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Brain & Development 29 (2007) 413–420

Original article

Disentangling the effects of Tourette syndrome and attention deficithyperactivity disorder on cognitive and behavioral phenotypes

Renata Rizzo a,*, Paolo Curatolo b, Mariangela Gulisano a, Marina Virzı̀ a,Carla Arpino b, Mary M. Robertson a

a Section of Child Neuropsychiatry, Department of Pediatrics University of Catania, Italyb Section of Child Neuropsychiatry, Department of Neurosciences, University Tor Vergata, Rome, Italy

Received 9 June 2006; received in revised form 17 November 2006; accepted 14 December 2006

Abstract

Eighty participants (62 males; 18 females; age range: 6–16 years) took part in the study, comprising four groups of 20 subjectseach: TS-only, ADHD-only, TS + ADHD, controls. The age distributions, did not differ significantly among the four groups. Theseverity of symptoms, assessed by the TSGS, did not differ significantly between the two TS groups. Standardised measures wereused throughout. The ‘‘cases’’ (i.e. TS-only, TS + ADHD, ADHD-only) were significantly different from controls on most measuresof behavior. There were also differences amongst the various clinical subgroups, with, in general, TS-only participants being similarto controls with regards to both ‘‘total behavior’’ ratings and cognitive testing results. A diagnosis of ADHD, either or its own or inassociation with TS, was associated with greater maladaptive behavior and worse cognitive functioning. With regards to affectivesymptoms and anxiety, the three clinical groups did not differ from each other, but each of them was more affected than the controlgroup. One finding in our study which differed from previous literature was that TS-only patients were rated as more ‘‘delinquent’’than controls by their parents: possible reasons for this are discussed. Oppositional defiant disorder (ODD) was seen in a few (2,3,3ODD patients in each clinical group), but as numbers were small no statistics were undertaken. Family histories were in accord withboth TS and ADHD being genetic disorders, but sharing an overlap in only some cases. The ‘‘additive effect’’ hypothesis is discussedin detail in the light of our results and recent literature.� 2007 Elsevier B.V. All rights reserved.

Keywords: Tourette; ADHD; Comorbidity; Cognitive and behavioral phenotype

1. Introduction

Tourette’s syndrome (TS) and attention deficit hyper-activity disorder (ADHD) are common neurodevelop-mental disorders which tend to occur frequently ascomorbid conditions, often accompanied by other psy-chiatric disorders, such as obsessive compulsive disorder[1,2] and mood disorders [3]. Although recent advancesof neuroimaging, molecular genetics and neurocognitivetesting have enhanced the knowledge of brain regions,

0387-7604/$ - see front matter � 2007 Elsevier B.V. All rights reserved.

doi:10.1016/j.braindev.2006.12.003

* Corresponding author. Tel.: +39095494654; fax: +39095495673.E-mail address: rerizzo@unict.it (R. Rizzo).

neuronal circuits, and neurotransmitters involved inTS and ADHD [4–9], and favored studies on the associ-ation between specific genotypes and behavioral pheno-types, many aspects of the pathophysiology of bothdisorders remain unclear. The high rate of comorbiditysuggests a shared, but still unknown, neurobiologicalbasis, and the clinical spectrum of the two disorderstends to overlap. To date, several studies have investi-gated the behavioral, affective, and cognitive pheno-types in youngsters with TS [10–17] and/or ADHD,but the results from the studies are conflicting. In othercontrolled studies, for example [18]. Further conflictingevidence comes from a study in which no increase

414 R. Rizzo et al. / Brain & Development 29 (2007) 413–420

of depressive symptomatology was found in TSyoungsters.

The present study was conducted in order to evaluatewhether or not youngsters presenting with only onecondition, namely TS-only or ADHD-only, differfrom those with the combined disorders, TS + ADHD,with respect to behavioral, affective and neuropsycho-logical characteristics and family history. The studywas also undertaken as previous studies have producedconflicting results and few have been published fromEurope.

