European Psychiatry 56 (2019) 14–34 Contents lists available at ScienceDirect European Psychiatry journal homepage: http://www.europsy-journal.com Original article Updated European Consensus Statement on diagnosis and treatment of adult ADHD J.J.S. Kooija,b,* , D. Bijlengaa , L. Salerno9 , R. Jaeschke1, I. BitterJ , J. Balázsc , J. ThomeS, G. DomX , S. Kasperd, C. Nunes Filipe7, S. Stese, P. MohrW, S. Leppämäkif , M. Casasg, J. BobesO , J.M. Mccarthyh , V. Richartei, A. Kjems Philipsenj , A. Pehlivanidis8 , A. Niemelak , B. Styrl , B. Semerci10 , B. Bolea-Alamanacm , D. Edvinssonn , D. Baeyenso , D. Wynchanka , E. SobanskiL , A. Philipsenp , F. McNicholas4 , H. CaciM , I. Mihailescuq , I. Manor3 , I. Dobrescur, T. SaitoH , J. Krause5 , J. Fayyads , J.A. Ramos-QuirogaN , K. Foekent , F. Radu , M. Adamouv, M. Ohlmeier6 , M. Fitzgeraldw, M. GillQ , M. LensingU, N. Motavalli Mukaddesx, P. Brudkiewiczy, P. Gustafsson11, P. Taniz , P. Oswald12 , P.J. CarpentierA , P. De RossiY, R. DelormeB, S. Markovska SimoskaC , S. PallantiD , S. YoungE , S. BejerotV , T. LehtonenF, J. KustowG , U. Müller-SedgwickK , T. HirvikoskiZ , V. Pironti2 , Y. GinsbergT, Z. FélegyházyI , M.P. Garcia-PortillaR , P. AshersonP a PsyQ Psycho-Medical Programs, Expertise Center Adult ADHD, Carel Reinierszkade 197, 2593 HR, The Hague, The Netherlands b Amsterdam UMC, LocationVUMc, Dept. of Psychiatry, Amsterdam, the Netherlands c Institute of Psychology, Eotvos Lorand University, Vadaskert Child Psychiatric Hospial and Outpatient Clinic, Budapest, Hungary d Medical University Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria e University Psychiatric Center, KU Leuven, Kortenberg, Belgium f Helsinki University Central Hospital, Department of Psychiatry, HUS, Finland g Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain; Psychiatric Genetics Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Catalonia, Spain; Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain h Visiting senior lecturer, King’s College London, United Kingdom; Midland Regional Forensic Service, Hamilton, New Zealand i Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona; Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain j DPC Naestved, Ladby, Naestved, Region Sjaelland, Denmark k Wellmind Terveys Oy, Oulu, Finland l Mccabi Health Services (H.M.O), Tel Aviv, Israel m General Systems Division, Centre for Addiction and Mental Health/ Dept. Of Psychiatry, University of Toronto, Toronto, Canada n Uppsala University, Uppsala University Hospital, Akademiska sjukhuset, Uppsala, Stockholm o Parenting and Special Education, KU Leuven, Leuven, Belgium p University of Bonn, Department of Psychiatry and Psychotherapy, Bonn, Germany q Alexandru Obregia Clinical Hospital of Psychiatry, Bucharest , Romania r University of Medicine and Pharmacy “Carol Davila”. Child and adolescent Psychiatry Department, Prof. Dr. Alex Obregia”Psychiatry Hospital, Bucharest, Romania s St George Hospital University Medical Center, Balamand University Faculty of Medicine, Institute for Development, Research, Advocacy and Applied Care, Department of Psychiatry and Clinical Psychology, St George Hospital, Achrafieh, Beirut, Lebanon t Vieux Chemin de Cagnes à La Gaude, la Gaude, France u University of Medicine and Pharmacy “Carol Davila”; Child and adolescent Psychiatry Department, Prof. Dr. Alex Obregia”Psychiatry Hospital, Bucharest, Romania v University of Huddersfield and South West Yorkshire Partnership NHS, Manygates Clinic, Wakefield, England w Trinity College, Blanchardstown Village, Dublin, Republic of Ireland x Istanbul Institute of Child and Adolescent Psychiatry, Istanbul, Turkey y Centrum Dobrej Terapii, Cracow, Poland z Department of Psychiatry, Clinic for Neuropsychiatry, Helsinki University Central Hospital, HUS, Finland A Reinier van Arkel Mental Health Institute,’s-Hertogenbosch, Netherlands B Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris, France C Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia D Stanford University Medical Center, University of Florence, INS Institute of Neuroscience, Florence, Italy E Psychology Services Limited, Croydon, England F Neuropsykologkonsult Taina Lehtonen, Hjärup, Sweden G Barnet Adult ADHD Service, Barnet, Enfield and Haringey NHS Mental Health Trust, London; Barnet Adult ADHD Service, Springwell Centre, Barnet Hospital, Barnet, England H Department of Child and adolescent Psychiatry, Graduate School of Medicine, Hokkaido University, North 15,West 7, Kita-ku, Sapporo, 060-8638 Japan http://dx.doi.org/10.1016/j.eurpsy.2018.11.001 0924-9338/© 2018 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 15 I ADHD Központ(center) Budapest, Budapest, Hungary J Semmelweis University, Department of Psychiatry, Budapest, Hungary K Adult ADHD Service, Barnet, Enfield & Haringey NHS Mental Health Trust, North London & Department of Psychiatry, University of Cambridge; Adult ADHD Service, Springwell Centre / Barnet Hospital, Barnet, London, England L Central Institute of Mental Health, Mannheim; University Medical Center Mainz, Mainz, Germany M Hopitaux Pediatriques de Nice CHU Lenval, Nice, France N Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain; Psychiatric Genetics Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Catalonia, Spain; Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain O Department of Psychiatry, School of Medicine, University of Oviedo - Centro de Investigación Biomédica and Red de Salud Mental, CIBERSAM, Oviedo, Spain P SGDP Building, Institute of Psychiatry Psychology and Neuroscience, Kings' College London, London, England Q Department of Psychiatry, Trinity College Dublin, School of Medicine, Dublin, Republic of Ireland R Dept. of Psychiatry, University of Oviedo, School of Medicine, Psychiatry, Oviedo, Spain S Thome, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitatsmedizin Rostock, Rostock, Germany T Stockholm Center for Eating Disorder R&D Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden U Oslo University Hospital, Department of Rare Disorders, NevSom - Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Oslo, Norway V Örebro Univerity, School of Medical Sciences, Campus USÖ, Örebro, Sweden W National Institute of Mental Health, Klecany, Czech Republic; Third Faculty of Medicine, Charles University Prague, Czech Republic X Antwerp University (UA, CAPRI), Boechout, Belgium Y Department of Neurology and Psychiatry, Sapienza University of Rome, Rome; Department NSMOS, Faculty of Medicine and Psychology, University “Sapienza”of Rome, Rome, Italy Z Center for Neurodevelopmental Disorders at Karolinska Institutet (KIND), CAP Research Center, Stockholm, Sweden 1 Jagiellonian University Medical College, Section of Affective Disorders, Department of Psychiatry, Krakow, Poland 2 Cambridge Adult ADHD & ASD Clinic, Cambridge, England 3 Geha MHC, Petach-Tikva, Israel 4 University College Dublin, Dublin, Republic of Ireland 5 Outpatient Clinic, Ottobrunn, Germany 6 Klinikum Kassel, Department of Psychiatry and Psychotherapy, Kassel, Germany 7 Nova Medical School. Universidade NOVA Lisboa, Lisboa, Portugal 8 National and Kapodistrian University of Athens Medical School, Eginition Hospital, Department of Psychiatry, Athens, Greece 9 INS, Institute of Neuroscience, Florence, Italy 10 Hasan Kalyoncu University, Poyracık Sokak. Istanbul, Turkey 11 Lund University, Clinical Sciences Lund, Child and Adolescent Psychiatry, Lund, Sweden 12 High Security Hospital, CRP Les Marronniers, Tournai, Belgium A R T I C L E I N F O A B S T R A C T Article history: Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric Received 9 July 2018 disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently Received in revised form 2 November 2018 underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and Accepted 3 November 2018 impairment, due to lack of, or ineffective treatment, and higher costs of illness. Available online 16 November 2018 Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and Keywords: knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to Adult ADHD Updated European Consensus Statement support clinicians with research evidence and clinical experience from 63 experts of European and other Diagnosis countries in which ADHD in adults is recognized and treated. Treatment Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of European Network Adult ADHD ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How EPA should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD. © 2018 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction: the European Network Adult ADHD provide this update of our first Consensus Statement on adult ADHD published in 2010 [1]. The European Network Adult ADHD (ENAA) was founded in 2003 to help improve the diagnosis and treatment of ADHD in 1.1. Objectives of the updated consensus statement for clinicians adults in Europe and beyond. ENAA represents mental health care professionals and researchers from 28 countries with expertise on Despite strong evidence on the clinical presentation, genetics, ADHD in adults (www.eunetworkadultadhd.com). The neurobiology, the burden of the disorder, and on safe and effective Section Neurodevelopmental Disorders Across the Lifespan (NDAL) treatment for ADHD in adults, many people are still under- of the European Psychiatric Association (EPA) joined our effort to diagnosed and undertreated. Specialized clinical services remain scarce in most parts of the world, including Europe [2,3]. Our aim is to provide an update of the literature on assessment and treatment * Corresponding author at: European Network Adult ADHD, VUMc, Amsterdam, of adult ADHD to [1] increase awareness on ADHD as an impairing EPA, The Netherlands. life-long neurodevelopmental condition up to old age [2]; update E-mail address: s.kooij@psyq.nl (J.J.S. Kooij). 16 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 the assessment procedure for diagnosing ADHD in adults; and [3] explained by common genetic variation. In total, twelve loci give updated recommendations for appropriate treatments. achieved genome-wide significance, including FOXP2; notable because prior work had implicated it in adult ADHD [29]. These 1.2. Methodology findings place ADHD firmly on the path to detecting very large numbers of associated common genetic variants as more samples Creating a Consensus Statement does not follow the same are accrued. procedure as required for the development of a guideline, such LD regression analyses that estimate genetic correlations as systematic reviews using formal ratings of the evidence. between disorders find strong genetic links between ADHD and Most of the authors participated in the development of a first a range of outcomes including educational performance, depres- Consensus Statement on adult ADHD in 2010, and were asked sion, obesity, smoking and lung cancer [28]. A further finding is the to provide an update of the previous text based on new findings very strong genetic correlation between the diagnosis of ADHD, in the literature since the time of publication. Subgroups and trait scores in general population samples, demonstrating that dealing with different subjects were formed. The subgroups ADHD represent the extreme of a continuously distributed trait in reached consensus on the text among themselves before the general population [30]. These finding confirm the polygenic sending it to the first author. The first author put all paragraphs nature of genetic liability to ADHD. together and edited the text with the help of a few other Rare copy number variants (CNVs) occurring on less than 1% of coauthors (DW, SY, PA, DB). This draft of the manuscript was chromosomes are also known to play a role in a subset of individuals send to all authors for their comments. The first author with ADHD [31,32]. CNVs were found to be 2-fold more common in checked the comments and implemented adjustments into the children with ADHD within the normal IQ range, and 6-fold higher in text, and send the final version to all authors for agreement. All those with IQs below 70 [32]. Specific genes suggested as CNVs authors agreed with the final version. linked to ADHD include the nicotinic alpha-7 acetylcholine receptor gene (e.g., [33]), several glutamate receptor genes [34] and 2. Heritability and environment neuropeptide-Y [35], although these findings remain inconsistent and hard to verify due to low frequency in the population. Family, twin and adoption studies from the last 20 years show that ADHD is a familial disorder with high heritability, indicating 2.3. Molecular genetic studies of adult ADHD that a significant genetic component influences risk for the disorder [4–12]. Environmental factors such as severe institutional Molecular genetic studies of adult ADHD are less advanced, but deprivation are also likely to play a role, either as main causal are expected to confirm some genetic associations identified in factors in a few cases [13] or by interaction with genetic risks. childhood and find other genetic associations related to persis- Family studies indicate a risk to first-degree relatives of 4–5 fold tence or remission of ADHD in adult life [20]. A preliminary report the population rate or higher, with prevalence rates around 20% at the International Neuropsychology meeting (Washington, 2018) among first degree relatives [14]. Data on ADHD in children and found the genetic correlation between child and adult ADHD to be adolescents find average heritability of around 76% [12]. Studies in greater than 80%. Most of the current research has been adult twins using self-rated ADHD symptoms consistently report coordinated in Europe by Barbara Franke from the Netherlands lower estimates of heritability, around 30–40% [15–17]. One reason for the International Multicentre Persistent ADHD Collaboration for lower heritability of adult self-reported ADHD symptoms may (IMPACT) group. This collaboration has successfully generated a be from the use of self-ratings. These lead to lower estimates of multi-site sample of more than 3500 patients and continues to heritability compared to informant ratings regardless of age, grow. To date several publications highlight potential associations perhaps due to variable levels of awareness among individuals with adult ADHD, some but not all of which are shared with genetic rating their own ADHD symptoms [18,19]. Studies combining data association findings in children [36–42]. across informants [20], or using clinical diagnostic information [21] find heritability estimates for adult ADHD in the same range (70–80%) as for children [22]. 2.4. Environmental factors 2.1. Candidate genes It has been known for a long time that environmental factors are associated with ADHD [43], particularly prenatal risk factors Early molecular genetic studies of ADHD in children reported such as exposure to alcohol and drugs, valproic acid, high blood genetic associations with several candidate genes. Genetic variants pressure, maternal stress during pregnancy, as well as preterm within or near the D4 and D5 dopamine receptor genes provided birth and low birth weight [44–46]. However sophisticated the most consistent findings supported by meta-analysis [23]. study designs are needed to clarify whether these association Other specific candidate genes were implicated in the early studies reflect direct effects of the environmental exposure or reflect [12,24,25], but none have provided consistent evidence or been genetically correlated risk measures. For example, although replicated in more recent large-scale genome wide association smoking during pregnancy is clearly associated with offspring studies. Taken together the traditional neurotransmitter system ADHD, this association appears to be entirely accounted for by genes appear to explain only a small amount of the variance in the genetic correlation between maternal smoking and off- ADHD [26]. There is also some converging evidence for the role of spring ADHD [47]. In contrast, evidence from Romanian genes that fit into a neurodevelopmental network involved in adoptees suggests that severe early deprivation is causally directed neurite outgrowth [27]. related to ADHD in a dose dependent way [13]. Gene by environment interactions (G x E) have been proposed and may 2.2. Genome wide association studies (GWAS) explain some of the missing heritability seen between heritability estimates derived from twin (0.76) and molecular More recent findings have emerged from genome-wide genetic (0.22) data. However, to date no G x E effects have been association studies [28]. The most recent dataset reported included clearly identified. The findings to date indicate that much more over 20,000 ADHD cases and 35,000 controls. These data were used work is needed to understand the interplay between genetic to estimate that around 30% of the heritability of ADHD is and environmental risks. J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 17 3. Neurobiology of ADHD overlap with regions showing differential task activations during inhibition, attention, or working memory tasks in ADHD compared 3.1. Neuro-imaging: evidence for atypical gray and white matter areas to controls [78]. Despite the wealth of established findings from fMRI and RS-fMRI studies of ADHD, cross-sectional neuroimaging Structural brain scans of adults with ADHD showed grey matter data is correlational in nature and causal inferences cannot yet be abnormalities in several brain areas, including the right frontal and made. prefrontal areas [48,49], anterior cingulate [50–52], the basal More recently outcome studies of children diagnosed with ganglia and the cerebellum [53–56] with some preliminary ADHD has been able to compare functional brain change in adults research also showing abnormalities of the visual cortex [57]. with persistent and remitted ADHD and compare these to age- Additionally, cortical thickness was found to be reduced in adult matched controls. The largest such follow-up study to date, of 205 ADHD [56,58,59]. Some evidence suggests that grey matter children with ADHD, found that persistence of ADHD was abnormalities, in some subcortical regions, are more pronounced associated with loss of the balance of connections within the in children than adults. This might reflect the effects of age, default mode network, and connections between the default mode medication, intrinsic heterogeneity of the ADHD syndrome, or a and those supporting attention and cognitive control. In contrast combination thereof [51,60–64]. there were no differences in these networks between those whose Despite these reported findings the latest mega-analysis ADHD had remitted and non-ADHD controls [79]. conducted by the Enigma consortium found no significant Overall, despite the wealth of established findings from fMRI and differences in brain structure between adult ADHD and controls; RS-fMRI studies of ADHD, cross-sectional neuroimaging data is although, small but significant differences were found in children correlational in nature and causal inferences cannot yet be made. The for subcortical regions including the accumbens, amygdala, finding that certain functional brain changes are seen to differ caudate, hippocampus, putamen and intracranial volume with between persistent compared to remitted cases of childhood ADHD effects ranging from d = .10–.15 [65]. These findings indicate that sheds some light on likely causal processes, but further longitudinal while there are structural changes in subcortical brain regions in data is still required before firm conclusions can be drawn. ADHD in children, these are relatively subtle effects that dissipate with increasing age. 3.3. Neuropsychological and electrophysiological tests Diffusion tensor imaging (DTI) highlighted that white matter tracts, including fronto-occipital, fronto-striatal, temporal and As a group, individuals with ADHD are characterized by altered temporo-occipital fasciculi and part of the corpus callosum, bear neuropsychological functioning across a variety of executive microstructural abnormalities [66–71]. Additionally, some find- function (EF) measures. However, thus far there is neither a ings also linked microstructure variability to symptomatology such neurobiological nor a neuropsychological test (battery) for ADHD that greater inattention but not hyperactivity-impulsivity was with sufficient positive predictive power to establish the diagnosis associated with significantly lower fractional anisotropy (that is at the individual level [80]. In one study, the vast majority of lower microstructural integrity) in the left uncinate and inferior neuropsychological instruments showed poor discriminative fronto-occipital fasciculi compared to controls [70]. These results ability compared to clinical assessment measures such as the indicate that structural deficits in ADHD are not just confined to ASRS Screener v1.1 and the DIVA 2.0 Diagnostic Interview for specific regions but involve interconnections among large scale ADHD in adults, with an overall classification accuracy ranging brain networks [68,71–73]. from 53% to 66% [81]. Nevertheless, when used in combination with the DIVA 2.0, objective cognitive performance tests measur- 3.2. Functional neuroimaging ing omission and commission errors, and physical activity, were found to increase the correct classification of adult ADHD [81]. Regarding functional MRI (fMRI) studies, task-based and There is currently insufficient evidence to warrant the use of resting-state findings converge. Meta-analyses show that ADHD neuropsychological testing to determine the diagnosis of ADHD is associated with dysfunctions in several