Childhood-Onset Schizophrenia
Childhood-Onset Schizophrenia
Childhood-Onset Schizophrenia
S c h i z o p h re n i a a n d E a r l y -
o n s e t S c h i z o p h re n i a S p e c t r u m
D i s o rd e r s : An Update
David I. Driver, MDa,*, Shari Thomas, MD
b
, Nitin Gogtay, MD
c
,
Judith L. Rapoport, MDd
KEYWORDS
Schizophrenia Childhood-onset schizophrenia Childhood psychosis
KEY POINTS
Childhood-onset schizophrenia (COS) is an extraordinarily rare illness, with an incidence
less than 0.04%. In both healthy children and children with a variety of other psychiatric
illnesses, hallucinations are not uncommon; diagnosis should not be based on these
alone.
The evaluation of a child with suspected COS includes collecting extensive collateral in-
formation, observing patients/families over several visits, excluding underlying medical ill-
nesses, and evaluating, with a high index of suspicion, for speech/language/educational
deficits and comorbid mood or anxiety disorders.
Once a diagnosis is established and other comorbidities are addressed, treatment plan-
ning should encompass aggressive psychopharmacologic, psychotherapeutic, and psy-
chosocial interventions.
Clozapine is an excellent third-line medication for use in COS. Epidemiologic studies
demonstrate that its use often occurs much later than recommended by the clinical guide-
lines, despite having superior efficacy in the treatment refractory population.
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72 Driver et al
INTRODUCTION
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Childhood-Onset Schizophrenia 73
outcome.14,15 Furthermore, a 2016 review found that the mean DUP for EOS was
3.5-times longer than the mean DUP for adult-onset patients,16 This may be due
to the prevalence of comorbidities that complicate the presentation for EOS
patients.
Although a measured, thoughtful approach to diagnosis is essential, making a timely
diagnosis is also important.
PREMORBID PHENOTYPE
Of children with COS, 67% show premorbid disturbances in social, motor, and lan-
guage domains as well as demonstrating learning disabilities and having what seem
to be comorbid mood or anxiety disorders.
In addition, although not reported in studies of the premorbid history of adult-onset
schizophrenia (AOS),16,17 27% have met criteria for autism/autism spectrum disorders
(ASD) before the onset of their psychotic symptoms.18 Outcome and prognosis have
been positively correlated with the presence and severity of these developmental ab-
normalities,16,19–21 with some studies suggesting the severity of these deficits may
actually represent a premorbid phenotype for COS.22–27
The data on the premorbid functioning and symptomatology of the NIMH patients
confirm and extend these findings. A review of the authors’ cohort (n 5 47) in 2000
showed that 55% had language abnormalities, 57% had motor abnormalities, and
55% had social abnormalities several years before the onset of psychotic symptoms.
There was also a high rate of failed grades and special education placement.24,28
Gender, familial psychopathology, and familial eye-tracking dysfunction have shown
significant relationships with at least some aspect of the probands’ premorbid devel-
opment (Table 1).24
These results have been strengthened by a 2012 review of the authors’ cohort (n 5
118). Of the 118 children in the cohort, 65 (55.08%) had premorbid academic impair-
ments, 85 (72.03%) had premorbid social/behavioral impairments, 60 (50.85%) had
Table 1
Relation of premorbid impairments to schizophrenia risk factors for 49 patients with
childhood-onset schizophrenia
Premorbid Impairment and Risk Factor Present (N) Absent (N) P Value
Speech and language impairment
Sex 27 22 .57
Score for family loading for schizophrenia spectrum 27 21 .04
disorders
Mean family score for eye tracking 22 17 .04
Motor impairment
Sex 28 21 .009
Score for family loading for schizophrenia spectrum 28 20 .50
disorders
Mean family score for eye tracking 22 17 .25
Social impairment
Sex 27 22 .56
Score for family loading for schizophrenia spectrum 27 21 .15
disorders
Mean family score for eye tracking 19 20 .37
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74 Driver et al
Table 2
Realms of premorbid developmental problems based on 2012 chart review
N (%)
Social/behavioral 85 (72.03)
Academic 65 (55.08)
Language 60 (50.85)
Motor 52 (44.07)
Pervasive developmental disorder 24 (20.34)
DEFINITION/SYMPTOM CRITERIA
Since Kolvin’s classic studies,29 it is generally agreed on that COS can be diagnosed
with the unmodified Diagnostic and Statistical Manual of Mental Disorders (Fourth Edi-
tion, Text Revision) (DSM-IV-TR) criteria for schizophrenia.30 In addition, the NIMH
study has defined COS, whereby the onset of psychotic symptoms is before the
13th birthday, combined with a premorbid intelligence quotient of 70 or above and
absence of any significant neurologic problem. The Diagnostic and Statistical Manual
of Mental Disorders (Fifth Edition) amends the criteria to reflect a gradient of psycho-
pathology, from least to most severe, and provided updated severity dimensions.31
CLINICAL FINDINGS
Physical Examination
A diagnosis of COS requires exclusion of an underlying medical or psychiatric illness.
