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8/6/2019 Schizophr Bull 1994 Gordon 697 712

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VOL. 20, NO. 4, 1994 Childhood-OnsetSchizophrenia: An NIMHStudy in Progress69 7

by Charles T. Gordon, JeanA. Frazier, KathleenMcKenna, Jay Giedd, AlanZametkin, Theodore Zahn,Dan Hommer, Walter Hong,Debra Kaysen, Kathleen E.Albus, and Judith L.Rapoport

AbstractAn ongoing study of the phe-nomenology, genetics, neuropsy-chology, physiology (eye track-ing, autonomic responsivity),neuroimaging, biochemistry, andpharmacology of childhood-onsetschizophrenia is described, andpilot data are presented for thefirst 22 subjects. Differentiationfrom autism "spectrum" disor-ders and other poorly defined,severe neurodevelopmental disor-ders is needed. Eye tracking andautonomic results are similar topatterns seen in later-onsetschizophrenia and possibly morestriking. Magnetic resonanceimaging showed larger leftfrontal ventricular horn area forthe schizophrenia subjects, largerleft caudate, and lack of normalcaudate asymmetry. Fluoro-deoxyglucose positron emissiontomography during an auditorycontinuous performance task re-vealed decreased right parietal/occipital glucose metabolic ratein the schizophrenia subjects,which may be secondary to poorattentional performance, and in-creased glucose metabolic rate inthree left frontal regions, a leftparietal region, and the rightputamen. Clozapine has been ef-fective and well tolerated in anopen trial with 12 adolescentswho responded poorly to typicalneuroleptics; 16 subjects havebeen enrolled in a double-blindcomparison of haloperidol andclozapine. Longitudinal study ofthis narrowly defined and possi-bly more homogeneous group ofvery early-onset schizophreniasubjects will be relevant to cur-rent neurodevelopmental theoriesaddressing the role of puberty,progression of pathology, andcontinuity or discontinuity with

later-onset schizophrenia.Schizophrenia Bulletin, 20(4):697-712, 1994.Schizophrenia, as defined in DSM-III (American Psychiatric Associa-tion 1980) has been described inchildren as young as 5 years(Green et al. 1984, 1992). How-ever, little systematic research hasfocused on childhood-onset schizo-phrenia. The major impediment isnot so much the rarity of the dis-order thought to be one-fiftieththe prevalence of the adult disor-der (Beitchman 1985)as sampleheterogeneity. Previous broad orunspecified criteria for "childhoodschizophrenia" grouped togethersubjects with autism, schizophre-nia, organic mental disorders, bor-derline disorders, and probablymajor affective disorders (Priorand Werry 1986).

Schizophrenia in adults is almostcertainly a heterogeneous disorder,with both genetic and environ-mental factors playing etiologicroles. Variability in age at onsethas been noted since the earliestdescriptions of the illness (Bleuler1911/1950; Kraepelin 1919/1921),but nothing is known about thecause of this variability. Further,no data confirm or refute etiologiccontinuity of childhood-onset andlater-onset schizophrenia.The National Institute of MentalHealth (NIMH) study of childhood-onset schizophrenia addresses thebiological correlates of early onsetand the question of continuitywith later-onset disorder. If thereis etiological continuity, then sys-Reprint requests should be sent toDr. J.A. Frazier, Child PsychiatryBranch, National Institute of MentalHealth, Bldg. 10, Rm. 6N240, 9000Rockville Pike, Bethesda, MD 20892.


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698 SCHIZOPHRENIA BULLETIN

tematic study of the childhood-onset subgroup may reveal moremarked and consistent findingsthan adult studies, since earlieronset might result from a "heav-ier" genetic load or a more potentenvironmental insult. Increased fa-miliality is observed in early-onsetcases of a variety of diseases ofmultifactorial origin (Childs andScriver 1986) and also has beenobserved in males who have schiz-ophrenia with onset of psychosisbefore age 17 (Pulver et al. 1990).If childhood-onset cases have aneven higher rate of familiality thanthose with adolescent onset, ge-netic studies should be particularlyrevealing in the childhood-onsetgroup. Alternatively, earlier onsetof illness may reflect a more sa-lient environmental insult (e.g., in-trauterine viral infection), prema-ture endocrine influence on braindevelopment, fewer protective fac-tors, or greater psychosocial stress.In general, genetic and environ-mental insults would likely resultin more consistent neurobiologicalfindings in a childhood-onsetgroup for whom there is less con-founding by institutionalization,chronic neuroleptic treatment, anddrug and alcohol abuse whencompared with adult patients.