domain-specific fronto- [82] or to predict impairment in major life domains [83]. striatal and fronto-cerebellar neural networks. Thus a meta- Moreover, clinicians should also be aware of the possibility that analysis of 39 child and 16 adult ADHD fMRI studies concluded that a few individuals may feign ADHD symptoms to gain external in ADHD there are significant dysfunctions in multiple neuronal incentives, like stimulant medication or special academic accom- systems involved in higher-level cognitive functions [74]. These modations. There is some evidence supporting the effectiveness of include hypoactivations in the frontoparietal executive control performance validity tests (PVTs) in differentiating between network, putamen, and ventral attention network, which is genuine and feigned ADHD compared to rating scales [84]. consistent with the classical model of ADHD as a disorder of Electrophysiological studies suggest that brain dysfunctions are deficient fronto-striatal activation. involved in the central components of ADHD in both children and Hyperactivations are also seen in regions of the default mode adults [85–89], although the finding of increased DAT density and visual networks, which support the contemporary view that remains controversial [90,91]. ADHD is associated with faulty regulation of relationships between Data from Electro Encephalography (EEG) is relatively scarce in default mode and task positive networks. Similar findings come adult ADHD. Generally, EEG studies of ADHD find similar deficits in from meta-analyses, which show consistent underactivation in adults and children, while some findings change with age and inferior fronto-striatal networks during cognitive tasks [75], in might be sensitive to developmental changes [92]. Despite US Food dorsolateral fronto-striato-parietal networks during attention and Drug Administration approval of an EEG device (2013) that tasks [75], and in fronto-cerebellar networks for timing functions assists in the diagnosis of ADHD subtypes [93–95], this remains [76]; in addition to abnormally enhanced activation in default controversial [96]. EEG tests are not sufficiently accurate but could mode regions [76]. be useful to increase diagnostic certainty. The recent focus on resting state fMRI (RS-fMRI) identified multiple intrinsic neural circuits, reflecting functional connectivity 4. ICD and DSM criteria for ADHD within and between regions which is continuously encoded in the spontaneous activity of the brain [77]. The intrinsic fronto-parietal, There are two diagnostic manuals used to diagnose ADHD: The dorsal attentional, visual, motor and default mode networks all Diagnostic and Statistical Manual of Mental Disorders (DSM) and 18 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 the International Statistical Classification of Diseases and Related solving problems, managing time and self-regulating (inhibiting) Health Problems (ICD). As ADHD has been recognized as a disorder behaviors. affecting individuals across the lifespan, the diagnostic criteria for DSM-5 also highlights the importance of mood lability and adolescents and adults have been adjusted in the DSM-5, emotional dysregulation as “an associated feature that support the published in May 2013: diagnosis”. Although emotional dysregulation may dominate the clinical presentation [103–105], it is not a criterion for classifying 1) ADHD is now in the chapter Neurodevelopmental Disorders, individuals as it lacks specificity, occurring in many other mental which includes conditions associated with factors affecting the health conditions. brain development. DSM-IV required that symptoms and impairment were 2) Diagnostic criteria have been adapted by adding some examples present before age 7, but as research demonstrated no differences describing how ADHD symptoms are expressed across the between children with an age of onset before and after age 7 [106] lifespan. this criterion was changed to several symptoms by age 12. Similar 3) The age of onset criteria has been changed requiring several findings have also been reported regarding adults reporting later- symptoms to be present before age of 12 years, instead of some onset of symptoms [107,108], and there is disagreement both symptoms and impairment by age 7. within and across sources concerning recall of symptom onset 4) The term “subtype” has been replaced by “presentation”, [109]. The fact that adults with ADHD frequently fail to recall reflecting the variation of ADHD symptoms within the same childhood behavior led to the suggestion that clinicians take note individual during the lifespan. that the onset of the disorder was during the developmental 5) The symptom threshold required has been reduced to 5 period, or they should use age 16 years as the upper age limit. symptoms instead of six for older adolescents and adults Using this criteria captured all cases of childhood ADHD and 99% (>17 years) in either the inattention or hyperactive/impulsive of adults with the disorder [110]. The decision of DSM-5 to extend domain. the age of onset to 12 instead of 16 may have a negative impact on 6) Criteria requiring significant impairment has been modified to adults with ADHD who have difficulties with retrospective recall “clear evidence that symptoms interfere with or reduce the of childhood behaviors, and may not receive the diagnosis for this quality of social, academic and occupational functioning”, with reason. This may be particularly true for those who had some specifiers regarding severity level. compensation due to high intelligence, or lived in a highly 7) The presence of Autism Spectrum Disorder (ASD) is no longer an structured or supported environment, or presented predomi- exclusion criterion, consistent with evidence showing their nantly with inattentive symptoms. In such cases, the presence of a frequent co-occurrence. collateral informant (generally a parent or spouse) is of great 8) ADHD Not Otherwise Specified (NOS) has been changed into value. Many adults with ADHD that are used to their lifelong Other Specified ADHD and Unspecified ADHD. symptoms, have limited awareness of how ADHD symptoms adversely impact their interpersonal relationships and affect their The revision of ICD-10, ICD-11 has been published in June 2018. life; some reporting higher symptoms but lower impairments or ICD-11, developed by the World Health Organization now refers to vice versa. ADHD as Attention Deficit Hyperactivity Disorder, instead of Such inconsistency has been attributed to a lack of introspec- previously Hyperkinetic Disorder (HKD) [97]. It now uses similar tion and an incoherent self-view [111,112], and supports the utility requirements as the DSM-5 regarding age of onset, and the same 3 of a collateral informant. If a significant other is not available, presentation types. In Europe, ICD codes are often used for school reports or social care reports may be helpful. statistics on mortality, morbidity and by insurance agencies for health-related reimbursements [98], whereas DSM is primarily 4.1. Clinical picture used in clinical practice by licensed mental health care profes- sionals [99]. 4.1.1. Inattention and hyperfocus The diagnostic assessment starts by evaluation of self-reported Patients with mainly inattention problems are often slow to symptomatology. The clinical interview is essential for diagnosing think and formulate due to distractions. They may formulate things ADHD in adults, which investigates the characteristic symptoms in a long-winded and tangential way, losing themselves in and impairments of ADHD in both childhood and adulthood. In irrelevant details and having difficulty making decisions. A children and adolescents, informants’ ratings are higher correlated difficulty for the clinician is that this may hinder the diagnostic with heritability and cognitive and EEG findings than self-ratings assessment. Patients may also over-concentrate or ‘hyperfocus’. [19]. Also prevalence and persistence rates increase when parent This phenomenon most commonly occurs when engaged in reports are used [19]. In adults this may be slightly different, as activities that the patient finds very interesting and/or provide some research shows that the adult patient is the best informant instant gratification, such as computer games or online chatting. [100]. The presence of a family member however (a parent and/or For such activities, concentration may last for hours on end, in a the partner) during the assessment can still provide valuable very focused manner. additional information, e.g. on severity and its translation into daily activities. 4.1.2. Hyperactivity There is compelling evidence that a cut-off of four current With respect to hyperactivity, adults do not present in the same symptoms is the most appropriate for an adult diagnosis [101,102]. way as children. Their hyperactivity usually manifests in a more However, due to concern about the possibility of an artificial subtle way. Clinicians need to assess their feelings of restlessness. A increase in the prevalence of the disorder, DSM-5 lowered the first impression of mobility is not definitive; sitting calmly during threshold for diagnosing ADHD from six to five symptoms for those the diagnostic assessment does not exclude any ADHD. Hyperac- older than 17 years of age. Several items have been expanded by tivity in adults often manifests itself as feelings of continuous inner some illustrative examples to facilitate the recognition of the restlessness or agitation, talking too much, ceaseless mental disorder throughout development. Although not included in activity, not being able to relax properly or needing alcohol or thecriteria as such, behaviors reflecting executive dysfunction drugs to relax and/or sleep. Hyperactivity and/or restlessness may usually appear clearly during the assessment, when patients be temporarily relieved by the patient engaging in excessive sport describe problems with organization, facing daily responsibilities, activities, and in such cases the person may suffer physical J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 19 ailments as the body may have insufficient time to recover and/or Table 1 Examples of ADHD-related symptoms. due to sustained injuries. Inattention  Forgetfulness 4.1.3. Impulsivity  Distractibility  Chaotic presentation Impulsive behavior and associated interpersonal conflicts often  Difficulty organizing & planning have consequences for relationships with family, friends, colleagues  Difficulty listening and employers. It may also seriously impact on personal finance  Difficulty with punctuality (arriving either too late or too when impulsive spending causes debt. Impulsive binge behaviors early) may also be present (e.g. binge eating), often to combat restlessness  Temporary hyperfocus for highly salient tasks, but no control of attention when required or for many essential or due to a need for immediate gratification. Closely related to activities of daily life impulsivity are ‘sensation seeking’ behaviors when patients may  Getting lost in details seek out excitement from novel and thrilling stimuli. These often  Doubtfulness – unable to make decisions or solve involve risk taking behaviors such as playing with fire, reckless problems  Needing too much time to complete tasks driving, sexual risks, and provocative behavior leading to fights.  Difficulty starting and finishing tasks  Mind Wandering: 4.1.4. Emotional dysregulation  Mental restlessness Emotional dysregulation is listed by DSM-5 as a characteristic  Unrelated spontaneous thoughts, constantly on the go, feature of ADHD, supporting the diagnosis [113]. The type of jumping and flitting, multiple thoughts at the same time emotional dysregulation seen in ADHD has been characterized as  Associative thinking deficient self-regulation of emotional symptoms such as irritabili- ty, frustration and anger [114], and low frustration tolerance, temper outbursts, emotional impulsivity, and mood lability [115]. Hyperactivity  (Inner) Restlessness  Difficulty relaxing Emotional dysregulation in ADHD is different from episodic  Pacing up and down symptoms such as marked sustained irritability occurring within  Talking too much and too loud the context of altered mood states, such as an episode of  Fidgeting, rocking or tapping depression or mania. In ADHD, emotional symptoms tend to  Not being able to bear an office job because of restlessness reflect short lived exaggerated changes, often in response to daily  Knocking things over because of excessive mobility events, with rapid return to baseline within a few hours [114].  Being able to sit still but this comes with muscle strain Whether the type of emotional instability seen in ADHD is  Restless sleep qualitatively different to that seen in other chronic conditions such as borderline personality disorder or post-traumatic stress remains Impulsivity  Acting without thinking unclear.  Difficulty waiting turn – linked to feelings of irritability  Blurting things out that cause distress to others 4.1.5. Excessive mind wandering  Interrupting others  Impatience and difficulty waiting turn Another common feature of adult ADHD is excessive mind  Spending too much wandering, also referred to as mental restlessness [116–118]. In  Walking out of jobs DSM-5 mind wandering is briefly mentioned as the occurrence of  Starting relationships quickly unrelated thoughts. Although mind wandering is a universal  Not being able to postpone gratification experience, some forms of mind wandering are detrimental  Sensation seeking and risk taking behaviors  Binge eating because they interfere with task performance. Adults with ADHD frequently report a distractible mental state with multiple unrelated thoughts that are constantly on the go and jump from Emotional  Mood lability one topic to another [119,120]. Mind wandering is also a feature of dysregulation  Low frustration tolerance  Emotional impulsivity other mental health disorders such as depressive or obsessive  Irritability disorders. However, in ADHD mind wandering is characterized by  Anger outbursts unfocused, short lived distractible thoughts with no pattern of  Premenstrual increase of symptoms repeated thoughts or abnormality of content. Research found that excessive mind wandering was strongly correlated with ADHD symptoms, was a strong predictor of the diagnosis (sensitivity and specificity around 90% for case-control differences), co-varied with correlate well with cognitive or neuropsychological tests of ADHD symptoms over a 6-month period, and was a better executive control [121–123]. A distinction needs to be made predictor of ADHD-related impairments than the inattentive and between rating scale measures of behaviours reflecting self- hyperactive-impulsive symptoms of ADHD [120]. In ADHD it can regulation of behavior referred to as EF (behavioral) deficits, and be measured using the Mind Excessively Wandering Scale the results of neurocognitive tests of EFs such as working memory [116,118,120] (Table 1). and inhibition. Neuropsychological test scores reflecting executive functioning lack ecological validity in that they have no significant 4.1.6. Behavioral self-regulation (executive function deficits) relationship to behavioural rating scale measures of EF [124]. The ADHD has been described as a disorder of executive functions EF test scores also are very poor at predicting impairment in a such as inhibition and working memory. These include problems variety of domains of major life activities, compared to EF organizing, prioritizing and initiating work; focusing, sustaining behavioural rating scales [125]. and shifting attention to tasks; regulating alertness, sustaining effort and processing speed; managing frustration and regulating 4.1.7. Burden of ADHD emotions; utilizing working memory and accessing recall; and The impairments associated with ADHD across the lifespan are monitoring and self-regulation of behavior [121,122]. Although impressive. ADHD is associated with learning difficulties, school clinically these are good descriptions of the types of difficulties dropout, underachievement at work [126], frequent job changes experienced by adults with ADHD, behavioral measures do not [127], chronic fatigue [128], financial problems, gambling and 20 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 internet use [129,130], home and traffic accidents leading to have less hyperactive/impulsive symptoms than boys; because of increased mortality rates [131–133], relationship difficulties and higher disruptiveness, boys are more likely to be referred by parents intimate partner violence [134,135], early onset of addiction and teachers, whereas girls remain undiagnosed [170]. Missed [136], teenage pregnancies and sexual transmitted diseases diagnosis may be due to a lack of knowledge and recognition of [137,138], a two-fold increased smoking rate [139], an increased ADHD in girls by health care professionals, and to the presence of other number of suicide attempts and self-harm in adolescents conditions: low self-esteem, anxiety as well affective disorders occur [140,141], and increased criminality [142,143]. Moreover, physical frequently in females with ADHD, and it is possible that ADHD disorders and ailments may become chronic due to forgetfulness, symptoms may be mistakenly attributed to such comorbidities health problems induced by a negative lifestyle, poor eating and [171,172]. Females with ADHD appear to develop better coping sleeping habits, and lack of health care follow-up [144–147]. strategies than males, and are better able to mask symptoms of ADHD ADHD has further been associated with auto-immune diseases throughout childhood. However, this may no longer work well when [148], obesity [149], and physical multi-morbidity. In one large they face salient life challenges, such as leaving school, attending study, individuals with more than 4 diseases had over more than college or university, commencing employment, managing intimate 3-fold higher odds of possible ADHD [146]. The risk of diabetes, relationships, and taking responsibility for their own life decisions hypertension, cardiovascular disease and cancer, that are related [173]. Different genetic liability between the sexes [174], as well to obesity, may be increased as well. An additional burden on neuroendocrine factors affecting the dopaminergic system, such as family life may be the presence of one or more children with thyroid and estrogen hormones [172,175], have all been also suggested ADHD, which happens frequently due to the high familial risks of to play a role in the masking of ADHD in girls and women. In addition, the disorder. girls and women with ADHD are less well studied than males. Clinicians should also be aware that high functioning adults with Women with ADHD are particularly vulnerable to early ADHD may not present with a typical pattern of functional impair- adversities, health and mental health problems compared to ments in their daily life. Adaptive or compensatory skills can develop controls [176]. A higher prevalence of insomnia, chronic pain, that mask the more overt behavioral problems related to ADHD [150]. suicidal ideation, generalized anxiety disorder, depressive disor- Some may find work that is well suited to their symptom profile. ders, a greater vulnerability to nicotine dependence [176,177] and Furthermore, in ADHD neurocognitive performance and inattentive an increased likelihood of risky sexual behaviors [138] has been symptoms are sensitive to the salience of task activities [151,152]. Such reported in women with ADHD in comparison with controls. people with ADHD mayexcel in certain aspects of their lives, but still be impaired in others, such as more routine and mundane tasks such as 5.2. Transition of adolescents to adult mental health services paying bills, looking after the house, or developing stable social relationships. Problems can include subjective distress from symp- As two-thirds or more of children with ADHD continue to have toms such as mental and physical restlessness, sleep problems, and impairment into adulthood [178], many require the transition from emotional instability; and the use of drugs such as cannabis or alcohol child to adult mental health services. However, transition between to reduce these symptoms. services is generally difficult, placing youths with ADHD in an even more vulnerable position [179]. Research shows that disruption of 5. Prevalence of ADHD across the lifespan care during transition adversely affects clinical outcome [180,181]. Clear recommendations have been formulated, mostly based on In childhood, ADHD is among the most common psychiatric clinical experience, to facilitate successful transition of patients disorders with a prevalence rate of 3–5 % [153]. For this age group, with ADHD from child to adult mental health services [1,182–185]. well established diagnostic and treatment services are available These are a) transition should ideally be completed by the age of 18 throughout most of Europe. In the last four decades, a large body of years, b) transition should be planned in advance by both child and evidence has accumulated, showing how in the majority of cases adult mental health services, c) young people with ADHD and their ADHD is a lifespan disorder, persisting as either the full blown parents should have sufficient information regarding the transition disorder, or in ‘partial remission’ with persistence of some process (e.g. psychoeducational material including available symptoms and continued clinical and psychosocial impairments services), d) both continued parental care and child’s growing [154–161]. The prevalence of ADHD in adults across twenty autonomy should be considered, e) if necessary a formal meeting countries was recently estimated at 2.8%, with a range between 1.4 involving child and adult mental health services (with specific - 3.6% [3]. ADHD was also found in a Dutch population study to knowledge on this age group) and patients and parents should be persist into old age (> 60 years) with a prevalence of 2.8–4.2% considered. All these can help to prevent the drop-out of young depending on cut-off (6 or 4 current symptoms respectively), and people with ADHD from services. However, the reality is quite associated with impairment [162–166]. ADHD in older adults is different, as indicated by two reviews [186,187]. Compared to other accompanied by increased rates of mood and anxiety symptoms, diagnostic groups, youth with ADHD were significantly less likely general health problems, conflicts, divorce, loneliness, and a lower to be referred, they were more likely to refuse referral, and a income, showing a similar pattern of problems as in younger age significant number remained in child services well beyond their groups. Research exploring the needs for treatment of older adults 18th year. Studies also have found transition policy deficits with ADHD has commenced, and the first treatment protocol of [186,188], suboptimal experience of transition when it does occur older adults with ADHD has been published [167]. [186,189], a dearth of adult ADHD services [190], and a lack of expertise on ADHD amongst adult clinicians [3,191]. This suggests 5.1. Sex issues there is an urgent need for a multifaceted approach combining transition specific clinical guidelines, and funding for the training Sex differences in ADHD diagnosis are well documented, with girls the training of clinicians, to ensure that those in need of ongoing being less likely to be diagnosed, and sex ratios ranging between 1:5 to intervention may successfully transition to adult services. 