outcomes of psychotherapeutic approaches and what follow-up approaches are needed toreinforce effects over time? Thus, various forms of structured, intensive, skills-based treat- background and natural history of ADHD, and many common co- ment may improve likelihood of remission, especially when com- morbidities, an accurate diagnostic attribution could also inform on bined with medication. Effects of psychotherapy on core the likely course and complications of the disorder. Much symptoms including disorganization seem substantial, with experience with co-morbidity comes from specialist paediatric potential effects on functioning and modest effects on co-morbid clinic populations, which are likely to have increased co-morbidity symptoms. The effect on self-esteem seems often poor or even compared with the general population. Specialist clinics need to negative, since skills-based treatment may reveal low function- have skills to differentiate or exclude key co-morbidities, as these ing. Psychotherapy data have particular implications for patients will impact on management, which in turn will impact on co- who have a poor response to or who are unable to take medica- morbidities. This is an argument for establishment of neurodevelop- tion (e.g. women who wish to become pregnant), while such mental clinics that can provide appropriate specialist training in interventions might be particularly helpful for patients who are assessment and management to patients of all ages (IV).
parents and others with a high-level need for learned skills,including those with few activities in their lives. A future direc-tion for research is on therapies that emphasize interventions to address disinhibition and impulsivity, interpersonal skills andstress management.
Evidence on co-morbidities is fairly strong – at all ages, the dis-ruptive and antisocial behaviours predominate; in childhood andadolescence, other neurodevelopmental disorders are the main Co-morbidity and special situations
additional co-morbidities, while in adults substance use and mooddisorders predominate. Several co-morbid studies of adults with Co-morbidity could be considered the rule rather than the exception ADHD have been completed (Kooij et al., 2001; Biederman, when ADHD persists into adulthood (IV), yet much of the available 2004; Secnik et al., 2005; Kessler et al., 2005, 2006; Torgersen evidence is from childhood populations. A key difficulty in the et al., 2006). Co-morbid disorders in adults can be classified into diagnostic process is determining the relationship between symp- (1) ongoing developmental disorders such as learning disabilities, toms attributable to ADHD and other symptoms. Thus, symptoms oppositional defiant disorder, conduct disorder, autism spectrum may represent core ADHD symptomatology, complications or con- conditions, Tourette and tic disorders, and developmental delay, sequences of ADHD, including self-medication, a separate co-mor- and (2) disorders that may first present in childhood but are famil- bidity, a differential diagnosis or even the effects of prescribed iar to adult psychiatry such as anxiety and mood disorders, post- medication. An accurate diagnostic attribution is important to deter- traumatic stress disorder, substance use/dependence, sleep mine the likelihood of a given treatment modality improving spe- disorders and personality disorders. Up to 90% of adults will have cific symptoms as well as to determine an individual diagnostic one or another of these co-morbidities. Epidemiological data hierarchy for targeting treatments. Given the neurodevelopmental suggest that at least a third of patients will have had a lifetime ADHD management in adolescents to adults history of mood or anxiety disorders or other disruptive behaviour A common finding in childhood is that stimulant medication disorders. The prevalence of current co-morbid disorders is lower does work in some individuals with neurodevelopmental co- than a history of co-morbid disorders. Some co-morbid presenta- morbidity but that non-response or adverse effects may be more tions such as problems with sleep and learning disabilities in common. If stimulants prove unsuitable in the individual case, med- adults have not yet been researched although they may be quite ication aimed at the co-morbid disorder or combined medication common. Clinically, this is of major importance since ADHD in might overall provide a better response than medication aimed at adults rarely exists in isolation and outcome may be determined by ADHD, as argued with autistic spectrum disorders and bipolar co-morbid disorders that either preclude treatment, require treat- symptoms. This begs the question of whether a diagnostic hierarchy ment in their own right or are more severe than ADHD itself. A exists for co-morbid disorders and the effect this has on treatment – good assessment for ADHD in adults therefore requires a full for example, bipolar symptoms, autistic spectrum disorders and mental status and psychiatric exam for other disorders as well as epilepsy treated before ADHD, which may be targeted before or familiarity with both the co-morbid conditions of childhood and alongside substance use disorders, conduct disorder and opposi- the co-morbid conditions of adulthood.
tional defiant disorder. Sleep problems, anxiety and depression may Childhood proportion of co-morbidities are given as follows: arise as a consequence of ADHD but may still require separate oppositional defiant disorder (40%); language disorders (30–35%); treatment, including antidepressants. Complex cases need to be con- conduct disorder (20%); specific learning disability (15–25%); sidered on an individual basis and may need further specialist refer- anxiety disorder (20–25%); mood disorder (15–20%); smoking ral (e.g. for sleep assessment), especially in adulthood, where (19%); substance use disorder (15%); autistic spectrum disorders existing evidence and experience is even less than in childhood.
