ADHD in Girls: Clinical Comparability of a Research Sample

ADHD in Girls: Clinical Comparability of a Research Sample WEN DY S. S HA R I~ M.S.W. , JAMES M. WALTER, M.A., WEN DY L. MARSH, B.A., GAIL F. RITCHIE , M.S.W., SUSAN D. HAMBURGER, M.A., M.S., AN D F. XAV IER CASTELLAN OS, M.D.

ABSTRACT Objective: The investigation of attention-deficit/hyperactivity disorder (ADHD) in girls raises complex questions of referral bias and selection criteria . The authors sought to determine whether they could recru it a research sample of comparably affected girls using a combination of sex-independent diagnosti c criteria and sex-normed cutoffs on teacher ratings . They also report on the largest placebo -controlled crossover comparison of methylphen idate and dextroamphetamine in girls with ADHD . Method: Subjects were 42 girls with DSM-III-RJDSM-IV ADHD (combined type) contrasted to 56 previously studied boys with ADHD on comorbid diagnoses , behavioral ratings , psychological measures, psychiat ric family history, and stimulant drug response . Results : Girls with ADHD were statist ically indistinguishable from comparison boys on nearly all measures. Girls exhibited robust benefic ial effects on both stimulants , with nearly all (95%) responding favorably to one or both drugs in this short-term trial. Dextroamphetamine produced significantly greater weight loss than methylphenidate. Conclusions: This highly selected group of ADHD girls was strikingly comparable with comparison boys on a wide range of measures. The results confirm that girls with ADHD do not differ from boys in response to methylphenidate and dextroamphetamine and that both stimulants should be tried when response to the first is not optimal. J. Am. Acad. Child Ado/esc. Psychiatry, 1999,38(1):40-47. Key Words: attent ion-deficit/hyperactivity disorder, sex differences, randomized clinical trials, methylphen idate, dextroamphetamine.

The lite rature on at te n tio n- d efic it/ hy peractiv ity di sorder (AD H D) in girls is scant and inconsiste n t. Alm ost all research on ADHD has focused exclusively on boys . This bias reflects male-female rati os in referred sam ples ranging from 4: 1 to 9: I (American Psychiatric Association, 199 4) and the perceived need for homogeneity in research sam p les. H owever, community-based stu dies h ave found male-fem ale sex rat ios as low as 2. 1: I Acap,," jllly.J I. I
K,"""

llt!<)O·t!';(,7 /'N!jt!O )- 0040 !$O.U )(I!O((") I')')') by th e Amc ric.m Acad emy o f Ch ild and Ado lescent l' sychi.nry.

40

(Szarrn ari, 1992; Taylor et al., 1998), confirming that girls with ADHD have been neglected by clin ician s a nd researchers (Berry er al., 1985). The discrepancy between clinic and community rates of ADHD in boy s and girls and the questions it raises were the focus of a National Inst itute of Mental Health (NIMH ) Conference on Sex Differences in ADHD (Arnold, 199Gb). The participants noted the existence of su bs tantial ev id enc e of norm ati ve sex differences th at influence the m anifestation s of ADHD , so that the issue of selecting co m parabl e sex- m atc hed su b jects for st ud y is not trivial. For exam ple, if identical criteria are used for both boys and girl s with ADHD , when the normative populations differ in symptom distribution , then the few girls who me et select io n criteria would be expected to exhibit markedly greater severity relative [0 their same-sex control s. On the other hand, using completely distinct criteria for both sexes, e.g., exceeding th e 95th percentile for th at sex on all measure s, might include girl s wh o are nor comparably impaired by their sym pto ms. When we embarked on the stu dy of ADHD in girl s in 1993, we d ecid ed to combine the 2 approach es. That

I . AM . A<:AI) . C IIIl.ll A[)OI.ESC. PS YC IlI AT R Y. .\H : l . J A N U A R Y

1~ ')~

AD HD IN GIRLS

we required that all subje cts meet full criteria for ADHD (initially DSM-III-R, later combined type DSM I V ). We also required that teachers' hyperacti vity ratin gs exceed the 95th percentile, but set distinct sex-norrned cutoffs for boys and girls. We hypothesized th at th is would allow us to recruit a sam ple of girls with ADHD of co mparable severity to th at of previously studied boys. We are now able to examine th e results of our recruitment and screening efforts as we prepare data anal yses of brain anatomy in girls with ADHD. T here has also been a paucity of randomized, con troll ed medication trials in girls with ADHD. Two small stu d ies found no differences betw een boys and girls in resp on se to meth ylphenid at e (Barkley, 1989; Pelh am et al., 198 9), but there have been no co nt rolled studies of the efficacyof dextroamphetam ine in girls. We now report o n th e largest sample of girls with ADHD to undergo a placebo-controlled crossover co mpa riso n of methylph enid ate (M PH) and dextro amphetamine (D EX). IS,