2. Materials and methods

2.1. Study population

The study population consisted of 60 children andadolescents (age range: 6–16 years), referred to the out-patient departments, of Child Neuropsychiatry andPediatrics Department, University of Catania, Italy,and presenting with TS, ADHD, and TS comorbid withADHD.

2.2. Study groups, assessments, and measures

TS was diagnosed according to the American Psychi-atric Association Diagnostic Criteria [19]; World HealthOrganization [20], the Tourette Syndrome Classificationstudy group criteria [21]. For the group with TS-only,scores of 10 or below on the Conner’s Abbreviated Par-ent Rating Scale (CPRS) and the Conner’s AbbreviatedTeacher Rating Scale (CTRS) were also required [22].ADHD was diagnosed according to DSM-IV criteriafor ADHD. In addition, scores on CTRS and CPRSP15 were required. Parents in all groups also completedthe Italian version of the Child Behavior Checklist 4–18(CBCL), [23]. A control group of 20 healthy participantswas recruited by general pediatricians (with similarpatient populations to family physicians in the USAand general practitioners in the UK): controls weredefined as individuals who had neither chronic diseasesnor psychiatric disorders, scores 610 on the abbreviatedCPRS and CTRS, and normal results on the CBCL.

The Italian version of The Multidimensional AnxietyScale for Children (MASC) [24] was also used to assessaffective and anxiety symptoms in all cases and controls,and the Italian version of the Wechsler Intelligence ScaleChild Version-Revised (WISC-R) [25] was used to mea-sure IQs and cognitive assessments in all participants.Furthermore, participants completed the Italian versionof the Child Depression Inventory (CDI) [26] which wasaccomplished in 56/60 cases and 17/20 controls to assessdepressive symptomatology.

The clinical assessments were performed by two expe-rienced child neuropsychiatrists (RR, PC). In the case of

any disagreements as to the diagnoses, the participantswere excluded. Information on TS, chronic tics disor-ders (CTD) and ADHD in the relatives of the probandsbelonging to the three clinical groups was obtainedthrough parents’ interviews.

Patients affected by mental retardation/learning dis-ability (DSM IV criteria), psychosis (DSM IV criteria),OCD assessed using the Children’s Yale-Brown Obses-sive Compulsive Scale [27] and Major Depressive Disor-der (MDD), (using both DSM IV criteria and ChildDepression Inventory (CDI)) scores >12 [26], wereexcluded. All participants were either drug naive orhad been drug free (with particular reference to psycho-tropics, including neuroleptics and stimulants), for atleast 4 weeks prior to the study.

The study was approved by the University Hospital’sEthics Committee (IRB). Written informed consent forthe participation at the study was obtained from thechildrens’ parents.

2.3. Statistical analysis

In order to compare the behavioral and cognitivecharacteristics among the different groups, statisticalanalysis was performed using ANOVA. To comparethe differences between each clinical group and the con-trol group, the Bonferroni correction was used. OddsRatios (OR) with 95% confidence intervals were calcu-lated to investigate the associations between clinicalgroups and a positive family history for the disordersunder investigation. Data analysis was performed usingthe PRIMER Statistical Package for Biomedical Scienc-es [28]. As the gender distribution differed between casesand controls, the analysis was repeated after the exclu-sion of the females.

3. Results

3.1. Demographic and clinical data

Eighty participants (62 males; 18 females; age range:6–16 years) were recruited into the study: 20 with TS-only (mean age: 9.6; SD + 2.51; 15 = m 5 = f), 20 withADHD-only (mean age: 9.23; SD = +2.52; 17 = m3 = f), 20 with TS + ADHD (mean age: 10.07;SD = +2.55; 18 = m 2 = f), and 20 controls (meanage: 9.10; SD = +2.45; 12 = m 8 = f). The age distribu-tion, did not differ significantly among the four groups.With regards to gender, 83.3% cases were males and16.7% females; amongst the controls, 60% were malesand 40% females. The severity of symptoms, calculatedfrom the scores of the TSGS, did not differ significantlybetween the group with TS-only compared with thegroup TS + ADHD [34.89 mean score (18.11 SD) versus40.70 mean score (14.05 SD) (p = 0.264)].