It is only after all other identifiable causes of organic psychosis have been excluded
that a diagnosis of COS can appropriately be considered. Details regarding the com-
ponents of the physical examination of individuals suspected of having a primary psy-
chiatric illness are discussed by Maja Skikic and Jose Alberto Arriola’s article, “First
Episode Psychosis Medical Workup: Evidence-Informed Recommendations and
Introduction to a Clinically-Guided Approach,” in this issue. A physical examination,
including a thorough neurological examination is essential to the diagnostic process
and clinicians should be vigilant to any abnormal physical and/or neurologic findings
because COS is a diagnosis of exclusion. It is also important to bear in mind the rare
medical causes and frequently missed diagnoses during the evaluation. Although dis-
cussed elsewhere in this issue, a select summary list is provided in Table 3.
Rating Scales and Diagnostic Modalities
For the NIMH COS study, the Social Communication Questionnaire, previously known
as the Autism Screening Questionnaire, and the Kiddie Schedule for Affective Disor-
ders and Schizophrenia–Present and Lifetime Version (K-SADS-PL) were used, with
the supplemental ratings as indicated by the results of the K-SADS-PL, for all pro-
bands. The Schedule for Affective Disorders and Schizophrenia and the Structured
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Childhood-Onset Schizophrenia 75
Table 3
Differential diagnoses of childhood-onset schizophrenia
Interview for DSM-III Personality Disorders were used to evaluate all family members
for axis I and axis II disorders, respectively. During follow-up visits, the probands were
evaluated using the Scale for the Assessment of Positive Symptoms, Scale for the
Assessment of Negative Symptoms, Brief Psychiatric Rating Scale for Children, Clin-
ical Global Impressions Scale, Children’s Global Impressions Scale, Bunny-Hamburg
Global Ratings, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale.34
As discussed previously, it is simply not feasible to apply what was done at NIMH in
the community. In clinical practice, it is routinely recommended to outpatient providers
that they use the Scale for the Assessment of Positive Symptoms and Scale for the
Assessment of Negative Symptoms to monitor clinical progress and the Abnormal
Involuntary Movement Scale to monitor for potential side effects of the medication
regimen (Table 4).
The NIMH COS branch developed a 2-item screen that identified children with COS
and distinguished them from peers with nontrivial levels of psychosis with sensitivity
and specificity of 79% and 78%, respectively.35–53 The 2 items are the NIMH global
scale depression and psychosis ratings, which are single items scored on a scale of
1 to 15, with higher numbers reflecting greater severity. This screen was validated
on the sample of patients who presented to the NIMH COS branch and thus does
not represent the heterogeneity of patients in the community.
Genetics
As discussed by Jennifer K. Forsyth and Robert F. Asarnow’s article, “Genetics of
Childhood-Onset Schizophrenia: 2019 Update,” in this issue, genetic studies of
COS and EOS demonstrate several variants, as opposed to a few highly penetrant
mutations, contribute to the genetic risk of schizophrenia54–58 and may even have
an impact on response to antipsychotics.59 Identification of common risk alleles in
schizophrenia has allowed for composite polygenic risk scores to be calculated.