METHOD Subjects Gi rls with a history o f severe hyperactivity. im pulsivity. an d inattent iveness that int erfered with home and schoo l functioning were recruited lor co ntrolled stimu lant trials and anatom ic brain imaging from local schoo ls and healt h care provide rs be ginni ng in 19 9 3 . St ruc tu red telephon e screenings were co nd ucted by research social work er s (G .E R., W.S.S.) to d eterm ine th at sym pto ms of ADH D were present in at least 2 sett ings and that Co nners Hyperactivity lactor scores from their home teacher were at least 2 SD greater th an age and sex norms (~I.O lor girls versus ~1 . 8 lo r boys, scored from 0 to 3) (We rry et al., 1975) . Exclusion criter ia were Full Scale IQ less tha n 80 o n th e W ISC -R (Wechsler, 1974 ) and chro nic medical or neu rological diseases, includin g Tourc rre's diso rde r and ch ron ic tic disorders. Fro m app roxima tely 150 initia l inquiries, 65 su bjects declined to pa rticipate (42 after teleph on e scree ning and 23 after sub mi tt ing initial rating scales) for a variety of reason s includ ing improvement in symp to ms, parent s' d isco m fo rt wit h medica tio n. or lack of loll owth rough. We excluded 25 subjects primarily because the ir hyperactivity sym pto ms were not sufficiently severe. O the r exclus ion reasons in clu ded th e following: IQ < 80 (II = 4 ), ot he r med ical con di tions (II = 5), and med icat ion s o the r th an stim ulants that co uld not be d isco nt inue d (11 = 2). Five sub jects arc no t incl uded in th e main ana lyses hecauSl' th ey did not also enter rhc ncu roi rn .ig ing study co m po nent. Two othe r subjects were excluded afte r co mp leti ng the study. In one case, we uncove red ongoing sexual ab use th at raised que stion s abo ut the valid ity of the AD H D d iagnosis. In th e ot her, we concl uded at the co mp letio n of th e 3 -mo nt h day program th at impa irm en t was mostly ascribable to severe m ult iple learn ing d isord ers rath er tha n AD HD sym pto ms. Of the rema ini ng 4 2 girls. 67% are whi te, 19 1Yn are African -American , and 14% are Lati na. T he mos t co m mon referr al sou rces were local schools 05%) and physicia ns (24%) . Children were also referred by program alum ni (10%), the National Institutes o f Health (N IH ) listing of clinical stud-

J . A 1\1 . ACA D . CH 11.l) A l) OI. F S C. I'SY C H I AT R Y. .\H : 1 . JAN LJA RY I ')') ')

ies (10%), friends (7%), and th e advocacy organizatio n C h ild ren an d Ad ults with Arrenrio na l D isorde rs (2%) ; 2% learn ed of o ur studv from med ia repo rts. Referral sou rces were un kn own lor IlJIVO. • Besides th e 32 girls who pa rti cipated in the co ntro lled st imu lan t tr ial describ ed below, a seco nd group (11 = 10) pa rt icipated in a pilot study co m pa rin g sustai ned-release DEX , place bo . and the mixe d am phe tam ine co m po u nd , Adderall'" (u np ublished , 199 8 ). Recr u itme nt stra tegies, the locat ion of th e study, the perso nnel, curr iculu m . sched uling, and the dura tion of the stu d ies were ident ical. The 2 gro ups o f girls di d no t differ signillcan tly o n an y measu re (d atil available o n request).

Comparison Group T he 56 comparison sub jects were all the subjects included in a prior publication (C astellan os er al., 199Gb) except for one boy with chro nic motor tics. All bur o ne of th e boys had also parti cip ated in con t ro lled st im ula nt t rials in th e sam e resea rch d ay p ro gram (Castellanos et al., 1996 a; Elia ct al.. 1991 ). Seventy- th ree percent of (he boys are whi te. 2 1'Vi, are Africa n-A me rican, 4% are Latino. and 2% are Asian-A merica n.

Measures Fina l DSM-IV d iagnoses were obtai ned by a ch ild and adolescent psychi atri st co m bini ng infor matio n fro m cli n ical int er views, staff obse rvat ions, teach er rat ings, and pa rent structu red int er view with the Di agn ost ic Int er view for C h ild re n and Ado lesce nts- Pare nt Versio n (Herjan ic and Campbell, 1977 ). Psychi atri c d iagn oses of day program p rob ands' biological parents were obtai ned by u n blind ed in- pe rson inte rviews using the Schedu le lo r Afl ecrive D isord ers and Sc hizo p hr enia (Spi tze r a nd En dicott. 19 8 2 ). We ob tai ne d the Wender Utah Rat ing Scale (WU RS) (Wa rd et al., 1993) from availab le biological parents to obtain a dim ensio nal measure of childhood AD H D sym p to ms. Provisio nal categor ical classificati on of parents int o ADHD or non-ADH D gro u ps was performed by using 95 th pe rcent ile cutolfs for each sex (32 or greater for females, 40 o r greater for males) (Ward et al., 1993). Infor mation on ADHD status of sibling s was gathered via gen ogr am s by requesting that paren ts ca tego rize the ADHD statu s of all full siblings aged 7 or old er as absent, prob able, o r definite. Siblings who had been given a medi cal d iagnosis o f AD H D and were receivin g o ngo ing st im ulant treatm ent were classified as havin g defin ir« AD HD. Psych oedu cat ional evaluation co nsisted of the Wl SC-R (Wechsle r. 1974) and Woodcoc k-Jo h nson Achieve me nt Battery (Woodcock and Jo h nso n. 1977 ), perfo rmed by a psycho logist (B.B.K.). Ten of th e mos t recentl y recruited girls were assessed with the u pda ted versions (W ISC- II1, Wec hsler. 1991 ; Woodcock-Jo hnso n Revised, Woo dcoc k and Johnson, 1989). C h ild ren were classified as havin g readi ng diso rde r if th eir IQ-Readin g discre pan cy z score exceed ed 1.G5 (Frick ct al.. 1991 ). We obta ined Conners H yperactivity and Co nduct fact o rs (range 0-., ) , th e C h ild Behavior C hec klist (C BCL) , and the Teac he r's Repo rt For m (T RF) (Achenbach and Ede lb roc k, 19 83 ) from parents and from th e children's hom e teacher. Overall impairme nt was qu ant ilied using th e C hild ren's G loba l Assessme nt Scale (C-GAS) (range 0-100) (Shaffer et al.. 1983) and the Cl inica l Global Impressions scale for Severity of Illness (CG I-SI. range 1- 7) (Clinical G lobal Impressions , 198 5), Co m mission and omission errors o n th e co nti nuo us performance test (C PT ) (Rosvo ld et al., 19 56 ) we re obtained during drug-free and/o r during placebo ph ase. M ost of the boys had been ad m inistered C PT during ba sel ine and dr ug d ouble-blind pe riod s, th us

41

SHARI' ET AL.

includi ng placeb o. Becau se of a change in th e C PT test ing sched ule, baselin e-only data were available for 2 1 girls (60 %) and placebo- only data for 14 girls (40%) . For co m pa riso n boys. we randoml y selected d ata fro m baseline for 52 boys (60 %) and for th e placebo period for 21 bo ys (40%) to co ntrol for pr act ice effect s.