(10%); tics (15–20%), often associated with Tourette’s syndrome Evidence on management of bipolar symptoms comes mainly and obsessive–compulsive disorder; epilepsy; sleep disorders; from expert experience outside Europe. One concern in this group is the potential for psychostimulants to enhance the likelihood of psy- Conversely, ADHD as a co-morbidity correlates strongly with chosis (DelBello et al., 2001), whether in children with prominent some disorders and needs to be specifically sought in these popu- mood instability or in those with a strong family history of bipolar lations. For example, with Tourette’s or chronic tic disorder, disorder. Risperidone and other atypical antipsychotics help with roughly one in two to three children will have ADHD while one in psychotic symptoms, mania and aggression but ADHD symptoms three will have obsessive–compulsive disorder, which will further respond poorly. Sodium valproate may be useful in rapid cycling impact on management. Many more may have poor social skills.
and mixed states. Since psychostimulants carry a potential risk of Autistic spectrum disorders is another area in which ADHD symp- worsening or triggering bipolar symptoms, expert paediatric groups toms occur commonly in the symptom profile, including: stereo- in Boston and Cincinnati treat mania prior to addressing the ADHD typed mannerism (70%), stereotyped utterances (65%), inattention separately; however, their views remain controversial.
(60%), morbid/unusual preoccupation (65%), compulsions or Depression can be treated with antidepressants, such as the rituals (50%), anxiety or fears (50%), hyperactivity (40%), depres- SSRIs, which can be used safely with psychostimulants. Nora- sion/irritability/agitation (25%), self-injury (30%), tics (8%).
drenergic agents (atomoxetine, reboxetine) might be sensible for In Europe, bipolar disorder is a controversial diagnosis along- use in people with co-morbid anxiety and depression, though no side a diagnosis of ADHD in childhood, and yet experts in other research studies have been done to confirm this supposition, while areas recognize that children with unstable mood and ADHD methylphenidate was used as an antidepressant in the 1950s.
symptoms do exist (Geller et al., 2000a, 2000b; Craney and With autistic spectrum disorders, one in two children respond Geller, 2003; Post et al., 2004). Moreover, the combination of to medication compared with two in three of children with ADHD hypersexuality, grandiosity and a family history of bipolar illness alone. Psychostimulant side effects are more common in autistic is common in paediatric bipolar presentations, particularly in the spectrum disorders, typically dysphoria and perseveration or cog- context of neurodevelopmental disorders. A subgroup of these nitive rigidity, which needs to be monitored. A final dose of 20 to children may therefore be at risk of later adult bipolar disorder, 30 mg/day of methylphenidate is usually sufficient. The key prin- which is conceptualized differently from childhood mood-related ciples with dosing are to start low, go slow and monitor more fre- symptoms, such as dysphoric conduct disorder, in which ADHD quently. Conversely, the effect of atypical antipsychotics on symptoms, conduct disorder and depression co-exist. Thus the ADHD symptoms particularly hyperactivity in ASD is good, with possibility exists that bipolar disorder is also a neurodevelopmen- an effect size of 1.4 (McCracken et al., 2002 Ia).
tal disorder that produces dysregulation of affect. This also implies Evidence on the link between ADHD and children with that an early mood complication or a strong family history is more epilepsy is somewhat stronger, occurring commonly in the context likely to predict a mood co-morbidity in the future.
of learning disabilities. Adequate anticonvulsant cover is essential, In initiating medication for co-morbidities, it is important to con- and treatment of ADHD with stimulants may be indicated once sider on an individual basis the effectiveness, risk–benefit ratio and anticonvulsant hyperactivity is ruled out. Little research exists in the likelihood of tolerance and other effects of a given treatment. Co- this area, and the research that does exist has studied morbidity may increase the need for a combined treatment strategy methylphenidate only (Gross-Tsur et al., 1997; Gucuyener et al., with one or more medications plus a specific psychotherapeutic man- 2003; Tan and Appleton, 2005; van der Feltz-Cornelis and agement – e.g. behavioural programmes for conduct disorder or cog- Aldenkamp, 2006). However, psychostimulants, atomoxetine and nitive–behavioural therapy for co-morbid mood disorders.
antidepressants can lower seizure threshold.
