signos neurológicos adolescentes con y sin psicosis

7/29/2019 Signos neurolgicos adolescentes con y sin psicosis

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266 http://neuro.psychiatryonline.org J Neuropsychiatry Clin Neurosci 19:3, Summer 2007

REGULAR ARTICLES

Neurological Signs andCognitive PerformanceDistinguish BetweenAdolescents With andWithout PsychosisDavid B. Arciniegas, M.D.Donald C. Rojas, Ph.D.

Michelle Ramos Kleman, M.S.W.Ryan Asherin, B.A.Martin L. Reite, M.D.

Received February 1, 2006; revised May 13, 2006; accepted August21, 2006. From the University of Colorado School of Medicine, Den-ver, Colorado. Address correspondence to Dr. Arciniegas, Neuro-psychiatry Service, University of Colorado School of Medicine, Cam-pus Box C268-25, 4200 East Ninth Avenue, Denver, CO 80262; [email protected] (e-mail)

Copyright 2007 American Psychiatric Publishing, Inc.

Neurological and cognitive aspects of adolescentpsychotic disorders are understudied. The authorsassessed 19 adolescents with psychosis and 16healthy comparison subjects using the Neurologi-cal Evaluation Scale (NES) and age-appropriateWechsler intelligence quotient (IQ) scales. NESscores were highest and IQ scores were lowest

among subjects with psychosis. Subjects with psy-chosis did not demonstrate age-related decreasesin NES score. The combination of NES and IQscores predicted both the presence of psychosis andpsychiatric diagnosis. There were no relationshipsbetween medication status and either NES or IQscores. These results support a broadly conceivedneurodevelopmental formulation of adolescentpsychotic disorders.

(The Journal of Neuropsychiatry and ClinicalNeurosciences 2007; 19:266273)

Schizophrenia and related psychotic disorders are in-creasingly regarded as neurodevelopmental disor-ders in which the structure and/or function of large-

scale distributed networks serving cognition, emotion,

behavior, and motor function are disturbed.1 These dis-

turbances manifest in adults not only as psychosis but

also as impairments in sensory integration, complexmo-

tor sequencing, coordination, primitive reflexes,2,3 eye

movements,4

visual and auditory information process-ing, sustained attention, working memory, verbal epi-

sodic memory, and executive function.5

Several studies suggest that subtle signs of neurolog-

ical dysfunction (soft signs) are relatively common

among children and adolescents with schizophrenia and

related psychotic disorders.68 Additionally, Karp et al.8

demonstrated a failure of age-expected reductions in the

number and severity of these signs among adolescents

with schizophrenia, suggesting that psychosis devel-

oping in this age range, and perhaps in older individ-

uals as well, is associated with other signs of aberrant

neurodevelopment.Studies pairing neurological assessment with either

symptom severity or cognitive performance among ad-

olescents with schizophrenia and related psychotic dis-


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J Neuropsychiatry Clin Neurosci 19:3, Summer 2007 http://neuro.psychiatryonline.org 267

ARCINIEGAS et al.

orders have not been published. Additionally, studies of

this population have not employed standardized neu-

rological assessment scales, thereby limiting the com-

parability of their findings to those of adults with these

conditions. The Neurological Examination Scale (NES)2

is a standardized clinical assessment of subtle (soft)

neurological signs with excellent construct validity and

interrater reliability,2,3 and is the most widely used neu-

rological assessment tool in studies of adults with psy-

chotic disorders. The NES may therefore be well suited

to the study of adolescents with these conditions.

We undertook the present study to investigate ado-

lescent psychotic disorders from a neurodevelopmental

perspective using structured psychiatric diagnostic in-

terviews, the NES, and standardized measures of cog-

nition. The overarching hypothesis of this study is that

psychosis is only one of several manifestations of aber-

rant neurodevelopment among adolescents with schizo-

phrenia, schizoaffective disorder, and bipolar disorder

with psychotic features. Specific study hypotheses in-

cluded: 1) adolescents with psychosis demonstrate a

greater frequency and severity of neurological signs on

the NES than healthy comparison subjects of a similar

age; 2) adolescents with psychosis perform more poorly

on standardized cognitive tests (full-scale, verbal, and

performance IQ) than healthy comparison subjects of a

similar age; 3) the severity of neurological dysfunction

on the NES is independent of the severity of cognitiveimpairment; 4) adolescents with psychosis will dem-

onstrate a failure of age-expected neurological matu-

ration on the NES; and 5) group membership (psy-

chotic versus nonpsychotic) is predicted by NES score

and full-scale IQ.

