Achieving Remission as a Routine Goal of Pharmacotherapy in Attention-Deficit Hyperactivity Disorder

Achieving Remission as a Routine Goalof Pharmacotherapy in Attention-DeficitHyperactivity DisorderJ. Antoni Ramos-Quiroga1,2 and Miguel Casas1,2

1 Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain

2 Department of Psychiatry and Legal Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171. The Concept of Remission in Attention-Deficit Hyperactivity Disorder (ADHD) . . . . . . . . . . . . . . . . . . . . 182. The Value of Establishing Remission Criteria in ADHD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193. Working Towards the Concept of Remission in ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

3.1 How has Remission in Children with ADHD Previously Been Defined? . . . . . . . . . . . . . . . . . . . . . . . . 193.2 Impact of Remission Definition on Outcomes: Syndromatic, Symptomatic and

Functional Remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213.3 Remission as Defined in Paediatric ADHD Studies Assessing Effectiveness of Treatments. . . . . . . . 223.4 How is Remission in Adult ADHD Defined?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.5 Clinical Studies Assessing Achievement of Remission in Adults with ADHD. . . . . . . . . . . . . . . . . . . . 27

4. Aetiology, Course and Correlates of ADHD Persistence or Remission. . . . . . . . . . . . . . . . . . . . . . . . . . . . 274.1 Associations Between Co-Morbidities and the Achievement of Remission . . . . . . . . . . . . . . . . . . . 274.2 The Influence of Genetic Components on the Course of ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

5. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.1 Current Complications in Assessing Remission in ADHD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.2 Validity of the Recently Proposed Definition of Remission in ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . 305.3 Influence of Co-Morbidities and Genetic Make-Up on the Achievement of Remission. . . . . . . . . 315.4 Effectiveness of Treatments in Achieving Remission in ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315.5 Achieving Remission in ADHD in Routine Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315.6 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Abstract Remission should be the goal of attention-deficit hyperactivity disorder(ADHD) treatment. However, there is no universally accepted definition ofremission in ADHD, although clinical studies use a number of criteria. Thisarticle examines current research into the concept of remission in ADHD byreviewing the literature for definition and achievement of remission in chil-dren and adults with ADHD. Results demonstrate that the concept of remis-sion in ADHD has been proposed by several study groups, using thresholdsof validated rating scales to indicate syndromic, symptomatic and functionalremission. Several studies have demonstrated the achievement of remission inADHD children utilizing methylphenidate delivered by an osmotic, control-led-release formulation (OROS�) and atomoxetine. However, none has defined

REVIEWARTICLECNS Drugs 2011; 25 (1): 17-36

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ª 2011 Adis Data Information BV. All rights reserved.

a time period over which these criteria must be met for an individual withADHD to be considered ‘in remission’. Standardized remission criteria in ADHDwill provide a tool for assessing the effectiveness of treatments for ADHD,and raise treatment standards.

Attention-deficit hyperactivity disorder (ADHD)is one of the most common chronic neuropsy-chiatric disorders in children and is characterizedby inattentiveness, impulsivity, disorganization andrestlessness inappropriate for age. Symptoms gen-erally begin in early childhood, are usually presentbefore 7 years of age, and persist into adolescenceor adulthood in around two-thirds of patients.[1]

Recent epidemiological studies report a world-wideADHDprevalence of 8–12% for children and1.2–7.3% for adults.[2,3] The impact of ADHD isapparent throughout the patient’s lifetime. Chil-dren with ADHD are at risk of impaired schoolperformance, emotional difficulties, poor peer re-lationships and accidents (especially bicycle andpedestrian).[4-7] In addition, they have been shownto be at a higher risk than the general populationfor a number of other psychiatric disorders, in-cluding mood disorders, conduct disorder, op-positional defiant disorder (ODD) and specificdevelopment disorders.[8] In adults, ADHD im-pairs multiple aspects of functioning, such as in-terpersonal relationships, academic performanceand occupational status.[9,10] Moreover, it increasesthe risk of motor vehicle accidents,[11] legal prob-lems[9] and co-morbid substance abuse.[12] No-tably, ADHD has also been calculated to presenta 3- or 4-fold increased risk of a substance usedisorder.[3,13] The proportion of individuals abus-ing alcohol, smoking and using recreationaldrugs is around 1.6-fold higher than in thosewithout ADHD.[14]

Stimulant medications have been evaluated ex-tensively in hundreds of empirical studies[15] andare considered a first-line treatment for ADHD.Until recently, the goal of treatment in ADHDhas been to reduce symptom burden and to im-prove functioning (i.e. to achieve a treatment‘response’). However, the term ‘response’ can en-compass a wide range of improvements, is oftennot predefined, and may not necessarily indicatethat the individual has achieved a level of func-

tioning whereby their ADHD symptoms haveonly a minimal impact upon their daily life. Assuch, the concept of ‘remission in ADHD’, asopposed to improvements in symptoms, has re-cently been introduced as the primary goal ofADHD treatment.[16] However, although work-ing definitions of remission in ADHD have beenput forward by several groups, there is currentlyno universal agreement over these.

The purpose of this review is to provide anoverview of the currently available literature fordefinitions of remission and its achievement inboth children and adults with ADHD. Relevantarticles were identified from an electronic litera-ture search of peer-reviewed English languagearticles using MEDLINE between January 2000and April 2010 and the following primary researchparameters: ‘atomoxetine’, ‘ADHD’, ‘amphet-amine’, ‘dextroamphetamine’, ‘dexamphetamine’,‘d-amphetamine’, ‘efficacy’, ‘effectiveness’, ‘methyl-phenidate’, ‘normalization’, ‘persistence’ and ‘re-mission’. No assessment of the quality of theoriginal trials was undertaken. Those studies thatspecifically assessed remission as an outcome mea-sure were identified and are presented in this review.

1. The Concept of Remission in Attention-Deficit Hyperactivity Disorder (ADHD)

The literature search identified a small numberof studies (n = 13) that have utilized ‘remission’ asan outcome measure and these will be discussed.The majority of these studies assessed the effec-tiveness of an osmotic, controlled-release deliverysystem of methylphenidate (OROS� methylpheni-date), immediate-release (IR) methylphenidate oratomoxetine in achieving remission in ADHD.However, one study examined symptom declinein ADHD using different definitions of remis-sion, whilst another examined the persistence ofADHD into adulthood. All studies reported pri-mary clinical data, including two meta-analyses

18 Ramos-Quiroga & Casas

ª 2011 Adis Data Information BV. All rights reserved. CNS Drugs 2011; 25 (1)

and a post hoc analysis. We also briefly summarizework in other psychiatric disorders, in which con-cepts of remission have previously been developedand are gainingmore acceptance, to help understandwhy a definition of remission in ADHD is war-ranted. Given that the concept of remission inADHD is relatively new and currently evolving, suchrelated terms as ‘persistence of ADHD’ and ‘nor-malization’ are also highlighted. In addition, studiesthat have investigated the potential influence of co-morbidities and geneticmake-up on the likelihood ofremission are overviewed, since these were identifiedas important contributors to the achievement of re-mission in children and adults with ADHD.