1:9 [168]. Such discrepancy is less evident in epidemiological research in children where the sex ratio is 1:3, suggesting under recognition of 5.3. Late-onset ADHD? ADHD in girls in the clinic. In both epidemiological and clinical studies of adult ADHD the sex ratio is closer to 1:1 [169]. Several factors may Recent longitudinal studies have indicated that besides typical explain the sex disparity during the lifespan. Girls with ADHD may childhood onset ADHD, with the full diagnostic criteria being met J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 21 before the age of 12 years, there may be later-onset cases with onset of depression, cyclothymia, personality disorder, bipolar disorder, the full diagnostic criteria beyond this age [104,189,190]. These substance use disorders, those with multiple physical diseases findings have proven controversial due to severe methodological [146], and those within the criminal justice system [197]. limitations [192,193], however the large majority of later onset cases appear to meet the DSM-5 age of onset criteria of several symptoms by 6.2. Diagnostic assessment the age of 12 [113]. Late onset of symptoms was evaluated in the control arm of the long-term follow-up of the Multimodal Treatment For diagnostic assessment, the use of a semi-structured study of ADHD (MTA). In most cases, other factors were present that diagnostic interview is advised, such as the Diagnostic Interview could discount the late onset of ADHD symptoms and exclude the for ADHD in adults, second edition (DIVA 2.0) [198], based on the diagnosis of ADHD [194], such as symptoms representing non- DSM-IV-TR criteria. DIVA 2.0 is available online without charge, impairing cognitive fluctuations, a comorbid disorder, or the cognitive currently in 19 languages (www.divacenter.eu). The Conner’s Adult effects of substance use [192]. However, there remained a very small ADHD Diagnostic Interview for DSM-IV (CAADID) has been sample of adolescent onset cases. Another population cohort study validated in English and Spanish [199]. DIVA 2.0 has been validated found that the majority of those with apparent late-onset ADHD had in two European populations [81,199], and is increasingly used in high ADHD scores at least one point in childhood, suggesting that they international research. A DIVA 2.0 app is available in the App and may have been misclassified on the basis of their score at age 12 years Google Play stores. The update of DIVA 2.0 for DSM-5 criteria into [195]. These cases with high score before the age of 12 years might not ‘DIVA-5’ in all languages is ongoing. DIVA-5-ID, for people with have met full criteria before the age of 12 years, but would meet the Intellectual Disability (ID) and Young DIVA, for children and current DSM-5 criteria for several symptoms in childhood. One adolescents, are new versions of DIVA-5. An alternative is ACE+ conclusion is that clinicians should be aware that subthreshold cases of (http://www.psychology-services.uk.com/resources.htm), a semi- ADHD during childhood might go on to meet the full diagnostic criteria structured diagnostic interview to assess ADHD in adults (>16 as older adolescents. Clinicians should take care to fully assess years). ACE + assesses the core symptoms of ADHD in both impairment, psychiatric history, and substance use when diagnosing adulthood and childhood, the extent to which they impair and treating cases with apparent later-onset ADHD [192]. functioning, and the presence of co-existing conditions. ACE + is currently online available in 7 languages, with more translations 6. Screening and diagnostic assessment underway. For these and other diagnostic tools, see Table 2. 6.1. Screening 6.3. The assessment process of ADHD and comorbidity Several screening tools are available for ADHD in adults. The Diagnosis of ADHD is based on a careful and systematic assessment validated tool recognized by the World Health Organization (WHO) of a lifetime history of symptoms and impairment. Central to this and updated for DSM-5 criteria is the Adult ADHD Self report process is the assessment of childhood-onset and current symptoms of Rating Scale (ASRS). This revised ASRS was studied in managed ADHD, and the presence of symptoms and impairment in at least two care, the general population and in a clinical group. The sensitivity domains (school, work, home, interpersonal contacts). For this lifetime was 91.4%; specificity 96.0%; AUC, 0.94; PPV, 67.3% [196]. The assessment, collateral information from family members and spouse previous version of the ASRS has been translated into many are useful. It is important to take a full medical history of psychiatric languages (see http://www.hcp.med.harvard.edu/ncs/asrs.php). and somatic conditions, as well as a family history of psychiatric and The Wender Utah Rating Scale assesses besides ADHD a broader neurological problems. High intelligence should be taken into account spectrum of symptoms that often accompany ADHD or are as a potential moderator in the diagnostic assessment, as ADHD is comorbid. Several other scales that ask about the 18 items as underdiagnosed in patients with high intelligence because they use defined in the DSM-5 to classify ADHD are available, see Table 2. more compensatory strategies [200]. Clinicians should also be aware A key question is who should be screened for ADHD. In general, that high functioning adults with ADHD may not present with a typical since the hallmark of adult ADHD is a chronic trait-like condition pattern of functional impairments in their daily life. Adaptive or that emerges out of childhood or early adolescence, anyone compensatory skills can develop that mask the more overt behavioral presenting with such a clinical picture should be screened [2]. This problems related to ADHD [150]. Some may find work that is well should include those with chronic histories of inattentive, restless suited to their symptom profile. Furthermore, in ADHD neurocognitive or impulsive behaviors, as well as those with emotional instability. performance and inattentive symptoms are sensitive to the salience of Targeted groups where rates of ADHD are significantly increased task activities [151,152]. Such people with ADHD may excel in certain and should therefore be screened include family members of aspects of their lives, but still be impaired in others, such as more people with ADHD, and those with a history of behavioral routine and mundane tasks such as paying bills, looking after the problems, any chronic mental health disorder including anxiety, house, or developing stable social relationships. Problems can include Table 2 Open access Scales and Interviews for Diagnostic Assessment of ADHD in adulthood. Scalesa Adult ADHD Self-Report Scale Developed by WHO; 6-item version, based on DSM-5 (ASRS), in many languages https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470397/ Wender Utah Rating Scale https://www.thecalculator.co/health/Wender-Utah-ADHD-Rating-Scale-Calculator-858.html Diagnostic Interviewsb DIVA-5 Structured Diagnostic Interview for ADHD in adults; according to DSM-5; in 19 languages www.divacenter.eu ACE+ Semi-structured Interview for ADHD in adults https://www.psychology-services.uk.com/adhd.htm a Other scales without open access are: Conners Adult ADHD Rating Scale (CAARS), and the Adult ADHD Investigator Rating Scale (AISRS). b Other interviews without open access are: Conners Adult ADHD Diagnostic Interview (CAADID), Adult ADHD Clinical Diagnostic Scale (ACDS). 22 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 subjective distress from symptoms such as mental and physical differences for gender and age [214]. Further, inmates with ADHD restlessness, sleep problems, and emotional instability; and the use of compared to those without are reported to have higher rates of drugs such as cannabis or alcohol to reduce these symptoms. psychiatric morbidity including substance misuse, an earlier onset Adult diagnoses may be missed in clinical practice due to lack of offending, more violent offences, criminal recidivism and more of knowledge about ADHD in adulthood among practitioners and frequent and severe institutional aggression [215,216]. due to the high frequency of comorbid psychiatric conditions [201]. The lifetime co-morbidity rate is 60–80%. Having three or 7. Treatment more disorders was associated with a ten-fold increase of the chance of having ADHD in a population study in 20 countries [3]. 7.1. Effective treatments Before treatment start, all comorbidities must be established so that the best order of treatment can be determined together with The treatment of adults with ADHD should follow a multimodal the patient. In the study by Fayyad et al, data on ADHD and and multidisciplinary approach, which includes psychoeducation, comorbidities was collected on 26,744 respondents [202]. In pharmacotherapy, cognitive behavior therapy (CBT) and coaching adults with ADHD having one comorbidity was found in 23% of for ADHD, which are all discussed in this article. cases, two in 14% of cases and three in 14% of cases. Rates were Ideally, the treatment plan also involves the adult’s partner, particulary high for any mood disorder (22%), any anxiety family or close relationships, and in some cases systemic (family) disorder (34%), substance use disorders (11%) and any behavioural therapy may be required when gross disruption to family disorder (15%). relationships and functioning is present. Psychiatric comorbidity is thus a clinically important dimen- sion of ADHD heterogeneity and a factor that contributes to the 7.2. Treatment focus in comorbid ADHD persistence of ADHD in adulthood [203,204]. It is important for the diagnosis of ADHD, as well as the correct targeting of treatments, to In the most recent report of 20 nationally or regionally identify mood, anxiety, eating, sleep, somatic and substance use representative World Mental Health surveys, data on ADHD and disorders, in addition to personality, tic and autistic spectrum comorbidities was collected on 26,744 respondents [202]. In adults disorders [205]. Because adults with ADHD often exhibit low self- with ADHD having one comorbidity was found in 23% of cases, two esteem, low mood, mood lability and irritability, these symptoms in 14% of case and three in 14% of cases. Rates were particulary high may sometimes be confused with dysthymia, cyclothymia, bipolar for any mood disorder (22%), any anxiety disorder (34%), substance disorder or borderline personality disorder. Furthermore, daily use disorders (11%) and any behavioural disorder (15%). Treatment mood changes in ADHD are very common, and represent a poorly of ADHD is therefore most often in the context of co-occuring regulated but essentially normal range of moods, rather than the disorders. more severe extremes of depression and elation as seen in bipolar Before treatment starts, all comorbidities must be established disorder. It has been argued that chronic mood instability should so that the best order of treatment can be determined together be considered part of the core syndrome of ADHD [206,207]. ADHD with the patient. In general, the most severe disorder is prioritized. and borderline personality disorder share symptoms of impulsivi- For instance, psychosis, bipolar disorder, substance abuse, severe ty, mood instability, anger outbursts and feelings of boredom depression and severe anxiety are usually treated first. Milder [158,208,209]. In the ADHD patient, impulsivity and anger are mood or anxiety disorders, and emotional instability, may respond usually short-lived and thoughtless rather than driven. Conflicts in to treatment of ADHD and can be treated at the same time as relationships, suicidal preoccupation, self-mutilation, identity ADHD. Drug and alcohol abuse should be stabilized but can be disturbances and feelings of abandonment are usually less intense treated at the same time as ADHD. than in borderline personality disorder. However, the differences may not be clear-cut because these symptoms are chronic and 7.3. Psychoeducation on ADHD trait-like in both conditions [210]. ADHD in children is also associated with increased rates of According to consensus based on good clinical practice and the neurodevelopmental disorders like autism spectrum disorder, need to work on an informed consent basis within a multimodal dyslexia and impaired motor coordination which are thought to treatment approach, psychoeducation should be the first step as a arise from overlapping genetic influences [211]. Such neuro- standard of care [217]. First evidence from an open trial and a developmental comorbidities are less well studied in adults, but randomized clinical trial shows, that patients and significant they are commonly observed in clinical practice and may lead to others who attend a structured psychoeducation program increase continued impairments. As the order of treatment will depend on their knowledge about ADHD, and improve the quality of their the presence and severity of comorbidities, evaluation of comorbid relationships and psychological well-being [218,219]. disorders is a key component of the ADHD assessment process, using appropriate clinical diagnostic approaches. 7.4. Pharmacotherapy for ADHD 6.4. ADHD and criminality 7.4.1. Introduction on pharmacotherapy In the first European Consensus Statement [1] psychostimu- The prevalence of ADHD is increased in forensic populations lants (methylphenidate and dexamphetamine) were recom- compared to the general population [212], and the risk of mended as the first-line pharmacotherapy for adult ADHD criminality is increased in individuals with ADHD, especially in [1,184,220], as they exert moderate-to-high clinical effects, with those with comorbid oppositional defiant disorder, conduct average effects higher than atomoxetine (ATX) and other non- disorder, substance misuse and antisocial personality disorder stimulant medications [2]. There were, however, no head-to-head [213]. A meta-analysis comprising 42 studies from 15 countries studies providing robust comparative analysis of efficacy differ- reported a 5-fold increased prevalence of ADHD in youth prison ences [221]. Across most of Europe, lisdexamfetamine (LDX) has populations (30%) and a 10-fold increased prevalence in adult been introduced as a slow release formulation of dexamphet- prison populations (26%) as compared to the general population amine. The recent systematic review and network meta-analysis [214]. When using diagnostic clinical interviews, the estimated on the comparative efficacy and tolerability of medications for ADHD prevalence in prisoners was 25.5%, without significant ADHD in children, adolescents and adults by Sam Cortese et al. J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 23 showed, that the first pharmacological choice for ADHD in children sudden cardiac death, ventricular arrhythmias or stroke no more and adolescents is methylphenidate, and amphetamines in adults than 0.2-0.4% higher in one study [248]. MPH might trigger [222]. In fact in adults, amphetamines were not only the most arrhythmias in patients with congenital heart diseases [249]. The efficacious compounds, as rated by clinicians and by self-report, consensus is caution in patients with known cardiac defects, but but also as well tolerated as methylphenidate and the only risks are small. compounds with better acceptability than placebo. 7.4.4. Atomoxetine 7.4.2. Licensing ATX yields moderate efficacy in reducing ADHD symptoms Licensing of ADHD medications for adults is more diverse than (SMD: –0.33 to –0.40) [227]. Onset of action is 1–2 weeks, and in 2009 [1], reflecting greater understanding of ADHD, and efforts full effects may take up to 6 months to develop [250]. If rapid to market ADHD medications in Europe. In Denmark, Ireland, onset of effect is not essential, ATX may be a good choice for Norway, Sweden, Switzerland, the Netherlands and the United high risk patients who need stable control of ADHD symptoms Kingdom, most ADHD medications can be prescribed, either with a [251]. full license (e.g. Medikinet1, Strattera1, Elvanse1) or transitional The use of ATX as first line in drug abusers continues to be licenses (e.g. Concerta XL1) and off-label prescribing is endorsed debated with other experts preferring stimulants due to rapid by national guidelines and formularies. Dexmethylphenidate onset and potentially greater effects [252]. Although in the past (Focalin XR1) is licensed in Switzerland only. In other countries, there were concerns that stimulants may increase the risk of only a limited selection of medications is available for funding by substance use disorders (SUD), there is now a wealth of data the state sector, but off label prescribing is possible. In another demonstrating reductions in SUD during periods of treatment of group of countries (e.g. Greece, Slovenia, Poland), only very few ADHD with stimulants [233,253]. ADHD medications are available, with off-label prescribing mostly ATX may be a good choice with co-occurring anxiety that in the private sector. The European Network on Adult ADHD might be exacerbated by stimulants, as a RCT of adults with (ENAA) and the Neurodevelopmental Disorders Across the Lifespan comorbid ADHD and social anxiety disorder found improvements (NDAL) section at EPA strongly recommend that evidence-based in both ADHD and social anxiety [254]. ATX does not appear to be treatments for adult ADHD are made more available and licensed effective in the treatment of comorbid depression in adolescents across European countries. [255]. 