Controlled Trial of Methylphenidate, Dextroamphetamine, and Placebo Child ren attended o ur accredi ted N IM H school 5 days a week for 3 months w ith acad emic ins truc tion in the morning an d recreat ion therapy activities in rhe afternoon . MPH , DEX, and placeb o were packaged in ident ical capsu les by the NIH Pha rmacy an d administered by NIH nurses in doubl e-blind, randomized ord er at breakfast and lu nch 5 days pe r week (an d by pare nt s o n weekends) after a 3-week me d icatio n-free baseli ne. Ind ividu al doses were packaged in coded bl ister packs. Weekend me dicatio n co m pliance was co nfirme d by weekly teleph one co nta cts. Ind ividual drug do sages we re selected for each subject pri or to stud y entry based o n bod y weight and med icatio n h istory; all sub jects un d er went stepwis e in creases in th eir stim ulant dose each wee k. Each do uble-blind ph ase lasted 3 weeks. Convent ional doses were used in girls, w ith daily d oses of MPH ranging from 10 mg to 70 mg/day and of D EX from 5 mg to 30 mgl d ay in 2 d ivided doses. Mean stimula nt doses were 0.45, 0.85 . and 1.28 mg/k g per d ose for MPH , an d 0.23. 0.43, and 0 .64 mg/kg per dose for D EX for weeks 1,2, and 3, respectively. The co mpa rison boys had received a higher range of da ily do ses (M PH 25- 90 mg, D EX 10-4 5 mg) . whi ch had been plan ned to m in im ize stimu lant no n resp on se due to potentially inad eq uate dosing (Elia er al., 1991 ). Weekl y o u tco me measures were parent an d NIMH teach er Conners ratings of hyperactivity and conduct , and ph ysician-rated glo ba l severity (Ce l-S I, C- GA S), glo ba l im p roveme n t (C lin ical Gl obal Imp ressio ns-Gl obal Imp ro vement [CC I-G I)) (citat io ns noted abo ve), sti m ulant- rela te d ad verse effect s (G uy, 1976 ), and bod y weight. T he st lld ies were ap proved by th e NIMH In sti tu tio n al Review Board, and signed co nsent and assent were obtai ned fro m all par ents and children, resp ect ively.

Statistical Analys is An alyses we re perform ed using SAS for Wi ndo ws, versio n 6 (SAS Institute, 1996 ). O ne-way AN O VA and t tests were used to co m pa re baselin e measures includ ing socio eco no m ic status (Holli ngshea d . 1975 ) berween rhe .12 girls in th e MPH/ D EX trial and the 10 girls who to ok part in the p ilot am ph et am in e tr ial. Sin ce th ey did not differ sign ificantly on any basel ine measure, the 2 sub samples wer e co m b ine d and co mpared with p reviously stud ied bo ys. Repeatedmeasure AN O VA was used to exa mi ne drug and d ose effects. Signifi cant ANOVA resul ts we re fu rt he r expl ored wi th p repl ann ed Bonferron i t tests. For exam ple, significant dr ug by dose int eracti on s were explo red by testin g the effects of th e high est MPH dose versus the effects of the high est D EX dose. C arryo ver effects were tested by compar ing the teach ers' ratings of hyperact ivity during th e first week across the 6 different random izat ion sch ed ules using ANOVA for MPH , D EX, and placebo. Drug respo nse was defined as a rating of "very m uch " o r "m uch im p rove d " on th e C G I-G I. D ime nsi o nal me asur es o f d ru g respon se were calcu lated as the difference betwee n th e average of each sub ject's 3 weekly teach ers' hyperacriviry ratin gs during th e placeb o ph ase and ratings for th eir best week during th e med icat ion pha ses (Rappo rt et al., 1986 ). Stepwise m ultiple regression was used to deter m ine signifi cant mod erator s of d rug respo nse.

42

Becau se of extreme o utlie rs, the med ian test was used to compare girls wit h boys o n C PT commission and omissio n erro rs. C hi-sq uare (or Fishe r exac t test when app ro priate) was used to analyze psychi atric d iagnoses in subjec ts and pare nts o f subjec ts. Parents' psych iat ric di agn oses wer e gro uped int o affective (majo r depression , dysthym ia, and b ipolar disor der), anxi ety (panic disorder, generalized anxiery di sord er, obse ssive-compulsive di sorder, and phobic disorder), and subst ance ab use di so rd ers (alco ho l ab use and su bs ta nce ab use). M issin g weekl y body we igh t d ata (9 %) were calculated by interpolat ion . Other missing d ata ( I% ) were repl aced by cell means. All tests we re 2-tai led wi th a = .0 5.

RESULTS

Table 1 shows characteristics of the study subjects and th e male co m pariso n group. Female subjects and th eir male coh orts did not differ significantly on demographic or psychoeducational measures, with 4 exceptions . Girl s had significantly lower Woodcock-Johnson Reading Standard Scores than boys (p = .04). Psychoeducational scores were unavailable for 1 boy and for 2 girls who were tested elsewhere too recently to allow valid retesting. Achievement scores of 13 boys who had been given a diffe rent test were not included . C o nners teacher, but not parent, ratings of hyperactivity were significantly higher for boys than for girls (p = .002), which was not surprising, since the normative sexappropriate cutoffs we used were higher for boys (1.8 versus 1.0 for girls) (Werry er al., 1975). For the C BC L and TRF facto rs relating to int ernalizing (Withdrawn, Somatic Co mplaints, Anxiou s/Depressed, Social Problems, and Thought Problems) and externa lizing beh aviors (Atte ntion Problems, Delinquent Behaviors, and Aggressive Behaviors), parent data were available for all 42 girls and 43 boys, and teacher data for 40 girls and 38 boys. No significant differences were found for girls with ADHD and comparison boys for either inte rnalizing or externa lizing sym pto ms except that parents rated Attent ion Problems as significantly more severe for girls (p = .04 ). Globally, girls were rated as significantly more impaired (p = .000 1) on the categorical CGI-SI, but the sexes d id not differ on the continuous C-GAS measure of global fun ctioning. Comparison boys made more om ission and commission errors than girls, although these differences did not reach significance (median test , p = .19, P = .38, respectively). Comorbidity