R. Rizzo et al. / Brain & Development 29 (2007) 413–420 415

3.2. Family history of CTD, TS, and ADHD

3.2.1. TS-only group

13/20 (65%) participants had at least one relative,usually the father, affected by CTD (n = 10) or TS(n = 2); in two cases there were two relatives affectedby CTD and 5 participants had both parents affected.None amongst these relatives, reported symptomscompatible with the diagnosis of ADHD duringchildhood.

3.2.2. TS + ADHD group

9/20 (45%) participants had at least one relative witha history of CTD, 3/20 (15%) had a relative affected byTS + ADHD (n = 2) and CTD + ADHD (n = 1),whereas 2/20 (10%) reported symptoms compatible withan ADHD diagnosis.

3.2.3. ADHD-only group

4 of 20 (20%) of cases had a at least one relative witha history of ADHD and 2/20 (10%) had a relative affect-ed by CTD and CTD + ADHD. None of the relativeshad a diagnosis of TS. Amongst the relatives, 6/50(12%) in the group of TS-only, 2/56 (3.6%) in the groupTS + ADHD, and none in the group ADHD-only hadOCD. The frequency of CTD in the relatives of TS-only,TS + ADHD and ADHD-only was 28%, 23%, and3.8%, respectively.

The proportion of affected relatives was higher in theTS-only and TS + ADHD groups, where 16/50 (32%)and 17/56 (30.4%) of the relatives had CTD or TS,respectively, compared to the ADHD-only group, whereonly 6/52 relatives (11.5%) were affected (the OR were3.61, 95% exact CI: 1.17–12.33 and 3.34, 95% CI:1.11–11.28); the difference was statistically significant(p = 0.027).

Table 1Child Behaviour Checklist scores in cases and controls

CBCL items TS-only TS + ADHD

Total behavior problems 63.01 (8.91) 70.57b (8.05)Internalizing problems 67.95b (3.60) 70.68b (3.02)Externalizing problems 58.33 (3.53) 63.27b (3.05)Withdrawn 57.07 (3.50) 63.83 (2.57)Somatic complaints 63.88b (2.60) 66.56b (2.60)Anxious/depressed 65.00b (3.00) 65.89b (2.80)Social problems 55.00b (2.45) 72.77b (3.54)Though problems 71.50b (2.30) 63.06 (2.75)Attention problems 63.56 (2.75) 75.19b (3.45)Delinquent behavior 65.39b (2.53) 60.39b (2.23)Aggressive behavior 55.94b (3.05) 62.88b (3.43)

TS-only, Tourette syndrome-only; ADHD-only, attention deficit hypersyndrome + attention deficit hyperactivity disorder.Mean values are shown with SD in parentheses.p values denote the significant difference between each clinical group and th

a Significant <.05.b Highly significant <.01.

3.3. Behavioral ratings (CBCL)

Patients in all three groups had higher scores com-pared to the control group with regards to overallbehavior (Table 1); however, the difference betweenthe TS-only and the control group was not statisticallysignificant. The ADHD-only and the combinedTS + ADHD groups, which were significantly differentfrom controls, obtained similar scores.

3.4. Internalizing problems (CBCL)

Patients in all three groups had significantly higherscore compared to controls, with the highest scoresbeing those of the combined TS + ADHD group. Wheneach single subgroup of disorders within the ‘‘internaliz-ing problems’’ category was taken into consideration,patients with TS-only did not differ from controls withregards to the ‘‘withdrawn’’ category, whereas all thegroups of patients significantly differed from controlswith regards to ‘‘somatic complaints’’ and ‘‘anxious/de-pressed’’ behaviour.