METHOD

After complete description of the study to the subjects

and their legal guardians, we obtained written informed

consent for study participation from the legal guardianand assent from the subjects in accordance with the pol-

icies and procedures of the Colorado Multiple Institu-

tional Review Board.

Subjects

Nineteen subjects with psychosis ages 9 to 17 years (six

female) with schizophrenia, schizoaffective disorder, or

bipolar disorder with psychotic features were recruited

via referrals from child psychiatrists, mental health

agencies, and mental health advocacy organizations in

the Denver, Colo., metropolitan area, and through ad-

vertisements in this locale. Sixteen adolescents of similar

age (five female) with no personal or family history of

mental illness or neurological disease were similarly re-cruited and served as comparison subjects.

General Clinical AssessmentTwo of the investigators (D.B.A. and M.L.R.) performed

general clinical assessments inclusive of developmental,

medical, surgical, neurological, psychiatric, and sub-

stance histories, and also assessment of pubertal status

using the Pubertal Development Scale.9 Psychotropic

medication use was recorded and categorized as: anti-

psychotics; lithium in any formulation; anticonvulsant

mood-stabilizers; antidepressants (all classes); stimu-

lants; and benzodiazepines.

Psychiatric Diagnoses

We administered the Schedule for Affective Disorders

and Schizophrenia for School-Age ChildrenPresent

and Lifetime version (K-SADS-PL)10 under the super-

vision of one investigator (M.L.R.). A DSM-based clini-

cal interview was performed by a second investigator

(D.B.A.). These assessments were used to arrive at a con-

sensus-based study diagnosis by the lead investigators

(M.L.R., D.B.A., D.C.R.) which were completed without

consideration of neurological and cognitive assessment

findings.

Neurological Assessment

Physical examinations, elemental neurological exami-

nations, and examinations for subtle neurological signs

using the NES2 were performed by a single investigator

(D.B.A.). This investigator remained blind to K-SADS-

PL diagnoses (and hence consensus-based study diag-

noses) until the neurological assessments were com-

pleted and scored. NES findings were categorized into

eight domains of neurological function (Table 1).

Cognitive AssessmentA trained professional research assistant blinded to

study diagnosis performed cognitive assessments. As-

sessment of cognition was performed using the WAIS,

3rd edition (WAIS-III)11 or WISC, 3rd edition (WISC-

III)12 as appropriate for age. Some participants (three

subjects with psychosis, two comparison subjects) were

administered the 4-subtest version of the Wechsler Ab-

breviated Scale of Intelligence (WASI).13 Dependent

variables derived from the Wechsler scales included full


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NEUROLOGICAL SIGNS AND COGNITIVE PERFORMANCE IN ADOLESCENTS

TABLE 1. Mean (SD) Scores on Neurological Examination Scale (NES) and Intelligence Quotient (IQ), and Puberty Development Scale(PDS) Assessments Among Adolescents With Psychosis, Schizophrenia (Schz) or Schizoaffective Disorder (SchzA), BipolarDisorder with Psychosis (BD-P), and Adolescents Without Psychosis (Comparators)

Psychosis (N 19) Schz/SchzA (N 11) BD-P (N 8) Comparators (N 16)

Age at NES assessment in years 14.6 (2.3) 14.9 (2.5) 14.1 (2.1) 14.4 (1.9)NES Total 20.1 (5.7) 21.6 (5.1) 18.0 (6.1) 9.2 (3.9)

Primitive reflexes 2.5 (1.3) 2.7 (1.1) 2.3 (1.5) 0.4 (0.5)