7.4.3. Efficacy and adverse effects of stimulants 7.4.5. Guanfacine and clonidine Meta-analyses of randomized controlled trials (RCTs) demon- In Europe, guanfacine extended-release (GXR), an alfa-2 strate the efficacy of stimulants and ATX in the reduction of ADHD adrenergic agonist, is licensed for the treatment of children and symptoms in adults [223–227]. Standardized mean differences adolescents with ADHD for whom stimulants are not suitable, not (SMDs) range from 0.4 to 0.7, with stimulants showing greater tolerated or where shown to be ineffective [256,257]. Notably, efficacy than ATX [224]. The longest RCT in adults still found there are currently no RCTs in adult patients to support the use of significant effects of MPH after one year [228]. National registry GXR in this age group, only a study using GXR or placebo as an data also suggest long term benefits. Although these studies are not adjunct to stimulant treatment that had insufficient effect. Both definitive due to lack of randomization and controls, they treatments did not differ in efficacy [258]. demonstrate ‘real-world’ societal benefits associated with the Extended-release (ER) clonidine is approved in the US for use of ADHD medications. These studies show that during periods treatment of ADHD in 6–17- year olds as monotherapy or an of receiving medications for ADHD there are marked reductions in adjunct to stimulants. There are RCTs on both ER clonidine transport accidents and mortality rates [132,229], criminal [259,260] and IR clonidine [261,262] in children and adolescents convictions [230], suicidal behavior [231], violent reoffending with ADHD, but no equivalent studies in adults. [230], depression [232] and substance misuse [233]. Similar analyses with antidepressants find no effects, suggesting the 7.4.6. Bupropion effects are specific to ADHD medications. There are conflicting findings for bupropion from a small A 2011 meta-analysis [225] revealed that MPH (mean dose number of adult studies. Positive results were reported with higher 41.2–82 mg/day) exerted a moderate effect on ADHD symptoms, doses (400–450 mg per day) [263,264]. Due to a limited evidence with large effects observed at doses of >77.4 mg/day. Immediate base, bupropion use should be restricted to cases who do not release (IR) MPH has a short duration of action of maximum 4 h. tolerate other ADHD medications. Due to difficulties with compliance when needing to take medication up to several times a day, long-acting MPH prepara- 7.4.7. Other medications tions have been developed, with durations of action ranging Selective noradrenaline reuptake inhibitors such as reboxetine between 6–12 h. may be an alternative to ATX [265,266]. There is limited evidence The recommended dose range of Immediate Release dexam- for tricyclic antidepressants [267,268]. Selective serotonin reup- phetamine (IR) is 5–60 mg/day [220]. Lisdexamfetamine (LDX) has take inhibitors (SSRIs) are not effective for the treatment of ADHD a slow release profile giving the drug a relatively low abuse profile [229,230,269]. Modafinil, a wakefulness-promoting agent used in [234]. LDX is taken once daily with a mode of action of up to 14 h the treatment of narcolepsy, has not been demonstrated as an [235]. Three RCTs in adults indicate moderate to large effects on effective treatment for adult ADHD in a phase 3 trial that had high ADHD symptoms [236–238] (SMD = 0.97) [239], comparable to rates of side effects (86%) and drop-out (47%) possibly resulting MPH. The safety and tolerability profile is similar to other from excessive doses (210–510 mg/day) [270]. stimulants [240,241]. The main adverse effects of stimulants are increased heart rate 7.4.8. Long-term safety concerns and blood pressure, and reduced appetite and sleep [242–245]. Currently there is no evidence of significant long-term risks Heart rate, blood pressure, sleep problems and weight are using stimulants. Tomography scans find higher striatal dopamine therefore assessed before, and monitored at least twice a year transporter availability in ADHD patients treated with stimulants during treatment. Serious cardiac complications are rare [271]. The clinical implications of this up-regulation are not clear. [243,246,247] with reported risks for myocardial infarction, Potential toxicity on heart valves of medications with an agonist 24 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 effect on 5-HT2B receptors have been discussed [272], including symptoms without worsening the SUD, and should not be avoided MPH and guanfacine. Some argue that echocardiography should be [287]. routinely performed prior to treatment with potential valvulo- pathic drugs [273]. This risk is not however established, and we 7.5.3. Cognitive enhancement in students and others do not recommend routine echocardiograms Another group where screening for ADHD is appropriate is the [184,252,274], except in older adults (> age 50) [167]. student population. This is because we know that ADHD specially interferes with educational attainment. Further, this has been 7.4.9. Combined psychopharmacology highlighted be the finding that genetic risks for ADHD overlap with The high rate of psychiatric comorbidity in adult ADHD those for educational outcomes [28]. Student groups with frequently necessitates combined psychopharmacology [275]. particularly high rates of ADHD include those presenting with Accordingly, the risk of possible drug-drug interactions when specific learning difficulties [288] and mental health problems treating adults with ADHD must be considered. These include the [202]. Related to this, there are concerns, particularly in countries following: with a higher rate of stimulant prescriptions, that students may seek the diagnosis of ADHD to receive stimulants for cognitive – Monoamine oxidase inhibitors are generally contraindicated due enhancement. Some studies show that although most students use to the risk of hypertensive crisis. their ADHD medication as prescribed, misuse and diversion is not – Although MPH is mainly metabolized in the liver, drug uncommon [289]. Care must therefore be taken to ensure that interactions via CYP enzymes are uncommon. Amphetamines, students are diagnosed and treated for ADHD when appropriate, however, are metabolized primarily via the CYP 2D6 enzyme while minimising risks of diversion. system making drug interactions possible (with inhibitors or inducers of this enzyme system, e.g. fluoxetine and paroxetine) 7.5.4. Pregnancy and breastfeeding [276]. There is only limited information on the effects of ADHD – Treatment with medications that act on the noradrenaline medication on the fetus and new-born [290]. As suggested by system, including certain antidepressants (e.g. duloxetine, population-based studies, MPH or amphetamine exposure during venlafaxine), will have an additive effect and may increase the pregnancy is not related to higher rates of any congenital risk of hypertension and other adverse cardiovascular events. malformations [291–293]. For cardiac malformations, MPH use – Due to its metabolism by the CYP 2D6 enzyme system, ATX levels was associated with a small increased risk (RR 1.28 (95% CI, 0.94– can increase in combination with enzyme-inhibiting SSRIs (e.g. 1.74), where amphetamines were not. There is some evidence fluoxetine and paroxetine) [277]. suggesting that treatment with MPH or ATX might increase the risk of miscarriage [294,295], although there were several confounding factors such as younger age and social disadvantage, that could 7.5. Considerations when treating special groups with explain the association [296]. Another study found that the use of pharmacotherapy stimulant medication during pregnancy is associated with miscarriage to the same degree as having ADHD itself [295], these 7.5.1. ADHD with comorbid bipolar disorder findings need further investigation. Potential adverse effects on the A pharmaco-epidemiological study found that MPH mono- fetus from intra placental exposure to medication in pregnancy therapy in patients with bipolar disorder increased the risk of should be considered against the possible adverse effects of switch to a manic episode (hazard ratio 6.7). However, when interrupting treatment abruptly in women with ADHD combined with a mood stabilizer, MPH reduced the risk of mania [184,297,298]. Each case should be assessed individually taking (hazard ratio 0.6) [278]. This supports the current recommenda- into account possible risks of both treating and interrupting tion to treat ADHD in bipolar disorder patients with stimulants, so treatment. long as they are also taking mood stabilizers. Amphetamines may be given preference over other medica- tions. Some authors do not consider Atomoxetine because of lack of 7.5.2. ADHD with comorbid substance use safety data [299,300]. MPH seems to be safe during breastfeeding. Meta-analysis of RCTs in adults found that most ADHD The amounts of medication excreted in breast milk, and consumed medications reduce the core symptom severity of ADHD, but have by the infant, are very small (with the Relative Infant Dose (RID) (< limited effect on comorbid substance use [279]. However, a large 1%) [290,299], and no drug-related side effects have been were Danish Registry study showed a decrease of substance use in ADHD reported. The impact of ATX, guanfacine, and clonidine on patients when using MPH [280]. Recent RCTs using higher doses of breastfeeding-related outcomes is largely unknown [301–303], ER Mixed Amphetamine Salts (Adderall XR1) or OROS MPH and they are not recommended [299]. (Concerta1), combined with CBT found better effects on both Until now no adverse reactions were reported among infants of ADHD and substance use, compared to studies using lower dosages mothers receiving LDX or dexamphetamine (RID: 4–10.6%). There [281,282]. The relevance of higher doses is supported by a are some preliminary reports suggesting that dexamphetamine pharmaco-epidemiological study from Sweden showing that treatment may lead to a suppression of prolactin secretion in higher MPH dose was associated with long-term treatment postpartum women, though with unclear clinical implications adherence in patients with ADHD and substance use disorders [304]. Bupropion was found to produce low levels in milk, (SUD) [283]. Immediate-release stimulants should be avoided in suggesting relative safety. Of note, there are two known cases of patients with ADHD and SUD, whereas OROS-MPH and LDX have seizures developed by children breastfed by women receiving lower abuse potential [284]. Further recommendations for treating bupropion [305]. comorbid substance use disorders can be found in Bolea-Alamanac et al. [184], and in the recently published international Consensus 7.5.5. ADHD and sleep problems Statement on diagnosis and treatment of substance use disorders In the majority of cases, ADHD in children and adults is with comorbid ADHD [285]. This Consensus Statement mentions associated with a circadian rhythm disorder with delayed sleep that the use of stimulant treatment for ADHD does not precipitate onset [306–308]. Meta-analysis of nine studies investigating the the onset of SUD in adults without previous SUD [286]; also that in effects of stimulant medication on sleep in children and SUD patients, treatment of ADHD can be useful to reduce ADHD adolescents found that stimulants can lead to longer sleep latency, J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 25 worse sleep efficiency, and shorter sleep duration [309]. Similar mentoring partnership. Coaching aims to provide structure, findings have been reported in adults [310]. Careful titration of support and feedback for building life skills and changing negative stimulants and psychoeducation around sleep optimization can outcomes related to ADHD in daily living [217,327,328]. However, improve the quality of sleep, possibly due to improved daytime there is no standard methodology and the coaching process varies structure, the maintenance of regular physical activity and considerably, including face-to-face contact, telephone calls and/ improved mood [198,309,311]. In children with ADHD and chronic or email contact. To date, there are no controlled studies assessing insomnia, melatonin has been shown to advance the sleep onset, the efficacy of coaching as a therapeutic means in the treatment of and increase sleep duration [312]. A trial targeting insomnia in adults with ADHD. Nevertheless there is some preliminary adults with ADHD is ongoing, and clinical experience points in the support for positive outcomes from uncontrolled studies same direction of possible efficacy of treatment with melatonin at [327,328]. Similarly there is some support for the effectiveness night, and also of light therapy in the morning [308]. Treatment of of mindfulness based cognitive therapy (MBCT) for adults with insomnia should always start with sleep hygiene education and ADHD [329–331]. optimizing the stimulant or non-stimulant treatment of ADHD [311]. A low dose of IR MPH (usually 5 mg) taken at night time can 8. Cost and cost effectiveness reduce ceaseless mental activity to a degree that allows sleep in some cases. Because of the broad impact of ADHD on general functioning, the disorder is likely to have serious economic implications for 7.6. Cognitive behavior therapy (CBT) and coaching for ADHD children, families, and society. The studies which calculate costs however are so far limited as they typically examine only one Although pharmacological treatment of ADHD is very effective, aspect of the costs, for example “from the perspective of a major many patients continue to experience significant symptoms and German health insurance fund” [332]. Particularly for adults with functional impairment in daily living. Empirical evidence from ADHD, estimates should include not only direct costs (the costs of numerous uncontrolled studies, more than ten randomized labor, supplies, and equipment to provide direct patient care controlled trials (RCTs) and a meta-analysis has shown that in services) but also indirect costs (mainly related to the loss of group or individual settings, cognitive behavioral therapy (CBT) productivity) such as costs to family, costs due to impairment in reduces ADHD-core symptoms, associated symptoms such as employment, costs due to accidents [333], smoking and substance emotion dysregulation, anxiety and depression, and functional misuse, and costs due to involvement with the criminal justice impairments across different areas of daily living in adults system. [228,313–315]. CBT is best used within a multi-modal treatment Direct costs have been examined [334–336], but are heavily approach and as an adjunct to medication as current research does depending on the healthcare system from which they are derived not fully support the efficacy of CBT as a sole treatment for adult and the type of pathway/care package provided. These estimates ADHD [274,316–318]. Most controlled studies have been con- therefore, although potentially useful for comparisons between ducted in patients taking ADHD medication and demonstrate an disorders within the same healthcare system, should not be additional significant treatment effect [313,318–322]. The largest generalized to different contexts. The most comprehensive controlled multi-center CBT-study to date has demonstrated that approach to calculate the total costs of ADHD in the Danish psychological interventions result in better outcomes when Psychiatric Central Register, showed that there is an economic combined with MPH as compared to psychological interventions burden of ADHD which is considerable and falls both on the in unmedicated patients [228]. In a systematic review of 51 individual and the state [337]. pharmacological and non-pharmacological interventions [316], Apart from the costs (either direct or indirect) of ADHD, there is the highest proportion of improved outcomes (83%) was for also the question of cost benefit for treating ADHD. This first asks patients receiving combination treatment. However, not all adults whether a treatment of a disorder is worthwhile when compared with ADHD desire or tolerate pharmacological treatment. In these against alternatives in terms of allocation of healthcare funds, and cases CBT may be the best option. second which ADHD intervention brings the most benefit at the Across all studies there are some consistent characteristics of lowest cost. For the former, an argument can be made that adult CBT treatment, both in form and content. All approaches are highly ADHD is a condition which is cost effective to treat from the structured. Most are manualized, and establish psychoeducation as societal perspective because of the efficacy and relatively low cost the first step. Most programs are skills-based and focus on of the medicines used for its treatment [224,338]. For the latter, organizational and time management skills, emotional regulation/ among children and adolescents with ADHD, there is consistent control, problem solving skills, prosocial competence and strate- evidence [339–343] that pharmacotherapies are cost effective gies to improve attention and impulsivity management. In addition compared with no treatment or behavioral therapy [344]. to behavioral interventions that require patients to try out and Unfortunately there is insufficient research to conclude the same rehearse in daily life techniques suggested in the therapy session, for adults with ADHD (Table 3). programs include cognitive strategies, such as the identification of negative automatic thoughts, methods to address ‘thinking errors’ 9. Stigma surrounding ADHD and the introduction of cognitive restructuring techniques [323]. There is emerging evidence that cognitive distortions and Substantial stigmatization and myths continue to surround dysfunctional cognitive schemes related to a biographic accumu- ADHD [345]. A recent study on negative coverage of ADHD and lation of negative experiences associated with ADHD-symptoms autism in Flemish newspapers found a 2-fold more negative than contribute to negative functional outcomes and lead to avoidance neutral or positive coverage of ADHD than of autism [346]. Stigma behavior, failure-orientation, reduced self-efficacy, procrastina- arises from lack of awareness, of prejudice about symptom etiology tion, depressive symptoms and anxiety [324–326]. Furthermore, (e.g. poor parenting, lack of moral), incompetence (e.g. laziness) most programs highlight the importance of including significant and perceived dangerousness (e.g. unpredictable and potentially others in the treatment process to reduce dysfunctional inter- violent behavior) [347]. Other variables contributing to stigma are actions and stigmatization associated with ADHD symptoms. doubts about the validity and reliability of an ADHD diagnosis, Coaching or mentoring is a derivative of the cognitive along with age, gender, ethnicity and the public's skepticism behavioral paradigm involving the development of a collaborative toward ADHD medication. Also, the restricted regulatory status for 26 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 Table 3 Summary of key points. Neurobiological and High heritability (60-80%), environmental risk factors and their interaction, are involved in the majority of ADHD cases. environmental background Abnormalities in grey matter, cortical thickness and white matter microstructure have been shown in ADHD compared to controls, indicating that structural deficits in ADHD involve interconnections among large scale brain networks. Functional neuroimaging shows dysfunctions in several domain-specific fronto-striatal and fronto-cerebellar neural networks, as well as an enhanced activation of default mode regions. These findings, as well as the effectiveness of pharmacological treatments with dopamine agonists, support the neurobiological underpinnings of ADHD. Diagnosis The clinical diagnosis of ADHD depends on self-report during a structured diagnostic interview, whenever possible with collateral information about lifetime symptoms and impairment. It cannot be established using solely neuropsychological tests. Recent research shows that besides inattention, hyperactivity and impulsivity, emotional dysregulation and excessive mind wandering are common symptoms associated with ADHD in adults. The underdiagnosis of girls and women with ADHD may be due to a different expression of symptoms and comorbidities, to referral bias, and to interaction of hormones with the dopaminergic system. Further research is needed. The concept of late-onset ADHD refers to an age of onset after 12 years, and needs further study concerning the overlap and differences with childhood onset ADHD. High rates of psychiatric comorbidity, physical multi-morbidity, increased mortality and suicide rates, and criminality may ‘mask’ the underlying ADHD condition. Stigma leads to misconceptions about ADHD and underdiagnosis. DSM-5 criteria Main changes in the DSM-5 criteria for ADHD are: ADHD is placed in the chapter of Neurodevelopmental Disorders The age of onset of symptoms is before age 12, instead of age 7 The cut off for current symptoms in adults is 5/9 instead of 6/9 A diagnosis of ADHD can now be combined with Autism Spectrum Disorder (ASD) Prevalence The mean prevalence of ADHD in adults across 20 countries is estimated at 2.8%. In people above age 60, a similar prevalence rate has been found. The prevalence of ADHD in prisons is 25%, a 10-fold increase compared to the general population. Transition Two-thirds of children with ADHD continue to have ADHD symptoms associated with impairments in adulthood, therefore adjustments in the health care system to support the transition from child to adult services are needed. Treatment Psychoeducation for adults with ADHD and their significant others is recommended as a first treatment step. Stimulants are the treatment of choice for adults with ADHD. Long-lasting, extended release formulations are preferred for reasons of adherence to treatment, for the protection against abuse, to avoid rebound symptoms, for safer driving, and to provide cover throughout the day without the need for multiple dosing. Licensing of stimulants for adult ADHD is urgently needed in European countries and beyond. The non-stimulant atomoxetine is recommended as a second line treatment. There is limited evidence in adults for guanfacine, bupropion, tricyclic antidepressants and reboxetine in controlled studies. Cognitive Behavior Therapy reduces ADHD-core symptoms, associated symptoms such as emotion dysregulation, anxiety and depression, and functional impairments across different areas of daily living in adults. CBT is best used within a multi-modal treatment approach and as an adjunct to medication, as research does not fully support the efficacy of CBT as a sole treatment for adult ADHD. Pharmacological In patients with ADHD and substance use disorder, to be effective, treatment with stimulants may use higher dosages than normal. treatment of special groups In patients with ADHD and bipolar disorder, the combined approach of a mood stabilizer with a stimulant has been shown to treat both disorders effectively without inducing (hypo)manic states. During pregnancy stimulants are not advised, though large cohort data showed no increased risk for congenital malformations using stimulants during the first trimester. The risk for cardiac malformations using MPH however was slightly increased, while this was not the case for amphetamines. Research on the wishes of older people with ADHD regarding treatment, and trials on the safety and efficacy of medicines are needed. Based on data from large cohort studies, following treatment, the negative outcomes associated with ADHD significantly diminish, i.e. traffic accidents, mortality, criminality, depression and suicide, and substance abuse. Costs The economic burden of ADHD is considerable and falls both on the individual and the state. Pharmacotherapy in children is cost effective compared to no treatment and behavioral therapy, but data in adults are still lacking. ADHD medications in many countries adds to the stigma within the identified, alongside a reluctance of GPs to become involved in mental health profession and the media. Public stigmatization of shared care practice. If access to services is to be improved for ADHD, and the following self-stigma and courtesy stigma are people with ADHD, there needs to be a focused and collaborative underestimated risk factors for treatment adherence, treatment approach to training [351]. efficacy, symptom aggravation, life satisfaction, and mental well- being of individuals affected by ADHD [348]. 