3.5. Externalizing problems (CBCL)

Patients with TS-only did not differ from controls,whereas those with ADHD-only and combinedTS + ADHD had significantly higher scores than con-trols, with the ADHD-only group scoring the highest.When a separate analysis for specific ‘‘externalizingproblems’’ was performed, the ADHD-only and thecombined TS + ADHD groups showed higher scoreswith regards to aggressive behaviour, whereas the TS-only and ADHD-only, but not the combinedTS + ADHD group, obtained higher scores with regardto delinquent behavior.

ADHD-only Controls p value

70.00b (5.75) 58.80 (5.66) 0.00068.35b (3.51) 60.00 (2.87) 0.00067.35b (3.55) 58.03 (2.57) 0.00058.24b (2.75) 55.50 (2.78) 0.00064.11b (2.58) 57.30 (2.10) 0.00066.00b (2.60) 61.20 (2.89) 0.00072.05b (2.55) 61.00 (2.75) 0.00063.00a (2.53) 61.07 (2.47) 0.00074.07b (3.57) 62.70 (4.01) 0.00066.47b (2.75) 60.21 (2.90) 0.00066.88b (3.73) 57.01 (3.79) 0.000

activity disorder-only; TS + ADHD, combined disorder Tourette

e control group.

Table 2Multidimensional Anxiety Scale for Children (MASC), Child Depression Inventory (CDI), and Child Behaviour Checklist (CBCL) scores in casesand controls

TS-only TS + ADHD ADHD-only Control p value

CBCL anxious and depression scales 65.00 (3.00) 65.89 (2.80) 66.00 (2.60) 61.20 (2.89) 0.000MASC 50.25a (15.05) 50.50a (13.39) 49.75a (7.75) 38.50 (5.65) 0.002CDI 11.4a (1.60) 13.71a (1.70) 12.35a (1.95) 4.75 (0.95) 0.000

TS-only, Tourette syndrome-only; ADHD-only, attention deficit hyperactivity disorder-only; TS + ADHD, combined disorder Tourettesyndrome + attention deficit hyperactivity disorder.Mean values are shown with SD in parentheses.p values denote the significant difference between each clinical group and the control group.

a Highly significant <.01.

416 R. Rizzo et al. / Brain & Development 29 (2007) 413–420

3.6. Social domains (CBCL)

Patients with TS + ADHD and those with ADHD-only obtained higher scores, whereas TS-only patientshad significantly lower scores than controls. Patientswith TS-only, compared with controls, had higher scoreswith regards to ‘‘thought problems’’: the differenceremained statistically significant when comparingTS + ADHD, and TS-only and TS + ADHD (datanot shown). When ‘‘attention problems’’ were analysed,TS-only had similar scores compared to controls,whereas ADHD-only and TS + ADHD patients hadsignificantly higher scores than controls.

3.7. Affective and anxiety symptoms

(MASC, CDI, CBCL)

Within the clinical groups, 56/60 (93%) of the chil-dren completed the MASC and the CDI. Within thecontrol group, 17/20 (85%) completed the CDI, andall 20/20 (100%) completed the MASC. With regardsto anxious/depressive symptoms, as shown by CBCLscores, all three clinical groups were more affected thanthe control group, and the TS-only group was not signif-icantly different from TS + ADHD or ADHD-only.With regards to the MASC and CDI, all three groupsof patients had significantly higher scores than controls.As far as CDI was concerned, the combinedTS + ADHD group showed significantly higher scorescompared to the TS-only group, whereas the differencewas not statistically significant compared to theADHD-only group (Table 2).

3.8. Oppositional defiant disorder (ODD),

(DSM-criteria)

In the TS-only group, 2/20 were diagnosed withODD, of whom one had a family history of tics. Inthe TS + ADHD group 3/20 had ODD and all threehad a family history of tics, one also having a family his-tory of ADHD. In the ADHD group 3/20 had ODD butnone had a relevant positive family history.