Complex motor sequencing 6.4 (2.1) 7.2 (1.4) 5.4 (2.6) 2.9 (1.9)Motor coordination 4.0 (1.8) 2.3 (1.4) 2.8 (2.4) 0.6 (0.5)Short-term memory 1.5 (1.2) 1.5 (1.1) 1.4 (1.3) 0.4 (1.1)Cerebral dominance 1.2 (0.2) 1.2 (0.3) 1.2 (0.2) 1.0 (0.1)Integrative sensory function 2.9 (2.2) 3.4 (2.6) 2.1 (1.4) 1.6 (1.7)Eye movements 1.2 (1.4) 1.2 (1.5) 1.3 (1.2) 0.4 (0.8)Motor inhibition 3.2 (1.4) 3.4 (2.6) 2.9 (1.0) 2.6 (1.3)

Age at IQ assessment in years 14.1 (2.2) 14.2 (2.3) 13.8 (2.0) 14.1 (2.2)Full Scale IQ 92.5 (9.9) 87.2 (7.2) 99.8 (8.6) 111.4 (11.2)Verbal IQ 100.1 (11.6) 95.5 (10.3) 106.3 (11.0) 114.8 (13.6)Performance IQ 86.1 (11.4) 81.0 (11.8) 93.1 (6.4) 105.9 (9.7)Verbal IQ-Performance IQ 13.9 (14.1) 14.5 (17.6) 13.1 (8.2) 8.9 (12.5)PDS Score 2.5 (0.6) 2.5 (0.9) 2.5 (0.9) 2.8 (0.6)

scale (FS) IQ, verbal (V) IQ, and performance (P) IQ,

which were available from all of these assessments.

Inclusion Criteria

Subjects with a diagnosis of schizophrenia, schizoaffec-tive disorder, or bipolar disorder with psychosis and no

current or past diagnoses of alcohol or substance abuse/

dependence, no history or examination findings sugges-

tive of neurological (including traumatic brain injury or

epilepsy) or developmental disorders, and no current

major medical illness were included. Comparison sub-

jects were included if their evaluations revealed no per-

sonal or family history of mental illness or neurological

disease.

Statistical Analyses

All statistical analyses were performed using Statistica6.1 (StatSoft, Inc., Tulsa, Okla.). Students t tests were

used to test the hypothesis that NES scores are higher

and IQ scores are lower among adolescents with psy-

chosis than among comparison subjects. A one-sided

test for differences between proportions was used to test

the hypothesis that subjects with psychosis demonstrate

a higher frequency of neurological subtle signs than

healthy comparison subjects. Separate one-way analysis

of variance (ANOVA) tests were employed to test for

differences in NES and IQ scores between diagnostic

groups (schizophrenia/schizoaffective disorder versus

bipolar disorder with psychotic features versus never

mentally ill). We employed within-group Pearsons

product-moment correlations to test the hypothesis that

adolescents with psychosis demonstrate a failure of age-

expected neurological maturation on the NES, and to

investigate the relationship between NES scores and

VIQ, PIQ, and FSIQ scores. We performed binomial lo-

gistic regression analysis to examine whether group

membership (psychotic versus nonpsychotic) is pre-dicted by total NES and FSIQ. Multinomial logistic re-

gression analysis was used to determine whether diag-

nosis (schizophrenia/schizoaffective disorder versus

bipolar disorder with psychotic features versus never

mentally ill) is predicted by total NES and FSIQ. Fishers

exact test was used to examine differences in the pro-

portion of subjects treated with each of the classes of

psychotropic medications described above. Addition-

ally, an exploratory analysis using simple linear regres-

sion was employed to investigate whether total NES,

FSIQ, VIQ, and PIQ scores predicted psychotropic med-

ication treatment status (i.e., treatment versus no treat-

ment) among subjects with psychosis.

RESULTS

The psychotic group (N 19) consisted of seven subjects

with schizophrenia (one female), four subjects with schi-

zoaffective disorder (one female), and eight subjects

with bipolar disorder with psychotic features (four fe-

males). All subjects with bipolar disorder with psychotic

features were euthymic (i.e., not in a manic, hypomanic,

manic, or mixed episode and also not psychotic) at the

time of study assessments. The mean age of onset for

first psychiatric diagnosis in the psychotic group was

6.9 (SD 2.5) years (range 4 to 11 years) and included


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ARCINIEGAS et al.

attention-deficit hyperactivity disorder (42.1%), schizo-

phrenia (10.5%), bipolar disorder (type unspecified or

not otherwise specified, 31.6%), aggressiveness

(5.3%), and no formal diagnosis (10.5%). The mean age

of onset for study diagnosis was 9.7 (SD 2.8) years(range 4 to 13 years).