9.1. Combatting stigma Self-stigma has been studied in children and adolescents and is characterized by a sense of feeling different from peers, and Disclosure of mental health problems can be a challenge [352], negative self-evaluation as a consequence of that perception. but an increasing number of celebrities have cast aside stigma by However, some young people were prepared to challenge the revealing they had ADHD and, in some cases, have been stigma by self-disclosure and openness about their condition pharmacologically treated for many years (https://www.additu- [349]. Lower stigma in teachers towards adult ADHD seems to demag.com/successful-people-with-adhd-learning-disabilities/). relate to greater knowledge about the condition [350]. Among This is of course supportive for patients but it is strongly general practitioners (GPs) from the UK, Europe and Australia, recommended that psychoeducation about ADHD should be there is mixed and often unhelpful attitudes regarding the validity included in anti-stigma programs [347]. Of note, adult ADHD is of ADHD as a construct, the role of medication and how parenting rarely included in college programs for medical and psychology contributes to the presentation [351]. A paucity of training was students, or in the training of professionals working in adult J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 27 mental health services. This contributes to misconceptions, conflict of interest. Thome, J.: No conflict of interest. Dom, G.: No underdiagnosis and undertreatment among professionals [2,3]. conflict of interest. Kasper, S.: Grants/research support, consulting Psychoeducation programs therefore need to target all clinical fees and/or honoraria within the last three years from Angelini, disciplines at all stages of professional development (e.g. from AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, students through to primary and secondary care physicians, KRKAPharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, psychologists and nurses) to ensure that appropriate early Schwabe and Servier. Nunes Filipe, C.: No conflict of interest. Stes, recognition, diagnosis and treatment is provided. S.: Principal Investigator before 2016 in studies funded by Janssen- Internationally recognized guidelines are available on the Cilag, Lilly and Novartis; speaker fees and advisory board for Lilly, assessment, treatment and management of adults with ADHD, Novartis, Janssen-Cilag, and Shire. Since 2016 no conflicts of as well as the development and provision of clinical services interest. Mohr. P.: consultant and speaker for Eli Lilly, Janssen- [182,184,274,353]. The current lack of licensed indications for the Cilag, and Lundbeck. Leppämäki, S.: No conflict of interest. Casas, use of stimulants in adults in most European countries (but not in M.: speaker fees from Janssen- Cilag, Bristol-Mayers Squibb, Ferrer- the US or Canada) is not supported by available data, but rather Brainfarma, Pfizer, Lundbeck, Otsuka, Servier, Lilly, Shire, GSK, Rovi results from the outdated focus that ADHD is a ‘child disorder’, and Adamed. Advisory board for Janssen-Cilag, Lilly, and Shire. caution from regulators regarding potential cardiovascular side Bobes, J.: research grants and/or consultant, advisor or speaker effects, and commercial manipulation by the pharmaceutical within de last 3 years for: AB-Biotics, Acadia Pharmaceuticals, industry. In Europe, this situation may change in the coming years Casen Recordati, D&A Pharma, Gilead, Ferrer, Hoffman La Roche, as formulations of methylphenidate and dexamphetamine are Indivior, Janssen-Cilag, Indivior, Lundbeck, Mundipharma, Otsuka, being put forward for registration. Pfizer, Reckitt-Benckiser, Servier and Shire, research funding from Stigma prevents patients to ask for help and increases their the Spanish Ministry of Economy and Competiveness – Centro de suffering and impairment. Hence the successful management of Investigación Biomedica en Red area de Salud Mental (CIBERSAM) ADHD by prescribers will include an awareness of the potential and Instituto de Salud Carlos III, Spanish Ministry of Health, Social stigma that may be perceived by the patient and its consequences Services and Equality - Plan Nacional sobre Drogas- and the 7th on treatment initiation and maintenance. The only way to reduce Framework Program of the European Union. McCarthy, J.M.: No stigma surrounding ADHD is community, health and education conflict of interest. Kjems Philipsen, A.: No conflict of interest. systems in Europe and beyond working together by education of Pehlivanidis, A.: No conflict of interest. Niemela, A.: No conflict of professionals and the public, and by a unified licensing of interest. Bolea-Alamanac, B.: Honoraria on one occasion for an medications for ADHD in adults. educational lecture for Janssen pharmaceuticals. Edvinsson, D.: No conflict of interest. Baeyens, D.: No conflict of interest. Wynchank, 10. Conclusions D.: Advisory boards of Janssen BV, Novartis and Eli Lilly for activities outside the scope of this paper (2009–2014). Sobanski, E.: This consensus statement reflects agreement on the state of lectures paid by Shire within the last two years. Philipsen, A.: ADHD, but by definition it is provisional. It does not negate the Advisory boards, lectures, performed phase 5 studies, or travel ongoing scientific debate in the field and the different opinions and grants within the last 5 years from Eli Lilly and Co, Janssen-Cilag, hypotheses about adult ADHD among experts. Yet none of that Lundbeck, MEDICE Arzneimittel, Pütter GmbH and Co KG, Novartis, undercuts the legitimacy or validity of the construct, or of the Servier, and Shire; and has authored books and articles on ADHD conclusions one can make about the current status of the published by Elsevier, Hogrefe, Oxford Press, Schattauer, Kohl- consistency of the evidence. ADHD is a neurodevelopmental and hammer, Karger, and Springer. McNicholas, F.: Received an heritable disorder with a lifespan perspective: starting in unrestricted educational grant from Shire Pharmaceuticals in childhood, persisting in adulthood until old age, with significant 2016, and grant support for a UCD Newman Fellow 2014-2015. psychosocial impairment, a high comorbidity rate and multi- Caci, H.: No conflict of interest. Manor, I.: Honoraria, counseling morbidity. It is associated with high levels of personal distress, and and advisory boards for Jansen-Cilag, Israel, Teva Israel, Novartis a substantial economic burden for society if left unidentified and Israel, Medison Israel. Asking for a research grant: Shire. Krause, J.: untreated. DSM-5 has changed some of the criteria that facilitate No conflict of interest. Fayyad, J.: No conflict of interest. Ramos- the diagnosis in adolescents and adults. Assessment should include Quiroga, J.A.: speakers’ bureau and/or consultant for Eli-Lilly, a detailed account of the developmental history, of both current Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, and retrospective ADHD symptoms and impairment, and associ- Sincrolab, and Rubió in the last 5 years. Travel awards (air ated comorbidities. To prevent under-reporting of symptoms, tickets + hotel) for meetings from Janssen-Cilag, Rubió, Shire, and external validation is desirable by collateral information. Multi- Eli- Lilly. The Department of Psychiatry chaired by him received modal treatment is required, comprising of psychoeducation, unrestricted educational and research support in the last 5 years pharmacotherapy, and cognitive behavior therapy and/or coach- from: Eli-Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, and ing. Psychoeducational European programs to combat stigma and Rubió. Foeken, K.: No conflict of interest. Adamou, M.: No conflict of to inform the public and (mental) health professionals about new interest. Ohlmeier, M.: No conflict of interest. Fitzgerald, M.: No knowledge on the lifespan perspective of ADHD are needed to conflict of interest. Gill, M.: No conflict of interest. Lensing, M.: improve and increase diagnostic and treatment services for adult Noconflict of interest. Motavalli Mukaddes, N.: advisor and speaker ADHD. Research on the different presentation of ADHD in women, of Sanofi Drug Company. Brudkiewicz, P.: No conflict of interest. and on treatment of ADHD in old age should be further developed Gustafsson, P.: Former member of advisory board for Lilly, advisory in order to improve their treatment options. board for Elvanse and Intunive (Shire). Tani, P.: No conflict of interest. Oswald, P.: No conflict of interest. Carpentier, P.J.: No conflict of Conflicts of interest interest. De Rossi, P.: No conflict of interest. Delorme, R.: No conflict of interest. Markovska Simoska, S.: No conflict of interest. Pallanti, S.: Kooij, J.J.S.: No conflict of interest. Bijlenga, D.: No conflict of No conflict of interest. Young, S.: Honoraria for consultancy, travel, interest. Salerno, L.: No conflict of interest. Jaeschke, R.: No conflict educational talks and/or research from Janssen, Eli Lilly, HB Pharma, of interest. Bitter I.: Honoraria or consultation fees from EGIS, and/or Shire. She is author of the Young-Bramham CBT Programme. EGRIS, Eli Lilly, Gedeon Richter, Janssen/Janssen-Cilag, Lundbeck, Lehtonen, T. No conflict of interest. Hirvikoski, T.: no conflict of MedAvante, Pierre Fabre, PSI (CRO) and Servier. Balázs, J.: No interest related to this article. Royalties for text books and manuals 28 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 from Hogrefe. Pironti, V.: No conflict of interest. Ginsberg, Y.: Speaker [16] van den Berg SM, Willemsen G, de Geus EJ, Boomsma DI. Genetic etiology of fees, reimbursement for travel costs and/or consultant for Novartis, stability of attention problems in young adulthood. Am J Med Genet B Neuropsychiatr Genet 2006;141B(1):55–60. HB Pharma, Shire, Eli Lilly, Hogrefe, Broadman Clarke Partners, [17] Larsson H, Asherson P, Chang Z, Ljung T, Friedrichs B, Larsson JO, et al. Genetic Medscape, Medibas and Natur & Kultur. Félegyházy, Z.: No conflict of and environmental influences on adult attention deficit hyperactivity interest. Richarte, V.: Speakers’ bureau for Eli-Lilly, Shire in the last 5 disorder symptoms: a large Swedish population-based study of twins. Psychol Med 2013;43(1):197–207. years. Travel awards (air tickets + hotel) for psychiatric meetings [18] Brikell I, Kuja-Halkola R, Larsson H. Heritability of attention-deficit from Shire. The Department of Psychiatry received unrestricted hyperactivity disorder in adults. Am J Med Genet B Neuropsychiatr Genet educational and research support in the last 5 years from: Eli-Lilly, 2015. [19] Merwood A, Greven CU, Price TS, Rijsdijk F, Kuntsi J, McLoughlin G, et al. Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, and Rubió. Kustow, Different heritabilities but shared etiological influences for parent, teacher J.: Consultancy services to Eli Lilly and Shire and speaker fees from Eli and self-ratings of ADHD symptoms: an adolescent twin study. Psychol Med Lilly, Jansen Cilag and Shire. Müller, U.: Advisory board / consultancy (Paris) 2013;43(9):1973–84. [20] Chang Z, Lichtenstein P, Asherson PJ, Larsson H. Developmental twin study of fees or speaker honorarium from Eli Lilly, Heptares and Shire, attention problems: high heritabilities throughout development. JAMA Educational grants / travel expenses from Eli Lilly, Flynn Pharma / Psychiatry 2013;70(3):311–8. Medice, Janssen-Cilag, Lundbeck, Shire and Sunovion (all United [21] Larsson H, Chang Z, D’Onofrio BM, Lichtenstein P. The heritability of clinically Kingdom). Bejerot, S.: No conflict of interest. Semerci, B.: No conflict diagnosed attention deficit hyperactivity disorder across the lifespan. Psychol Med (Paris) 2013;1–7. of interest. Dobrescu, I.: No conflict of interest. Styr, B.: No conflict of [22] Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. interest. Rad, F.: No conflict of interest. Mihailescu, I.: No conflict of Mol Psychiatry 2018. interest. Garcia-Portilla, M.P.: No conflict of interest. Asherson, P.: [23] Li D, Sham PC, Owen MJ, He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder Kings College London research support account for Asherson (ADHD). Hum Mol Genet 2006;15(14):2276–84. received honoraria for consultancy to Shire, Eli-Lilly and Novartis; [24] Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta- educational/research awards from Shire, Lilly, Novartis, Vifor analytic review. Hum Genet 2009;126(1):51–90. [25] Kuntsi J, Neale BM, Chen W, Faraone SV, Asherson P. The IMAGE project: Pharma, GW Pharma and QbTech; speaker at sponsored events for methodological issues for the molecular genetic analysis of ADHD. Behav Shire, Lilly and Novartis. Brain Funct 2006;2:27. [26] Neale BM, Medland SE, Ripke S, Asherson P, Franke B, Lesch KP, et al. Meta- analysis of genome-wide association studies of attention-deficit/hyperactivity Acknowledgement disorder. J Am Acad Child Adolesc Psychiatry 2010;49(9):884–97. [27] Poelmans G, Pauls DL, Buitelaar JK, Franke B. Integrated genome-wide association study findings: identification of a neurodevelopmental network This project did not receive any financial support from funding for attention deficit hyperactivity disorder. Am J Psychiatry 2011;168 agencies in the public, commercial, or not-for-profit sectors. (4):365–77. [28] Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for ADHD. Nat Genet 2018 In Press. References [29] Ribases M, Sanchez-Mora C, Ramos-Quiroga JA, Bosch R, Gomez N, Nogueira M, et al. An association study of sequence variants in the forkhead box P2 [1] Kooij SJ, Bejerot S, Blackwell A, Caci H, Casas-Brugue M, Carpentier PJ, et al. (FOXP2) gene and adulthood attention-deficit/hyperactivity disorder in two European consensus statement on diagnosis and treatment of adult ADHD: European samples. Psychiatr Genet 2012;22(4):155–60. The European Network Adult ADHD. BMC Psychiatry 2010;10:67. [30] Middeldorp CM, Hammerschlag AR, Ouwens KG, Groen-Blokhuis MM, [2] Asherson P, Buitelaar J, Faraone SV, Rohde LA. Adult attention-deficit Pourcain BS, Greven CU, et al. A genome-wide association meta-analysis of hyperactivity disorder: key conceptual issues. Lancet Psychiatry 2016;3 Attention-Deficit/Hyperactivity disorder symptoms in population-based (6):568–78. pediatric cohorts. J Am Acad Child Adolesc Psychiatry 2016;55(10)896–905 e6. [3] Fayyad J, Sampson NA, Hwang I, Adamowski T, Aguilar-Gaxiola S, Al- [31] Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT, et al. Rare structural variants Hamzawi A, et al. The descriptive epidemiology of DSM-IV adult ADHD in the found in attention-deficit hyperactivity disorder are preferentially associated world health organization world mental health surveys. Atten Defic Hyperact with neurodevelopmental genes. Mol Psychiatry 2009;15(6):637–46. Disord 2017;9(1):47–65. [32] Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, et al. [4] Faraone SV, Doyle AE. The nature and heritability of attention-deficit/hyperactivity Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder. Child Adolesc Psychiatr Clin North Am 2001;10(2) 299-2ix. disorder: a genome-wide analysis. Lancet 2010;376(9750):1401–8. [5] Faraone SV. Genetics of adult attention-deficit/hyperactivity disorder. [33] Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, et al. Genome- Psychiatr Clin North Am 2004;27:303–21. wide analysis of copy number variants in attention deficit/hyperactivity [6] Sprich S, Biederman J, Crawford MH, Mundy E, Faraone SV. Adoptive and disorder confirms the role of rare variants and implicates duplications at biological families of children and adolescents with ADHD. J Am Acad Child 15q13.3. Am J Psychiatry 2012;169(2):195–204. Adolesc Psychiatry 2000;39(11):1432–7. [34] Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, et al. Genome- [7] Moore J, Fombonne E. Psychopathology in adopted and nonadopted children: wide copy number variation study associates metabotropic glutamate a clinical sample. Am J Orthopsychiatry 1999;69(3):403–9. receptor gene networks with attention deficit hyperactivity disorder. Nat [8] Gilger JW, Pennington BF, DeFries JC. A twin study of the etiology of Genet 2012;44(1):78–84. comorbidity: attention-deficit hyperactivity disorder and dyslexia. [35] Lesch KP, Selch S, Renner TJ, Jacob C, Nguyen TT, Hahn T, et al. Genome-wide JAmAcadChild AdolescPsychiatry. 1992;31(2):343–8. copy number variation analysis in attention-deficit/hyperactivity disorder: [9] Sherman DK, Iacono WG, McGue MK. Attention-deficit hyperactivity disorder association with neuropeptide Y gene dosage in an extended pedigree. Mol dimensions: a twin study of inattention and impulsivity-hyperactivity. Psychiatry 2011;16(5):491–503. JAmAcadChild AdolescPsychiatry. 1997;36(6):745–53. [36] Franke B, Hoogman M, Arias Vasquez A, Heister JG, Savelkoul PJ, Naber M, [10] Rietveld MJ, Hudziak JJ, Bartels Mv B, C.E, Boomsma DI. Heritability of et al. Association of the dopamine transporter (SLC6A3/DAT1) gene 9-6 attention problems in children: longitudinal results from a study of twins, haplotype with adult ADHD. Am J Med Genet B Neuropsychiatr Genet age 3 to 12. J Child Psychol Psychiatry 2004;45(3):577–88. 2008;147B(8):1576–9. [11] Levy F, Hay DA, McStephen M, Wood C, Waldman I. Attention-deficit [37] Johansson S, Halmoy A, Mavroconstanti T, Jacobsen KK, Landaas ET, Reif A, hyperactivity disorder: a category or a continuum? Genetic analysis of a et al. Common variants in the TPH1 and TPH2 regions are not associated with large-scale twin study. J Am Acad Child Adolesc Psychiatry 1997;36(6):737–44. persistent ADHD in a combined sample of 1,636 adult cases and 1,923 [12] Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. controls from four European populations. Am J Med Genet B Neuropsychiatr Molecular genetics of attention-deficit/hyperactivity disorder. Biol Genet 2010;153B(5):1008–15. Psychiatry 2005;57(11):1313–23. [38] Ribases M, Hervas A, Ramos-Quiroga JA, Bosch R, Bielsa A, Gastaminza X, et al. [13] Stevens SE, Sonuga-Barke EJ, Kreppner JM, Beckett C, Castle J, Colvert E, et al. Association study of 10 genes encoding neurotrophic factors and their Inattention/overactivity following early severe institutional deprivation: receptors in adult and child attention-deficit/hyperactivity disorder. Biol presentation and associations in early adolescence. J Abnorm Child Psychol Psychiatry 2008;63(10):935–45. 2008;36(3):385–98. [39] Ribases M, Ramos-Quiroga JA, Hervas A, Bosch R, Bielsa A, Gastaminza X, et al. [14] Faraone SV, Biederman J, Monuteaux MC. Toward guidelines for pedigree Exploration of 19 serotoninergic candidate genes in adults and children with selection in genetic studies of attention deficit hyperactivity disorder. Genet attention-deficit/hyperactivity disorder identifies association for 5HT2A, Epidemiol 2000;18(1):1–16. DDC and MAOB. Mol Psychiatry 2009;14(1):71–85. [15] Boomsma DI, Saviouk V, Hottenga JJ, Distel MA, de Moor MH, Vink JM, et al. [40] Franke B, Faraone SV, Asherson P, Buitelaar J, Bau CH, Ramos-Quiroga JA, et al. Genetic epidemiology of attention deficit hyperactivity disorder (ADHD The genetics of attention deficit/hyperactivity disorder in adults, a review. index) in adults. PLoS One 2010;5(5)e10621. Mol Psychiatry 2012;17(10):960–87. J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 29 [41] Landaas ET, Johansson S, Jacobsen KK, Ribases M, Bosch R, Sanchez-Mora C, [67] Konrad A, Dielentheis Tf Fau - El Masri D, El Masri D Fau - Dellani PR, Dellani et al. An international multicenter association study of the serotonin Pr Fau - Stoeter P, Stoeter P Fau - Vucurevic G, Vucurevic G Fau - Winterer G, transporter gene in persistent ADHD. Genes Brain Behav 2010;9(5):449–58. et al. White matter abnormalities and their impact on attentional [42] Sanchez-Mora C, Ribases M, Ramos-Quiroga JA, Casas M, Bosch R, Boreatti- performance in adult attention-deficit/hyperactivity disorder. 2012(1433- Hummer A, et al. Meta-analysis of brain-derived neurotrophic factor p. 8491 (Electronic)). Val66Met in adult ADHD in four European populations. Am J Med Genet B [68] Cortese S, Imperati D, Zhou J, Proal E, Klein RG, Mannuzza S, et al. White Neuropsychiatr Genet 2010;153B(2):512–23. matter alterations at 33-year follow-up in adults with childhood attention- [43] Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for deficit/hyperactivity disorder. Biol Psychiatry 2013. attention-deficit hyperactivity disorder. Acta Paediatr 2007;96(9):1269–74. [69] Onnink AM, Zwiers MP, Hoogman M, Mostert JC, Dammers J, Kan CC, et al. [44] Botting N, Powls A, Cooke RW, Marlow N. Attention deficit hyperactivity Deviant white matter structure in adults with attention-deficit/ disorders and other psychiatric outcomes in very low birthweight children at hyperactivity disorder points to aberrant myelination and affects 12 years. JChild PsycholPsychiatry. 