2. The Value of Establishing RemissionCriteria in ADHD

The concept of remission in psychiatry is notnew, with definitions now developed for a numberof conditions.[17] A remission definition was firstdeveloped for major depressive disorder in 1988,where it was objectively defined, not by the com-plete absence of symptoms, but rather by minimalsymptoms with mild disability.[18] To this end, re-mission in major depressive disorder was definedas the maintenance of an endpoint score £7 on theHamilton Rating Scale for Depression (HAM-D)for at least 2, but less than 6 months.[18]

Syndromal, symptomatic and functional re-mission have been described more specifically forother psychiatric disorders, such as bipolar dis-order and schizophrenia, incorporating rating scalesymptom thresholds and finite time periods.[19,20]

In bipolar disorder, syndromal remission (i.e. lossof full diagnostic status) is defined as 8 consecu-tive weeks during which a patient no longer meetsthe criteria for a manic, depressed or mixed epi-sode, as defined by the DSM-IV.[21] Symptomaticremission (i.e. loss of partial diagnostic status)is considered as the achievement of minimal or nosymptoms (Young Mania Rating Scale totalscore £5, HAM-D score £10 or Scale for the As-sessment of Positive Symptoms [SAPS] globalitem score £2) for 8 consecutive weeks. Finally,functional remission (i.e. loss of partial diagnosticstatus plus functional recovery [full recovery]) isdefined as a return to pre-morbid levels of func-

tioning for at least 8 consecutive weeks.[19] Simi-larly, in patients with schizophrenia, symptomaticremission is defined as a score of ‘mild or less’ onall pre-specified items of the Positive and NegativeSyndrome Scale, Brief Psychiatric Rating Scale,SAPS and Scale for the Assessment of NegativeSymptoms for at least 6 months.[20] However, thereremains no uniform concept around remission inpsychiatric disorders.

To date, there are no data indicating how useful astandardized definition of remission may be. How-ever, the establishment of remission of ADHDsymptoms as a working goal of therapy may offerboth children and adults a way to improve overallfunctioning, perhaps decreasing the risk of long-term consequences, such as substance abuse, per-sonal and familial distress, and self-injury due toaccidents, while increasing the likelihood of educa-tional and social re-integration. Consequently, adefinition for remission in ADHD may be poten-tially valuable from a clinical, scientific and publichealthcare perspective. Clinically, a remission defi-nition may help in the design of appropriate treat-ment strategies to hasten remission. In addition,implementation of remission criteria could provideclinicianswith a robust, well defined outcome goal inthe long-termmanagement of ADHD, enhancingcross-study comparisons of effectiveness acrosstherapeutic interventions. This, in turn, may help toraise treatment expectations and further define theremitted state itself. Scientifically, it may help inidentifying predictors of remission, which will betterguide treatment decisions and allow targeted ther-apeutic interventions. Finally, from a public healthperspective, this knowledge may help to focus med-ical resources towardsADHDchildren at higher riskfor persistent illness. However, further research isrequired to fully assess the impact of standardizedremission criteria in ADHD.

3. Working Towards the Conceptof Remission in ADHD

3.1 How has Remission in Children with ADHDPreviously Been Defined?

Previously, a response to therapy in ADHDclinical trials has usually been defined as a 15% or

The Concept of Remission in ADHD 19


30% improvement in symptom scores.[22-25] How-ever, using a percentage reduction in symptomsdoes not take into consideration the initial se-verity of the illness and, as a result, ‘responders’may include patients who continue to remain highlysymptomatic.[16] Consequently, in 2006, Steeleet al.[16] undertook an extensive review of the lit-erature in order to define more precisely the con-cept of remission in ADHD. Their conclusion wasthat ADHD remission should go beyond symp-tom relief, and should also include optimal func-tioning in emotional, behavioural, academic andsocial realms. As such, the authors proposed thatremission in ADHD should be defined as a loss ofdiagnostic status, with minimal or no symptoms(as defined using validated rating scales) and op-timal functioning, regardless of whether the patientis receiving medication. This proposed definitionof remission in ADHD appears to be a validconcept for daily clinical practice, as it focuses onboth a reduction in ADHD symptoms and animprovement in quality of life. Although manysymptom scales are available, Steele et al.[16] notedthat over the past decade the most commonlyused scales to define symptomatic remission inclinical trials were the Swanson,Nolan and PelhamScale, version IV (SNAP-IV),[26] the ADHDRating Scale, version IV (ADHD-RS-IV)[27] and theClinical Global Impression of Severity (CGI-S).[28]

The SNAP-IV is a teacher and parent ratingscale used for diagnosingADHD in children. Itemsfrom the DSM-IV criteria for ADHD are in-cluded for the two subsets of symptoms: inatten-tion (items 1–9) and hyperactivity/impulsivity (items11–19). In addition, items are also included fromthe DSM-IV criteria for ODD, since this condi-tion is often present in children with ADHD.Items have been added to summarize the inatten-tion domain and the hyperactivity/impulsivitydomain of ADHD. Two other items have beenadded: an item fromDSM-III-R[29] that was not in-cluded in the DSM-IV list for ODD, and an itemto summarize the ODD domain. The SNAP-IV isbased on a 0–3 rating scale: not at all = 0; just alittle = 1; quite a bit = 2; or very much = 3.

The original ADHD Rating Scale (ADHD-RS) is a rating scale designed for children. Eachof its questions corresponds to one of the symp-

toms in the DSM-III-R. However, in 1998, theADHD-RS-IV, which is based on the 18 symptomsin the DSM-IV, replaced the ADHD-RS. Boththe original ADHD-RS and the ADHD-RS-IVwere designed for parents or teachers to rate thefrequency of a child’s symptoms on a scale of 0–3:for the ADHD-RS, 0 =not at all, 1 = just a little,2= pretty much, or 3= very much; for the ADHD-RS-IV, 0= never or rarely, 1= sometimes, 2=often,or 3= very often. These scales have been validatedand, although designed for children, can bemodifiedby trained clinicians and administered to adults.[30]

The CGI-S is a 7-point scale that requires theclinician to rate the severity of the patient’s illnessat the time of assessment, relative to the clin-ician’s past experience with patients who have thesame diagnosis. Considering total clinical expe-rience, a patient is assessed on severity of mentalillness at the time of rating using: 1 =normal, notat all ill; 2 = borderline mentally ill; 3 =mildly ill;4 =moderately ill; 5 =markedly ill; 6 = severely ill;or 7 = extremely ill. The CGI-S can be used forboth children and adults.

In common, all of these instruments define theachievement of a behavioural cut-off score, suchthat the patient no longer fulfils DSM-IV criteriafor ADHD and the patient is ‘not at all’ or ‘min-imally’ ill. It was therefore proposed that symp-tomatic remission be operationalized as a meantotal score of £1 on most standardized ques-tionnaires. This cut-off point has been found in therange of a matched control population withoutADHD, and may be useful in clinical practice.[31]

The SNAP-IV, and potentially the Conners’ Rat-ing Scales,[32] are currently the most quantifiablerating scales used to assess remission in ADHD,as these scales cover a range of symptom domainsthat encompass the spectrum of ADHDmanifes-tations. The Conners’ Rating Scales assess ADHDin children and adolescents (aged 3–17 years), andcan measure treatment changes and outcome as-sessment purposes. The Conners’ Rating Scalesare composed of the parent rating scale, teacherrating scale and adolescent self-report scale, allof which come in a long version, taking 15–20minutes to complete, and a short version, taking5–10 minutes to complete. The use of the CGI-Sscale, which takes into account a patient’s baseline



illness severity and where severity is defined as ‘nor-mal, not at all ill’ or ‘borderline mentally ill’ mayalso be particularly appropriate for an assess-ment of remission in patients with ADHD.