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76 Driver et al
Table 4
Tools used by the National Institute of Mental Health child branch in the evaluation of
childhood-onset schizophrenia
Tool Description
Initial evaluation
Social Communication Questionnaire, Brief instrument helps evaluate
previously known as the Autism Screening communication skills and social
Questionnaire functioning in children who may have
autism or ASDs. Completed by a parent or
other primary caregiver in less than 10 min
K-SADS-PL A semistructured diagnostic interview
designed to assess current and past
episodes of psychopathology in children
and adolescents according to Diagnostic
and Statistical Manual of Mental Disorders
(Third Edition Revised) and DSM-IV criteria
Psychotic disorders supplementa Supplements to the K-SADS-PL used for
Affective disorders supplementa diagnostic exploration and clarification;
Anxiety disorders supplementa administered in the order in which
Behavioral disorders supplementa symptoms appeared
Substance abuse and other disorders
supplementa
Follow-up
Scale for the Assessment of Positive Assessment of positive symptoms of psychosis
Symptomsb devised primarily to focus on
schizophrenia
Scale for the Assessment of Negative Assessment of negative symptoms of
Symptomsb psychosis devised primarily to focus on
schizophrenia
Brief Psychiatric Rating Scale for Children A 21-item, clinician-based rating scale
designed for use in evaluating psychiatric
problems of children and adolescents
Clinical Global Impressions Scaleb A primary outcome frequently used in
medical care and clinical research to
measure in studies evaluating the efficacy
of treatments
Children’s Global Impressions Scaleb An adaptation of the Clinical Global
Impressions Scale for children
Bunny-Hamburg Global Ratings Two subscales that, when used together, best
Psychosis subscaleb exclude COS as a viable diagnosis (62%
Depression subscaleb accuracy at screening, 85% accuracy at the
medication-free period)34
Simpson-Angus Scale An established instrument for neuroleptic-
induced parkinsonism
Abnormal Involuntary Movement Scale 12-item clinician administered and scored
anchored scale used to detect and follow
the occurrence of tardive dyskinesia in
patients receiving neuroleptic medications
a
Used as indicated by the results of the K-SADS-PL.
b
Available in the Handbook of Psychiatric Measures (book with CD-ROM for Windows) by the
American Psychiatric Association.
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Childhood-Onset Schizophrenia 77
Using the results from the Psychiatric Genomic Consortium analysis of genome-
wide association study data for schizophrenia, an association test was created us-
ing a set of 80 single nucleotide polymorphisms and 108 schizophrenia risk loci.
The COS probands had higher polygenic risk scores compared with their siblings,
and the polygenetic risk scores effectively predict COS. The risk score for autism
was also calculated and was higher for the probands compared with their
siblings.54
Many studies have shown that there are large and rare copy number variants (CNVs)
associated with schizophrenia. The CNV burden was increased for genes controlling
synaptic function and neurobehavior. Those with COS have a higher rate of common
and rare CNVs compared with both their healthy siblings and AOS patients.54,56
Although a deletion at 15q13.3 has been shown to be an etiologic factor in psychi-
atric disorders, there were 2 patients with COS who had duplications at 15q13.3. The
rate of this duplication is higher than what is seen in AOS, AOS controls, intellectual
disability (ID) controls, and ASD controls. The rate of the duplication, however, was
not significantly higher than what is seen in COS siblings, attention deficit
hyperactivity disorder (ADHD), ADHD controls, ID, and ADHD.55
Despite these research findings, as well as the increased incidence of 22q11.2 dele-
tion syndrome in individuals with schizophrenia versus the general popula-
tion,54,55,60–63 the American Academy of Child and Adolescent Psychiatry Treatment
Guidelines do not recommend routine genetic screening for the evaluation of individ-
uals with COS or EOS, unless there are phenotypic indicators of an underlying or co-
morbid genetic abnormality.65
Imaging
Structural brain abnormalities are an established feature of schizophrenia, character-
ized by decreased total gray matter (GM) volume reduction in cortex, hippocampus,
and amygdala.54,55,60–66 COS patients present with smaller brain volume and a pro-
gressive decline over adolescence.67,68 They also have been shown to have larger