1997;38(8):931–41. neuropsychological performance. Prog Neuropsychopharmacol Biol [45] Milberger S, Biederman J, Faraone SV, Guite J, Tsuang MT. Pregnancy, delivery Psychiatry 2015;63:14–22. and infancy complications and attention deficit hyperactivity disorder: [70] Shaw P, Sudre G, Wharton A, Weingart D, Sharp W, Sarlls J. White matter issues of gene-environment interaction. Biol Psychiatry 1997;41(1):65–75. microstructure and the variable adult outcome of childhood attention deficit [46] Cohen MJ, Meador KJ, Browning N, May R, Baker GA, Clayton-Smith J, et al. hyperactivity disorder. Neuropsychopharmacology 2015;40(3):746–54. Fetal antiepileptic drug exposure: adaptive and emotional/behavioral [71] Konrad A, Dielentheis TF, El Masri D, Bayerl M, Fehr C, Gesierich T, et al. functioning at age 6years. Epilepsy Behav 2013;29(2):308–15. Disturbed structural connectivity is related to inattention and impulsivity [47] Gustavson K, Ystrom E, Stoltenberg C, Susser E, Suren P, Magnus P, et al. in adult attention deficit hyperactivity disorder. Eur J Neurosci 2010;31 Smoking in pregnancy and child ADHD. Pediatrics 2017;139(2). (5):912–9. [48] Depue BE, Burgess GC, Bidwell LC, Willcutt EG, Banich MT. Behavioral [72] van Ewijk H, Heslenfeld DJ, Zwiers MP, Faraone SV, Luman M, Hartman CA, performance predicts grey matter reductions in the right inferior frontal et al. Different mechanisms of white matter abnormalities in attention- gyrus in young adults with combined type ADHD. Psychiatry Res 2010;182 deficit/hyperactivity disorder: a diffusion tensor imaging study. J Am Acad (3):231–7. Child Adolesc Psychiatry 2014;53(7) 790-9.e3. [49] Pironti VA, Lai MC, Muller U, Dodds CM, Suckling J, Bullmore ET, et al. [73] Liston C, Cohen MM, Teslovich T, Levenson D, Casey BJ. Atypical prefrontal Neuroanatomical abnormalities and cognitive impairments are shared by connectivity in attention-deficit/hyperactivity disorder: pathway to disease adults with attention-deficit/hyperactivity disorder and their unaffected or pathological end point? Biol Psychiatry 2011;69(12):1168–77. first-degree relatives. Biol Psychiatry 2014;76(8):639–47. [74] Cortese S, Kelly C, Chabernaud C, Proal E, Di Martino A, Milham MP, et al. [50] Makris N, Seidman LJ, Valera EM, Biederman J, Monuteaux MC, Kennedy DN, Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. et al. Anterior cingulate volumetric alterations in treatment-naive adults Am J Psychiatry 2012;169(10):1038–55. with ADHD: a pilot study. J Atten Disord 2010;13(4):407–13. [75] Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K. Meta-analysis of functional [51] Frodl T, Skokauskas N. Meta-analysis of structural MRI studies in children and magnetic resonance imaging studies of inhibition and attention in attention- adults with attention deficit hyperactivity disorder indicates treatment deficit/hyperactivity disorder: exploring task-specific, stimulant medication, effects. Acta Psychiatr Scand 2012;125(2):114–26. and age effects. JAMA Psychiatry 2013;70(2):185–98. [52] Amico F, Stauber J, Koutsouleris N, Frodl T. Anterior cingulate cortex gray [76] Hart H, Radua J, Mataix-Cols D, Rubia K. Meta-analysis of fMRI studies of matter abnormalities in adults with attention deficit hyperactivity disorder: timing in attention-deficit hyperactivity disorder (ADHD). Neurosci Biobehav a voxel-based morphometry study. Psychiatry Res 2011;191(1):31–5. Rev 2012;36(10):2248–56. [53] Seidman LJ, Biederman J, Liang L, Valera EM, Monuteaux MC, Brown A, et al. [77] Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, et al. Gray matter alterations in adults with attention-deficit/hyperactivity The organization of the human cerebral cortex estimated by intrinsic disorder identified by voxel based morphometry. Biol Psychiatry 2011;69 functional connectivity. J Neurophysiol 2011;106(3):1125–65. (9):857–66. [78] Castellanos FX, Proal E. Large-scale brain systems in ADHD: beyond the [54] Almeida Montes LG, Ricardo-Garcell J, Barajas De La Torre LB, Prado Alcantara prefrontal-striatal model. Trends Cogn Sci (Regul Ed) 2012;16(1):17–26. H, Martinez Garcia RB, Fernandez-Bouzas A, et al. Clinical correlations of grey [79] Sudre G, Szekely E, Sharp W, Kasparek S, Shaw P. Multimodal mapping of the matter reductions in the caudate nucleus of adults with attention deficit brain’s functional connectivity and the adult outcome of attention deficit hyperactivity disorder. J Psychiatry Neurosci 2010;35(4):238–46. hyperactivity disorder. Proc Natl Acad Sci U S A. 2017;114(44):11787–92. [55] Makris N, Liang L, Biederman J, Valera EM, Brown AB, Petty C, et al. Toward [80] Wasserman T, Wasserman LD. The sensitivity and specificity of defining the neural substrates of ADHD: a controlled structural MRI study in neuropsychological tests in the diagnosis of attention deficit hyperactivity medication-naive adults. J Atten Disord 2015;19(11):944–53. disorder. Appl Neuropsychol Child 2012;1(2)90–9, doi:http://dx.doi.org/ [56] Proal E, Reiss PT, Klein RG, Mannuzza S, Gotimer K, Ramos-Olazagasti MA, 10.1080/21622965.2012.702025 Epub 2012 Jul 10. et al. Brain gray matter deficits at 33-year follow-up in adults with attention- [81] Pettersson R, Soderstrom S, Nilsson KW. Diagnosing ADHD in adults: an deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatry examination of the discriminative validity of neuropsychological tests and 2011;68(11):1122–34. diagnostic assessment instruments. J Atten Disord 2015. [57] Ahrendts J, Rusch N, Wilke M, Philipsen A, Eickhoff SB, Glauche V, et al. Visual [82] Mostert JC, Onnink AM, Klein M, Dammers J, Harneit A, Schulten T, et al. cortex abnormalities in adults with ADHD: a structural MRI study. World J Cognitive heterogeneity in adult attention deficit/hyperactivity disorder: a Biol Psychiatry 2011;12(4):260–70. systematic analysis of neuropsychological measurements. Eur [58] Duerden EG, Tannock R, Dockstader C. Altered cortical morphology in Neuropsychopharmacol 2015;25(11):2062–74. sensorimotor processing regions in adolescents and adults with attention- [83] Barkley RA, Fischer M. Predicting impairment in major life activities and deficit/hyperactivity disorder. Brain Res 2012;1445:82–91. occupational functioning in hyperactive children as adults: self-reported [59] Almeida LG, Ricardo-Garcell J, Prado H, Barajas L, Fernandez-Bouzas A, Avila executive function (EF) deficits versus EF tests. Dev Neuropsychol 2011;36 D, et al. Reduced right frontal cortical thickness in children, adolescents and (2):137–61. adults with ADHD and its correlation to clinical variables: a cross-sectional [84] Musso MW, Gouvier WD. Why is this so hard?: A review of detection of study. J Psychiatr Res 2010;44(16):1214–23. malingered ADHD in college students. J Atten Disord 2014;18(6):186–201. [60] Nakao T, Radua J, Rubia K, Mataix-Cols D. Gray matter volume abnormalities [85] Bekker EM, Overtoom CC, Kenemans JL, Kooij JJ, De Noord I, Buitelaar JK, in ADHD: voxel-based meta-analysis exploring the effects of age and et al. Stopping and changing in adults with ADHD. Psychol Med 2005;35 stimulant medication. Am J Psychiatry 2011;168(11):1154–63. (6):807–16. [61] Rubia K, Alegria AA, Brinson H. Brain abnormalities in attention-deficit [86] Bekker EM, Kenemans JL, Hoeksma MR, Talsma D, Verbaten MN. The pure hyperactivity disorder: a review. Rev Neurol (Paris) 2014;58(Suppl 1) S3-16. electrophysiology of stopping. Int J Psychophysiol 2005. [62] Onnink AM, Zwiers MP, Hoogman M, Mostert JC, Kan CC, Buitelaar J, et al. [87] Seidman LJ, Valera EM, Bush G. Brain function and structure in adults with Brain alterations in adult ADHD: effects of gender, treatment and comorbid attention-deficit/hyperactivity disorder. Psychiatr Clin North Am 2004;27 depression. European neuropsychopharmacology: the journal of the (2):323–47. European College of Neuropsychopharmacology. 2014;24(3):397–409. [88] Seidman LJ, Doyle A, Fried R, Valera E, Crum K, Matthews L. [63] Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, et al. Neuropsychological function in adults with attention-deficit/hyperactivity Effect of psychostimulants on brain structure and function in ADHD: a disorder. Psychiatr Clin North Am 2004;27(2):261–82. qualitative literature review of magnetic resonance imaging-based [89] Seidman LJ, Valera EM, Makris N. Structural brain imaging of attention- neuroimaging studies. J Clin Psychiatry 2013;74(9):902–17. deficit/hyperactivity disorder. Biol Psychiatry 2005;57(11):1263–72. [64] Hoekzema E, Carmona S, Ramos-Quiroga JA, Richarte Fernandez V, Picado M, [90] Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, et al. Bosch R, et al. Laminar thickness alterations in the fronto-parietal cortical Effects of stimulant medication on growth rates across 3 years in the MTA mantle of patients with attention-deficit/hyperactivity disorder. PLoS One follow-up. J Am Acad Child Adolesc Psychiatry 2007;46(8):1015–27. 2012;7(12)e48286. [91] Volkow ND, Wang GJ, Newcorn J, Fowler JS, Telang F, Solanto MV, et al. Brain [65] Hoogman M, Buitelaar JK, Faraone SV, Shaw P, Franke B, group E-Aw. dopamine transporter levels in treatment and drug naive adults with ADHD. Subcortical brain volume differences in participants with attention deficit Neuroimage 2007;34(3):1182–90. hyperactivity disorder in children and adults - authors’ reply. Lancet [92] Retz W, Klein RG. Attention-deficit hyperactivity disorder (ADHD) in adults. Psychiatry 2017;4(6):440–1. Key issues in mental health. Basel: Karger; 2010. [66] Dramsdahl M, Westerhausen R, Haavik J, Hugdahl K, Plessen KJ. Adults with [93] Snyder SM, Rugino TA, Hornig M, Stein MA. Integration of an EEG biomarker attention-deficit/hyperactivity disorder - a diffusion-tensor imaging study of with a clinician’s ADHD evaluation. Brain Behav 2015;5(4)e00330, doi:http:// the corpus callosum. Psychiatry Res 2012;201(2):168–73. dx.doi.org/10.1002/brb3.330 Epub 2015 Mar 5. 30 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 [94] Arns M, Conners CK, Kraemer HC. A decade of EEG Theta/Beta ratio research [122] Barkley RA. Differential diagnosis of adults with ADHD: the role of executive in ADHD: a meta-analysis. J Atten Disord 2013;17(5)374–83, doi:http://dx. function and self-regulation. J Clin Psychiatry 2010;71(7):e17. doi.org/10.1177/1087054712460087 Epub 2012 Oct 19. [123] Bijlenga D, Jasperse M, Gehlhaar SK, Sandra Kooij JJ. Objective QbTest and [95] Liechti MD, Valko L, Muller UC, Dohnert M, Drechsler R, Steinhausen HC, subjective evaluation of stimulant treatment in adult attention deficit- et al. Diagnostic value of resting electroencephalogram in attention- hyperactivity disorder. Eur Psychiatry 2015;30(1)179–85, doi:http://dx.doi. deficit/ hyperactivity disorder across the lifespan. Brain Topogr 2013;26 org/10.1016/j.eurpsy.2014.06.003 Epub Aug 27. (1) 135-51. [124] Toplak ME, West RF, Stanovich KE. Practitioner review: do performance- [96] Arns M, Loo SK, Sterman MB, Heinrich H, Kuntsi J, Asherson P, et al. Editorial based measures and ratings of executive function assess the same construct? Perspective: how should child psychologists and psychiatrists interpret J Child Psychol Psychiatry 2013;54(2):131–43. FDA device approval? Caveat emptor. J Child Psychol Psychiatry 2016;57 [125] Barkley RA, Fischer M. Predicting impairment in major life activities and (5):656–8. occupational functioning in hyperactive children as adults: self-reported [97] Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of executive function (EF) deficits versus EF tests. Dev Neuropsychol 2011;36 ADHD: is it an American condition? World Psychiatry 2003;2(2):104–13. (2):137–61. [98] Goodheart CD. A primer for ICD-10-CM users: psychological and behavioral [126] de Graaf R, Kessler RC, Fayyad J, ten Have M, Alonso J, Angermeyer M, et al. conditions. Washington, DC: American Psychological Association; 2014. The prevalence and effects of adult attention-deficit/hyperactivity disorder [99] Kupfer DJ, Kuhl EA, Wulsin L. Psychiatry’s integration with medicine: the role (ADHD) on the performance of workers: results from the WHO World Mental of DSM-5. Annu Rev Med 2013;64:385–92, doi:http://dx.doi.org/10.1146/ Health Survey Initiative. Occup Environ Med 2008;65(12):835–42. annurev-med-050911-161945. [127] Fredriksen M, Dahl AA, Martinsen EW, Klungsoyr O, Faraone SV, Peleikis DE. [100] Kooij JJS, Boonstra AM, Swinkels SH, Bekker EM, de Noord I, Buitelaar JK. Childhood and persistent ADHD symptoms associated with educational Reliability, validity, and utility of instruments for self-report and informant failure and long-term occupational disability in adult ADHD. Atten Defic report concerning symptoms of ADHD in adult patients. J Atten Disord Hyperact Disord 2014;6(2):87–99. 2008;11(4):445–58. [128] Rogers DC, Dittner AJ, Rimes KA, Chalder T. Fatigue in an adult attention [101] Solanto MV, Wasserstein J, Marks DJ, Mitchell KJ. Diagnosis of ADHD in deficit hyperactivity disorder population: a trans-diagnostic approach. Br J adults: What is the appropriate DSM-5 symptom threshold for hyperactivity- Clin Psychol 2017;56(1):33–52. impulsivity? J Atten Disord 2012;16(8):631–4. [129] Altszuler AR, Page TF, Gnagy EM, Coxe S, Arrieta A, Molina BS, et al. [102] Kooij JJ, Buitelaar JK, van den Oord EJ, Furer JW, Rijnders CA, Hodiamont PP. Financial dependence of young adults with childhood ADHD. J Abnorm Internal and external validity of attention-deficit hyperactivity disorder in a Child Psychol 2016;44(6):1217–29, doi:http://dx.doi.org/10.1007/s10802- population-based sample of adults. Psychol Med (Paris) 2005;35(6):817–27. 015-0093-9. [103] Barkley RA. Barkley adult ADHD rating Scale-IV (BAARS-IV). New York, NY: [130] Bielefeld M, Drews M, Putzig I, Bottel L, Steinbuchel T, Dieris-Hirche J, et al. Guilford Press; US; 2011. Comorbidity of Internet use disorder and attention deficit hyperactivity [104] Skirrow C, Asherson P. Emotional lability, comorbidity and impairment in disorder: two adult case-control studies. J Behav Addict 2017;6(4):490–504, adults with attention-deficit hyperactivity disorder. J Affect Disord 2013;147 doi:http://dx.doi.org/10.1556/2006.6.17.073. (1-3):80–6. [131] Barkley RA, Cox D. A review of driving risks and impairments associated with [105] Brown TE. A new understanding of ADHD in children and adults. New York: attention-deficit/hyperactivity disorder and the effects of stimulant Routledge; 2013. medication on driving performance. J Safety Res 2007;38(1):113–28. [106] Polanczyk G, Laranjeira R, Zaleski M, Pinsky I, Caetano R, Rohde LA. ADHD in [132] Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG. a representative sample of the Brazilian population: estimated prevalence Mortality in children, adolescents, and adults with attention deficit and comparative adequacy of criteria between adolescents and adults hyperactivity disorder: a nationwide cohort study. Lancet 2015;385 according to the item response theory. Int J Methods Psychiatr Res 2010;19 (9983):2190–6. (3):177–84. [133] Chang Z, Quinn PD, Hur K, Gibbons RD, Sjolander A, Larsson H, et al. [107] Faraone SV, Kunwar A, Adamson J, Biederman J. Personality traits among Association between medication use for Attention-deficit/hyperactivity ADHD adults: implications of late-onset and subthreshold diagnoses. Psychol disorder and risk of motor vehicle crashes. JAMA Psychiatry 2017;74 Med (Paris) 2009;39(4)685–93, doi:http://dx.doi.org/10.1017/ (6):597–603. S0033291708003917 Epub 2008 Jun 30. [134] Guendelman MD, Ahmad S, Meza JI, Owens EB, Hinshaw SP. Childhood [108] Chandra S, Biederman J, Faraone SV. Assessing the validity of the age at onset attention-deficit/hyperactivity disorder predicts intimate partner criterion for diagnosing ADHD in DSM-5. J Atten Disord victimization in young women. J Abnorm Child Psychol 2015. 2016;27:1087054716629717. [135] Buitelaar NJ, Posthumus JA, Buitelaar JK. ADHD in childhood and/or [109] Moffitt TE, Houts R, Asherson P, Belsky DW, Corcoran DL, Hammerle M, et al. adulthood as a risk factor for domestic violence or intimate partner Is adult ADHD a childhood-onset neurodevelopmental disorder? Evidence violence: a systematic review. J Atten Disord 2015;20: from a four-decade longitudinal cohort study. Am J Psychiatry 2015;172 (1087054715587099):1087054715587099. (10):967–77. [136] Kaye S, Gilsenan J, Young JT, Carruthers S, Allsop S, Degenhardt L, et al. Risk [110] Kieling C, Kieling RR, Rohde LA, Frick PJ, Moffitt T, Nigg JT, et al. The age at behaviours among substance use disorder treatment seekers with and onset of attention deficit hyperactivity disorder. Am J Psychiatry 2010;167 without adult ADHD symptoms. Drug Alcohol Depend 2014;144:70–7. (1):14–6, doi:http://dx.doi.org/10.1176/appi.ajp.2009.09060796. [137] Chang Z, Lichtenstein P, D’Onofrio BM, Almqvist C, Kuja-Halkola R, Sjolander [111] Morstedt B, Corbisiero S, Bitto H, Stieglitz RD. Attention-deficit/hyperactivity A, et al. Maternal age at childbirth and risk for ADHD in offspring: a disorder (ADHD) in adulthood: concordance and differences between self- population-based cohort study. Int J Epidemiol 2014;43(6)1815–24, doi: and informant perspectives on symptoms and functional impairment. PLoS http://dx.doi.org/10.1093/ije/dyu204 Epub 2014 Oct 29. One 2015;10(11)e0141342. [138] Hosain GM, Berenson AB, Tennen H, Bauer LO, Wu ZH. Attention deficit [112] Prevatt F, Proctor B, Best L, Baker L, Van Walker J, Taylor NW. The Positive hyperactivity symptoms and risky sexual behavior in young adult women. J Illusory Bias: Does it Explain Self-Evaluations in College Students With Womens Health (Larchmt). 2012;21(4)463–8, doi:http://dx.doi.org/10.1089/ ADHD? J Atten Disord 2012;16(3):235–43. jwh.2011.825 Epub 2 Feb 3. [113] APA. Diagnostic and Statistical Manual of Mental Disorders - DSM 5 - 5th ed. [139] McClernon FJ, Kollins SH. ADHD and smoking: from genes to brain to Force. APAD-T, editor. Washington, DC: American Psychiatric Publishing; behavior. Ann N Y Acad Sci 2008;1141:131–47. 2013. [140] Furczyk K, Thome J. Adult ADHD and suicide. Attent Defic Hyperact Disord. [114] Skirrow C, Asherson P. Emotional lability, comorbidity and impairment in 2014;6(3):153–8. adults with attention-deficit hyperactivity disorder. J Affect Disord 2013;147 [141] Swanson EN, Owens EB, Hinshaw SP. Pathways to self-harmful behaviors in (1-3):80–6. young women with and without ADHD: a longitudinal examination of [115] Surman CB, Biederman J, Spencer T, Miller CA, McDermott KM, Faraone SV. mediating factors. J Child Psychol Psychiatry 2014;55(5)505–15 Epub 2013 Understanding deficient emotional self-regulation in adults with attention Dec 23. deficit hyperactivity disorder: a controlled study. Atten Defic Hyperact Disord [142] Ginsberg Y, Hirvikoski T, Lindefors N. Attention deficit hyperactivity disorder 2013;5(3):273–81. (ADHD) among longer-term prison inmates is a prevalent, persistent and [116] Seli P, Smallwood J, Cheyne JA, Smilek D. On the relation of mind wandering disabling disorder. BMC Psychiatry 2010;10:112. and ADHD symptomatology. Psychon Bull Rev 2015;22(3):629–36. [143] Young S, Gudjonsson G, Asherson P, Theobald J, Oliver B, Scott C, et al. [117] Shaw GA, Giambra L. Task-unrelated thoughts of college students diagnosed Attention deficit hyperactivity disorder and critical incidents in a Scottish as hyperactive in childhood. Dev Neuropsychol 1993;9(1):17–30. prison population. Pers Individ Dif 2009;46:265–9. [118] Weyandt LL, Iwaszuk W, Fulton K, Ollerton M, Beatty N, Fouts H, et al. The [144] Bijlenga D, van der Heijden KB, Breuk M, van Someren EJ, Lie ME, Boonstra internal restlessness scale: performance of college students with and AM, et al. Associations between sleep characteristics, seasonal depressive without ADHD. J Learn Disabil 2003;36(4):382–9. symptoms, lifestyle, and ADHD symptoms in adults. J Atten Disord 2013;17 [119] Asherson P. Clinical assessment and treatment of attention deficit (3):261–74. hyperactivity disorder in adults. Expert Rev Neurother 2005;5(4):525–39. [145] Spencer TJ, Faraone SV, Tarko L, McDermott K, Biederman J. Attention-deficit/ [120] Mowlem FD, Skirrow C, Reid P, Maltezos S, Nijjar SK, Merwood A, et al. hyperactivity disorder and adverse health outcomes in adults. J Nerv Ment Validation of the mind excessively wandering scale and the relationship of Dis 2014;202(10):725–31. mind wandering to impairment in adult ADHD. J Atten Disord 2016. [146] Stickley A, Koyanagi A, Takahashi H, Ruchkin V, Inoue Y, Kamio Y. Attention- [121] Brown TE. ADD/ADHD and impaired executive function in clinical practice. deficit/hyperactivity disorder and physical multimorbidity: a population- Curr Psychiatry Rep 2008;10(5):407–11. based study. Eur Psychiatry 2017;45:227–34. J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 31 [147] Instanes JT, Klungsoyr K, Halmoy A, Fasmer OB, Adult ADHD Haavik J. [176] Fuller-Thomson E, Lewis DA, Agbeyaka SK. Attention-deficit/hyperactivity Comorbid somatic disease: a systematic literature review. J Atten Disord disorder casts a long shadow: findings from a population-based study of 2018;22(3):203–28. adult women with self-reported ADHD. Child Care Health Dev 2016;42 [148] Hegvik TA, Instanes JT, Haavik J, Klungsoyr K, Engeland A. Associations (6):918–27. between attention-deficit/hyperactivity disorder and autoimmune diseases [177] Van Voorhees EE, Mitchell JT, McClernon FJ, Beckham JC, Kollins SH. Sex, are modified by sex: a population-based cross-sectional study. Eur Child ADHD symptoms, and smoking outcomes: an integrative model. Med Adolesc Psychiatry 2017;5(10):017–1056. Hypotheses 2012;78(5):585–93. [149] Cortese S, Moreira-Maia CR, St Fleur D, Morcillo-Penalver C, Rohde LA, [178] Faraone SV, Biederman J, Mick E. The age-dependent decline of attention Faraone SV. Association between ADHD and obesity: a systematic review and deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol meta-analysis. Am J Psychiatry 2016;173(1):34–43. Med (Paris) 2006;36(2):159–65. [150] Asherson P, Akehurst R, Kooij JJ, Huss M, Beusterien K, Sasane R, et al. Under [179] Casey BJ, Jones RM. Neurobiology of the adolescent brain and behavior: diagnosis of adult ADHD: cultural influences and societal burden. J Atten implications for substance use disorders. J Am Acad Child Adolesc Psychiatry Disord 2012;16(5 Suppl) 20S-38S. 2010;49(12)1189–201, doi:http://dx.doi.org/10.1016/j.jaac.2010.08.017 quiz [151] Tegelbeckers J, Bunzeck N, Duzel E, Bonath B, Flechtner HH, Krauel K. Altered 285, Epub Oct 8. salience processing in attention deficit hyperactivity disorder. Hum Brain [180] Singh SP. Transition of care from child to adult mental health services: the Mapp 2015;36(6):2049–60. great divide. Curr Opin Psychiatry 2009;22(4):386–90, doi:http://dx.doi.org/ [152] Bozhilova NS, Michelini G, Kuntsi J, Asherson P. Mind wandering perspective 10.1097/YCO.0b013e32832c9221. on attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev [181] While A, Forbes A, Ullman R, Lewis S, Mathes L, Griffiths P. Good practices that 2018;92:464–76. address continuity during transition from child to adult care: synthesis of the [153] Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual Research evidence. Child Care Health Dev 2004;30(5):439–52. Review: a meta-analysis of the worldwide prevalence of mental disorders in [182] NICE. Attention deficit hyperactivity disorder: diagnosis and management: children and adolescents. J Child Psychol Psychiatry 2015;56(3):345–65. national Insitute for Health and Care Excellence. 