Since Kolvin's work in the early1970s (Kolvin et al. 1971), autismand childhood-onset schizophreniahave generally been consideredseparate disorders. However, con-troversy continues over possibleoverlap, with reports of a highfrequency of autistic symptoms inchildhood-onset schizophrenia(Watkins et al. 1988), negativesymptoms of schizophrenia in bothdisorders (Rumsey et al. 1985b,1986) and, albeit rarely, childrenwith autism diagnosed with schiz-ophrenia as adults (Petty et al.1984). Schizophrenia patients with

pathophysiology similar to subjectswith autism would presumably beoverrepresented in cases withchildhood onset, and neurobiolog-ical comparisons of such subjectswith subjects who have autismwould be enlightening.This article reports pilot datafrom an NIMH study of childhood-onset schizophrenia examiningphenomenology, neurobiology, anddrug treatment. Data are presented

for phenomenology, family historyand chromosome analyses, smoothpursuit eye movements, autonomicphysiology, magnetic resonanceimaging (MRI), positron emissiontomography (PET), and responseto typical (haloperidol) and atypi-cal neuroleprics. Although prelimi-nary, these are some of the firstneurobiological and pharmacologi-cal data available for well-diag-nosed childhood-onset schizophre-nia subjects.PhenomenologyThe few studies that have exam-ined the phenomenology of child-hood-onset schizophrenia by DSM-111 criteria (Green et al. 1984, 1992;Russell et al. 1989) indicate thatsymptomatology and other diag-nostic features are similar enoughto those in adults that there isno justification for separate diag-nostic criteria. Thus, in DSM-III-R(American Psychiatric Association1987), identical criteria were usedfor diagnosis, no matter what theage at onset, and this practice con-tinues in DSM-IV (American Psy-chiatric Association 1994).

Childhood-onset schizophreniamu st be differentiated from anarray of severe child psychiatricdisorders with overlapping symp-tomatology. Social impairments,oddities of verbal and nonverbalcommunication, unusual perceptual

experiences, and peculiar fantasiesare characteristic of children withmild autism (Rumsey et al. 1986),Asperger's syndrome, and schizoid/schizotypal personality disorders inchildhood (Kay and Kolvin 1987;Szarmari et al. 1989; McKenna etal. 1994a, 1994b). Also included inthe differential diagnosis of psy-chosis in childhood are affectivedisorders with psychotic features(Chambers et al. 1982), multiplepersonality disorder (Malenbaumand Russell 1987), and severeobsessive-compulsive disorder(Hermesh et al. 1989). In addition,it is our experience that develop-mental expressive language disor-der is sometimes misdiagnosed asthought disorder and interpretedas a psychotic symptom.

Over the past 5 years NIMH,through the American Academy ofChild and Adolescent Psychiatryand the National Alliance for theMentally 111, has nation ally re-cruited 6- to 18-year-old subjectsmeeting DSM-HI-R criteria forschizophrenia with onset of psy-chosis before age 12. As of June1994, medical records had been re-viewed for more than 350 patients,and 98 patients and their parentshad been screened in person. Pa-tients were chosen for in-personscreening if they met the abovecriteria, had an IQ above 70, andhad no medical or neurologicalproblems apparent from medicalrecords and telephone interviewswith parents and treating physi-cians. Travel and lodging expenseswere paid by NIMH for thosewho could not afford them.

Consensus best-estimate primarydiagnosis of the patients seen inperson was made by two childpsychiatrists on the basis of medi-cal records, information from refer-ring physician, and unstructuredand structured interviews of the


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VOL. 20, NO. 4, 1994 6 9 9

child alone and parents alone. Thestructured interview consisted ofportions of the Schedule for Affec-tive Disorders and Schizophreniafor School-Age Children-Epidemio-logic Version (Orvaschell and Puig-Antich 1987; Ambrosini et al. 1989)and the Diagnostic Interview forChildren and Adolescents-Revised(Herjanic and Campbell 1977;Welner et al. 1987). The interviewcovered all major areas of psycho-pathology in childhood andadolescence.

Table 1 shows the consensusbest-estimate primary diagnoses ofthe first 98 patients screened forthe study. Using a narrow defini-tion of schizophrenia in an effortto increase diagnostic homogeneity,we diagnosed 28 of these 98 pa-tients with schizophrenia. Mostdisorders were anticipated, withthe exception of a group of 21patients who at first glance metDSM-HI-R criteria for schizophre-nia and whom other investigatorsmight have so diagnosed. But thisgroup of patients had a clinical

pres entatio n that differed fromschizophrenia in affective and so-cial impairments as well as thefrequency and type of psychoticsymptoms. No DSM-II1-R diag-nosis adequately describes thisgroup of patients, and we havecalled them "multidimensionallyimpaired" (MDI). This diagnosisindicates that these children havemultiple impairments in manyareas of cognitive functioning butthey differ from children with per-vasive developmental disorders intheir play interests and in theiraffective, social, and motor im-pairments (McKenna et al. 1994a,1994b). The DSM-IV definition ofborderline personality disordercomes closest to describing thisgroup (American Psychiatric Asso-ciation 1994).