ventricles with a greater progressive increase in ventricular size, with a particular
difference in the lateral ventricles.69
The number of imaging studies of childhood and EOS is growing, with most them
coming from the NIMH cohort. Advances in computational image analysis permit
regional GM density, or cortical thickness measurements, which, when automated,
can be applied to large samples, increasing statistical power,56–59,60 which pro-
vides unprecedented anatomic detail of cortical GM change across both the entire
cortex and the age (Fig. 1).59,64 Prospective longitudinal brain magnetic resonance
imaging rescan measures for the NIMH COS sample show progressive changes in
COS, particularly during adolescence, and slowing as these COS patients reach
age 20,70–72 highlighting this period as critical and particularly vulnerable to treat-
ment influences. As it is, the GM volume of COS is 8% to 10% less than that of
age-matched controls. The result is a fixed volume deficit of 6% to 7% bilaterally.73
There is no gender influence on the degree of cortical thinning seen in COS, but, for
all subcortical structures, male patients had more volume than female patients.74
These changes occur only during a limited period because the rate and degree
of cortical loss if continued would resemble the extreme loss seen in some demen-
tias.59,64 These studies also support the previous findings that, although represent-
ing a more severe form, COS is continuous with its adult-onset counterpart. The
total, frontal, temporal, and parietal GM loss, not seen in healthy children and ad-
olescents or in those with atypical psychosis, seems to be diagnostically specific
for COS.70
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78 Driver et al
Fig. 1. Progression of cortical GM loss in COS (n 5 70, 162 scans) relative to age-matched,
sex-matched, and scan interval–matched healthy controls (n 5 72, 168 scans) from adoles-
cence to young adulthood (ages, 12–24 years).67,69 Analyses were performed using mixed-
model regression statistics and covaried from mean cortical thickness. Side bar shows t-sta-
tistic with threshold to control for multiple comparisons using the false discovery rate pro-
cedure with q 5 0.05. Differences are from mixed model regression with age centered at
approximately 3-year intervals for middle 80% of the age range; colors represent areas of
statistically significant thinning in COS.64
PATHOLOGIC CONDITION
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Childhood-Onset Schizophrenia 79
DIAGNOSTIC DILEMMAS
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80 Driver et al
compared with the later-onset cases,22–24,28,80 they are not diagnostic and do not
cumulatively represent a reliable premorbid phenotype. In addition, not only do healthy
children experience hallucinations but also children with various other psychiatric and
behavioral disturbances present with positive symptoms.81,82 Pressure from families,
the severity of the clinical picture, and time limitations placed on providers coalesce
to make a diagnosis of COS a tedious process fraught with pitfalls. The most common
disorders misdiagnosed as COS are affective disorders, organic psychosis, pervasive
developmental disorders, and a group referred to as having atypical psychosis or as
multidimensionally impaired (MDI). Details regarding these disorders, the last of which
is an important differential, will be described in detail later, and achieving diagnostic
clarity are described elsewhere in this issue.
The NIMH study was conducted from 1990 to 2017 and used nationwide recruit-
ment. More than 3000 referrals were screened during this period. Of these, 90%
were rejected from further consideration because they failed to meet the criteria for
COS. More than 300 children were screened in person, of whom approximately
60% received other psychiatric diagnoses, such as affective disorders, anxiety, or
behavioral disorders. More than 200 children who seemed likely to meet criteria for
COS were admitted to the research unit and underwent an initial observation period
followed by complete medication washout. After being observed off medications for
up to 3 weeks, an additional 20% of children did not meet criteria for COS and
received an alternative diagnosis. A 4-year to 6-year follow-up study of the ruled-
out cases indicated good stability of the alternative diagnoses and nonschizophrenic
status.76 The most frequent alternative diagnoses have been affective disorders and
anxiety disorders. A subgroup of children has also shown a form of atypical psychosis
provisionally labeled MDI28,96,97 based on a unique set of features, which warrants
further description.