3.9. Neuropsychological findings

There were no statistically significant differences inthe WISC-R (IQ) scores when comparing the TS-onlywith the control group, whereas, the ADHD-only andTS + ADHD patients obtained significantly lowerscores than controls. In addition, TS + ADHD andADHD-only scored significantly lower than TS-onlyand controls on 4 WISC-R subscales (information,similarities, arithmetic, digit span). ADHD-only scoredsignificantly lower on two WISC-R subscales (compre-hension and picture completion), while TS + ADHDshowed significantly lower scores than the rest onblock design (see Table 3). When repeating the analysisafter having excluded females, the results did notchange (data not shown). With regards to severity ofthe symptoms, as rated by the TSGS, there were nosignificant differences between the groups with TS-onlyand the group with the combined disorders(TS + ADHD).

4. Discussion

In our study, individuals affected by TS-only,TS + ADHD or ADHD-only were different from con-trols in almost all instances, and there were also differ-ences amongst the specific clinical subgroups. Ingeneral, TS-only participants were similar to controlswith regards to both total behavior ratings and cognitiveaspects. However in our study, unlike previous studieseven our TS-only patients scored higher than controlson ‘‘delinquent behavior’’. The three clinical groupshad similar numbers of patients with ODD in them.A diagnosis of ADHD, either alone or in associationwith TS, was associated with maladaptive behaviorand worse cognitive functioning. With regards to affec-tive symptoms and anxiety, the three clinical groupsdid not differ from each other, but each of them wasmore affected than the control group. Our family historydata support the fact that both TS and ADHD aregenetically determined, and concord with most literature

Table 3WISC-R scores in cases and controls

TS-only TS + ADHD ADHD-only Controls p values

Full scale IQ (FIQ) 101.67 (5.86) 94.60a (5.35) 92.55a(5.15) 101.54 (6.03) 0.000Verbal IQ (VIQ) 102.92 (5.22) 95.40a (4.65) 92.22a (5.12) 100.04 (5.85) 0.000Performance IQ (PIQ) 100.33 (5.33) 92.40a (5.20) 92.55a (4.50) 102.32 (5.45) 0.000Information 10.42 (1.04) 8.70a (0.90) 8.33a (0.89) 10.30 (1.24) 0.000Similarities 10.67 (1.01) 9.10a (1.14) 8.44a (0.81) 10.01 (0.89) 0.000Arithmetic 10.42 (0.90) 8.44a (1.12) 8.89a (1.53) 10.55 (2.01) 0.000Vocabulary 10.58a (0.76) 10.01a (0.56) 9.44 (1.12) 9.50 (0.97) 0.000Comprehension 9.92 (1.65) 8.07 (0.80) 7.55a (1.97) 11.01 (1.02) 0.000Digit span 10.32 (1.01) 7.05a (0.75) 6.75a (0.91) 11.05 (1.25) 0.000Block design 9.50 (1.12) 8.50a (0.83) 8.67 (1.03) 9.15 (1.15) 0.013Picture arrangement 10.58 (0.98) 9.00 (0.50) 8.89 (0.55) 10.01 (2.05) 0.000Picture completion 11.25 (0.80) 10.10 (1.76) 9.33a (0.76) 10.75 (0.75) 0.000Object assembly 10.17 (2.01) 9.50 (1.75) 9.56 (1.37) 10.30 (1.05) 0.267Coding 9.42 (0.97) 7.20 (1.01) 6.89 (1.11) 9.57 (0.80) 0.000

TS-only, Tourette syndrome-only; ADHD-only, attention deficit hyperactivity disorder-only; TS + ADHD, combined disorder Tourettesyndrome + attention deficit hyperactivity disorder.Mean values are shown with SD in parentheses.p values denote the significant difference between each clinical group and the control group.

a Highly significant <0.1.

R. Rizzo et al. / Brain & Development 29 (2007) 413–420 417

that in general, the two disorders are not geneticallyrelated.