2008. [154] Wood DR, Reimherr FW, Wender PH, Johnson GE. Diagnosis and treatment of [183] Nutt DJ, Fone K, Asherson P, Bramble D, Hill P, Matthews K, et al. Evidence- minimal brain dysfunction in adults: a preliminary report. Arch Gen based guidelines for management of attention-deficit/hyperactivity disorder Psychiatry 1976;33(12):1453–60. in adolescents in transition to adult services and in adults: recommendations [155] Weiss G, Hechtman L, Milroy T. Psychiatric status of hyperactives as adults: a from the British Association for Psychopharmacology. J Psychopharmacol controlled prospective 15-year follow-up of 63 hyperactive children. J Am 2007;21(1):10–41. Acad Child Psychiatry 1985;24:211–20. [184] Bolea-Alamanac B, Nutt DJ, Adamou M, Asherson P, Bazire S, Coghill D, et al. [156] Mannuzza S, Klein RG, Addalli KA. Young adult mental status of hyperactive Evidence-based guidelines for the pharmacological management of boys and their brothers: a prospective follow-up study. J Am Acad Child attention deficit hyperactivity disorder: update on recommendations from Adolesc Psychiatry 1991;30(5):743–51. the British Association for Psychopharmacology. J Psychopharmacol (Oxford) [157] Lie N. Follow-ups of children with attention deficit hyperactivity disorder 2014;28(3):179–203. (ADHD). Review of literature. Acta Psychiatr Scand Suppl 1992;368:1–40. [185] Young S, Adamou M, Asherson P, Coghill D, Colley B, Gudjonsson G, et al. [158] Wender PH, Wolf LE, Wasserstein J. Adults with ADD: an overview. Ann N Y Recommendations for the transition of patients with ADHD from child to Acad Sci 2001;931(pp 1-16). adult healthcare services: a consensus statement from the UK adult ADHD [159] Barkley RA, Fischer M, Smallish L, Fletcher K. The persistence of attention- network. BMC Psychiatry 2016;16(301), doi:http://dx.doi.org/10.1186/ deficit/hyperactivity disorder into young adulthood as a function of reporting s12888-016-1013-4. source and definition of disorder. J Abnorm Psychol 2002;111(2):279–89. [186] Singh SP, Paul M, Ford T, Kramer T, Weaver T, McLaren S, et al. Process, [160] Mannuzza S, Klein RG, Moulton 3rd JL. Persistence of Attention-Deficit/ outcome and experience of transition from child to adult mental healthcare: Hyperactivity Disorder into adulthood: what have we learned from the multiperspective study. Br J Psychiatry 2010;197(4):305–12, doi:http://dx. prospective follow-up studies? J Atten Disord 2003;7(2):93–100. doi.org/10.1192/bjp.bp.109.075135. [161] Asherson P, Chen W, Craddock B, Taylor E. Adult attention-deficit [187] Tatlow-Golden M, Gavin B, McNamara N, Singh S, Ford T, Paul M, et al. hyperactivity disorder: recognition and treatment in general adult Transitioning from child and adolescent mental health services with psychiatry. Br J Psychiatry 2007;190:4–5. attention-deficit hyperactivity disorder in Ireland: case note review. Early [162] Michielsen M, Semeijn E, Comijs HC, van de Ven P, Beekman AT, Deeg DJ, et al. Interv Psychiatry 2017. Prevalence of attention-deficit hyperactivity disorder in older adults in the [188] McNamara N, McNicholas F, Ford T, Paul M, Gavin B, Coyne I, et al. Transition Netherlands. Br J Psychiatry 2012;201(4):298–305. from child and adolescent to adult mental health services in the Republic of [163] Michielsen M, de Kruif JT, Comijs HC, van Mierlo S, Semeijn EJ, Beekman AT, Ireland: an investigation of process and operational practice. Early Interv et al. The burden of ADHD in older adults: a qualitative study. J Atten Disord Psychiatry 2014;8(3)291–7, doi:http://dx.doi.org/10.1111/eip.12073 Epub 2015. 2013 Jul 4. [164] Semeijn E, Kooij JJS, Comijs H, Michielsen M, Deeg DJ, Beekman AT. Attention- [189] Swift KD, Hall CL, Marimuttu V, Redstone L, Sayal K, Hollis C. Transition to deficit/hyperactivity disorder, physical health, and lifestyle in older adults. J adult mental health services for young people with Attention Deficit/ Am Geriatr Soc 2013;61(6):882–7. Hyperactivity Disorder (ADHD): a qualitative analysis of their experiences. [165] Goodman DW, Mitchell S, Rhodewalt L, Surman CB. Clinical presentation, BMC Psychiatry 2013;13(74). diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD) [190] Hall CL, Newell K, Taylor J, Sayal K, Hollis C. Services for young people with in older adults: a review of the evidence and its implications for clinical care. attention deficit/hyperactivity disorder transitioning from child to adult Drugs Aging 2016;33(1):27–36. mental health services: a national survey of mental health trusts in England. J [166] Torgersen T, Gjervan B, Lensing MB, Rasmussen K. Optimal management of Psychopharmacol (Oxford) 2015;29(1)39–42, doi:http://dx.doi.org/10.1177/ ADHD in older adults. Neuropsychiatr Dis Treat 2016;12:79–87. 0269881114550353 Epub 2014 Sep 18. [167] Kooij JJ, Michielsen M, Kruithof H, Bijlenga D. ADHD in old age: a review of the [191] Coghill D. Services for adults with ADHD: work in progress: commentary on. literature and proposal for assessment and treatment. Expert Rev Neurother Specialist adult ADHD clinics in East Anglia. BJPsych Bull. 2015;39(3):140–3, 2016;16(12):1371–81. doi:http://dx.doi.org/10.1192/pb.bp.114.048850. [168] Rucklidge JJ. Gender differences in attention-deficit/hyperactivity disorder. [192] Sibley MH, Rohde LA, Swanson JM, Hechtman LT, Molina BSG, Mitchell JT, Psychiatr Clin North Am 2010;33(2):357–73. et al. Late-onset ADHD reconsidered with comprehensive repeated [169] Barkley RA, Murphy KR, Fischer M. ADHD in adults: what the science says. assessments between ages 10 and 25. Am J Psychiatry 2018;175(2):140–9. New York: Guildford Press; 2010. [193] Faraone SV, Biederman J. Can attention-deficit/hyperactivity disorder onset [170] Biederman J, Mick E, Faraone SV, Braaten E, Doyle A, Spencer T, et al. Influence occur in adulthood? JAMA Psychiatry 2016;73(7):655–6. of gender on attention deficit hyperactivity disorder in children referred to a [194] Caye A, Sibley MH, Swanson JM, Rohde LA. Late-onset ADHD: understanding psychiatric clinic. Am J Psychiatry 2002;159(1):36–42. the evidence and building theoretical frameworks. Curr Psychiatry Rep [171] Vingilis E, Erickson PG, Toplak ME, Kolla NJ, Mann RE, Seeley J, et al. Attention 2017;19(12):106. deficit hyperactivity disorder symptoms, comorbidities, substance use, and [195] Cooper M, Hammerton G, Collishaw S, Langley K, Thapar A, Dalsgaard S, et al. social outcomes among men and women in a canadian sample. Biomed Res Investigating late-onset ADHD: a population cohort investigation. J Child Int 2015;2015:982072. Psychol Psychiatry Allied Discip 2018;59(10):1105–13. [172] Quinn PO, Madhoo M. A review of attention-deficit/hyperactivity disorder in [196] Ustun B, Adler LA, Rudin C, Faraone SV, Spencer TJ, Berglund P, et al. The world women and girls: uncovering this hidden diagnosis. Prim Care Companion health organization adult attention-deficit/hyperactivity disorder self-report CNS Disord 2014;16(3). screening scale for DSM-5. JAMA Psychiatry 2017;74(5):520–6. [173] Ptacek R, Kuzelova H, Papezova H, Stepankova T. Attention deficit [197] NICE. Diagnosis and management of ADHD in children, young people and hyperactivity disorder and eating disorders. Prague Med Rep 2010;111 adults. London The British Psychological Society and The Royal College of (3):175–81. Psychiatrists; 2018. [174] Arnett AB, Pennington BF, Willcutt EG, DeFries JC, Olson RK. Sex differences in [198] Kooij JJ. Adult ADHD: diagnostic assessment and treatment. 3rd ed. London: ADHD symptom severity. J Child Psychol Psychiatry 2015;56(6)632–9, doi: Springer; 2013. http://dx.doi.org/10.1111/jcpp.12337 Epub 2014 Oct 4. [199] Ramos-Quiroga JA, Bosch R, Richarte V, Valero S, Gomez-Barros N, Nogueira [175] Argumedo GS, Sanz CR, Olguin HJ. Experimental models of developmental M, et al. Criterion and concurrent validity of Conners Adult ADHD hypothyroidism. Horm Metab Res 2012;44(2)79–85, doi:http://dx.doi.org/ Diagnostic Interview for DSM-IV (CAADID) Spanish version. [Spanish] 10.1055/s-0031-1297941 Epub 2011 Dec 27. Validez de criterio y concurrente de la version espanola de la Conners Adult 32 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 ADHD Diagnostic Interview for DSM-IV. Rev Psiquiatr Salud Ment 2012;5 [224] Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult (4):229–35. attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J [200] Rommelse N, van der Kruijs M, Damhuis J, Hoek I, Smeets S, Antshel KM, et al. Clin Psychiatry 2010;71(6):754–63. An evidenced-based perspective on the validity of attention-deficit/ [225] Castells X, Ramos-Quiroga JA, Rigau D, Bosch R, Nogueira M, Vidal X, et al. hyperactivity disorder in the context of high intelligence. Neurosci Biobehav Efficacy of methylphenidate for adults with attention-deficit hyperactivity Rev 2016;71:21–47. disorder: a meta-regression analysis. CNS Drugs 2011;25(2):157–69. [201] Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, [226] Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M. Amphetamines et al. Co-morbidity of adult attention-deficit/hyperactivity disorder with for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane focus on personality traits and related disorders in a tertiary referral center. Database Syst Rev 2011(6) CD007813. Eur Arch Psychiatry Clin Neurosci 2007;257(6)309–17 Epub 2007 Apr 1. [227] Cunill R, Castells X, Tobias A, Capella D. Atomoxetine for attention deficit [202] Fayyad J, Sampson NA, Hwang I, Adamowski T, Aguilar-Gaxiola S, Al- hyperactivity disorder in the adulthood: a meta-analysis and meta- Hamzawi A, et al. The descriptive epidemiology of DSM-IV adult ADHD in the regression. Pharmacoepidemiol Drug Saf 2013;22(9):961–9. world health organization world mental health surveys. Atten Defic Hyperact [228] Philipsen A, Jans T, Graf E, Matthies S, Borel P, Colla M, et al. Effects of group Disord 2017;9(1):47–65. psychotherapy, individual counseling, methylphenidate, and placebo in the [203] Faraone SV, Asherson P, Banaschewski T, Biederman J, Buitelaar JK, Ramos- treatment of adult Attention-Deficit/Hyperactivity disorder: a randomized Quiroga JA, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis clinical trial. JAMA Psychiatry 2015;72(12):1199–210, doi:http://dx.doi.org/ Primers 2015;1:15020, doi:http://dx.doi.org/10.1038/nrdp.2015.20. 10.1001/jamapsychiatry.2015.2146. [204] Roy A, Hechtman L, Arnold LE, Sibley MH, Molina BS, Swanson JM, et al. [229] Chang Z, Lichtenstein P, D’Onofrio BM, Sjolander A, Larsson H. Serious Childhood factors affecting persistence and desistence of attention-deficit/ transport accidents in adults with attention-deficit/hyperactivity disorder hyperactivity disorder symptoms in adulthood: results from the MTA. J Am and the effect of medication: a population-based study. JAMA Psychiatry Acad Child Adolesc Psychiatry 2016;55(11), doi:http://dx.doi.org/10.1016/j. 2014;71(3):319–25. jaac.2016.05.027 937-44.e4, Epub Sep 2. [230] Lichtenstein P, Larsson H. Medication for attention deficit-hyperactivity [205] Instanes JT, Haavik J, Halmoy A. Personality traits and comorbidity in adults disorder and criminality. N Engl J Med 2013;368(8):776. with ADHD. J Atten Disord 2016;20(10)845–54, doi:http://dx.doi.org/ [231] Chen Q, Sjolander A, Runeson B, D’Onofrio BM, Lichtenstein P, Larsson H. Drug 10.1177/1087054713511986 Epub 2013 Nov 22. treatment for attention-deficit/hyperactivity disorder and suicidal [206] Skirrow C, McLoughlin G, Kuntsi J, Asherson P. Behavioral, neurocognitive and behaviour: register based study. BMJ 2014;348:g3769. treatment overlap between attention-deficit/hyperactivity disorder and [232] Chang Z, D’Onofrio BM, Quinn PD, Lichtenstein P, Larsson H. Medication for mood instability. Expert Rev Neurother 2009;9(4):489–503, doi:http://dx. attention-deficit/hyperactivity disorder and risk for depression: a doi.org/10.1586/ern.09.2. nationwide longitudinal cohort study. Biol Psychiatry 2016;80(12): [207] Corbisiero S, Morstedt B, Bitto H, Stieglitz RD. Emotional dysregulation in 916–22. adults with attention-deficit/hyperactivity disorder-validity, predictability, [233] Chang Z, Lichtenstein P, Halldner L, D’Onofrio B, Serlachius E, Fazel S, et al. severity, and comorbidity. J Clin Psychol 2017;73(1)99–112, doi:http://dx.doi. Stimulant ADHD medication and risk for substance abuse. J Child Psychol org/10.1002/jclp.22317 Epub 2016 May 6. Psychiatry Allied Discip 2014;55(8):878–85. [208] Ferrer M, Andion O, Matali J, Valero S, Navarro JA, Ramos-Quiroga JA, et al. [234] Sharman J, Pennick M. Lisdexamfetamine prodrug activation by peptidase- Comorbid attention-deficit/hyperactivity disorder in borderline patients mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatr Dis defines an impulsive subtype of borderline personality disorder. J Pers Disord Treat 2014;10:2275–80. 2010;24(6):812–22. [235] Setyawan J, Hodgkins P, Guerin A, Gauthier G, Cloutier M, Wu EQ, et al. [209] O’Malley GK, McHugh L, Mac Giollabhui N, Bramham J. Characterizing adult Comparing treatment adherence of lisdexamfetamine and other medications attention-deficit/hyperactivity-disorder and comorbid borderline for the treatment of attention deficit/hyperactivity disorder: a retrospective personality disorder: ADHD symptoms, psychopathology, cognitive analysis. J Med Econ 2013;16(7):962–75. functioning and psychosocial factors. Eur Psychiatry 2016;31:29–36, doi: [236] Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S, Zhang Y, et al. http://dx.doi.org/10.1016/j.eurpsy.2015.09.012 Epub Dec 3. Double-blind, placebo-controlled study of the efficacy and safety of [210] Van Dijk FE, Lappenschaar M, Kan CC, Verkes RJ, Buitelaar JK. Symptomatic lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity overlap between attention-deficit/hyperactivity disorder and borderline disorder. J Clin Psychiatry 2008;69(9):1364–73. personality disorder in women: the role of temperament and character traits. [237] Wigal T, Brams M, Gasior M, Gao J, Squires L, Giblin J, et al. Randomized, Compr Psychiatry 2012;53(1):39–47. double-blind, placebo-controlled, crossover study of the efficacy and safety [211] Gillberg C. Deficits in attention, motor control, and perception: a brief review. of lisdexamfetamine dimesylate in adults with attention-deficit/ Arch Dis Child 2003;88(10):904–10. hyperactivity disorder: novel findings using a simulated adult workplace [212] Foreman DM, Foreman D, Prendergast M, Minty B. Is clinic prevalence of ICD-10 environment design. Behav Brain Funct 2010;6:34. hyperkinesis underestimated? Impact of increasing awareness by a questionnaire [238] Dupaul GJ, Weyandt LL, Rossi JS, Vilardo BA, O’Dell SM, Carson KM, et al. screen in an UK clinic. Eur Child Adolesc Psychiatry 2001;10(2):130–4. Double-blind, placebo-controlled, crossover study of the efficacy and safety [213] von Polier GG, Vloet TD, Herpertz-Dahlmann B. ADHD and delinquency–a of lisdexamfetamine dimesylate in college students with ADHD. J Atten developmental perspective. Behav Sci Law 2012;30(2):121–39. Disord 2012;16(3):202–20. [214] Young S, Moss D, Sedgwick O, Fridman M, Hodgkins P. A meta-analysis of the [239] Maneeton N, Maneeton B, Suttajit S, Reungyos J, Srisurapanont M, Martin SD. prevalence of attention deficit hyperactivity disorder in incarcerated Exploratory meta-analysis on lisdexamfetamine versus placebo in adult populations. Psychol Med (Paris) 2015;45(2):247–58. ADHD. Drug design. development and therapy. 2014;8:1685–93. [215] Young S, Thome J. ADHD and offenders. World J Biol Psychiatry 2011;12 [240] Coghill DR, Caballero B, Sorooshian S, Civil R. A systematic review of the (Suppl 1):124–8. safety of lisdexamfetamine dimesylate. CNS Drugs 2014;28(6):497–511. [216] Young S, Goodwin E. Attention-deficit/hyperactivity disorder in persistent [241] Adler LA, Dirks B, Deas PF, Raychaudhuri A, Dauphin MR, Lasser RA, et al. criminal offenders: the need for specialist treatment programs. Expert Rev Lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity Neurother 2010;10(10):1497–500, doi:http://dx.doi.org/10.1586/ern.10.142. disorder who report clinically significant impairment in executive function: [217] D’Amelio R, Retz W, Philipsen A, Rösler M. Psychoedukation und Coaching results from a randomized, double-blind, placebo-controlled study. J Clin ADHS im Erwachsenenalter. Manual zur Leitung von Patienten- und Psychiatry 2013;74(7):694–702. Angehörigengruppen. München: Urban & Fischer Elsevier; 2009. [242] Epstein T, Patsopoulos NA, Weiser M. Immediate-release methylphenidate [218] Hirvikoski T, Waaler E, Lindstrom T, Bolte S, Jokinen J. Cognitive behavior for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane therapy-based psychoeducational groups for adults with ADHD and their Database Syst Rev 2014(9) CD005041. significant others (PEGASUS): an open clinical feasibility trial. Atten Defic [243] Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious Hyperact Disord 2015;7(1):89–99. cardiovascular problems with medications for attention-deficit [219] Hirvikoski T, Lindström T, Carlsson J, Waaler E, Jokinen J, Bölte S. hyperactivity disorder. CNS Drugs 2013;27(1):15–30. Psychoeducational groups for adults with ADHD and their significant [244] Coghill D, Banaschewski T, Zuddas A, Pelaz A, Gagliano A, Doepfner M. Long- others (PEGASUS): a pragmatic multicenter and randomized controlled trial. acting methylphenidate formulations in the treatment of attention-deficit/ Eur Psychiatry 2017;9(44):141–52. hyperactivity disorder: a systematic review of head-to-head studies. BMC [220] Volkow ND, Swanson JM. Clinical practice: adult attention deficit- Psychiatry 2013;13:237. hyperactivity disorder. N Engl J Med 2013;369(20):1935–44. [245] Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and [221] Bushe C, Day K, Reed V, Karlsdotter K, Berggren L, Pitcher A, et al. A network blood pressure associated with CNS stimulant treatment of ADHD in adults. meta-analysis of atomoxetine and osmotic release oral system European neuropsychopharmacology: the journal of the European College of methylphenidate in the treatment of attention-deficit/hyperactivity disorder Neuropsychopharmacology. 