Among the psychotic subjects, 31.6% had a history of

maternal drug use during pregnancy, including expo-

sure to stimulants (21.1%), alcohol (21.1%), and nicotine

(5.3%), alone or in combination, and 16 of 19 subjects

(84.2%) had a history of treatment with stimulant med-

ications prior to or since the onset of study diagnosis.

At the time of NES assessment, medications used among

subjects with psychosis included antipsychotics (84.2%),

lithium in any formulation (36.8%), anticonvulsant

mood-stabilizers (42.1%), antidepressants (36.8%), stim-

ulants (31.6%), and benzodiazepines (21.1%). At the

time of IQ assessment, medications used among subjects

with psychosis included antipsychotics (78.9%), lithium

in any formulation (42.1%), anticonvulsant mood-sta-

bilizers (47.4%), antidepressants (42.1%), stimulants

(36.8%), and benzodiazepines (15.8%). Subjects with bi-

polar disorder with psychotic features differed from

those with schizophrenia/schizoaffective disorder with

respect to the frequency of treatment with lithium (75%

versus 18%, Fishers exact p0.03) and anticonvulsant

mood-stabilizers (88% versus 18%, Fishers exact p

0.005).There was no effect of diagnosis on Pubertal Devel-

opment Scale (PDS) scores (F 0.6, df 2.32, p 0.57).

Post-hoc comparison using Tukeys Honest Significant

Difference (HSD) test for unequal sample sizes demon-

strated no differences in PDS scores between diagnostic

subgroups.

Comparison of NES Scores Between Groups

Total NES scores were significantly higher among sub-

jects with psychosis than among comparison subjects

(t 6.5, p0.001). There also was a significant effect of

diagnosis on total NES score (F 23.2, df 2,32, p0.001), primitive reflexes (F 19.5, df 2,32, p0.001),

complex motor sequencing (F 15.7, df 2,32, p0.001),

motor coordination (F 8.2, df 2,32, p0.002), and

short-term memory (F 3.5, df 2,32, p0.04) scores.

Post-hoc comparison using Tukeys HSD test for un-

equal sample sizes demonstrated a significant difference

in total NES scores between both subject groups and the

comparison subjects (p0.001 and p0.003, respec-

tively), but no difference between subjects with schizo-

phrenia/schizoaffective disorder and subjects with bi-

polar disorder with psychotic features. A similar pattern

was observed in post-hoc comparisons of primitive re-

flex, complex motor sequencing, and motor coordina-

tion scores: subjects with schizophrenia/schizoaffectivedisorder did not differ from subjects with bipolar dis-

order with psychotic features, but both groups differed

significantly from the comparison subjects (all p0.05).

Mean total and subscale NES scores among subjects

with schizophrenia/schizoaffective disorder, bipolar

disorder with psychotic features, and the never mentally

ill comparison subjects are presented in Table 2. Item-

level data on the NES for the psychosis and healthy

comparison groups as well as differences using a one-

sided test for difference in proportions are described in

Table 1.

Comparison of Neurological Maturation Between Groups

There was an inverse relationship between age at time

of NES assessment and total NES among the healthy

comparison subjects (r 0.68, p0.004), but not among

subjects with psychosis, collectively (Figure 1) or by

diagnostic group (schizophrenia/schizoaffective disor-

der and bipolar disorder with psychotic features).

Comparison of Cognitive Assessments Between Groups

FSIQ, VIQ, and PIQ scores were significantly loweramong subjects with psychosis than among compari-

son subjects (Table 1). There was a significant effect of

diagnosis on FSIQ (F 21.0, df 2,32, p0.001), VIQ

(F 8.3, df 2,32, p0.002), and PIQ (F 21.2, df 2,32,

p0.001). Post-hoc comparison using Tukeys HSD for

unequal sample sizes demonstrated a significant dif-

ference between subjects with schizophrenia/schizoaf-

fective disorder and subjects with bipolar disorder

with psychotic features (p0.04), as well as a signifi-

cant difference between subjects with schizophrenia/

schizoaffective disorder and the comparison subjects

(p0.001). We also observed a trend towards a similardifference between subjects with bipolar disorder with

psychotic features and the comparison subjects

(p 0.05). Post-hoc comparison of VIQ scores demon-

strated significant differences between subjects with

schizophrenia/schizoaffective disorder and the com-

parison subjects (p0.003), but not the subjects with

bipolar disorder with psychotic features. VIQ scores

among subjects with bipolar disorder with psychotic

features did not differ from those of the comparison


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TABLE 2. Percentage of Adolescents With and Without Psychosis Demonstrating Abnormalities (Score0) on all NES AssessmentItems*