Our data differ however, to some extent, from severalcontrolled studies to date. In general, these studies haveindicated that children with TS-only did not differ fromunaffected controls, on many ratings including aggres-sion, delinquency and/or conduct problems. In contrast,children with TS + ADHD had significantly higherscores indicating difficulties with behavior and aggres-sion when compared to controls, and similar to thosewith ADHD-only, on the indices of disruptive behav-iors: studies have also shown that children withTS + ADHD had poorer social adaptation than TS-on-ly children or controls (14–17). In our study, the TS-onlygroup obtained higher scores than controls on ‘‘delin-quent behavior’’ which is in contrast to these previousfindings. This could have several possible explanations.First, we cannot exclude that this association was dueto chance, as ours is the only study to report such find-ings. Second, 2/20 of the TS-only patients had ODD andthis may well have affected parents ratings on ‘‘delin-quent behavior’’ scores. Third, the TS-only parentscould be identifying ‘‘rage’’ in the setting of TS-alone,even without other comorbidities, including ADHD.Rage has been described in TS, and while it is usuallyassociated with the comorbid disorders of OCD, ADHDand ODD [29], a study showed that rage attacks signif-icantly diminished with paroxetine [30], which to thebest of our knowledge, is not recognized in the treat-ment of ADHD nor delinquent behavior, thus suggest-ing that all rage may not be as a result of associatedADHD. A subsequent paper from the same group [31]demonstrated four sub-groups of TS children with rage,suggesting that rage in TS is both complex and heteroge-neous. Finally, stress and parenting style have been doc-

umented to be associated with behavior problems inyouth [32,33] and, in our experience, parents of TSyoungsters have greater care–care giver burden and psy-chopathology when compared to physically ill children[34] and often punish or ‘‘tell-off’’ TS youngsters specif-ically about their tics (unpublished data). This is in con-trast to the results of Sukhodolsky et al. [17] who alsostudied family functioning. They reported no significantdifferences in family functioning between TS-only,ADHD-only, and controls: the only significant differ-ences were between the TS + ADHD group andcontrols on the conflict and cohesion subscales. Never-theless, we suggest that parents of TS youngsters (evenour TS-only group with their ODD) may well be underpersonal stress, commenting on their children’s tics andmay have even punished them, which in turn could leadto worsening of the children’s behavior. Clearly morework has to be undertaken in this area, and also withregards to ODD in TS-only patients.

With regards to affective and anxiety symptoms, ourresults agree with those of Carter et al. [16] who reportedthat youngsters with ADHD-only, the combined diag-nosis TS + ADHD, and also those with TS-only, havemore depressive and anxious symptoms than controls,but disagree with Sukhodolsky et al. [17] who reportedthat TS-only were no different from controls on theCDI. Depression is common in TS, occurring in between13% and 76% of patients, and in almost all of 13 con-trolled studies TS patients were more depressed thanmatched controls [3], only one study differing [18], inwhich TS were not more depressed than controls. Thus,more research on depression in patients with TS-onlyneeds to be undertaken.

The results of our studies of cognitive functioning arein agreement with previous studies, in that TS-only

418 R. Rizzo et al. / Brain & Development 29 (2007) 413–420

obtain similar scores when compared to normal con-trols, whereas the ADHD groups, either isolated orcombined with TS, appear to be more impaired thanTS-only [10–13].

With regards to family history of TS, CTD, andADHD, our data show that youngsters affected by TS-only are more likely to have relatives with TS or CTD,but none of them had a positive family history forADHD. ADHD-only patients did not have relativeswith TS, but 10% of them had relatives affected byCTD + ADHD. A positive family history for both con-ditions was found amongst the relatives of patients withcombined disorder, TS + ADHD. These data confirmthat TS is genetically determined [35], but also suggestthat TS and ADHD may not genetically related in themajority of cases [36,37]. As expected, CTD were morecommon among relatives of patients with TS andTS + ADHD; amongst relatives of patients withADHD-only, 2/20 (10%) had a relative affected byCTD and CTD + ADHD: none of the relatives had adiagnosis of TS. This is broadly compatible the findingsof Pauls et al. [38] who found that in some, but not allcases, TS and ADD were related.