In 1996, Biederman et al.[33] evaluated the pre-dictors of persistence and timing of remission ofADHD in a prospective, 4-year follow-up studyin Caucasian, non-Hispanic boys (aged 6–17 years)with (n = 140) and without (n = 120) ADHD. Inthis study, ‘persistent ADHD’ was defined as a life-time DSM-III-R diagnosis by the age of 7 years,with a chronic course of ADHD symptomatologypersisting into adulthood (i.e. at least 18 years ofage) and meeting the full diagnostic criteria forADHD in adulthood. A lifetime diagnosis ofADHD was considered to be present if the DSM-III-R criteria for ADHDwere met at baseline andagain at the 1- and 4-year follow-up assessments(i.e. at least 8 of 14 possible DSM-III-R symp-toms), or subthreshold ADHD (i.e. at least fiveDSM-III-R symptoms) with significant impair-ment (i.e. Global Assessment of Functioning[GAF] score <60).[34] Of the 128 children withADHD for whom follow-up information was avail-able, 109 (85%) met full (n= 87) or subthreshold(n= 22) criteria for ADHD, indicating that only15% had achieved remission. Of those who remitted,nine (47%) did so after the age of 12 years (lateremitters) and ten (53%) remitted by the age of12 years (early remitters). These findings thereforeconfirm and extend previous work documentingthat ADHD is a highly persistent disorder.[4,6,35]

In 1998, Biederman et al.[36] analysed data froma 4-year longitudinal study of referred childrenwith ADHD to assess normalization of func-tioning and its predictors among boys with per-sistent ADHD. These patients were assessed atbaseline and follow-up visits by using measuresfrom three domains of functioning: school, socialand emotional. School functioning was measuredby the need for in-school tutoring, placement inspecial classes or repeated grades. Emotional func-tioning during the last 6 months was evaluated byusing the Child Behaviour Checklist Total Be-haviour Problems T-score, which incorporatesboth the internalizing and externalizing clinicalsubscales.[37] Social functioning was assessed byusing the Social Adjustment Inventory for Chil-

dren and Adolescents[38] total score, calculated asthe arithmetic summation of all global rating sub-scales.[36] For each of these domains, the authorsdefined boys with ADHD as having normalizedfunctioning if they attained scores above the fifthpercentile of scores in the non-ADHD group.[36]

Using indices of emotional, educational and so-cial adjustment, it was found that 20% of childrenwith persistentADHD functioned poorly at follow-up in all three domains, 20% did well in all threedomains and 60% had intermediate outcomes. In-creased exposure to maternal psychopathology,larger family size, psychiatric co-morbidity andsymptoms of impulsivity predicted failure to nor-malize functioning among children with persis-tent ADHD.[36] These results demonstrated thatchildren with ADHD have a variable emotional,educational and social adjustment despite syn-dromatic persistence, suggesting that normaliza-tion of functioning and syndromatic persistenceof ADHD may be partially independent.[36]

3.2 Impact of Remission Definition onOutcomes: Syndromatic, Symptomaticand Functional Remission

Subsequently, the same study group analysedsymptom decline in 128 ADHD children with4-year follow-up data using three different defi-nitions of remission.[39] Using the definition ofremission in bipolar disorder as a model, they de-fined syndromatic remission as the presence offewer than eight of the 14 DSM-III-R symptomsof ADHD, symptomatic remission as the pre-sence of fewer than five of the 14 DSM-III-Rsymptoms of ADHD, regardless of impairment,and functional remission as the presence of fewerthan five of the 14 DSM-III-R symptoms ofADHD, with no functional impairment (score>60 on the GAF scale).[39] The prevalence of eachtype of remission for all ADHD symptoms andfor each symptom cluster was modelled as a func-tion of the following age categories: <6, 6-8,9-11, 12-14, 15-17 and 18-20 years. Resultsdemonstrated that age was significantly asso-ciated with a decline in total ADHD symptomsand in symptoms of hyperactivity, impulsivityand inattention (figure 1). However, the prevalence



of remission varied considerably. For example,in the oldest age group (18-20 years), the pre-valence of syndromatic remission was >60%, whilethe rate of functional remission was only 10%. Inaddition, the prevalence of remission of inatten-tiveness was lower than the rate of remission ofeither hyperactivity or impulsivity. This was mostapparent for the syndromatic and symptomaticdefinitions of remission and less so for the func-tional definition of remission (figure 1). Crucially,the proportion of patients experiencing remissionvaried considerably with the definition used (highestfor syndromatic remission, lowest for functionalremission), indicating that differences in reported

remission rates reflect the definition used ratherthan the course of the disorder.[39]

3.3 Remission as Defined in Paediatric ADHDStudies Assessing Effectiveness of Treatments

Over the past decade, a number of differentdefinitions of remission have been used to assesstreatment effectiveness in achieving remission inchildren with ADHD (table I).

In an 8-week, open-label, Canadian clinicalstudy, which evaluated the efficacy and safetyof OROS� methylphenidate taken once daily(mean daily dose 37.8mg) and IRmethylphenidate

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<6 6−8 9−11 12−14 15−17 18−200

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9−11 12−14 15−17 18−20

0

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(%

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<6 6−8 9−11 12−14 15−17 18−20

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c

a

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b

Syndromatic remissionSymptomatic remissionFunctional remission

Fig. 1. Age-specific prevalence of remission among 128 boys with attention-deficit hyperactivity disorder (ADHD).[39] Syndromatic remission:failing tomeet the full diagnostic criteria for ADHD; i.e. having fewer than 8 of 14 possible DSM-III-R symptoms. Symptomatic remission: havingfewer than the number of symptoms required for a subthreshold diagnosis (i.e. fewer than five symptoms). Functional remission: having fewer thanfive ADHD symptoms and no impairment (score on the Global Assessment of Functioning [GAF] scale >60). Each graph shows the age-specificprevalence of remission for DMS-III-R ADHD criteria (a), for inattention symptoms (b), for hyperactive symptoms (c) and for impulsive symptoms(d) [reproduced from Biederman et al.,[39] with permission from the American Journal of Psychiatry, ª 2000 American Psychiatric Association].



prescribed twice or three times daily (mean dailydose 33.2mg) in 147 children with ADHD, re-mission was defined as a score of ‘0’ or ‘1’ foreach of the 18 ADHD items of the parent-ratedSNAP-IV-18 rating scale.[40] Using this criterion,remission rates were significantly higher withOROS� methylphenidate compared with IRmethylphenidate at endpoint, defined as the lastprotocol mandate post-baseline observation car-ried forward (LOCF) [44% and 16%, respectively;p= 0.0002]. In addition, remission rates were higherin the OROS�methylphenidate group than in theIR methylphenidate group at weeks 4 (p = 0.01)and 8 (p = 0.0003) [figure 2].[40]

The MTA (Multimodal Treatment study ofADHD) in 579 children, which was a randomizedclinical trial of four treatment strategies (medica-tion treatment, behavioural therapy, a combina-tion of medication management and behaviouraltherapy, and an active control condition based onusual treatment available in the community), alsoutilized the parent- and teacher-rated SNAP-IV-18, defining low symptom severity (‘just a little’)

as the cut-off point for successful treatment (i.e.remission).[31] Overall, 68% of children receiv-ing combined behavioural and medical therapyachieved remission, compared with 56% of chil-dren receiving medical therapy alone, 34% of chil-dren receiving behavioural intervention alone and25% of children receiving community care.[31] Sim-ilarly, the Preschool ADHD Treatment study,[41]

a six-centre, randomized, controlled study, whichevaluated IR methylphenidate given three timesdaily in children aged 3–5.5 years over a total of70 weeks, used the remission definition set out inthe MTA. Using this criterion, only 21% of chil-dren receiving IR methylphenidate 2.5–7.5mgtwice daily achieved remission, compared with13% receiving placebo (p < 0.06).[41] In a post hocanalysis of data from a phase III clinical trial,teacher-rated remission using the SNAP-IV-18(defined as a mean item score £1.0) was used tocompare IR methylphenidate with dexmethyl-phenidate.[42] After 4 weeks of treatment, teachersrated 72% of children receiving dexmethylpheni-date as excellent responders or achieving full

Table I. Definitions of remission of attention-deficit hyperactivity disorder (ADHD) in children in clinical trials using specific interventions

Scale utilized Description of scale Remission criteria utilized Studies (year)

SNAP-IV-18 First 18 items on a 90-item scale assessing

inattention and hyperactivity; items are rated

from 0 =not at all, to 3= very much

Mean score £1 (not at all or just a

little)[31,40,41] or £1 on each item[42]