% of Subjectswith Psychosis (N 19)

% of ComparisonSubjects (N 16) p Value

Primitive ReflexesGlabellar response 78.9 25.0 0.002Snout response 52.6 0.0 0.001Grasp reflex 31.6 18.8 0.20Suck reflex 5.3 0.0 0.18

Complex Motor SequencingFist-Ring Test 73.7 50.0 0.08Fist-Edge-Palm Test 63.2 31.3 0.04Ozeretski Test 73.7 37.5 0.02

Rhythm Tapping Part A 89.5 43.8 0.004Rhythm Tapping Part B 89.5 50.0 0.007

Motor CoordinationTandem Gait 31.6 12.5 0.09Romberg Sign 10.5 0.0 0.10Rapid Alternating Movements (dominant) 31.6 0.0 0.01Rapid Alternating Movements (nondominant) 47.4 6.3 0.006Finger-Thumb Opposition 42.1 18.8 0.07Finger-to-Nose Test 21.1 18.8 0.43

Motor InhibitionAdventitious movements 78.9 87.5 0.25Tremor 15.8 0.0 0.05Mirror movements 84.2 56.3 0.04Synkinesis 36.8 37.5 0.48

Eye MovementsConvergent gaze 10.5 0.0 0.10Gaze impersistence (right visual field) 42.1 25.0 0.15

Gaze impersistence (left visual field) 26.3 6.3 0.06Short-Term Memory

Short-term memory 5 minutes 73.7 18.8 0.002Short-term memory 10 minutes 52.6 12.5 0.01

Integrative Sensory FunctionAudio-visual integration 15.8 12.5 0.39Stereognosis 10.5 6.3 0.33Graphesthesia 80.0 56.3 0.07Extinction (Face-Hand Test) 26.3 6.3 0.06Right-left confusion 42.1 25.0 0.15

*Excluding cerebral dominance items (hand, foot, eye). Listed p values reflect the results of one-sided tests for differences betweenproportions.

subjects. However, PIQ scores were lower among sub-

jects with schizophrenia/schizoaffective disorder than

among subjects with bipolar disorder with psychotic

features (p0.05) and the comparison subjects (p

0.0002), and PIQ scores were lower among subjectswith bipolar disorder with psychotic features than

among comparison subjects (p0.04).

Relationships Between Neurological and CognitiveFunction

Total NES scores did not correlate significantly with

FSIQ, VIQ, or PIQ scores among the subjects with psy-

chosis, either collectively or by psychiatric diagnosis

(schizophrenia/schizoaffective disorder and bipolar dis-

order with psychotic features), or among the compari-

son subjects.

Prediction of Psychiatric Diagnosis Using Neurologicaland Cognitive AssessmentsBinomial logistic regression demonstrated that the com-

bination of total NES score (Wald statistic 6.9,

p0.009) and FSIQ (Wald statistic 4.2, p0.04) cor-rectly predicted membership in the psychotic group in

18 of 19 subjects (94.7%) and in the comparison group

in 15 of 16 subjects (93.8%), yielding a log odds ratio of

5.6. Multinomial logistic regression indicated that the

combination of total NES (Wald statistic 7.0, p0.04)

and FSIQ (Wald statistic 7.8, p0.03) modeled psychi-

atric diagnosis well. The model correctly identified

schizophrenia/schizoaffective disorder in 10 of 11 cases

(91.0%), with one case classified as bipolar disorder with

psychotic features. The model also correctly classified

five out of eight subjects with bipolar disorder with psy-


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ARCINIEGAS et al.

FIGURE 1. Total NES Score by Age Among Adolescents Withand Without Psychosis

0

4

8

12

16

20

24

28

32

TotalN

ESScore

Subjects withpsychosis

Comparisonsubjects

9 10 11 12 13 14 15 16 17 18 19

Age (years)

chotic features (63.0%), with two cases misclassified as

schizophrenia/schizoaffective disorder and one case

misclassified as never mentally ill. Finally, the model

correctly classified 15 of 16 never mentally ill subjects

(93.8%), with one case misclassified as bipolar disorderwith psychotic features.