Whether tic disorders plus ADHD reflect a separateentity and not merely two-coexisting disorders, as sug-gested by [39], is still controversial: our results do nothelp the debate. There are many points to be raisedin this complex discussion. ADHD and TS have a closerelationship [40], as demonstrated by the high rate ofcomorbidity: as many as 60–80% of TS probands havecomorbid ADHD [1,2,40,41]. There have been bothsuggestions and refutations that the two disorders aregenetically related. Others have shown that there maybe two types of TS with ADHD: those in whomADHD is independent of TS and those in whomADHD is secondary to TS. Another possibility is that‘‘pure’’ ADHD and TS + ADHD are different phe-nomenologically, but the exact relationship is unclear(for review see [40]). The work of the Rothenbergergroup has examined the additive effect in detail. Theirfirst study [42] indicated no additive effect at the psy-chophysiological level, while the second [43] only par-tially supported that the additive model. The third[44] did provide evidence for additive effects at the levelof motor system excitability, while their latest support-ed the notion that TS + ADHD was indeed a separatenosological entity [45]. Thus, it would appear that theadditive model is becoming more convincing, but theresults are from one group and need to be replicatedby others. As said, our study not help this argumenteither way. However, we would point out that as TSis not a unitary condition, with ‘‘pure TS’’ being onlyone factor [46]. Our results do suggest however, thateven within patients with TS-only (i.e. ‘‘pure TS’’)there may well be behavioral difficulties and ODD:the reasons for this are unclear. In addition, in our

study CTD are present in the relatives of all threegroups: this finding could be possibly be related tothe fact that both TS and ADHD have many interact-ing neuronal-circuits and possibly genes in common,and some of these may well involve dopamine, norepi-nephrine, serotonin, and other neurotransmitter recep-tor or transporter genes [35,47–49], albeit that in TS nogenes have been both positively identified and replicat-ed. Our data suggests that ‘‘pure’’ TS (TS-only) and‘‘pure’’ ADHD (ADHD-only) differ in terms of behav-ioral and cognitive phenotypes while the combined dis-order (i.e. TS + ADHD) appears somewhat to lie inbetween the two separate disorders from a behavioralpoint of view, but appears substantially closer toADHD-only regarding behavioral and cognitive mea-sures. In contrast to previous studies [14], TS + ADHDdoes not seem to be a more severe condition thanADHD alone. We suggest that the suggestions andexplanations are not mutually exclusive and moreresearch is needed in the area as has been suggestedpreviously by us [40]. Thus, the debate remains withno clear answer at present.

4.1. Limitations of the study

There are some limitations to our study. First, caseswere recruited from a tertiary pediatric neuropsychiatryuniversity clinic, thus, our results may not be generalizedto all affected children. A further limitation is the inves-tigation is the relatively small sample size; studies withlarger samples are needed in order to confirm or refuteour results and those of others, particularly in the areaswhere we did not concord with other studies. However,in our defense, our assessments were extensive and theresults confirm the hypothesis suggested by previousstudies indicating different phenotypes in the threeconditions. Finally, with regards to the reporting ofADHD amongst relatives, we cannot rule-out the possi-bility of a recall bias, since the diagnosis was made ret-rospectively through interviews of the parents aboutthemselves when children, and not by interviewing theirown parents.

5. Conclusions

In conclusion, according to other studies, our resultsshow that ADHD is an important factor responsible ofTS patients malfunctioning. We suggest, as before [40]that ADHD, in the setting of TS, should be adequatelyassessed and appropriately treated. With regards todepression, the clinical implications are also important:TS patients, with or without comorbidity for ADHD,need to be screened and examined for this disorder. Fur-ther clinical, genetic, and neurobiological investigationsare needed in order to improve the knowledge of the

R. Rizzo et al. / Brain & Development 29 (2007) 413–420 419

complex relationship between TS and ADHD, and tobetter investigate the possibility of a specific type ofADHD peculiar to TS and different from that of pureADHD.

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