MDI children from an early ageexhibit marked affective instabilityand recurrent inappropriate out-bursts of aggression or rage. Theirrelationships with adults are im-mature, overdependent, or clingy,and with peers they exhibit mark-

Table 1. Best estimate primary diagnosis of first 98 subjectsscreened for childhood-onset schizophrenia study (as ofAugust 1994)Diagnosis nSchizophrenia 28Multidimens ionally impaired 21Bipolar disorder 11Major depress ion 8Asperger's syndrome/pervasive developmental disorder NOS 7Schizotypa l person ality disorder 4Attention-deficit hypera ctivity disorder/co nduct disorder/opp ositional 7defiant disorderDissociative disorder, NOS /PTSD 4Obsessive compulsive disorder 2Schizoaffective disorder 2Organic psychosis 3Tourette's syndrome 1Note.NOS = not otherwise specif ied; PTSO = posttraumatic stress disorder.

edly impaired social judgment,which often results in their beingteased or scapegoated. They verymuch desire social contact but areinept. Their thinking is immature,and fantasy and reality may ap-pear to mergethey live in a"cartoon world." Suspiciousnessand ideas of reference are com-mon, but firmly held, systematized,or bizarre false beliefs are absent.Perceptual aberrationssuch as ex-cessive hypnogogic and hypno-pompic hallucinations, illusions, orfleeting hallucinations with stressare common, but there are no per-sistent hallucinations in the ab-sence of severe, acute stress. Thereis no formal thought disorder asin schizophrenia, but developmen-tal language disorders are commonand may result in speech that ap-pears "disjointed," particularlywhen the patient is anxious. Spe-cific developmental disorders andattention deficit hyperactivity dis-order are nearly always comorbid.Symptoms are severe and usuallydate to the preschool years; firstcontact with mental health pro-fessionals is usually at age 6 orearlier and hospitalization usuallyoccurs by age 8. The MDI grouphas been reliably diagnosed usingempirically derived criteria (kappaof 0.81 with two child psychiatristsindependently diagnosing 53 psy-chotic patients) and will serve asan important contrast group forthe childhood-onset schizophreniasubjects in neurobiological studies.Clinical characteristics of the 22schizophrenia subjects (14 male, 8female) enrolled as of July 1994(from 98 patients screened in per-son) are shown in table 2. Of thechildren screened, those given thediagnosis of schizophrenia rangedin age from 10 to 18. At the timeof the study, only one subject wasprepubertal, and retrospective as-


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Ta ble 2. Clin ical charac teristics of sub jects in NIMHchildhood-onset schizophrenia study (n = 22)Measure Mean (SD) RangeSex:Female: 8Male: 14Type:Subacute: 8Insidious: 14Age (yrs) seen at NIHAge (yrs) at onset of psychosisNeuroleptic exposure (mo)Hospitalization (mo)

14.410.422.07.8

(2.0)(1.3)(15.2)(10.2)

10-187-122-540-37

Note.NIMH = National Institute of Mental H ealth; NIH = National Institutes of Health; SD =standard deviation.

sessment showed that the othersubjects were prepubertal or inearly puberty (Tanner stage II) atthe onset of psychosis (all but 3had onset between 9-12). Onsetwas subacute (deterioration frombaseline to psychosis = 1-6months) in 8 subjects and insidi-ous (deterioration over more than6 months) in 14. Despite theiryoung age, the group was rela-tively chronic, with significantneuroleptic exposure.

Surprisingly, the distinction be-tween positive and negative symp-toms has not been systematicallyexamined for childhood-onsetschizophrenia, in which negativesymptomatology is less confoundedby secondary negative symptomsfrom chronicity of illness, long-term institutionalization, andchronic drug treatment. All 22subjects had severe and persistentdelusions and/or hallucinations,and all bu t 1 subject had formalthought disorder. Negative symp-toms such as flat affect, alogia, ap-athy, asociality, and inattentionwere also common, however, andsevere as measured by theSchedule for the Assessment of

Negative Symptoms (Andreasen1982).Family History and ChromosomeAnalysis. First-degree relatives ofthe 23 schizophrenia probands un-derwent nonblind structured inter-views by an experienced clinicianusing the Schedule for AffectiveDisorders and Schizophrenia(Spitzer and Endicott 1978); 3 ofthe families (13.6%) had first-degree relatives with nonaffectivepsychotic disorders. In one family,the mother was diagnosed withdelusional disorder and therewere also nonaffective psychoticdiagnoses in the maternal uncle,grandfather, grandmother, andgreat-aunt but none on the pater-nal side. In the second family, themother had schizoid disorder witha history of multiple episodes ofhallucinations requiring treatment,several siblings had schizoid orschizotypal disorders, and onesibling had schizophrenia. In thethird case, the child's father had ahistory of nonaffective psychoticdisorder. While greater familialitywas hypothesized for childhood-onset cases, a larger sample will

of course be needed to addressthis issue. Moreover, selection biasmay be a factor in producingfewer familial cases, as it maytake more adequate coping style todeal with the telephone contactand long distance travel that werenecessary for participation in thisstudy.One of the 22 patients (a 12-year-old male) had an apparentlybalanced translocation involving

chromosomes 1 and 7 (46,XY,t[l;7][p22;q22]) (Gordon et al. 1994) anda previously reported case of a6-year-old boy with autism showeda complex chromosomal rearrange-ment involving the same chromo-some 1 breakpoint (p22), chromo-some 7 (different breakpoint), andchromosome 21 (Lopreiato andWulfsberg 1992). Since chromo-somal rearrangements may disruptcritical genes within the breakpointregions, further study of the Ip22region is warranted in develop-mental brain disorders.