Girl s and boys with ADHD were sim ilar in cornor-

bidiry, whether defined in gener al (AD H D plus at least on e other diagnosis) (girls 69 % , boys 7 1% ) or by indi-

J . AM . AC AIl . C H I l. D AI)( ll. ESC . PSYCH IATRY..lll : l . JANUA RY I? ??

Al>Hl> IN (; IRl.S

TABLE 1 Means and Standard De viation s of C linica l C haracterist ics of Girls and Comparison Boys Wit h ADHD Girl s With ADH D (11 =

Age (y r) Age range (y r) Age at onset (y r) SES WISC- R Full Scale IQ WISC- R Verbal IQ W ISC- R Perfo rm ance IQ Wood cock-Johnson Reading Standard Score Woodco ck-Joh nso n Math Standard Sco re

c.cxs cc isr

Teacher Conners H yperact ivity Factor C o nd uct f.1 ctor Parent Conners Hyperactivity f.lcror C o nd uct f.lCtor C h ild Behav ior C hecklist Attention Prob lems Extern alizing Behav iors" Internalizing Behavi or s" Tot al Behavior Problems Tea cher's Report Form Atte ntion Problems Extern alizing Behavior s" Int ern alizing Behavi ors " To tal Behavior Problems

C o m pariso n Boys (II = 56)

42)

tlf

P

X.') ± 1.7 6.2-1 2.7 .1,(, ± 2. I -iR .O ± 25.8 \05.2 ± 12.R 105.6 ± 14.7 104.0 ± 12.9 95 .6 ± 14.3 % .6 ± 14.5 44 .6 ± 4.8 5.0 ± 0.9

').5 ± 1.7 6.0-12.5 LX ± I.') 52A ± 26.') 10'U ± 17.7 109.7 ± 19.R 107.0 ± 15.R JO.1.H ± 16.5 102.7 ± 19.5 45.3 ± 5.') 4A ± 0.7

- 1.2 1

')(,

.25

- 1.7 1 - 0.8 1 - 1. \0 -O.')S - 0.8H -2 . 10 - \ AO -0.66 4 . 10

74 ')4 H2 S2 H2 67 67 94 H9

.0 ')

2.0 ± 0.6 0.') ± 0.7

2A±0.5 1.1 ± 0.5

- 3. 17 -1 .H5

90 63

.002' .07

2.5 IA

2A

± 0.5 I A ± 0.6

0.% - O. IH

H') H')

34 .86

72.4 ± R.2 6H.0 ± ').0 63. 7 ± 9.7 6') .9 ± 7A

2.07 \ .39 -0 .08 0.70

H3 8.1 H.1 8.1

.04 ' .17 .')4

0.14 0.74 -1.08 -0.6.1

76 76 76 76

.H,)

± ±

0.5 0.6

76.0 ± 7A 70.7 ± 8.8 6.1 .6 ± 7.8 7 1.0±7.0 70.3

±

m .7

±

61.0 6').3

±

±

H.O H.5 8. 1 (13

70.0

±

68 A

±

(,.13 70.2

± ±

').5 6.6 10.1 6.9

A2 .2H .33 3H .04 ' . 17 .5 I .0001'

A') A(, .2H .53

N ote: SES = socioeconomi c sta tus: C-GAS = Children 's (;I obal Assessment Scale; ce l-SI = Cl inical Global Impressions, Severity of Illness. " Atte nt ion Prob lems, Del inquent Behaviors, Aggressive Behaviors. t. Wi thd raw n, Somatic Co m plaint s, Anxio us/ Depressed , Social Problems, T ho ught Problems.

'p

<

.05.

vidua l analyses for all diagnoses that we re pr esen t in either group. T hose rates were oppositional defiant d isorder (girls 50%, boys 33 %, P = .09), conduct disorder (girls 2%, boys 7%), major depression (girls 7%, boys 0% , P = .08), separation anx iery (girls 2%, boys 0%), specific phobias (girls 7%, boys 0%, P = ,08), trichotillomania (girls 0% , boys 2%), tic d isorders not otherwise specified (girls 2%, boys 13% , P = . 13), enuresis (girls 12% , boys 18%) , and reading disorder (girls 8%, boys 5%). Parents' Diagnos es

There were no significant differen ces berween pare nts of day program girls and parents of comparison boys on affective disorders (30 % and 39 % , respectively), anxiery disorders (25 % and 14% , respectively, p = .08), or substance abuse d isord ers (I9 % and 16 % , respectively) . Twenty pare nts of girls (24 %) and 30 pa rents of boys (24%) did not meet criteria for any psychiatric diagn osis.