Relationships Between NES Scores, IQ Scores, andTreatment With Psychotropic Medications

We utilized simple linear regression to investigate

whether total NES, FSIQ, PIQ, or VIQ predicted treat-

ment status (treatment versus no treatment) with each

of the classes of psychotropic medication described

above. Total NES scores did not predict treatment status

with any class of medication (all p0.26). Initial analy-

ses suggested that FSIQ predicts antipsychotic medica-

tion treatment status (adjusted R2

0.23, p0.03) andthat VIQ predicts antipsychotic and antidepressant

medication treatment status (adjusted R2 0.23, p0.03,

and adjusted R2 0.17, p0.05, respectively). However,

these findings failed to remain significant after Bonfer-

roni correction for multiple comparisons.

DISCUSSION

Subtle neurological signs were significantly more com-

mon and more severe among adolescents withpsychosis

than among similarly aged healthy comparison subjects.

The neurological domains demonstrating the widest di-

vergence between the subjects with and without psy-

chosis included primitive reflexes, complex motor se-

quencing, motor coordination, and short-term memory.Total NES scores did not distinguish between subjects

with schizophrenia/schizoaffective disorder and bipolar

disorder with psychotic features, but NES scores in both

groups differed significantly from those of the compar-

ison subjects. Additionally, adolescents with psychosis

failed to demonstrate age-expected reductions of NES

scores.

These findings suggest that neurological dysfunction

as assessed by the NES is strongly associated with the

presence of psychosis, regardless of whether that psy-

chosis is persistent or mood episode-related. Although

the possibility of medication effect on neurological signs

in this population may be of immediate concern, the

regression analyses performed here suggest that this is

an unlikely explanation for this finding. This suggestion

is supported by the lack of association between NES

scores and antipsychotic medication use reported else-

where.2,1416

Similarly, IQ scores were lower among subjects with

psychosis than among the comparison subjects. Al-

though the mean full scale IQ for the psychosis group

was within the normal ranges described for these mea-

sures, population-based studies demonstrate highermean IQ levels ( 1 SD) in the Denver metropolitan

region than in the Wechsler scale standardization sam-

ple.17 The IQ scores of the psychotic adolescents in this

study therefore reflect a greater departure from expected

performance than might otherwise be apparent by these

scores. Since deterioration of IQ in childhood-onset

schizophrenia may begin up to 2 years prior to psycho-

sis onset and stabilize within 2 years thereafter,18 it is

also possible that among the subjects with psychosis

studied here, and particularly those with schizophre-

nia/schizoaffective disorder, IQ may not yet have

reached its final (and possibly even lower) level.In contrast to neurological signs, and similar to IQ

findings among adults with these conditions,19,20 there

was a significant effect of diagnosis on IQ: scores were

lowest among subjects with schizophrenia/schizoaffec-

tive disorder, highest among the healthy comparison

subjects, and intermediate among subjects with bipolar

disorder with psychotic features. Simple logistic regres-

sion did not identify a predictive relationship of FSIQ,

VIQ, or PIQ on psychotropic medication treatment


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status. Although it is possible that treatment history

may have influenced the IQ differences between adoles-

cents with schizophrenia/schizoaffective disorder and

bipolar disorder with psychotic features observed here,

data adequate to the task of examining this issue statis-tically were not available for analyses. However, Zam-

mit et al.,21 in a population-based sample of more than

50,000 male subjects, identified lower IQ as a risk factor

for schizophrenia but not bipolar disorder. This suggests

that cognitive differences between these conditions an-

tedate both their onset and treatment with psychotropic

medications. This finding supports framing IQ differ-

ences between schizophrenia/schizoaffective disorder

and bipolar disorder with psychotic features subjects ob-

served in the present study as reflective of differences

in neurodevelopment between these disorders rather

than as a consequence of them or their treatments.