Smooth Pursuit EyeMovement (SPEM)Abnormalities in SPEM have beenobserved in 50 to 85 percent ofadults with schizophrenia (com-pared with 8% of normals) evenin remission (Iacono and Koenig1983; Holzman 1989). SPEM dys-function has been associated withnegative symptoms (Sweeney et al.1989) and lateral ventricular en-largement (Weinberger and Wyatt1982), appears to be trait related,and cannot be attributed to typicalneuroleptic use, inattention, poormotivation, or generalized deficits(Mather 1985; Smeraldi et al. 1987;Holzman 1989).

The developmental sequence forsmooth pursuit tracking abilities,assessed by infrared oculography,


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parallels that of other frontal lobefunctions. Age is correlated withsmooth pursuit system perform-ance in 8- to 15-year-old subjects;this performance reaches adultlevels by age 14 (Ross et al. 1993).Eye movements have been meas-ured in 10 childhood-onset schizo-phrenia patients (mean age = 14.9years) and 12 normal control sub-jects (mean age = 12.8 years); 8were on clozapine and 2 on halo-peridol (figure 1). Intervals forsmooth pursuit and saccadic eyemovements were measured byhigh-resolution infrared oculogra-phy. Testing was technically diffi-cult, and sometimes impossible,with medication-free subjects. Eyemovements were analyzed onlywhen it was clear that the subjectwas attempting to track the target.Performance was compared be-tween groups with Mests (two-tailed).

SPEM gain (eye velocity relativeto target velocity) was significantlylower in schizophrenia subjects(0.69 0.17) than in normal con-trols (0.84 0.09) (t = 2.7, df =22, p < 0.01). Furthermore, thedistance covered (degrees per sec-ond) by total saccades, catchupsaccades, and intrusive saccadeswas greater in the schizophreniasubjects (total: schizophrenia sub-jects 10.4 7.9 vs. control subjects4.0 1.9 [t = -2.8, df = 22, p


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other, and two additional patientscould not do the RT task. Thus,the us ranged from 14 to 18 fordifferent variables. The schizophre-nia subjects are compared by2-sample Mests with a controlgroup of 54 normal volunteers (35male, 19 female) of the same age,except where noted. In addition,the scores for each patient on se-lected variables were converted toZ scores based on the normalmean and standard deviation forthat sex group. The distributionsof these Z scores for selectedvariables are plotted in figure 2.Rest Period. Three indices ofresting autonomic nervous systemactivity ("arousal") were examined.

The rate of nonspecific fluctuationsof SC in the rest and tones peri-ods were higher in the patients(p = 0.02; figure 2), although SCLwas not different from that of con-trols; HR was also elevated in theschizophrenia subjects (p < 0.03).SCL normally declines during therest period and can be interpretedas a measure of adaptation to thesituation. The rate of change in SCwas less negative in the patientsthan in the controls (p = 0.0001;figure 2).

The results for all four of thesevariables (nonspecific fluctuations,SCL, HR, and change in SCL dur-ing the rest period) are very simi-lar to what this laboratory hasfound in earlier studies of adult

Figure 2. Z scores for the schizophrenia subjects for severalvariables based on the mean and standard deviations forage- and sex-matched normal controls (n = 53)

o

(0ooa0)1 ou(0oN - 3

: o

0 0

Boyso Girls

"" : o _ "

" , " S 2 B -

o" "

Rest:: NSFluct /mln

Rest: ChangeIn SC L

Orienting SCR RTT ask : RTTa sk: RT Stimulus:Magnitude SCR Mag. Change In SCL No. ofS CR s

NS Fluct/min = number of nonspecific fluctuations of skin conductance per minute; SC = skinconductance; SCL = SC level; SCR = SC response; RT = reaction time; Mag. = magnitude.

acute schizophrenia patients (Zahnet al. 1981a).Skin Conductance Orienting Re-spon se (SCOR). A SCOR wasdefined as an increase in conduc-tance of a least 0.02 \iS with anonset latency between 1 and 4 sec-onds. Over all trials, the patientsgave fewer SCORs than controls(p < 0.05), but more importantly,47 percent of the patients versus 2percent of the controls failed torespond to the first tone (p


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baseline autonomic activity, slowadaptation and habituation, andimpaired phasic and tonic auto-nomic responses to novel and sig-nificant stimuli and situations ofthe experimental protocol. The re-sults are qualitatively similar tothose obtained in adult schizophre-nia patients in this laboratory(Zahn et al. 1981a) and elsewhere(reviewed in Zahn et al. 1991).However, the high degree of con-sistency on these markers shownby the present childhood-onsetgroup is unusual in studies inadult schizophrenia. In this respect,they resemble more closely acuteschizophrenia patients selected onthe basis of a poor short-term out-come (Zahn et al. 1981b). The datathus suggest that in that sensethey may be considered severelyafflicted with the illness.Finally, the findings have diag-nostic specificity, since they con-trast with results of studies usingthe same protocol on children withdisruptive behavior disorders orobsessive-compulsive disorder(Berg et al. 1986; Zahn and Kruesi1993) and adult men with autisticdisorder (Zahn et al. 1987).