Steele et al.[40] (2006)

Swanson et al.[31] (2001)

Greenhill et al.[41] (2006)

Weiss et al.[42] (2004)

ADHD-RS-IV 18 items assessing inattention and

hyperactivity; items are rated from 0 =not atall, to 3 = very much

Total score £18 (never, rarely or

sometimes ill)[43]; score £9 on the

inattentive subscale;[43] ‡40%reduction from baseline in total

score[44]

Stein et al.[43] (2003)

Bangs et al.[44] (2008)

CGI-S Single-item clinician assessment of the

severity of ADHD symptoms; severity of

impairment is rated from 1 =not at all ill, to7 =maximal, profound impairment

Score £2 (not at all or minimally

ill)[22,43,45]Stein et al.[43] (2003)

Michelson et al.[22] (2002)

Hong et al.[45] (2008)

CGI-S plus RCI Patients were classified as normalized when

they achieved a significant (p <0.05) RCI,indicating reliable symptoms improvement

Score £2 or £3 on CGI-S plus

significant RCI score[43]Stein et al.[43] (2003)

CGI-ADHD-S Single-item rating based on clinician’s total

experience of ADHD patients; severity is

rated from 1 =normal, not at all ill, to

7 = among the most extremely ill subjects

Score of 1 or 2 (normal or minimally

ill)[23]Kelsey et al.[23] (2004)

K-ARS 18 items assessing DSM-IV criteria for

inattention and hyperactivity; items are rated

on a 4-point scale from 0= not at all, to3 = very frequent

Score £18 on the K-ARS (not ill or

slightly ill); for the ADHD inattentive

subtype, a score £9 on the inattentive

subscales of the K-ARS[45]

Hong et al.[45] (2008)

ADHD-RS-IV =ADHDRating Scale, version IV[27];CGI-ADHD-S =Clinical Global Impression-ADHD-Severity scale[46];CGI-S =Clinical Global

Impression of Severity scale[46]; K-ARS =Korean ADHD Rating Scale[47]; RCI =Reliable Change Index[48]; SNAP-IV-18 = first 18 items on the

Swanson, Nolan and Pelham, version IV rating scale[26].



remission compared with 51% of children receiv-ing IR methylphenidate (p = 0.046).[42]

Of note, a placebo-controlled, crossover studyby Stein et al.[43] evaluated the effects of OROS�

methylphenidate 18, 36 and 54mg/day in 47 chil-dren with ADHD, aged 5–16 years, using a num-ber of different criteria to assess remission. Inchildren with a diagnosis of ADHD combined-type, ‘normalization’ (i.e. remission) was definedas a score £18 on the ADHD-RS-IV. In thosechildren with predominantly inattentive ADHD,‘normalization’ was described as a score £9 on the

inattentive subscale of the ADHD-RS-IV. In thesame study, an excellent treatment response wasdefined as ‘no or mild impairment’, defined as ascore £2 on the CGI-S. Results are summarized intable II. Using the ADHD-RS-IV to assess remis-sion, there were no dose-related differences in theproportion of patients with predominantly in-attentive ADHDwhose scores were ‘normalized’.However, within theADHDcombined-type group,there were few placebo responders, and greaterimprovement was reported at higher doses ofOROS� methylphenidate (table II). Using theCGI-S, severity of impairment for more thantwo-thirds of patients (‡67%) in the ADHD pre-dominantly inattentive group diminished to sub-clinical levels (e.g. CGI-S £3) at 36 and 54mg/dayof OROS� methylphenidate. Within this group,43% displayed an excellent response as indicatedby ‘no or mild impairment’ (CGI-S £2) at 36mg/day, and 58% showed ‘no or mild impairment’ at54mg/day of OROS� methylphenidate. For theADHD combined-type group, CGI-S decreasedto subclinical levels for 65% of patients at 36mg/day and for 72% of subjects at 54mg/day ofOROS� methylphenidate (table II).

A further measure of treatment effectivenesswas applied to this study population by defining‘normalization’ as a clinical improvement (achieve-ment of CGI-S £2 or £3), plus a significant Reli-able Change Index score, indicating statistically

100

90

80

70

60

Rem

issi

on r

ate

(%)

50

40

30

20

10

0

33

47 44

16 1614

Week 4 Week 8 Endpoint

OROS® MPHIR MPH

Fig. 2. Percentage of children with attention-deficit hyperactivitydisorder achieving remission with osmotic, controlled-releasemethylphenidate (OROS� MPH) and immediate-release methyl-phenidate (IR MPH) as determined by a score of £1 on the first 18items on the Swanson, Nolan and Pelham Scale, version IV (SNAP-IV-18).[40]

Table II. Patients with attention-deficit hyperactivity disorder (ADHD) achieving remission as measured by a score £18 on the ADHD Rating

Scale, version IV (ADHD-RS-IV) and a score £2 or £3 on the Clinical Global Impression of Severity (CGI-S) in a placebo-controlled, crossover

study by Stein et al.[43] (reproduced with permission from Pediatrics, Vol. 112, page e404, Copyright ª 2003 by the AAP)

Treatment Remission rates, n (%)

ADHD-RS-IV £18 CGI-S £2 CGI-S £3

Combined subtype (n = 32)

Placebo 4 (14) 2 (7) 4 (14)

OROS� MPH 18mg/day 10 (32) 8 (25) 14 (44)

OROS� MPH 36mg/day 12 (40) 14 (45) 20 (65)

OROS� MPH 54mg/day 19 (66) 15 (52) 21 (72)

Inattentive subtype (n =15)

Placebo 5 (33)a 2 (14) 5 (36)

OROS� MPH 18mg/day 6 (43)a 3 (21) 9 (64)

OROS� MPH 36mg/day 9 (60)a 6 (43) 10 (71)

OROS� MPH 54mg/day 7 (50)a 7 (58) 9 (75)

a For children with inattentive subtype ADHD, remission was described as a score £9 on the inattentive subscale of the ADHD-RS-IV.

OROS� MPH = osmotic, controlled-release methylphenidate.



reliable symptom improvement. This state wasdescribed as a post-treatment level of functioningresulting in a child being rated closer to the meanof the functional (non-ADHD) population thanto the mean of the dysfunctional (ADHD) pop-ulation. For the 32 children with combined-typeADHD, the proportion of patients who met cri-teria for normalization on attention symptomsranged from more than one-third at 18mg/day ofOROS� methylphenidate to more than two-thirdsat 54mg/day ofOROS�methylphenidate (figure 3).The proportion of patients whomet criteria for nor-malization on hyperactivity symptoms increasedfrom one-quarter at 18mg/day of OROS� methyl-phenidate to two-thirds at 54mg/day of OROS�

methylphenidate (figure 3).[43]

In order to satisfy both the ‘normalization’ cri-teria and the ‘excellent response’ criteria of Steinet al.,[43] a recent 8-week, open-label, Korean studywas undertaken to identify differences in clinicalcharacteristics of remission and non-remissionpatients by evaluating the efficacy of OROS�

methylphenidate in 59 children and adolescents(aged 6–15 years) with ADHD.[45] In this study,remission was defined using both a score £18 onthe Korean ADHD Rating Scale (K-ARS) [for

the ADHD inattentive subtype, a score £9 on theinattentive subscales of K-ARS] and a score £2 onthe CGI-S as rated by a clinician.[45] After 8 weeksof treatment, 47.5% of the children fulfilled thesecriteria. The investigators found that the non-remission group had significantly higher meanCGI-S scores at baseline (p = 0.037) than those inthe remission group. However, other variables –such as the severity of parent-reported symptomsat baseline, co-morbidities or OROS� methyl-phenidate dose – were apparently not linked tothis outcome.[45]