.I, AM . ACA D, CIII!.D AD()!. I'.SC . PS YC H IAT RY. ,\ H; I . .IANl lAR Y I'J'J')

Parenta l self-report of childhood ADH D symptoms, as quantified by WURS scores, did not di ffer significantly in dimensio nal analysis. Group means were 25.0 ± 18.1 and 33 .7 ± 17 .6 for father s and mothers of girls, respectively; and 29 .0 ± 15. 1 and 26 .1 ± 20.4 for fathers and mothers of boys, respectively. When we used categorical cutoffs (~40 for fathers and ~32 for moth ers), a larger proport ion of the parents of girls than of boys had scores in the AD HD clin ical range (47% versus 24%, p = .007). Th is difference was found only in mothers of girls compared wit h mothers of boys (62 % versus 3 1% , P = .008) ; th e difference between fath ers of gi rls and fat hers of boys was not significant (30 % versus 21 % , respectively), AD HD in Siblings

A significa ntly higher proportio n of full siblings (aged 7 or older) of girls with ADHD were categorized as having defi n ite or prob able ADHD com pared with siblings

43

SHAR I' ET AI..

of comparison boys (50 'Yl, versus ]6%.p = .004). regard less of whe ther th e sib ling was male o r femal e. Controlled Comparison of Methylphenidate, Dextroamphetamine, and Placebo

All subjects completed th e trial with the exception of one G-year-old for who m the placebo pha se was blindl y truncated to 2 wee ks becau se of h er seve n: ph ysi cal impul sivity, with out informing sta ff. parents, or the child. In th is case, last observations were carried forward . Remarkably, none of the 180 po ssible pairwise com parisons (4 mea sur es X 3 d rug pha ses X 15 pairs) yielded significa ntly different results o n ca rry ove r a na lysis. Individual weekl y ratin gs demonstr at ed highl y signi ficant main effects of drug (F > 58.22, P < .0( 0 1) and of dose (F > 15.06, P < .000 1) o n all measures demon st rating robust dose-related st im u la n t effects relative to placebo. Absence o f "dose-related " change on placebo was highl ighted by more moderate, alth ough still sign ificant, d rug by d ose intera cti on s fo r all 4 weekly me asur es: C C I-SI (F = 2.56, p = .04) , C- CAS (F= 6.76,p = .( 00 1), and Conners teacher and parent Hyperactivity f:lCtor (F = 9.2 1, P = .000 1; F = 4.08, P = .004 , respectivel y). Global improvement (C CI -CI) is illustrated in Figure I. Five girls (16% ) were jud ged to ha ve im pro ved substa n tially o n placebo. T wenry-r w o girls (69%) im p roved substa n tially on both MPH and D EX. N ine of the rema in ing 10 responded to on e stimu lan t hut not the other (4 to MPH, 5 to D EX). Thu s the resp on se rate to either MPH or DEX for study cornplcters was 97%. We found the same high total rate of response (37139 = 95% ) when we included all init ially enrolled subjec ts. For th e com100 90

.Female

80

oMale

70 60 50 40 30

Placebo

MPH

DEX

Either MPH or Delli

Fig. 1 I'l' ,,~ n ( a~l" ' of .\ 2 ~ i rl , .md · l ~ " ,,'" with a u cntio n-d cficit / hvpc ractivity di' ordl'r who h.HI dOllhlt.·-hlilld Cl in ic.il { ;Iohall lllprc..,\.\ion\ -( ;!oh.ll lmprovcmcn r r.lring' of "very much improved" o r "m uch improved ." l\IP. 1:.. m ct hyl plu-n id .u« : I)EX = d c-xtro.unplu-r.uuinc

44

parison boys, 69 % responded to MPH and 7 2% to D EX, with a response rate of 87% to on e or the other stim ulant . M ean ben efi cial and adve rse effects o f DEX a nd M PH were nearly identi cal for all ratings, including ratings of appetite problems. However, objectively verified significant de creases in bod y weight (d ru g main effect, F = 10.27 , P = .000 2) were signi fIca ntly great er for DEX (mean change -1.1 ± 1.0 kg from baseline, p = .01 ) than for M PH (- 0.4 ± 1.1 kg, not signi ficant). Th e o n ly sig ni fican t predi ctor o f improvement o n tea ch er ratin gs of hyper activity was baseline severity (R2 = 0.54, P < .000 1). Thirty-one o f the 32 female subjects were prescribed a stim u lant at di scharge: 47% received M PH (29 .0 mg/day ± 15.1) and 500ft) received D EX (18.1 mg/day ± 6 .2). Stim u lant medications were not recommended at d isch arge for o ne subject becau se neith er medi cation substantially improved her ADHD beh aviors beyond placebo. One chi ld who was classified as a nonrcsponder o n all 3 phases while in th e da y program exhibited moderately improved beh aviors on D EX at home and was d isch arged on D EX 7.5 mg h.i .d. O f th e co m pa riso n boys, 5 1% had been di sch arged o n MPH (4(J. 1 mg/day ± 20.9), 45 % on D EX (27 . 1 m gl day ± 8 .9), and 2 children with th e recommendation o f either stim ulant. Ten boys were in a pem oline/placebo study, a nd th eir results are nor included . DISCUSSION

In this referred and highly selected sampl e (<30 % of initi al inquiri es), girl s with DSM-IV combined type ADHD were stri kingly sim ilar to th e bo ys with ADHD we p rev iously st u di ed. O n the o t he r hand , with th e except ion o f th e C o n ners teachers' ratings of hyperactivity, whe n the re were sign ificant di fferen ces, th ey wer e in the direction o f greater severity for girls than for boys. Thus, girls had sign ifIca ntly lowe r reading sco res th an d id boys, th ou gh the prevalence of reading d isorder was low in both groups. O f the C BC L factors, th e Attention Probl em s score is the best positive predicto r o f ADHD di agnosis (H udz ia k, 1997 ). Pa rent-rat ed Atten tion Probl ems T sco res were sign ifican tly higher in the girls than in the boys, but thi s differen ce was not sup po rted by th e co m parable teach er ratings. O n ph ysician-rated globa l impa irment, girls had h igher severity than boys on on e sca le (CC I-S I) but not o n a no t he r (C-C AS). D iagn osticall y, th ere were no sign ificant d ifferences in co rnor bidi ry patterns in probands o r in th eir b iologi cal

I . Ato.t. :\ C A Il. C II I I. Il

:\ 1l (1 1.1. ~ C.