MRI. Both anatomic and func-tional developmental abnormalitieshave been proposed as etiologicalfactors in later-onset schizophrenia(Weinberger 1987). Extension ofthese studies to pediatric sampleswill test some assumptions ofthese theories.

Ventriculomegaly has been re-ported in adults with schizophre-nia in more than 90 computed to-mography (CT) and MRI studies(Casanova et al. 1991) and may beassociated with negative symptoms(Andreasen et al. 1990). Reducedvolume of medial temporal lobestructures has also been found inmultiple MRI studies (Suddath et

al. 1989, 1990; Dauphinais et al.1990), with gray rather than whitematter accounting for the temporallobe pathology (Suddath et al.1989).Several studies have demon-strated abnormalities in the corpuscallosum in adult schizophreniasubjects (Nasrallah et al. 1986;Stratta et al. 1989; Casanova et al.1990b; Swayze et al. 1990). Becausethe corpus callosum develops em-bryologically in association withlimbic structures (hippocampalformation, fornix, hippocampalcommissure, septum pellucidum,cingulate gyrus), which are alsoimplicated in schizophrenia, cal-losal abnormalities support aneurodevelopmental basis of adultschizophrenia (Swayze et al. 1990).To date, MRI has been carriedout for 19 adolescent schizophreniasubjects and 37 normal controlsmatched for age, height, weight,Tanner stage, and handednessusing a 1.5-tesla General Electricscanner (spoiled gradient recall ac-quisition at steady state, time toecho = 5 ms, time to repetition =24 ms, flip angle = 45) with 1.5mm sagittal and 2 mm coronal

contiguous slices. The volume ofcortical (right and left total brain,frontal, prefrontal, and anterior,middle, and posterior temporallobes) and 11 subcorrical (rightand left caudate, cingulate, hippo-campus, and ventricular volume,total and subdivisions of thecorpus callosum, midbrain, andpons) structures were measured(Giedd et al., submitted forpublication).Schizophrenia patients had an 8percent smaller total brain volumeand a trend for larger left ventric-ular volume (p = 0.09, two-tailed).In addition, they had significantlygreater caudate volume particularlyon the left. This is of considerableinterest since the normal develop-ment across this age range is for arobust decrease in caudate volume(Castellanos et al., in press), sug-gesting that normal "pruning,"programmed cell death, or otherpossible mechanisms may havefailed to occur. The findingsshown in table 3 have also beenreported in adult schizophrenia pa-tients. The pattern of abnormality,even with this incomplete analysis,already appears more pronounced

Table 3. Anatom ic brain magnetic resonance imagingmeasures for subjects with childhood-onset schizophrenia(n = 19) and age-, sex-, and height-matched controls

CorticalRight occipitalLeft occipitalSubcorticalLeft caudateSplenium of corpus callosum (area)Left ventricle

F 1

4.047.397.213.382.99

P 2

0.040.0090.0090.070.09

AdjustedmeansN > SN > SS > NS > NS > N

'Analysis of covariance with total brain volume (schizophrenia subjects total brain volume 8%less than normal volunteers).Two-tailed.


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on the left.The preliminary rinding ofenlarged left ventricular volumesupports the hypothesis that ven-tricular enlargement is presentearly in the course of the illnessand is consistent with asymmetricinvolvement (Crow 1990). How-ever, ventricular enlargement doesnot seem more marked than foradult patients. These findings arenot seen in age-matched subjectswith attention deficit hyperactivitydisorder and this suggests somespecificity of these findings (Cas-tellanos and Giedd, personal com-munication 1994). An interestingfinding would be evidence forareas of greater developmental dis-ruption than seen for later-onsetdisorder. A prospective followupMRI study is ongoing for allschizophrenia subjects.Functional NeuroimagingFunctional brain imaging, such asPET and single photon emissioncomputerized tomography (SPECT),is an important counterpart to ana-tomic investigations. Excess pro-duction of neurons, synapses, anddendritic spines early in develop-ment, and synaptic pruning andprogrammed cell death occurringthroughout childhood and adoles-cence, parallel age-related changesin cerebral glucose metabolism.Metabolic rates rise until age 3 or4, and these levels are maintaineduntil age 9, followed by decline toadult levels by late adolescence(Chugani et al. 1987; Feinberg etal. 1990). PET studies of child-hood-onset cases might be partic-ularly illuminating; for example,such studies might indicate a dif-ferent global rate of metabolism,suggesting an abnormal pattern ofprogrammed cell death in early-onset schizophrenia (Feinberg