In a recent study, the medical charts of 134children and adolescents who had been taking IRmethylphenidate for at least 1 month were re-viewed retrospectively to record their clinical his-tory up to 36 months of monthly follow-up andto evaluate predictors of long-term adherence totreatment with IR methylphenidate.[49] In thisstudy, functional remission was defined as a de-crease in the number of symptoms to fewer thanfive per clinical dimension (inattention and hy-peractivity/impulsivity, considering both parentand teacher information) and a score on the GAFscale >60 lasting for a month during school timewithout medication. After 36 months, 62 children(46%) were still receiving treatment, 32 (24%) hadstopped IR methylphenidate due to functional re-mission and 40 (30%) had suspended IR methyl-phenidate for other reasons (poor compliance, n= 20;decrease of efficacy, n= 10; adverse effects, n= 5; andentry into an atomoxetine clinical trial, n= 5).[49]

Finally, three studies have evaluated the effi-cacy of atomoxetine, a highly selective inhibitorof the noradrenaline (norepinephrine) transpor-ter, in achieving remission in children withADHD.[22,23,44] The first was a 6-week, random-ized, double-blind, placebo-controlled study in170 children and adolescents with ADHD (aged6–16 years) who received atomoxetine 1.0–1.5mg/kg/day (n = 85) or placebo (n = 85). The majorityof patients included in this study were male. Thetwo groups were similar in age and other baselinedemographic and symptom severity measures. Inthis study, remission was defined as a CGI-S scoreof 1 or 2 (no or minimal symptoms).[22] At studyendpoint, a higher percentage of children receivingatomoxetine had achieved remission comparedwith

100

Rem

issi

on r

ate

(%)

90

80

70

60

50

40

30

20

10

0

36

26

OROS® MPH18 mg/day

OROS® MPH36 mg/day

OROS® MPH54 mg/day

4842

69 66

Attention subscaleHyperactivity subscale

Fig. 3. Percentage of children with a diagnosis of attention-deficithyperactivity disorder, combined type achieving remission with var-ious daily doses of osmotic, controlled-release methylphenidate(OROS� MPH) as determined by a score of £2 or £3 on the ClinicalGlobal Impression of Severity (CGI-S) and a significant ReliableChange Index score.[43]



children receiving placebo (p= 0.003)[22] [figure 4].In a separate, randomized, double-blind, placebo-controlled study, 197 children aged 6-12 years,with a diagnosis of ADHD, received atomoxe-tine (1.2–1.8mg/kg/day) for 8 weeks.[23] The ma-jority of children were male (71%), and 68% metcriteria for the combined subtype (both inat-tentive and hyperactive/impulsive symptoms). Thecommon psychiatric co-morbidity wasODD (35%).In this study, the single-item, 7-point ClinicalGlobal Impressions-ADHD-Severity scale (CGI-ADHD-S), a measure of a clinician’s overall ex-perience with ADHD children, was used to defineremission (score of 1 or 2 [normal or minimallyill] at endpoint).[23] After 8 weeks of treatment,27% of children receiving atomoxetine and 5% ofchildren receiving placebo had achieved this cri-terion.[23] Finally, a recent meta-analysis of pooleddata from 14 randomized controlled trials eval-uated suicide-related events in children with ADHD(aged 6–17 years) receiving atomoxetine, withtreatment periods of 6–12 weeks.[44] No patientsin atomoxetine trials committed suicide, althoughthe frequency of suicidal ideation was 0.37%(5/1357) in paediatric patients taking atomox-etine versus 0% (0/851) for the placebo group. Inthis analysis, remission was defined as a ‡40%reduction from baseline in ADHD-RS-IV score,and it was estimated that five children would needto be treated with atomoxetine for one child toachieve remission.[44]

3.4 How is Remission in Adult ADHD Defined?

In contrast to most other psychiatric disorders,investigators and clinicians debate the validity ofADHD in adults. Whilst some clinicians claimthat many cases of ADHD persist into adulthoodand should, therefore, be considered a valid dis-order,[50] some assert that most cases of ADHDremit in adulthood.[51] In addition, little is knownabout predictors of persistence of childhood casesinto adulthood. Indeed, a retrospective assessment ofchildhood ADHD, childhood risk factors and ascreen for adult ADHDwere included in a sample of3197 respondents (aged 18–44 years) in the NationalComorbidity SurveyReplication in order to examinepredictors of ADHD persistence into adulthood.[52]

However, whilst childhood ADHD severity andchildhood treatment significantly predicted persis-tence, none of the other variables (sociodemogra-phics, childhood adversity, traumatic life experiencesand co-morbid child-adolescent disorders [anxiety,mood, impulse-control and substance disorders])significantly predicted persistence into adulthood,even though they were significantly associated withchildhood ADHD.[52]

It has been proposed that the remission ofADHD symptoms in adulthood may be due inpart to changes in striatal dopamine D2 receptordensity.[53] Results from a study in male and fe-male rats reported that, during puberty, striatalD2 receptor density increased by approximately140% in male rats but only by 30% in femalerats.[53] Subsequently, the number of these re-ceptors then decreased sharply by approximately55% in male rats by adulthood (‘pruning’), com-pared with little change in the female rats. Thismay account for the higher prevalence of ADHDin men, with remission occurring during aging,thus reflecting the ‘pruning’ of the D2 receptors.Conversely, it has been suggested that the per-sistence of ADHD symptoms into adulthood isrelated to the degree of D2 receptor density in-crease and a delay in ‘pruning’ of these receptornumbers in the prefrontal cortex.[53]

To date, there is no relevant literature regardingthe definition of remission of ADHD in adults.The DSM-IV-TR states that adults retaining onlysome of the symptoms of ADHD from childhood

100

Rem

issi

on r

ate

(%) 80

60

40

20

0Atomoxetine

1.0−1.5 mg/kg/dayPlacebo

28.6

9.6

Fig. 4. Percentage of children and adolescents with attention-deficit hyperactivity disorder achieving remission with atomoxetine(n= 85) or placebo (n= 85) as determined by a score of 1 or 2 on theClinical Global Impression of Severity (CGI-S).[22]



should be considered as being in ‘partial remission’and that this diagnosis ‘‘applies to individuals whono longer have the full disorder, but still retain somesymptoms that cause functional impairment.’’[34]

3.5 Clinical Studies Assessing Achievementof Remission in Adults with ADHD

To date, virtually no studies have examined theachievement of remission in adults with ADHD.Faraone et al.[1] undertook a meta-analysis ofpublished follow-up studies to examine the per-sistence of ADHD into adulthood. All studies inthe meta-analysis included a control group, and ithad to be clear from the methods of each paperwhether the diagnosis of ADHDwas made basedon using the full criteria or using modified criteriathat required some ADHD symptoms and evi-dence of residual and impairing signs of the dis-order. When ‘persistent ADHD’ was defined asthose meeting the full DSM-IV-TR criteria forADHD, the rate of persistence was low, at ap-proximately 15% at 25 years of age. However,when the DSM-IV-TR definition of ‘partial re-mission’ was utilized, the rate of persistence wasmuch higher, at approximately 65%.[1] These find-ings confirm results from other researchers, in-cluding Biederman et al.,[39] who have concludedthat the apparent prognosis of ADHD dependson the definition of persistence that is used.[39,54]

4. Aetiology, Course and Correlatesof ADHD Persistence or Remission

A number of factors relating to the course of theillness and the neurobiology and aetiology ofADHDwere identified in the literature as potential factorsthat could influence the outcome of ADHD, andthus may impact on the achievement of remission.