I' S YCIII ,\ T RY. .IX:!. JA N U AR Y I') ') ')

ADIID IN CIRLS

parents, although there were statistical trends toward a higher prevalence of oppositional defiant disorder, major depression, and specific phobia in girls. The overall pattern of comparable impairment in referred girls with ADHD is consistent with a recent meta-analysis (Gaub and Carlson, 1997). The tendency toward somewhat greater severity on some measures also echoes recent findings in an epidemiologically ascertained sample (Heptinstall et al., 1998). Also in support of the hypothesis that girls who are referred represent a more extreme sample than clinicreferred boys was our finding of grt:ater familiality of ADHD for parents (at least for mothers) and siblings of girls with ADHD in comparison with relatives of boys. The largest community-based twin study found that females with ADHD have a higher frequency of firstdegree relatives with ADHD than do ADHD males (Rhee et al., in press). Their analyses were consistent with a multiple threshold model for the sex differences in ADHD, with diagnosed females having a higher threshold. In clinic-referred samples, results differ. Two studies found no significant difference in familiality based on sex (Faraone ct al., 1991; Mannuzza and Gittelman, 1984), but another study reported greater familiality in families of female probands (only in farnilies with antisocial disorders) (Faraone et al., 1995). Confirmation of greater familiality in families of female probands would have substantial implications for genetic studies. However, we view our results with caution for 3 reasons. First, we did not obtain the samples contemporaneously; thus we did not control cohort effects, such as the dramatic increase in the rate of diagnosis and stimulant treatment of ADHD in the 1990s (Safer ct al., 1996). Second, parental ADHD status was determined from a single self-report checklist (WURS) rather than from structured retrospective interviews, and we did not obtain collateral documentation (such as old report cards or grandparent reports). Finally, we did not obtain blinded structured psychiatric interviews for siblings, but rather used a brief genogram interview and/or family medical history to ascertain presence or absence of ADHD. Thus, our primary conclusion is that our sample of girls demonstrated very similar patterns of comorbidity and impairment and identical patterns of drug response. Their neurobiological data should be informative when compared with and contrasted to that of our previously studied boys, particularly because brain structures of interest in ADHD, such as the caudate nucleus (Swanson

I Mvl ACAIJ CIIIIIJ AI)()IFS(', I'S,'('IIIATRY, ,IS: I. IA:"IIARY I')')')

er al., 1998), are sexually dimorphic in healthy children, with proportionately larger volumes in girls (Giedd et al., 1997). Clinical Implications: Sex Differences in ADHD

There is a popular notion that girls with ADHD have primarily attentional difficulties and a later age at onset than boys. In our samples, age at onset did not differ significantly. We also found a higher frequency of oppositional defiant disorder in our sample of girls, possibly because of selection and referral bias. The following vignettes provide a qualitative "flavor" of a representative selection of our subjects. Case 1. A was a 6-year-old who began to take MPH at age 2)4 years, when ADHD was diagnosed. Her family history is negative for ADHD. She was asked to leave a prekindergarten program because of her "disruptive behavior." Although academically on grade level, she jumped from task to task, had difficulty focusing, marked furniture with crayons, and crawled and hid under her desk. At home, she was in constant motion; she ran into the street several times without checking for cars, narrowly avoiding serious accidents. During the study, A almost lost transportation privileges because she did not stay seated on the van. Her placebo phase was shortened because of severe impulsivity that endangered her safety. At the time of discharge, A was receiving 10 mg of DEX twice a day. emf' 2. B was a 7-year-old who began to take MPH at age 6 years, when ADHD was diagnosed. Her brother and mother also had ADHD. B's teacher noted that she reacted quickly and impulsively, without thinking about consequences, and that peers did not want to sit near her because she hit or kicked them. Her parents complained that B sat only briefly and often ate dinner swinging her legs or sitting on her knees. B ran away from her parents or hit them when frustrated. During the study, B was usually able to stay in her chair but the chair and desk would gradually move across the classroom as a result of her constant fidgeting. B also had oppositional defiant disorder; at discharge she was prescribed 5 mg of MPH each morning and 2.5 mg at lunch. Case 3. C was an l l-ycar-old whose ADHD was diagnosed at age 6 years. A brief trial of MPH was discontinued because of maternal concern. C's father may have had ADHD as a child; otherwise, the family history was reported as negative. Her mother described C as stubborn, impatient, and intrusive. Her performance was

45

S IIARP ET AI..

belo w grade level in math and read ing, and she co uld not stay in her seat at school. C was suspended twice for ph ysical aggressio n. D ur ing the study, C threatened students an d o nce shoved a classma te. C deni ed respo nsibility wh en co n fro nted, and she appeared un aware of oth ers' "perso nal space." C's artwork often di spl ayed po or self-co ntro l; she o nce cov ered her pap er wi th a th ick layer of black chalk and th en pro ceeded to smear black chalk o n the bat hroom walls. C also had oppos ition al defiant disorder; at discharge she was prescribed a 15-mg D EX Span sule'" each morn ing and a 5-m g DEX tabl et afte r school. Clin ical Implicat ions: Controlled Trial of Methylphenidate and Dextroamphetamine

Previou s sma lle r stu d ies of girls with ADH D have found th at the respo nse to M PH is co m parable in bo th sexes (Barkley, 1989; Pelh am et al., 1989). In th is, th e largest co nt rolled sti m ulant tr ial in girls with AD HD , we repl icated the pr io r observation in boys th at MPH and DEX are comparably effective and that th e rate of efficacy is even higher whe n both dr ugs are co nsidered (Elia er al., 1991 ). O ur find ings were strikingly rob ust, esp ecially co nside ring th at we used lowe r doses and a more conservative definition of d rug response th an had Elia cr al. (I 99 1). It th us suppo rts the recomme nd ation th at when ever the respon se to th e first stim ulant tested is subo pti ma l, th e a1tcrn ati vc stim ulant sho uld be tr ied (Arn old , 1996a ). H owever, our result s are deri ved from a short-term trial in a str uctured research day pro gram in highl y selected subj ects, and thus th ey may not apply to samples wit h more co mor bid disord ers (Ta nnoc k et al., 199 5) o r less distinct cases of co m bi ned typ e AD H D (Spencer er al., 1996). Regarding choice of first stim ulant, M PH and DEX were ind ist ingui shable o n all measu res of efficacy and ad verse effects with o ne exceptio n. DEX produced a signifi can t mean loss in bo dy weig ht, whereas MP H did not. O ur data thus provide additi on al suppo rt (see also Efron er al., 1997a ,b ) for the usual clinical pra cti ce of beginning most stim ulant trial s with M PH . Other Limitations