1982/83). In addition, any regionalabnormalities in glucose metabo-lism in childhood-onset schizophre-nia are of interest in relation tothose seen in adult schizophreniaand autism.Reduced frontal, temporal, andparietal metabolism have eachbeen noted in [18F]fluoro-2-deoxy-D-glucose (FDG) PET studies ofadult schizophrenia (Buchsbaum etal. 1982, 1984; Farkas et al. 1984;

Wolkin et al. 1988; Cleghorn et al.1989; Buchsbaum 1990). PET stud-ies in adults with autism have notshown any localized abnormality(Rumsey et al. 1985a; Herold et al.1988), although autism subjectsshowed fewer large positive cor-relations between cortical and sub-cortical regions (Horwitz et al.1988), a finding that is consistentwith mesolimbic dysfunction.To date, 9 subjects with child-hood-onset schizophrenia and 12

normal controls matched for ageand sex have undergone FDG PETscanning. All subjects were medi-cation free for at least 3 weeks.Subjects received 1.6-2.3 mCi (mili-curies) of FDG intravenously. Eyeswere closed and patched and sub-jects performed an auditory atten-tion task through headphonesthroughout the period of glucoseuptake. During this period, serialarterial or arterialized venousblood samples were taken fromthe arm for quantification of FDGuptake. After the uptake period,subjects were scanned for 30 min-utes with a Scanditronix PET (ringor pin transmission scans). Sliceswere parallel to the canthomeatalline (CM), and the interstice inter-val was 5-6 mm. Whole brain and60 regional measures of glucosemetabolic rate were examined. Forthe extraction of regional glucosemetabolic rates, boxes were placedover the regions of interest in five

standard planes: planes A (9.1 cmabove CM), B (7.8 cm above), C(6.5 cm above), D (5.2 cm above),and E (3.9 cm above).Global glucose metabolism ofsubjects did not differ significantlyfrom that of controls. With thedata normalized to minimize theeffects of individual variation inglobal metabolism on regionalcomparisons, schizophrenia subjectsshowed decreased metabolism inonly one region: plane C rightparietal (p < 0.05). Right parietalglucose metabolic rate was posi-tively correlated with auditory con-tinuous performance task perform-ance (Cohen et al. 1987) in bothschizophrenia subjects (p = 0.06)and normal controls (p = 0.21).When this region was reanalyzed,covarying for attentional perform-ance, there was no difference be-tween groups, indicating that met-abolic differences were probablysecondary to poor attention duringthe task for the schizophreniasubjects.

Increased glucose metabolism inthe schizophrenia group was seenin four cortical regions and onesubcortical region: plane E left in-ferior frontal (p < 0.01), plane Bleft parietal (p < 0.01), plane Bleft posterior frontal (p < 0.05),plane A left anterior frontal (p


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(Buchsbaum et al. 1987; Szechtmanet al. 1988). We cannot reject thisinterpretation for our finding ofincreased metabolic rate in theputamen because our subjects, al-though young, had an average of3 years of neuroleptic treatment.The right putamen metabolism didnot, however, correlate significantlywith duration of neurolepticexposure.These data are, of course, pre-

liminary because of the small sam-ple size. A larger sample, MRI-PET coregistration, and statisticalpattern analyses of the relation-ships between metabolism in corti-cal and subcortical structures willallow better comparison with later-onset schizophrenia and autism.NeurochemistryNo conclusions can be drawn fromthe few neurochemical studies ofchildhood-onset schizophrenia, es-pecially given the drawbacks ofsmall sample sizes and nonstan-dardized diagnostic criteria(Gillberg et al. 1983; Weizman etal. 1984; Rogeness et al. 1985). Theserotonin system is of particularinterest in our pediatric sample,since hyperserotonemia has beenfound consistently in 25 percent ormore of patients with autism andat an increased rate in their familymembers (Anderson et al. 1987;Cook 1990). In the NIMH study,we are focusing on dopaminergicand serotonergic function so thatwe can contrast our results withstudies of later-onset schizophreniaand autism. Cerebrospinal fluid,plasma, and 24-hour urine speci-mens are collected during a medi-cation-free state, as well as duringtreatment with haloperidol andclozapine. These cerebrospinal fluidchemistries of children with schiz-ophrenia will be compared with

those of age-matched subjects withattention deficit disorder, conductdisorder, and obsessive-compulsivedisorder, since it has not beenpossible to obtain spinal fluid fromnormal controls. On the basis ofresearch in adult schizophreniaand autism studies of norepineph-rine (Breier et al. 1990), neuropep-tides (Weizman et al. 1984; Bissetteet al. 1986), cyclic adenosine-3':5'-monophosphate (Belmaker et al.1984), nerve cell adhesion moleculeserum fragment (Lyons et al. 1988;Plioplys et al. 1990), and epineph-rine (Berger et al. 1984) are alsobeing considered.TreatmentAnecdotal reports have suggestedthat neuroleptic medication is lesseffective in children with schizo-phrenia than in patients withadult-onset illness (Kydd andWerry 1982; Campbell and Spencer1988). Recently, the first controlledstudy of neuroleptics in childrenwith schizophrenia has been car-ried out in 20 such subjects, ages5-11 years (Spencer et al. 1991).Moderate improvement was seenin a variety of symptoms withhaloperidol (0.5-3.5 mg/day) com-pared with placebo in a crossoverdesign with 4 weeks on eachtreatment.