The course of ADHDhas been shown to changewith maturation: ADHD appears and peaksduring childhood and wanes with the transitionfrom adolescence to adulthood. In addition, al-though ADHD is more often diagnosed in malesthan females (2- to 9-fold more prevalent inmales),[55,56] females seek treatment at a higherrate than males, suggesting that sex differencesmay exist in the severity and course of the ill-

ness.[53] Neurochemical studies have highlightedthat alternations in catecholaminergic, mainly do-paminergic and noradrenergic, transmitter func-tions markedly contribute to the symptoms ofADHD,[57] whilst MRI studies have demonstrat-ed localized abnormalities in the prefrontal cortex,basal ganglia and corpus callosum of childrenwith ADHD.[57,58] Family, twin and adoption stud-ies have consistently shown that genetic factorsplay an important role in ADHD aetiology, witha mean heritability estimate of 76%.[59] A meta-analysis of candidate gene studies has confirmeda small but significant association with the D4

(DRD4) and D5 (DRD5) receptor genes.[59] Todate, seven independent genome-wide ADHD link-age scans have been published, and several chro-mosome regions (e.g. 5p13, 14q12 and 17p11) havebeen linked to ADHD in multiple studies.[60-67]

However, although significant linkage signals wereidentified in several studies, there have been lim-ited replications between the various independentdatasets. To address this, a recent study gathered theresults from all seven of the ADHD linkage scansand performed a genome scan meta-analysis toidentify the genomic region with the most con-sistent linkage evidence across the studies.[68]

Genome-wide significant linkage was identifiedon chromosome 16 between 64 and 83Mb. Inaddition, there were nine other genomic regionsfrom the genome scan meta-analysis showingnominal or suggestive evidence of linkage.[68]

Consequently, any definition of remission inADHD should consider the clinical characteristics ofADHD, the course of the disorder, the age and sex ofthe patient and the level of functional impairment, asassessed by MRI. It would therefore be logical thatpatients with a reduction in the symptoms ofADHDadjusted by age, improvements in quality of life (i.e.increased satisfaction with family, social or profes-sional life) and a decrease in neurobiological dys-function have a higher chance of achieving remission.

4.1 Associations Between Co-Morbiditiesand the Achievement of Remission

To date, two studies have investigated the poten-tial influence of co-morbidities on the likelihoodof remission of ADHD in children.[33,69] In the



4-year follow-up study in Caucasian, non-Hispanicboys (aged 6–17 years) conducted by Biedermanet al.,[33] predictors of persistence of ADHD werefamiliality of ADHD, psychosocial adversity andco-morbidity with conduct, mood and anxietydisorders. Indeed, indices of familiality and psy-chosocial adversity, as assessed by the Index ofFamily Conflict, were markedly elevated amongchildrenwith persistentADHD, intermediate amonglate remitters and low among early remitters. Pat-terns of familiality and psychosocial adversitywere indistinguishable between early remittersand controls. Likewise, persistent ADHD chil-dren and late remitters differed from early re-mitters in the higher rates of co-morbid conductdisorder, bipolar disorder and multiple anxiety dis-orders.[33] A further analysis of this study evaluatedthe nature of the association betweenmajor depres-sion and ADHDby examining predictors of persis-tence and remission of major depression in relationto issues of familiality, adversity and co-morbidityin 76 ADHD children with depression.[69] Resultsdemonstrated that ADHD children in remissionwere not significantly more likely to have remittedfrommajor depression than were persistent cases ofADHD (p= 0.1), indicating that ADHDandmajordepression have independent and distinct courses.Instead, bipolar disorder and high incidences of in-terpersonal problems were the leading predictors ofmajor depression persistence.[69]

4.2 The Influence of Genetic Componentson the Course of ADHD

Several studies have also investigated the in-fluence of genetic make-up on the likelihood ofremission of ADHD in both children and adults,although it is important to note that such data re-main provisional. Two recent studies conductedin China have suggested that there may be anunderlying genetic component influencing thelikelihood of ADHD remission.[70,71] The firststudy examined the association between adoles-cent outcome of ADHD and serotonin systemgenes, including the -1438A>G polymorphism ofthe serotonin 5-HT2A receptor gene (HTR2A)and the -759C>T polymorphism of the 5-HT2C

receptor gene (HTR2C).[70] In this study, asso-

ciations of these polymorphisms were examinedfor each of the remission categories proposed byKeck et al.[72] (syndromal remission, symptomaticremission and functional remission). Overall, the-1438A>G polymorphism was reported to be pos-itively related to remission in ADHD, especiallyfunctional remission (p = 0.029). Those childrenwith functional remission had higher frequenciesof the A allele of the -1438A>Gpolymorphism ofHTR2A.[70] However, no significant differencesin allele frequencies of the -759C>T polymor-phism of HTR2C were observed among any ofthe remitted or non-remitted patients.[70] How-ever, due to the relatively small sample size andthe potential phenotypic and aetiological hetero-geneity in ADHD, the results of this study mustbe replicated in additional samples before theycan be generalized to other populations.

The second study examined the associationbetween adolescent outcome of ADHD and se-lected polymorphisms in the monoamine oxidase(MAO) gene, including the 941T>G polymor-phism in exon 8 and the 1460C>T polymorphismin exon 14 of the MAO-A gene, and the A>Gpolymorphism in intron 13, C>T polymorphismin the 30 untranslated region and 2327T>C poly-morphism in exon 15 of the MAO-B gene.[71]

Significant positive associations were observedbetween the MAO-A gene polymorphisms andADHD remission. However, no evidence for asso-ciation was observed for any of the threeMAO-Bpolymorphisms.[71] Once again, due to the smallsample size and the possibility of phenotypic andaetiological heterogeneity of ADHD outcomesacross ethnic or geographic groups, further studiesare required to confirm these results before the as-sociations between these MAO-A polymorphismsand symptom reduction and remission can be ac-cepted generally as phenomena of clinical relevance.

To test the hypothesis that alterations in theactivity of neurotrophic factors (NTFs) might con-tribute to the genetic susceptibility to childhoodand adulthood ADHD, a separate group per-formed a population-based association study in546 ADHD patients (330 children and 216 adults)and 546 sex-matched unrelated control subjects, with183 single-nucleotide polymorphisms covering tencandidate genes that encode five neurotrophins



(nerve growth factor [NGF], brain-derived neurotro-phic factor [BDNF], NTF3 andNTF4/5), amemberof the cytokine family of NTFs (ciliary neurotrophicfactor [CNTF]) and their receptors (neurotrophictyrosine kinase receptor type 1 [NTRK1], NTRK2,NTRK3, NGFR and CNTFR).[73] Results fromthe single-marker and haplotype-based analysesdemonstrated evidence of a positive associationbetween CNTFR and both adulthood (p= 0.0077;odds ratio [OR] = 1.38) and childhood ADHD(p = 0.00091; OR = 1.40), as well as suggestinga childhood-specific contribution of NTF3(p = 0.0003; OR = 1.48) and NTRK2 (p = 0.0084;OR = 1.52) to ADHD. This led the authors toconclude that variations in NTFs might be in-volved in genetic susceptibility to ADHD, al-though further genetic analyses in other largerpopulation datasets are required to confirm theseresults and elucidate the genetic component un-derlying predisposition to ADHD.[73]

To further test the hypothesis that alterationsin serotonin neurotransmission may be involvedin genetic susceptibility to ADHD, the same groupperformed another population-based associationstudy in 451 ADHD patients (263 children and188 adults) and 400 controls with single nucleo-tide polymorphisms across 19 candidate genesthat encode serotonin receptors (5-HT1A, 5-HT1B,5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C,5-HT3A, 5-HT3B, 5-HT4, 5-HT5A, 5-HT6 and 5-HT7),the serotonin transporter (solute carrier family6, member 4 [SLC6A4]) and enzymes involvedin serotonin synthesis (tryptophan hydroxylase1 [TPH1] and dopa decarboxylase [DDC]) anddegradation (MAO-A and MAO-B).[74] Overall,results supported the positive contribution ofthe serotoninergic system in the genetic predis-position to ADHD, with several significant as-sociations reported: the DDC gene was stronglyassociated with both adulthood (p = 0.00053;OR = 2.17) and childhood ADHD (p = 0.0017;OR = 1.90), the MAO-B gene was found specifi-cally associated in the adult ADHD sample(p = 0.0029; OR = 1.90) and the HTR2A geneshowed evidence of association with only the com-bined ADHD subtype in both adults (p = 0.0036;OR= 1.63) and children (p= 0.0084; OR= 1.49).[74]However, these three genes need further evaluation

to improve the understanding of their relative im-portance in the different ADHD subtypes and agegroups.