As not ed above, th e prese nt sam ple and th e co mpariso n boys were not stu die d contem poraneo usly. Neverthel ess, th e co nti n uity of pro gram , s ta ff~ referral sources, and d iagn ost ic instrum ents appears to have m itigated this pot ential co nfo und. We also co m bi ne d su bjec ts

46

from 2 separate clinical trials, but we found that the 2 subsarnples were statistically ind istinguishable, and our con cl us io ns would have been un changed if we had red uced th e samp le of girls to 32 . Finally, in the inte rest of co nt in uity, we used o lde r versio ns of psych oeducation al instruments, thus necessitat ing caution in co mparin g our specific numerical values to other sam ples.

REFERENCES Arhcn bach T. Ldclbrock C ( 1 ') 8,~ ) . Millll/SM-!V), Was h ington. DC: American l'sych i.u ric Associ.n ion Arnold I.E ( 1')')6a ). Responders a nd non resp onders (Iell er ).} A lii Amrl Child Adoles.. !'> yc-!litltry .l~ : I ~ (")- I ~ 70 A rno ld l. E ( I ')') 6 h) , Sex d ifferences in ADHD: co n fe re nce su m m ary, } Abnorm Child I's ycho!2 4 : )) ~ -~6,) Bar kley RA ( 19 89 ): H yper activ e girl s and hoy" st im ulant d rug elleets u n mot her-c h ild illleract io l\s. } O Jild I'sy..ho!/'sychitilry .lO:.F ')- J 'JO Ik rr v C A. Shavwitz SE , Shavw irz BA (I ')il ~) . ( ;i;ls wi lh at ten tio n d efi cit d is;nd(,.·r: a \il~nt min ority ?' A report on beh avio ral and cognitive characterisrics. Pediatrics 76 :80 !- 80') C avtcllanos FX, Elia J. Kruesi MJ l' er al. ( I')')(,a ), Ce rebrospinal horn ovanillic acid predi cts beh avior al re' po nse to stimulants in 4~ boys wi th a tte n tio ndcficir/ hyperacriviry d isord er, Nmroryd lOl'l",rnltlco!0f.Y 14 : 12 ~ -J.\ 7 Castellano ' I:X. Ci ed d IN. M ars h WI. er al. ( 1,),)6h), Quant itati ve brain ma gnet ic resuuancc im ag ing in at rcntio n-dc ficir /h yp eracnvity d isorder. Arch (;en I'Jyt-J,i,IIr,' ~j :(,07-6 1 (, Clinical ( ;'loh ..l(mpres.siu ns ( 1 'J 8 ~) . l'~ydJOI'I",mJtI((}I B,,1/ 21 :8 j C)- 84 j Efro n D, Jarman F. Barke r M (I ')') 7a) . Mcrhylphcnidarc vers us dcxamphetami ne in chi ld ren with atte nt ion deficit hyp eracti vity d isorder: a do ublebl ind . c rossove r trial . Pediatrics JOO:E61- EC,7 Efrlln I) . J..rma n F. Bar ker M ( 1')')7 h) , Sid e ellecl s o f m et h ylphen id a te and dcx ..mphcra m inc in c h ild ren with .u tc n tio u d efi cit h yperact ivity di so rd e r: a double- blind. cro ssover tr ial. Pediatrics 100:662-('(,6 Elia J. Borc h erd ing B( ; , Rap o po rt JI.. Keysor C S (I 'J9 I ), M eth ylphenidate a nd d cxrroamphetam iue treatments o f hyperactivity: are ther e tr ue nonrespo nd e rs? Psychiatry Res ,\ 6 : 14 I-I ~ ~ brao ne SV, Bied er m an J . C he n W J. Milberger S, Wa rb u rton R. Ts ua ng MT ( I ,) ') ~ ) , Cenetic hcrcrogcn eiry in a tte nt ion deficit hypcracriviry d iso rder (A D H D ): gend er. p sychi a t ric cornorbid ity, a nd ma te rna l AD H D . }

Abuonn Psvcbo!

)()4 : .U 4 -.H~

Faraon e SV. Biederman J. Keenan K, T sua ng MT ( I'J') I) . A Ellllil y-gene tic study o f gi rls with IJSM-!II a tte nt io n deficit d isorder. Am .I I'sydJiatry 14H: 112 - 117 Frick 1'1 . Kam p hau s RW. La hey RR ct al. ( I')'J I ). Academ ic u nderach ievemcnr a nd rill' d isru pr ivc be ha vio r d iso rd er s, } Co nsu lt C!i" l'~ydJO! ~ ') :2 8')-2 ,)4