ADHD management in adolescents to adults Sleep disorders are a common complaint with some 40% of versely, medication for co-morbid disorders might impact on children with ADHD having sleep symptoms, which may be due ADHD. For example, our experience suggests that anticonvulsants to stimulant medication or due to inability to settle down at night might increase hyperactivity and restlessness as might drugs for due to ADHD. The latter will respond to a later dose of stimulant sleep disorders, while atypical antipsychotics can worsen many medication, although care should be given when administering late doses of psychostimulants as failure to clear medication com-pletely by the time of the next morning dose might lead to the development of a steady state, which may increase risks of toler-ance and sensitization. Another key co-morbidity that presents Substance use disorders are common in ADHD and may persist with sleep symptoms is an undiagnosed anxiety disorder (e.g.
into or arise in adulthood. Substance use may reflect a core deficit phobia of darkness). Treatment options include non-pharmacolog- in ADHD, i.e. reduced reward mechanisms and impulsivity, it can ical measures to regulate sleep (‘sleep hygiene’), melatonin, cloni- arise via conduct disorder and antisocial behaviours, or develop dine, trazodone and zolpidem. Recent clinical trials have through self-medication with stimulants, alcohol, cannabis or demonstrated that patients with co-morbid ADHD and anxiety or other sedatives. Substance use disorders thus represent a diagnos- tics may show improvement in both disorders with atomoxetine tic difficulty in people with possible ADHD; in the presence of core symptoms of ADHD, substance use disorders could be con- At follow-up, clinicians need to assess the effects of ADHD sidered a complication of ADHD. In childhood, stimulant medica- treatment on all key symptoms, including those of other diag- tion does not cause but in fact reduces the incidence of substance noses, since ADHD medication may have either a positive or use disorders (Wilens et al., 2003 Ia). However, effects in adult- negative impact on co-morbid diagnoses. Psychostimulants often hood may vary among individuals – adult substance use may worsen sleep, mood, appetite, emotional lability, cognitive rigidity reduce with ADHD medication but others could be predisposed to and other symptoms in practice so assessment of such effects is the development of tolerance, sensitization and increased sub- needed in future clinical trials and in populations that are excluded stance use, particularly with higher doses of psychostimulants (see from clinical trials. The relationship between tics and ADHD ‘Monitoring and adverse effects’ above).
grows stronger with time. Although research indicates that there is In general, substance use needs to be stable prior to initiating no statistically significant worsening of tics with stimulants or ato- medication treatment of ADHD, especially in primary care. Few moxetine in children, individuals may nonetheless experience trials have examined the effects of treatment in adults with sub- either improvement or deterioration in tics which needs to be stance use disorder but methylphenidate has been used effectively treated accordingly (Gadow et al., 1995; Allen et al., 2005). Con- in cocaine users (Levin et al., 1998 Ib), while history of drug Recommendations – co-morbid conditions
Clinicians need to screen for autistic spectrum, developmental disorders, communication difficulties, learning disabilities, ticsand Tourette’s syndrome, anxiety and affective disorders, substance use disorders and others (e.g. epilepsy, sleep disorders,sensory problems), but symptoms cannot be counted twice for ADHD and co-morbid disorders (C/D).
Further specialist input or advice may be needed regarding co-morbidity (e.g. learning disability teams), since co-morbiditycan have a greater impact on functioning than ADHD (D).
Likely co-morbidities vary according to age of presentation and will alter treatment responses and outcomes, including adverseeffects, but co-morbidity is not necessarily a barrier to treatment of ADHD (C/D).
Stiftung zur förderung der erforschung von ersatz- und ergänzungsmethoden zur einschränkung von tierversuchen
Stiftung zur Förderung der Erforschung von Ersatz- und Ergänzungsmethoden zur Einschränkung von Tierversuchen Mainzer Landstraße 55, 60329 Frankfurt am Main Completed Project Pharmacological Screening using human embryonic stem cell Dr. Michael Reppel, Institut für Neurophysiologie, Universität Köln Pharmacological Screening using human embryonic stem cell derived cardiomyoc