In addition, the effect of D4 receptor polymor-phism 7-repeat allele (DRD4 7R) on response toIR methylphenidate has been studied in 45 chil-dren (aged 7–15 years) with ADHD.[75] In thisstudy, ‘normalization’ was defined as a meanConners’ Global Index-Parent assessment scorenearer to that of the non-ADHD population thanto the ADHD population. In children with theDRD4 7R polymorphism, the mean daily doseof IR methylphenidate required to achieve ‘nor-malization’ was 47mg (1.70mg/kg) comparedwith 31mg (0.79mg/kg) for those children with-out this polymorphism (p= 0.0002). Furthermore,‘normalization’ was observed at an IR methyl-phenidate dose £50mg/day in 58% of childrenwith DRD4 7R, compared with 95% withoutDRD4 7R (p = 0.002), highlighting that childrenwith ADHD possessing the DRD4 7R allele re-quire higher doses of IR methylphenidate forsymptom improvement and ‘normalization’.[75]

Another recent study examined the associa-tion between ADHD-associated genes and thecourse of ADHD.[76] Patients were derived fromidentically designed case-control family studies ofboys and girls with ADHD as well as a geneticlinkage study of families with children who hadADHD. Boys from the family study were re-assessed at 4- and 10-year follow-ups and girlsfrom the family study were reassessed at a 5-yearfollow-up, while patients from the genetic linkagestudy and parents from the family studies wereassessed only once. Patients who met full criteriafor ADHD at their first (or only) assessment, hada current diagnosis of ADHD at their last (oronly) assessment and who had genetic data wereincluded in this analysis (n = 563). The course ofADHD was compared in patients with andwithout putative risk alleles (DRD4 7R allele,DAT1 10-repeat allele and 5HTTLPR long al-lele). Survival analyses revealed that, by 25 yearsof age, 76% of patients with a DRD4 7R allelewere estimated to have significantly more persis-tent ADHD compared with 66% of patientswithout the risk allele. In contrast, there were nosignificant associations between the course of



ADHD and the DAT1 10-repeat allele and5HTTLPR long allele.[76] These findings there-fore suggest that theDRD4 7R allele is associatedwith a more persistent course of ADHD.

It has also been observed that physiologicalchanges within certain brain regions may be im-plicated in the persistence of ADHD. Resultsfrom a recent MRI study reported that adoles-cent boys (n = 10) with persistent ADHD dem-onstrated significant differences in the activity ofthe ventrolateral prefrontal cortex during specificgo/no-go tasks compared with those who met theDSM-IV-TR criteria for partial remission andhealthy controls.[77] Likewise, a longitudinal studyof 163 children with ADHD and 166 healthycontrols used MRI to examine whether regionaldifferences in cortical thickness or cortical changesacross time characterize ADHD and predict orreflect its clinical outcome.[78] In this study, pa-tients with ADHD were divided into better andworse outcome groups on the basis of a meansplit in scores on the Children’s Global Assess-ment Scale[79] and persistence/remission of DSM-IV-defined ADHD. Overall, children with ADHDhad global thinning of the cortex (mean reduction-0.09mm; p = 0.02), most prominently in the me-dial and superior prefrontal and precentral re-gions. Children with worse clinical outcome hada thinner left medial prefrontal cortex at baselinethan the better outcome group (-0.38mm; p= 0.003)and controls (0.25mm; p = 0.002). Cortical thick-ness developmental trajectories did not differsignificantly between the ADHD and controlgroups, except in the right parietal cortex, wheretrajectories converged. However, this normaliza-tion of cortical thickness occurred only in thebetter outcome group.[78]

5. Discussion

The concept of remission as the goal of treatmentin psychiatric disorders is gaining more acceptance.In particular, remission as the goal of treatment inADHD may be of particular importance, since theearly onset of this illness can cause disruption ofeducation, career and social development. However,there is currently no consensus or universal defini-

tion of remission inADHD, although clinical studieshave used a number of criteria.

5.1 Current Complications in AssessingRemission in ADHD

Defining remission as simply no longer meetingthe full diagnostic criteria for ADHD may accountfor the substantial variation in reports of diseaseprevalence in adults, as it encompasses not onlypatients with minimal residual symptoms but alsosubjects with a substantial functional impairment.Indeed, in the study by Biederman et al.,[39] in which60% of patients achieved syndromatic remission(loss of full diagnostic status), there were still a con-siderable number of ADHD symptoms present(symptomatic remission rate of 30%), and most pa-tients with ADHD continued to report low levels offunctioning despite remission of the full diagnosticcriteria (functional remission rate of only 10%).Using only a percentage reduction in symptoms doesnot take into consideration the initial severity ofthe illness and, as a result, ‘responders’ may includethose who continue to be highly symptomatic.[22,23]

Of note, it has been demonstrated that patternsof remission of ADHD are highly sensitive to thedefinition of remission used,[1,39] suggesting thatthe differences in remission reported in the litera-ture reflect the variable definitions of remissionemployed rather than the natural history of thedisorder. Indeed, it has been suggested that theinconsistent levels of persistence of ADHD intoadolescence and adulthoodobserved inmany follow-up studies may be explained by the use of dif-ferent definitions of remission across the studies.[80]

Consequently, there is a need for standardized remis-sion criteria in ADHD, which will provide a bench-mark for assessing the effectiveness of treatmentsfor ADHD. Moreover, from a patient perspec-tive, such criteria will support a more optimisticapproach regarding outcomes in ADHD.

5.2 Validity of the Recently ProposedDefinition of Remission in ADHD

The proposed definition of remission ofADHD put forward by Steele et al.[16] appears tobe valid. Indeed, a number of studies have alreadyassessed the appropriateness of the cut-off score



outlined by Steele et al.[16] (a mean total score £1on most standardized questionnaires).[31,40,41] Forexample, in the MTA,[31] remission was definedas a mean score £1 on the first 18 items of theSNAP-IV, which equates to a low symptom se-verity (‘not at all ill’ or ‘just a little ill’). Patientsachieving this score no longer met the DSM-IVcriteria for ADHD. Moreover, this standard wasachieved by 88% of comparable children withoutADHD,[31] highlighting that the remission cri-teria proposed by Steele et al.[16] appear to equateto the average optimally functioning child with-out ADHD. However, it is important to note thatthis proposed definition of remission in ADHDdoes not include aminimum continuous time periodfor which individuals must remain below a certainsymptom threshold to qualify as remitted, a factorthat should be addressed in future clinical trials.