2013;23(6):534–41. in adult patients. J Psychopharmacol 2016;30(5):444–58. [246] Westover AN, Halm EA. Do prescription stimulants increase the risk of [222] Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, adverse cardiovascular events?: a systematic review. BMC Cardiovasc Disord et al. Comparative efficacy and tolerability of medications for attention- 2012;12:41. deficit hyperactivity disorder in children, adolescents, and adults: a [247] Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, et al. systematic review and network meta-analysis. Lancet Psychiatry 2018;5 ADHD medications and risk of serious cardiovascular events in young and (9):727–38. middle-aged adults. JAMA : J Am Med Assoc 2011;306(24):2673–83. [223] Koesters M, Becker T, Kilian R, Fegert JM, Weinmann S. Limits of meta- [248] Schelleman H, Bilker WB, Kimmel SE, Daniel GW, Newcomb C, Guevara JP, analysis: methylphenidate in the treatment of adult attention-deficit et al. Methylphenidate and risk of serious cardiovascular events in adults. Am hyperactivity disorder. J Psychopharmacol (Oxford) 2009;23(7):733–44. J Psychiatry 2012;169(2):178–85. J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 33 [249] Shin JY, Roughead EE, Park BJ, Pratt NL. Cardiovascular safety of [275] Sobanski E, Bruggemann D, Alm B, Kern S, Deschner M, Schubert T, et al. methylphenidate among children and young people with attention- Psychiatric comorbidity and functional impairment in a clinically referred deficit/hyperactivity disorder (ADHD): nationwide self controlled case series sample of adults with attention-deficit/hyperactivity disorder (ADHD). Eur study. BMJ 2016;353:i2550. Arch Psychiatry Clin Neurosci 2007;257(7):371–7. [250] Asherson P, Bushe C, Saylor K, Tanaka Y, Deberdt W, Upadhyaya H. Efficacy of [276] Sharma A, Couture J. A review of the pathophysiology, etiology, and atomoxetine in adults with attention deficit hyperactivity disorder: an treatment of attention-deficit hyperactivity disorder (ADHD). Ann integrated analysis of the complete database of multicenter placebo- Pharmacother 2014;48(2):209–25. controlled trials. J Psychopharmacol (Oxford) 2014;28(9):837–46. [277] Bazire S. Psychotropic drug directory 2010. Aberdeen: HealthComm UK Ltd; [251] Asherson P, Young S, Adamou M, Bolea B, Coghill D, Gudjonsson G, et al. 2010. Handbook for Attention Deficit Hyperactivity Disorder in Adults. UKAAN, [278] Viktorin A, Ryden E, Thase ME, Chang Z, Lundholm C, D’Onofrio BM, et al. The Springer Healthcare Communications; 2013. risk of treatment-emergent mania with methylphenidate in bipolar disorder. [252] Ginsberg Y, Ahlqvist-Rastad J, AM K, Barroso J, Bergquist F, Brodd G, et al. Am J Psychiatry 2016 appiajp201616040467. Läkemedel vid adhd – behandlingsrekommendation. Information från [279] Cunill R, Castells X, Tobias A, Capella D. Pharmacological treatment of Läkemedelsverket 2016;(2):13–23. attention deficit hyperactivity disorder with co-morbid drug dependence. J [253] Quinn PD, Chang Z, Hur K, Gibbons RD, Lahey BB, Rickert ME, et al. ADHD Psychopharmacol 2015;29(1):15–23. medication and substance-related problems. Am J Psychiatry 2017;174 [280] Steinhausen HC, Bisgaard C. Substance use disorders in association with (9):877–85. attention-deficit/hyperactivity disorder, co-morbid mental disorders, and [254] Adler LA, Liebowitz M, Kronenberger W, Qiao M, Rubin R, Hollandbeck M, medication in a nationwide sample. Eur Neuropsychopharmacol 2014;24 et al. Atomoxetine treatment in adults with attention-deficit/hyperactivity (2):232–41. disorder and comorbid social anxiety disorder. Depress Anxiety 2009;26 [281] Levin FR, Mariani JJ, Specker S, Mooney M, Mahony A, Brooks DJ, et al. (3):212–21. Extended-release mixed amphetamine salts vs placebo for comorbid adult [255] Bangs ME, Emslie GJ, Spencer TJ, Ramsey JL, Carlson C, Bartky EJ, et al. Efficacy Attention-Deficit/Hyperactivity disorder and cocaine use disorder: a and safety of atomoxetine in adolescents with attention-deficit/hyperactivity randomized clinical trial. JAMA Psychiatry 2015;72(6):593–602. disorder and major depression. J Child Adolesc Psychopharmacol 2007;17 [282] Konstenius M, Jayaram-Lindstrom N, Guterstam J, Beck O, Philips B, Franck J. (4):407–20. Methylphenidate for attention deficit hyperactivity disorder and drug relapse [256] Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: in criminal offenders with substance dependence: a 24-week randomized treatment for ADHD and related disorders. CNS Drug Rev 2007;13(4):465–74. placebo-controlled trial. Addiction 2014;109(3):440–9. [257] Huss M, Chen W, Ludolph AG. Guanfacine extended release: a new [283] Skoglund C, Brandt L, Almqvist C, D’Onofrio BM, Konstenius M, Franck J, et al. pharmacological treatment option in Europe. Clin Drug Investig 2016;36 Factors associated with adherence to methylphenidate treatment in adult (1):1–25. patients with attention-deficit/hyperactivity disorder and substance use [258] Butterfield ME, Saal J, Young B, Young JL. Supplementary guanfacine disorders. J Clin Psychopharmacol 2016;36(3):222–8. hydrochloride as a treatment of attention deficit hyperactivity disorder in [284] Perez de los Cobos J, Sinol N, Perez V, Trujols J. Pharmacological and clinical adults: a double blind, placebo-controlled study. Psychiatry Res dilemmas of prescribing in co-morbid adult attention-deficit/hyperactivity 2016;236:136–41. disorder and addiction. Br J Clin Pharmacol 2014;77(2):337–56. [259] Kollins SH, Jain R, Brams M, Segal S, Findling RL, Wigal SB, et al. Clonidine [285] Crunelle CL, van den Brink W, Moggi F, Konstenius M, Franck J, Levin FR, et al. extended-release tablets as add-on therapy to psychostimulants in children International consensus statement on screening, diagnosis and treatment of and adolescents with ADHD. Pediatrics 2011;127(6) e1406-13. substance use disorder patients with comorbid attention Deficit/ [260] Jain R, Segal S, Kollins SH, Khayrallah M. Clonidine extended-release tablets Hyperactivity disorder. Eur Addict Res 2018;24(1):43–51. for pediatric patients with attention-deficit/hyperactivity disorder. J Am [286] Torgersen T, Gjervan B, Rasmussen K, Vaaler A, Nordahl HM. Prevalence of Acad Child Adolesc Psychiatry 2011;50(2):171–9. comorbid substance use disorder during long-term central stimulant treatment [261] Palumbo DR, Sallee FR, Pelham Jr. WE, Bukstein OG, Daviss WB, McDermott in adult ADHD. Adhd Atten Deficit Hyperact Disord 2013;5(1):59–67. MP. Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and [287] Klassen LJ, Bilkey TS, Katzman M, Chokka P. Comorbid attention Deficit/ tolerability outcomes. J Am Acad Child Adolesc Psychiatry 2008;47(2):180–8. Hyperactivity disorder and substance use disorder: treatment [262] Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to considerations. Curr Drug Abuse Rev 2012. psychostimulant medication for hyperactive and aggressive children. J Am [288] Cheung CH, Frazier-Wood AC, Asherson P, Rijsdijk F, Kuntsi J. Shared cognitive Acad Child Adolesc Psychiatry 2003;42(8):886–94. impairments and aetiology in ADHD symptoms and reading difficulties. PLoS [263] Maneeton N, Maneeton B, Intaprasert S, Woottiluk P. A systematic review of One 2014;9(6)e98590. randomized controlled trials of bupropion versus methylphenidate in the [289] Rabiner DL, Anastopoulos AD, Costello EJ, Hoyle RH, McCabe SE, treatment of attention-deficit/hyperactivity disorder. Neuropsychiatr Dis Swartzwelder HS. The misuse and diversion of prescribed ADHD Treat 2014;10:1439–49. medications by college students. J Atten Disord 2009;13(2):144–53. [264] Hamedi M, Mohammdi M, Ghaleiha A, Keshavarzi Z, Jafarnia M, Keramatfar R, [290] Besag FM. ADHD treatment and pregnancy. Drug Saf: Int J Med Toxicol Drug et al. Bupropion in adults with attention-deficit/hyperactivity disorder: a Exp 2014;37(6):397–408. randomized, double-blind study. Acta Med Iran 2014;52(9):675–80. [291] Dideriksen D, Pottegard A, Hallas J, Aagaard L, Damkier P. First trimester in [265] Ghanizadeh A. A systematic review of reboxetine for treating patients with utero exposure to methylphenidate. Basic Clin Pharmacol Toxicol 2013;112 attention deficit hyperactivity disorder. Nord J Psychiatry 2015;69(4):241–8. (2):73–6. [266] Riahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J. Efficacy of [292] Pottegård A, Hallas J, Andersen JT, Løkkegaard EC, Dideriksen D, Aagaard L, reboxetine in adults with attention-deficit/hyperactivity disorder: a et al. First-trimester exposure to methylphenidate: a population-based randomized, placebo-controlled clinical trial. Hum Psychopharmacol cohort study. J Clin Psychiatry 2014;75(1):e88–93. 2010;25(7-8):570–6. [293] Huybrechts KF, Broms G, Christensen LB, Einarsdottir K, Engeland A, Furu K, [267] Otasowie J, Castells X, Ehimare UP, Smith CH. Tricyclic antidepressants for et al. Association between methylphenidate and amphetamine use in attention deficit hyperactivity disorder (ADHD) in children and adolescents. pregnancy and risk of congenital malformations: a cohort study from the Cochrane Database Syst Rev 2014(9) CD006997. international pregnancy safety study consortium. JAMA Psychiatry 2018;75 [268] Prince JB, Wilens TE, Biederman J, Spencer TJ, Millstein R, Polisner DA, et al. A (2):167–75. controlled study of nortriptyline in children and adolescents with attention [294] Diav-Citrin O, Shechtman S, Arnon J, Wajnberg R, Borisch C, Beck E, et al. deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2000;10 Methylphenidate in pregnancy: a multicenter, prospective, comparative, (3):193–204. observational study. J Clin Psychiatry 2016;77(9):1176–81. [269] Weiss M, Hechtman L, Adult ARG. A randomized double-blind trial of [295] Bro SP, Kjaersgaard MI, Parner ET, Sorensen MJ, Olsen J, Bech BH, et al. Adverse paroxetine and/or dextroamphetamine and problem-focused therapy for pregnancy outcomes after exposure to methylphenidate or atomoxetine attention-deficit/hyperactivity disorder in adults. J Clin Psychiatry 2006;67 during pregnancy. Clin Epidemiol 2015;7:139–47. (4):611–9. [296] Haervig KB, Mortensen LH, Hansen AV, Strandberg-Larsen K. Use of ADHD [270] Arnold VK, Feifel D, Earl CQ, Yang R, Adler LA. A 9-week, randomized, double- medication during pregnancy from 1999 to 2010: a Danish register-based blind, placebo-controlled, parallel-group, dose-finding study to evaluate the study. Pharmacoepidemiol Drug Saf 2014;23(5):526–33. efficacy and safety of modafinil as treatment for adults with ADHD. J Atten [297] McAllister-Williams RH, Baldwin DS, Cantwell R, Easter A, Gilvarry E, Glover Disord 2014;18(2):133–44. V, et al. British Association for Psychopharmacology consensus guidance on [271] Wang GJ, Volkow ND, Wigal T, Kollins SH, Newcorn JH, Telang F, et al. Long- the use of psychotropic medication preconception, in pregnancy and term stimulant treatment affects brain dopamine transporter level in postpartum 2017. J Psychopharmacol 2017;31(5):519–52. patients with attention deficit hyperactive disorder. PLoS One 2013;8(5) [298] Bolea-Alamanac BM, Green A, Verma G, Maxwell P, Davies SJ. e63023. Methylphenidate use in pregnancy and lactation: a systematic review of [272] Cavero I, Guillon JM. Safety pharmacology assessment of drugs with biased 5- evidence. Br J Clin Pharmacol 2014;77(1):96–101. HT(2B) receptor agonism mediating cardiac valvulopathy. J Pharmacol [299] Larsen ER, Damkier P, Pedersen LH, Fenger-Gron J, Mikkelsen RL, Nielsen RE, Toxicol Methods 2014;69(2):150–61. et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta [273] Droogmans S, Kerkhove D, Cosyns B, Van Camp G. Role of echocardiography Psychiatr Scand Suppl 2015;445:1–28. in toxic heart valvulopathy. Eur J Echocardiogr 2009;10(4):467–76. [300] Freeman MP. ADHD and pregnancy. Am J Psychiatry 2014;171(7):723–8. [274] Seixas M, Weiss M, Muller U. Systematic review of national and international [301] Atomoxetine [Internet]. U.S. National Library of Medicine. Date accessed: guidelines on attention-deficit hyperactivity disorder. J Psychopharmacol 22.10.2017. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r? (Oxford) 2012;26(6):753–65. dbs+lactmed:@term+@DOCNO+826. 34 J.J.S. Kooij et al. / European Psychiatry 56 (2019) 14–34 [302] Guanfacine [Internet]. U.S. National Library of Medicine. Date accessed: [327] Kubik JA. Efficacy of ADHD coaching for adults with ADHD. J Atten Disord 22.10.2017. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r? 2010;13(5)442–53, doi:http://dx.doi.org/10.1177/1087054708329960 Epub dbs+lactmed:@term+@DOCNO+631. 2009 Mar 10. [303] Clonidine [Internet]. U.S. National Library of Medicine. Date accessed: [328] Prevatt F, Yelland S. An empirical evaluation of ADHD coaching in college 22.10.2017. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r? students. J Atten Disord 2015;19(8)666–77, doi:http://dx.doi.org/10.1177/ dbs+lactmed:@term+@DOCNO+73. 1087054713480036 Epub 2013 Mar 18. [304] Lisdexamfetamine [Internet]. U.S. National Library of Medicine. Date [329] Hepark S, Janssen L, de Vries A, Schoenberg PL, Donders R, Kan CC, et al. The accessed: 22.10.2017. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/ efficacy of adapted MBCT on core symptoms and executive functioning in search2/r?dbs+lactmed:@term+@DOCNO+834. adults with ADHD: a preliminary randomized controlled trial. J Atten Disord [305] Bupropion [Internet]. U.S. National Library of Medicine. Date accessed: 2015;20:1087054715613587. 22.10.2017. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r? [330] Schoenberg PL, Hepark S, Kan CC, Barendregt HP, Buitelaar JK, Speckens AE. dbs+lactmed:@term+@DOCNO+321. Effects of mindfulness-based cognitive therapy on neurophysiological [306] Van der Heijden KB, Smits MG, Van Someren EJ, Gunning WB. Idiopathic correlates of performance monitoring in adult attention-deficit/ chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: a hyperactivity disorder. Clin Neurophysiol 2014;125(7):1407–16. circadian rhythm sleep disorder. Chronobiol Int 2005;22(3):559–70. [331] Cairncross M, Miller CJ. The effectiveness of mindfulness-based therapies for [307] van Veen MM, Kooij JJ, Boonstra AM, Gordijn MC, van Someren EJ. Delayed ADHD: a meta-analytic review. J Atten Disord 2016. circadian rhythm in adults with attention-deficit/hyperactivity disorder and [332] Braun S, Zeidler J, Linder R, Engel S, Verheyen F, Greiner W. Treatment costs of chronic sleep-onset insomnia. Biol Psychiatry 2010;67(11):1091–6. attention deficit hyperactivity disorder in Germany. Eur J Health Econ [308] Kooij JJ, Bijlenga D. The circadian rhythm in adult attention-deficit/hyperactivity 2013;14(6):939–45. disorder: current state of affairs. Exp Rev Neurother. 2013;13(10):1107–16. [333] Swensen A, Birnbaum HG, Ben Hamadi R, Greenberg P, Cremieux PY, Secnik K. [309] Kidwell KM, Van Dyk TR, Lundahl A, Nelson TD. Stimulant medications and Incidence and costs of accidents among attention-deficit/hyperactivity sleep for youth with ADHD: a meta-analysis. Pediatrics 2015;136(6):1144–53. disorder patients. J Adolesc Health 2004;35(4)346 e1-9. [310] Snitselaar MA, Smits MG, van der Heijden KB, Spijker J. Sleep and circadian [334] Birnbaum HG, Kessler RC, Lowe SW, Secnik K, Greenberg PE, Leong SA, et al. rhythmicity in adult ADHD and the effect of stimulants. J Atten Disord Costs of attention deficit-hyperactivity disorder (ADHD) in the US: excess 2017;21(1):14–26. costs of persons with ADHD and their family members in 2000. Curr Med Res [311] Barrett JR, Tracy DK, Giaroli G. To sleep or not to sleep: a systematic review of Opin 2005;21(2):195–206. the literature of pharmacological treatments of insomnia in children and [335] Marchetti A, Magar R, Lau H, Murphy EL, Jensen PS, Conners CK, et al. adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Pharmacotherapies for attention-deficit/hyperactivity disorder: expected- Psychopharmacol 2013;23(10):640–7. cost analysis. Clin Ther 2001;23(11):1904–21. [312] Van der Heijden KB, Smits MG, Van Someren EJW, Ridderinkhof KR, Gunning [336] Matza LS, Paramore C, Prasad M. A review of the economic burden of ADHD. WB. Effect of melatonin on sleep, behavior, and cognition in ADHD and Cost effectiveness and resource allocation: C/E. 2005;3:5. chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry 2007;46 [337] Daley D, Jacobsen RH, Lange AM, Sørensen A. Walldorf J. Costing adult (2):233–41. attention deficit hyperactivity disorder. New York: Oxford University Press; [313] Hirvikoski T, Waaler E, Alfredsson J, Pihlgren C, Holmstrom A, Johnson A, et al. 2015. Reduced ADHD symptoms in adults with ADHD after structured skills [338] Fredriksen M, Halmoy A, Faraone SV, Haavik J. Long-term efficacy and safety training group: results from a randomized controlled trial. Behav Res Ther of treatment with stimulants and atomoxetine in adult ADHD: a review of 2011;49(3):175–85. controlled and naturalistic studies. Eur Neuropsychopharmacol 2013;23 [314] Young S, Emilsson B, Sigurdsson JF, Khondoker M, Philipp-Wiegmann F, (6):508–27. Baldursson G, et al. A randomized controlled trial reporting functional [339] Gilmore A, Milne R. Methylphenidate in children with hyperactivity: review outcomes of cognitive-behavioural therapy in medication-treated adults and cost-utility analysis. Pharmacoepidemiol Drug Saf 2001;10(2):85–94. with ADHD and comorbid psychopathology. Eur Arch Psychiatry Clin [340] King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al. A Neurosci 2017;267(3):267–76. systematic review and economic model of the effectiveness and cost- [315] Jensen CM, Amdisen BL, Jorgensen KJ, Arnfred SM. Cognitive behavioural effectiveness of methylphenidate, dexamfetamine and atomoxetine for the therapy for ADHD in adults: systematic review and meta-analyses. Atten treatment of attention deficit hyperactivity disorder in children and Defic Hyperact Disord 2016;8(1)3–11, doi:http://dx.doi.org/10.1007/s12402- adolescents. Health Technol Assess (Rockv) 2006;10(23) iii-iv, xiii-146. 016-0188-3 Epub 2016 Jan 22. [341] Narayan S, Hay J. Cost effectiveness of methylphenidate versus AMP/DEX [316] Arnold LE, Hodgkins P, Caci H, Kahle J, Young S. Effect of treatment modality mixed salts for the first-line treatment of ADHD. Expert Rev Pharmacoecon on long-term outcomes in attention-deficit/hyperactivity disorder: a Outcomes Res 2004;4(6):625–34. systematic review. PLoS One 2015;10(2)e0116407, doi:http://dx.doi.org/ [342] Zupancic J, Miller A, Raina P, Lee S, Klassen A, Olsen L. Part 3: economic evaluation 10.1371/journal.pone eCollection 2015. of pharmaceutical and psychological/behavioural therapies for attention-deficit/ [317] Philipsen A. Psychotherapy in adult attention deficit hyperactivity disorder: hyperactivity disorde. In: Miller A, Lee SK, Raina P, editors. Review of therapies for implications for treatment and research. Expert rev. 2012;12(10):1217–25. attention-deficit/hyperactivity disorde. Ottawa, Canada: Canadian [318] Mongia M, Hechtman L. Cognitive behavior therapy for adults with attention- Coordinating Office for Health Technology Assessment; 1998. deficit/hyperactivity disorder: a review of recent randomized controlled [343] Donnelly M, Haby MM, Carter R, Andrews G, Vos T. Cost-effectiveness of trials. Curr Psychiatry Rep 2012;14(5):561–7. dexamphetamine and methylphenidate for the treatment of childhood [319] Safren SA, Otto MW, Sprich S, Winett CL, Wilens TE, Biederman J. Cognitive- attention deficit hyperactivity disorder. Aust N Z J Psychiatry 2004;38 behavioral therapy for ADHD in medication-treated adults with continued (8):592–601. symptoms. Behav Res Ther 2005;43(7):831–42. [344] Wu EQ, Hodgkins P, Ben-Hamadi R, Setyawan J, Xie J, Sikirica V, et al. [320] Safren SA, Sprich S, Mimiaga MJ, Surman C, Knouse L, Groves M, et al. Cost effectiveness of pharmacotherapies for attention-deficit Cognitive behavioral therapy vs relaxation with educational support for hyperactivity disorder: a systematic literature review. CNS Drugs medication-treated adults with ADHD and persistent symptoms: a 2012;26(7):581–600. randomized controlled trial. JAMA 2010;304(8):875–80. [345] Lebowitz MS. Stigmatization of ADHD: a developmental review. J Atten [321] Young S, Khondoker M, Emilsson B, Sigurdsson JF, Philipp-Wiegmann F, Disord 2016;20(3):199–205. Baldursson G, et al. Cognitive-behavioural therapy in medication-treated [346] Baeyens D, Moniquet A, Danckaerts M, van der Oord S. [A comparative study adults with attention-deficit/hyperactivity disorder and co-morbid of the structural stigmatisation of ADHD and autism spectrum disorder in psychopathology: a randomized controlled trial using multi-level analysis. Flemish newspapers]. Tijdschr Psychiatr 2017;59(5):269–77. Psychol Med (Paris) 2015;45(13)2793–804, doi:http://dx.doi.org/10.1017/ [347] Corrigan PW, Shapiro JR. Measuring the impact of programs that challenge S0033291715000756 Epub 2015 May 29. the public stigma of mental illness. Clin Psychol Rev 2010;30(8):907–22. [322] Emilsson B, Gudjonsson G, Sigurdsson JF, Baldursson G, Einarsson E, [348] Mueller AK, Fuermaier ABM, Koerts J, Tucha L. Stigma in attention deficit Olafsdottir H, et al. Cognitive behaviour therapy in medication-treated hyperactivity disorder. Atten Defic Hyperact Disord 2012;4(3):101–14. adults with ADHD and persistent Symptoms: a randomized controlled trial. [349] McKeague L, Hennessy E, O’Driscoll C, Heary C. Retrospective accounts of self- BMC Psychiatry 2011;11(116). stigma experienced by young people with attention-deficit/hyperactivity [323] Young S, Bramham J. Cognitive-behavioural therapy for ADHD in adolescents disorder (ADHD) or depression. Psychiatr Rehabil J 2015;38(2):158–63. and adults: a psychological guide to practice. 2nd edition ed Chichester: John [350] Fuermaier AB, Tucha L, Mueller AK, Koerts J, Hauser J, Lange KW, et al. Wiley & Sons Ltd; 2012. Stigmatization in teachers towards adults with attention deficit hyperactivity [324] Knouse LE, Safren SA. Current status of cognitive behavioral therapy for adult disorder. Springerplus 2014;3:26. attention-deficit hyperactivity disorder. Psychiatric Clin North Am 2010;33 [351] Tatlow-Golden M, Prihodova L, Gavin B, Cullen W, McNicholas F. What do (3):497–509. general practitioners know about ADHD? Attitudes and knowledge among [325] Newark PE, Stieglitz RD. Therapy-relevant factors in adult ADHD from a cognitive first-contact gatekeepers: systematic narrative review. BMC Fam Pract behavioural perspective. Atten Defic Hyperact Disord 2010;2(2):59–72. 2016;17(1):129. [326] Torrente F, Lopez P, Alvarez Prado D, Kichic R, Cetkovich-Bakmas M, [352] Brohan E, Henderson C, Wheat K, Malcolm E, Clement S, Barley EA, et al. Lischinsky A, et al. Dysfunctional cognitions and their emotional, behavioral, Systematic review of beliefs, behaviours and influencing factors associated and functional correlates in adults with attention deficit hyperactivity with disclosure of a mental health problem in the workplace. BMC Psychiatry disorder (ADHD): is the cognitive-behavioral model valid? J Atten Disord 2012;12:11. 2014;18(5)412–24, doi:http://dx.doi.org/10.1177/1087054712443153 Epub [353] CADDRA. Canadian ADHD practice guidelines. third edition Toronto, ON: 2012 May 24. Canadian Attention Deficit Hyperactivity Disorder Resource Alliance; 2011.