A single-blind comparison ofthiothixene and thioridazine in 21adolescents with schizophreniafound both neuroleptics equallyeffective in improving Brief Psychi-atric Rating Scale (BPRS; Overalland Gorham 1962) scores, but theadolescents remained quite im-paired (Realmuto et al. 1984). Theonly double-blind and placebo-controlled neuroleptic trial inadolescents with schizophrenia re-vealed only modest efficacy of lox-apine and haloperidol (Pool et al.

1976); only two of the symptomsmost important in schizophreniashowed a difference between drugand placebo after 4 weeks of treat-ment (BPRS hallucinations anddisorientation).Among the many neurolepticsavailable, haloperidol is the beststudied for nonschizophrenic men-tal disorders of children and ado-lescents. Controlled studies havedemonstrated safety and efficacyin the treatment of behavioraldifficulties in infantile autism(LeVann 1969; Faretra et al. 1970;Engelhardt et al. 1973; Perry et al.1989) and childhood-onset perva-sive developmental disorder (Joshiet al. 1988), tics in Tourette's dis-order (Feinberg and Carroll 1979;Bruun 1984), and undersocializedaggressive conduct disorder(Campbell et al. 1984). These re-sults suggest that a positive clini-cal response is not diagnostic.

Recently, open studies and casereports of the use of clozapine inadolescents with schizophreniawho are considered unresponsiveto or intolerant of typical neuro-leptics suggest that the subjectsimproved in both positive andnegative symptoms and that theytolerated the medication well(Siefen and Remschmidt 1986;Rem schm idt 1991; Birmaher et al.1992; Jacobsen et al. 1994; Mozeset al. 1994; Towbin et al. 1994).The NIMH study includes the firstcontrolled trial of clozapine in chil-dren and adolescents with schizo-phrenia who are nonresponsive totypical neuroleptics.

Following a 4-week medication-free period, subjects in the NIMHstudy are randomized in a double-blind fashion to haloperidol plusbenztropine or clozapine plusplacebo. Dosages are increasedtwice weekly over the course of 6weeks until positive effects, side


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effects, or maximum doses (36 mghaloperidol or 900 mg clozapine)are achieved. At the end of 6weeks, the blind is broken andthose patients who received halo-peridol may receive an open trialof clozapine if this is clinicallyindicated.Sixteen patients have completedthe double-blind trial to date, eightreceiving clozapine and eight re-ceiving haloperidol. However, be-

cause 4 subjects received openclozapine before the study began,a total of 12 adolescents havereceived open clozapine (meanweek-6 dose, 366.7 mg/day); dataon the first 11 have been reportedpreviously (Frazier et al. 1994).One patient had concomitant di-goxin for paroxysmal supraventric-ular tachycardia (diagnosed beforeinitiation of clozapine) and anotherhad concomitant valproic acid forsuspected complex partial seizuredisorder. The baseline BPRS totalscore for these 12 subjects was86.3 (13.2) and at week 6 of clo-zapine treatment was 53.5 (20.6).These results are not surprising forsuch impaired, treatment-refractorypatients receiving an experimentaltreatment. However, some patientshave shown dramatic improve-ments. For instance, one patient,poorly responsive to multipleneuroleptics, including haloperidol,went from a catatonic state (mute,feces smearing) to being coherent,articulate, and free of psychoticsymptoms within 3 months of clo-zapine treatment. Fifteen of the 20patients completing the programthus far have remained on cloza-pine (longest followup is 2Viyears). Side effects have been simi-lar to those seen in adults, withthe possible exception that weightgain may be more problematic inadolescents; mean weight gain for12 patients in 6 weeks was 14.4

lbs, as opposed to 13.9 lbs inadults over a 16-week period(Leadbetter et al. 1992). Two pa-tients experienced transient, benignneutropenia, but were able to re-main on medication.Clozapine therapy had to be ter-minated in 5 out of 20 patientscompleting the protocol thus far.Two of the five developed recur-rent neutropenia despite medica-tion interruption and rechallenge