5.3 Influence of Co-Morbidities and GeneticMake-Up on the Achievement of Remission

Recent investigations on correlates of ADHDpersistence or remission have demonstrated thatunderlying genetic components, psychosocial adver-sity and psychiatric co-morbiditiesmay influence thecourse of ADHD. The identification of such pre-dictors of persistence is of great clinical importance,since it can aid in the development of appropriatetreatment strategies to hasten remission, whilst alsohelping to identify subgroups with a higher or lowerlikelihood of persistence, which could aid in thedesign of treatment outcome studies in ADHD.Crucially, results from a recent review by Faraoneet al.[81] have suggested that, to produce consistentlyreplicated results, molecular genetic studies shouldeither usemuch larger samples or should select thosefamilies in which genes exert the largest effect.More-over, they have suggested two dimensions of geneticheterogeneity that might be useful for selectingADHDpatients formolecular genetic studies: (i) co-morbidity with conduct disorder; and (ii) persis-tence of ADHD into adulthood.[81]

5.4 Effectiveness of Treatments in AchievingRemission in ADHD

In the studies reviewed here, remission ratesreported with OROS� methylphenidate were

higher than those reported with IR methylpheni-date or atomoxetine. However, only one study(Steele et al.[40]) provided a direct comparisonbetween two agents (OROS� methylphenidateand IR methylphenidate), and this was an open-label study with its obvious limitations. In thisstudy, remission rates were significantly higherwith OROS�methylphenidate compared with IRmethylphenidate (44% and 16%, respectively;p < 0.001), which may be attributable to the factthat compliance was better with the OROS�

formulation compared with the IR formulationofmethylphenidate (mean number ofmissed doses1.9 vs 10.4; p< 0.0001).[40] Indeed, it has beensuggested that the use of IR methylphenidate,which requires dosing two to four times a day,may be a major barrier in achieving optimaloutcomes (including remission) in children withADHD. In particular, the necessity for in-schooldosing, which requires time and effort from schoolpersonnel to store and dispense a controlled drug,coupled with the stigma and embarrassmentassociated with taking medication in public atschool, is thought to be the main reason why IRmethylphenidate tends to be prescribed by phy-sicians at a twice-daily dosage even though athree-times-daily dosage has been shown to bethe most efficacious.[82,83]

Similarly, remission rates reported with theselective noradrenaline reuptake inhibitor ato-moxetine have been reported to be in the range of27–29%.[22,23] Interestingly, both the studies re-viewed here assessed the efficacy of a once-dailydosage of atomoxetine. However, the dose rangeused in these studies was based on the results of adose-response study that employed twice-dailydosing, and it is possible that a different rangewould be optimal for once-daily dosing. As such,there is a need for randomized, controlled, head-to-head studies to directly evaluate and comparethe effectiveness of these agents in achieving re-mission in ADHD.

5.5 Achieving Remission in ADHD in RoutineClinical Practice

Methylphenidate is the best-studied stimulantmedication for ADHD, with results from a



number of studies demonstrating that it signifi-cantly improves behavioural and attention-relatedsymptoms of ADHD and academic and socialfunctioning,[84-87] and at the same time reducessequelae, such as the development of psychiatricdisorders[82] and substance abuse.[88] Interest-ingly, results from a randomized, double-blindstudy in 13 medication-naive children, whichutilized MRI, concluded that methylphenidatenormalized attention differences between childrenwith ADHD and healthy age-matched controls,by both upregulation of dysfunctional fronto-striato-thalamo-cerebellar and parieto-temporalattention networks and downregulation of hy-persensitive orbitofrontal activation for rewardprocessing.[89] Atomoxetine, which has been shownto be effective in relapse prevention,[90,91] is con-sidered a second-line treatment option.

Both OROS� methylphenidate and atomox-etine can be administered once daily. In order tomaximize the chance of achieving remission inroutine clinical practice, it is important to pre-scribe agents with a once-daily dosage regimen inorder to improve patient compliance. Indeed,results from a recent chart review of 70 adultswith ADHD conducted in Spain reported thatswitching treatment from IR methylphenidateadministered three times daily to OROS�methyl-phenidate administered once daily was associatedwith an improvement in compliance, as ratedby the Simplified Medication Adherence Ques-tionnaire.[92,93] Overall, the proportions of pa-tients rated as mildly, moderately and highlynoncompliant were 37.1%, 11.4% and 4.7%, re-spectively, for those taking IR methylphenidate,and 2.9%, 0% and 0%, respectively, for thosetaking OROS� methylphenidate.[92]

It is also crucial to use adequate doses ofmedication, with results from the study by Steinet al.[43] highlighting the importance of a highdose of methylphenidate in achieving optimaloutcomes. Results from this study demonstratedthat remission rates (as assessed by a score of £18on the ADHD-RS-IV) increased with higherdoses of OROS� methylphenidate: 40–66% withOROS� methylphenidate 36 mg/day and 54mg/day versus 32% with OROS� methylphenidate18mg/day. For atomoxetine, dosages should also

be adjusted for weight (1.2mg/kg). Given thatepidemiological studies have documented highrates of learning disorders and co-morbid psy-chiatric difficulties among children and adultswith ADHD – most commonly ODD and con-duct, mood and anxiety disorders[55,94,95] – it is ofparamount importance that such co-morbid con-ditions are also treated in order to increase thelikelihood of patients achieving remission.

Although safety concerns have been raised withboth the stimulant medications[85,96-98] and atomox-etine,[99,100] research demonstrates that decreasingsymptom burden is associated with improved func-tioning and ultimately remission from symptoms.A full discussion on the safety profile of stimulantsand atomoxetine is beyond the scope of this review.However, the European Medicines Agency Com-mittee for Medicinal Products for Human Use hasconcluded that the benefits of ADHD treatment arelikely to outweigh potential risks.[101]

5.6 Future Directions

Remission should be the goal of therapy inADHD, and management of ADHD should con-sider those medication strategies with the greatestchances of achieving remission. In order to max-imize the chance of achieving remission, continuingeffective treatment is required. The little publishedevidence available suggests that current therapiessuch as OROS� methylphenidate and atomoxetinecan increase the likelihood of achieving remission inchildren with ADHD; no data are available foradults with ADHD. Future clinical studies should,therefore, be designed with a well defined primaryendpoint of remission in both adults and children,as this will help in the comparison of interventionsand raise standards of treatment.

Importantly, in the future, attempts should bemade to standardize remission criteria in ADHD,as well as defining a time period over which thesecriteria must be met for an individual withADHD to be considered as ‘in remission’.

6. Conclusions

Remission as the goal of treatment in ADHDmay be of particular importance, since the early



onset of this illness can cause disruption of edu-cation, career and social development. However,there is currently no consensus or universal defi-nition of remission in ADHD, although clinicalstudies have used a number of criteria.

There is a need for standardized remissioncriteria in ADHD, which will provide a bench-mark for assessing the effectiveness of treatmentsfor ADHD. The proposed definition of remissionof ADHD put forward by Steele et al.[16] (a meantotal score £1 on most standardized question-naires) appears to be valid.

Remission should be the goal of therapy inADHD, and management of ADHD should con-sider those medication strategies with the greatestchances of achieving remission. It is crucial to useadequate doses of medication. To maximize thechance of achieving remission in routine clinicalpractice, it is important to prescribe agents with aonce-daily dosage regimen in order to improvepatient compliance.

Acknowledgements

Drs Ramos-Quiroga and Casas would like to thankFrances Gambling, Medicus International, for her editorialassistance, which included assistance with the literature searchand proofreading of the manuscript. Editorial assistance wasfunded by Janssen-Cilag. Grants were also received from theDepartment of Health of the Government of Catalonia(Generalitat de Catalonia, Spain) and from Fundacion AlıciaKoplowitz.

Dr Ramos-Quiroga has received lecture and consultingfees from Janssen-Cilag, Laboratorios Rubio, Shire and EliLilly, and research funding from Janssen-Cilag and Labor-atorios Rubio. Dr Casas has received lecture and consultingfees from Janssen-Cilag and Laboratorios Rubio, and re-search funding from Janssen-Cilag.

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Correspondence: Dr J. Antoni Ramos-Quiroga, Departmentof Psychiatry, Hospital Universitari Vall d’Hebron, Uni-versitat Autonoma de Barcelona, Passeig Vall d’Hebronno. 119-129, 08035 Barcelona, Spain.E-mail: [email protected]



Achieving Remission as a Routine Goal of Pharmacotherapy in Attention-Deficit Hyperactivity Disorder

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