Collectively, the present findings suggest that NES

and IQ reflect dependent domains in which aberrant

neurodevelopment occurs among adolescents with psy-

chosis. The utility of including neurological and cogni-

tive assessments in the evaluation of adolescents with

these conditions is evidenced by the robust prediction

of group membership (psychotic versus nonpsychotic)

using the combination of total NES and FSIQ scores: the

discrimination between schizophrenia/schizoaffective

disorder and never mentally ill subjects was excellent,

with no member of either group misclassified as a mem-ber of the other.

The present findings also suggest that diagnosis (i.e.,

disorders with persistent psychosis versus disorders

with mood episode-related psychosis) may differen-

tially influence development in these domains of neu-

ropsychiatric function. If similar findings are observed

in a larger sample of adolescent subjects with schizo-

phrenia/schizoaffective disorder and bipolar disorder

with psychotic features, inclusion of neurological and

cognitive examinations in the clinical assessment of

adolescents with psychotic disorders might improve

diagnostic accuracy. However, this suggestion is neces-sarily speculative, as the present data indicate that NES

and IQ alone are not sufficient to the task of discrimi-

nating fully between bipolar disorder with psychotic

features and the other diagnostic groups included

herein. The single subject in each of those two groups

that was diagnostically misclassified by the model was

predicted to be a member of the bipolar disorder with

psychotic features group. Additionally, three of the eight

subjects in the bipolar disorder with psychotic features

group were diagnostically misclassified, with two iden-

tified as members of the schizophrenia/schizoaffective

disorder group and one identified as never mentally ill.

These observations suggest that inclusion of additional

factors in the model is needed to separate the bipolardisorder with psychotic features subjects from those

with schizophrenia/schizoaffective disorder and

healthy comparison subjects. Alternatively, if NES and

IQ assessments are more strongly related to the neuro-

biology of these conditions than are phenomenological

psychiatric diagnostic assessments, then cross-sectional

K-SADS-PL and clinical interview-based diagnoses may

not be the optimal method by which to discriminate be-

tween adolescents with these diagnoses.2224

Several limitations of the present study require con-

sideration. It is possible that examiner knowledge of

subject diagnosis may contribute to NES scores, and that

examiner-subject interactions may influence the perfor-

mance of subjects on both neurological and cognitive

assessment measures. To the latter point, the blinded

cognitive assessment by a trained technician is consis-

tent with the methodology of other studies of this popu-

lation and should minimize the potential effect of cli-

nician bias on subject performance. The structured

administration and anchored scoring methods of the

NES limit the likelihood of clinician influence on subject

performance, although this concern cannot be assuaged

entirely. However, the magnitude of the NES differencesbetween adolescents with and without psychosis ob-

served here, as well as the comparability of total NES

scores among subjects with and without psychosis to

those reported in previous studies,2,3 argue against eval-

uator bias as an explanation for the present findings.

The present findings also argue against psychotropic

medication administration as an explanation for differ-

ences in NES and IQ scores between subjects with and

without psychosis, as well as for differences in IQ scores

between the psychotic subgroups. However, the absence

of treatment-nave subjects precludes a more definitive

assessment of this issue.The subject groups were not identical with respect to

gender, particularly for diagnostic subgroup compari-

sons. Though there is no a priori rationale for suggesting

an effect of gender on NES score,2,14,25 careful matching

of subjects is needed in future studies in order to more

fully evaluate the effect, if any, of gender in this context.

The size of the present sample precludes evaluation

of a larger number of predictor variables, including

medications (individually or by class), gender, and so-


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ARCINIEGAS et al.

cioeconomic status, and also reduces the power neededto investigate significant predictor variables with

smaller effect sizes. Similarly, the nature of the cognitive

assessments employed in the present study precludes

evaluation of the relationships, if any, between specificdomains of cognition and neurological dysfunction.Further studies of a larger sample of adolescents with

psychotic disorders inclusive of these variables, includ-ing longitudinal studies with periodic diagnostic reas-sessment, symptom severity assessments, and structural

or functional neuroimaging using magnetic resonance

imaging, neurophysiological assessments (e.g., electro-

encephalography, evoked or event-related potentials,

and/or magnetoencephalography) are needed to ad-

dress these issues.

This work was supported by a grant from NIMH (R01MH63442) and a grant from the Developmental Psychobiol-ogy Research Group (DPRG) of the University of Colorado

Health Sciences Center, Denver, Colorado.

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