(; ..u b M . C a rlso n CI. ( It)')7) . Cender di tlc renc cs in AD H D : a m eta -a nalysi s a nd crit ical tcvi cw] A lii Ar,id CJ,i!rlAdolrs« Psvchia trv ,~6 : 1O .l6 -104~ C iedd IN, Castellanos rx . Rajapakse j c, V..ituzi; AC, Rap op o rt J I. (1997), Sexua ! d im o rp h ism of t he developin g hu m an brain . Frog NeuropsycboI'h,m ll""o! Bio! l'rythi,ltry 21 : 1 1 8 ~ -1 2 0 I C uy W ( I'n(,) . Suh jecr's Trcarme m Emergent Sym pto m Sca le. 10 : Assessment M" JJ/t,d j iJr I'syrho/,htlm hl,·o!ogy. Cuy W. cd . Was hi n gton . D C : U S ( ;OVl'rnmelll Pri nt ing Otli ce, pp .\4 7-.\ ~ O H ep rin srall E. Taylor E. So n uga- Barkc EJ. Sa nd hcrg S. Bow yer J ( 1')')8 ). Sex di ffere nces in t he ..sso ci a rio n o f h ype rac t ivi ry a n d co ndu ct d isord e r. Presen ted at Royal Co llege of Psych i..t rists, An n ua l Sc ient ific Meeting . l.o ndo n, Ja nu a ry I lc rj.m ic R. C a m pbell W ( 1')77 ), Difl e re n li'lling psych iat rical ly d ist urbed c h ild ren o n th e h..sis of a st ructu red int erv iew, I Abn orm Child Ps ychol ~ : 127- 1.\4

'

.

I A M , ACA ll , C H I l. ll A IJ U l. E S C. P S YC HI AT R Y. ,\ 8 : 1. JAN U AR Y 1')')')

A D H D I N GIR LS

H ollingshead AB (197 5). Four Factor Index ofSocial Status. New H aven. CT: Yale University De partme nt of Socio logy Hudziak JJ (1997), Ident ification of ph eno types for molecular genetic stud ies of co m mo n chi ld hoo d psychop ath ology. In: Handbook of Psychiatric Gmetics, Blum K. No ble EP,eds. Boca Raton , I'L: C RC Press. pp 20 1..· 2 17 Mannuzza S. Gi ttelma n R (1984). T he ado lescent o utco me of hyperact ive girls. f'sy.-hia try Rrs 13: 19- 29 Pelham W E Jr. Walker JL . Sturges J. Ho za J (1989). Co mparative dTens of me rhylphenida te on ADD girls and ADD boys. j Am Acad Child Adolrsc Psychiatry 28:7n -776 Rapport MD. DuPaul GJ. Ston er G. Jo nes TJ (1986), Comparing classroo m and clinic measures of atte ntio n deficit diso rde r: different ial. idiosyncrat ic. and do se-respon se effects of methylphe nidate. j CO/IJult Clin f'sycho I 54:334- 34 1 Rh ee SH . Waldman 10. Hay DA . Levy F (in press). Sex differences in genet ic and environmental influen ces o n DSM- JII-R artenrion -defi cit hyperactivity disorder (ADHD). j Abnarm Psychol Rosvold HE. Mirsky AI'. Sarason I. Bransom e ED. Beck LH (1956 ). A Lontinu ou s performance test of brain dam age. j Consult Psycho! 20:343 - 350 Safer OJ . Zi to JM. Fine EM (19%), Increased meth ylphe nid ate usag<' for m ent ion deficit d isorder in the 1990s. Pediatrics 98 : 1084-108 8 SAS Insrirure ( 1996) . SAS® Companion [or thr Microsoft \Vi1ldo/lls Environment, Ca ry. NC : SAS lnstitur e Inc Shaffer D . Go uld MS . Brasie J er al, ( 1983). A child ren's global assessment scale (CGAS). Arch Gm Psychiatry 40:1228- 1231 Spencer T, Biederma n J. Wi lens T (1996) , Respond ers and nonrespon ders (lette r). jAm Acad Child Adolesc Psychiatry 35 :1569-1570

J.

AM . ACAD . C H I L D AD O L ESC. PSY CHIAT RY,

.~ 8 : 1 ,

JA N U ARY 1999

Spitzer Rl., End icott J (1982 ). Schedule fO r Affictivr Disorders and Schizophrenia (SA DS). New Yor k: New Yor k Stare Psychiat ric Insti tut e Swanso n JM . Sergeant JA. Taylor E. Son uga- Barke EJS. Jensen PS. Ca ntwe ll DP (1998), Semi nar: m ent io n-de ficit hyperactivity d isord er and hyperkinet ic d isorder. La ncet 351 :429- 433 Szarmari P ( 1992). T he epidemiology of attention-d eficit hyperact ivity d isorder. Child Adolesc Psychiatr Gill North Am 1:36 1- 371 Tannock R. Ickowicz A. Schach ar R (1995) . Differentia l effects of meth ylph enidate o n worki ng mem or y in ADHD child ren wirh and withou t co mo rbid anxiety. j Am Acad Child AdolescP'y chiatry .H :886-896 Taylor E, Heptinstall E, Son uga-Barkc EJ, Sandberg S (1998). Sex d ifferences in the prevalence of hyperactivity. Presented at Royal Co llege of Psychiatr ists. Annual Scientifi c Meet ing, Londo n. January Ward MF, Wender PH . Reimh err FW (1993 ), The WURS: a rarin g scale to aid in the rerrospecrive diagnosis of att ent ion deficit disorder in childhood. Am j Psychiatry 150:885- 890 Wechsler 0 (1974). Manual fOr the WrclJJ!a Intelligence Scalej or ChildrenRevised. New York: Psychological Co rpo ration Wechsler 0 (199 1). Wrchsla Intelligm c« Scale [or Ch ildren-Third Edition. San Anto nio, TX : Psychological C o rpo ralion Werry JS. Sprague RL. Co hen M N (1975) . Con ners' Teache r Rat ing Scale for usc in drug studies with chi ldren: an empirical study, j Almorm C"MId Psychol3:217-229 Woodcock RW. Joh nson BB (19 77). Woodcock-johm0 1l Psychorducational Bartery. Allen. TX : DLM Teaching Resources Woodcock RW. Joh nson MB (1989). Woodcock-jo/ms01l Psvcho-Edurational Bartrry-Rruised. Allen, TX : DLM Teachi ng Resour ces .

47