(absolute neutrophil counts be-tween 1,100-1,500). Two patientsexperienced tonic-clonic seizures,and even with anticonvulsant ther-apy, were unable to tolerate cloza-pine due to ongoing cortical epi-leptiform activity. Finally, the fifthpatient stopped clozapine therapydue to excessive weight gain.Changes in blood, urine, andcerebrospinal fluid levels of mono-amines and their metabolitesduring haloperidol (typical neu-

roleptic) treatment and clozapine(atypical neuroleptic) treatment willbe compared and correlated withclinical response. Pharmacokineticsand plasma level monitoring ofhaloperidol and clozapine andtheir major metabolites are alsobeing carried out to compare thepharmacokinetics in psychotic chil-dren and adolescents with datafrom adults (Piscitelli et al., inpress).In summary, data from our

open treatment suggest that cloza-pine is possibly efficacious in 12ado lesce nts (mean age 14.1 1.6)with childhood-onset schizophreniawho had been unresponsive totypical neuroleptics. Our double-blind comparison of the responseof children with schizophrenia tohaloperidol and clozapine alongwith a study of the phenomenol-ogy, neuropsychology, and biologyof these children will better char-acterize the disorder. Given its

efficacy against negative symptoms(Stephens 1990) and serotonin (5-HT2) blocking activity (Wilmot andSzczepanik 1989), clozapine maybe particularly beneficial in child-hood-onset schizophrenia patients,since negative symptoms appearprominent and a relative hyper-serotonemia is predicted for thissubgroup.SummaryStudies of the phenomenology, de-velopmental course, and neuropsy-chological profile, as well as com-plementary genetic, neurobiological,and pharmacological responsestudies of childhood-onset schizo-phrenia are under way at NIMH.A number of developmental disor-ders may mimic childhood-onsetschizophrenia, including twogroups with disorders unique tochild psychiatry: the MDI groupand the pervasive developmentaldisorder/Asperger 's syndromegroup.

The 22 narrowly defined schizo-phrenia subjects (ages 12-18) en-rolled to date in the NIMH studywere severely ill with prominentpositive and negative symptoms,had onset of psychosis betweenages 7 and 12, and were prepu-bertal or in early puberty (TannerII) at onset of psychosis (whichwas subacute or insidious); mosthad significant neuroleptic expo-sure. Pilot data from studies ofSPEM and autonomic activity indi-cate continuity with later-onsetschizophrenia. Preliminary quanti-tative MRI measurements showedlarger left ventricular volume andsmaller total brain volume. FDGPET showed decreased metabolismin a right parietal region, which isassociated with poor attentionalperformance in individuals withschizophrenia, and increased me-


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tabolism in three left frontal, a leftparietal, and a right basal gangliaregion. Clozapine has appearedefficacious in an open trial with12 subjects, but its efficacy is yetto be established in an ongoingdouble-blind comparison withhaloperidol.To date, systematic study of thechildhood-onset subgroup of schiz-ophrenia subjects has not beenactively pursued because of the

rarity of the disorder and its diag-nostic heterogeneity. However, therecent refinement of diagnosticclassification, which began withDSM-1I1, together with recentadvances in genetic methodology,brain imaging, and psychopharma-cology, make such study timely.

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AcknowledgmentThe authors acknowledge the con-tribution of Jean Nelson in thepreparation of this manuscript.

The AuthorsCharles T. Gordon, M.D., is SeniorStaff Fellow, Jean A. Frazier, M.D.,

is Senior Staff Fellow, KathleenMcKenna, M.D., is Senior Staff Fel-low, Jay Giedd, M.D., is SeniorStaff Fellow, Alan Zametkin, M.D.,is Senior Staff Psychiatrist, DebraKay sen, B.A., is Research Assistant,Kathleen E. Albus, B.A., is Re-search Assistant, and Judith L.Rapoport, M.D., is Branch Chief,Child Psychiatry Branch, NationalInstitute of Mental Health (NIMH),Bethesda, MD. Theodore Zahn,Ph.D., is Senior Staff Research Psy-chologist, Laboratory of Psychologyand Psychopathology, NIMH, Beth-esda, MD. Walter Hong, M.D., isSenior Staff Fellow, Laboratory ofNeurosciences, National Instituteon Aging, Bethesda, MD. DanHommer, M.D., is Section Chief,Laboratory of Clinical Studies, Na-tional Institute on Alcohol Abuseand Alcoholism, Bethesda, MD.

Available FromNIMHFree single copies of New De-velopments in the PharmacologicTreatment of Schizophrenia areavailable to requesters. This issuefocuses on the important progressthat is being made in medicationdevelopment and in our ability touse available treatments and treat-ment combinations in the mosteffective manner. Topics discussedinclude: the role of blood levels;alternative somatic treatments fornonresponding patients; the role ofclozapine; putative mechanisms ofaction of novel antipsychotics; anoverview of potential antipsychoticdrugs under development; new

findings in maintenance treatment;a review of the impact of neuro-leptic treatment on the long-termcourse of schizophrenia; and a dis-cussion of obstacles which must beovercome to ensure that the prom-ise of treatment research can befully realized.Readers who wish to receive acopy of New Developments in thePharmacologic Treatment ofSchizophrenia should write to theResearch Projects and Publica-tions Branch, NIMH, Rm. 18C-06,5600 Fishers Lane, Rockville, MD20857.

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