Thirty three children have been given the provisional diagnosis of MDI after the medi-
cation washout period and have been followed prospectively along with the COS chil-
dren. This heterogeneous group of children, in general, has severe functional
impairment associated with transient psychotic symptoms, multiple developmental
abnormalities, abnormal neuropsychological test profiles, eye movement abnormal-
ities, and familial risk factors that are not adequately characterized by existing Diag-
nostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV)
categories.96,98,99 Despite the presence of overlapping symptoms with childhood
and EOS, there are distinct features that have been used as operational diagnostic
criteria by the NIMH group to distinguish these individuals96,98:
1. Brief, transient episodes of psychosis and perceptual disturbance, typically in
response to stress
2. Nearly daily periods of emotional lability disproportionate to precipitants
3. Impaired interpersonal skills despite the desire to initiate peer friendships (distinc-
tion from COS)
4. Cognitive deficits as indicated by multiple deficits in information processing
5. No clear thought disorder (clinically can be difficult to define, especially in the pres-
ence of communication disorder)
ADHD is highly comorbid in the MDI group.
At first glance, the symptom cluster these patients present suggests these
children will likely progress to develop schizophrenia spectrum disorders; in the
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Childhood-Onset Schizophrenia 81
PROCESS OF ELIMINATION
It has long been known that hallucinations, delusions, and disordered thoughts can
occur in healthy nonpsychotic children106 but usually diminish after age 6.89 Transient
anxiety-related and stress-related visual hallucinations also are occasionally reported
in preschool children,107 and the prognosis of these phenomena is benign. When
psychotic phenomena occur in school-aged children, however, they generally tend
to be more persistent and associated with drug toxicity or more significant mental
illness.1,108–110
COMORBIDITIES
COS is highly correlated with other illnesses and disorders (Box 1).24 During the eval-
uation of children with suspected COS, it is imperative they are screened, with a high
index of suspicion, for other comorbid illnesses and disorders, both psychiatric18 and
medical112 (see Table 4),111 the latter of which accounts for almost 60% of premature
deaths not related to suicide in adult schizophrenia patients.112,113
Box 1
Select comorbidities for childhood-onset schizophrenia
Psychiatric comorbidities
Obsessive-compulsive disorder
ADHD
Expressive language disorders
Receptive language disorders
Auditory processing deficits
Executive functioning deficits
Mood disorder, primarily major depressive disorder
Medical comorbidities associated with treatment
Diabetesa
Hyperlipidemiaa
Cardiovascular diseasea
Obesitya
Hyperprolactinemiaa
Dyskinesia
a
Highly correlated with the treatment of schizophrenia.111
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82 Driver et al
TREATMENT
REFERENCES
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Childhood-Onset Schizophrenia 83
5. Werry JS. Child and adolescent (early onset) schizophrenia: a review in light of
DSM-III-R. J Autism Dev Disord 1992;22(4):601–24.
6. McKenna K, Gordon CT, Rapoport JL. Childhood-onset schizophrenia: timely
neurobiological research. J Am Acad Child Adolesc Psychiatry 1994;33(6):
771–81.
7. Gordon CT, Frazier JA, McKenna K, et al. Childhood-onset schizophrenia: an
NIMH study in progress. Schizophr Bull 1994;20(4):697–712.
8. Gogtay N, Weisinger B, Bakalar JL, et al. Psychotic symptoms and gray matter
deficits in clinical pediatric populations. Schizophr Res 2012;140(1–3):149–54.
9. Rapoport JL, Gogtay N. Childhood onset schizophrenia: support for a progres-
sive neurodevelopmental disorder. Int J Dev Neurosci 2011;29(3):251–8.
10. Nicolson R, Malaspina D, Giedd JN, et al. Obstetrical complications and
childhood-onset schizophrenia. Am J Psychiatry 1999;156(10):1650–2.
11. Nicolson R, Giedd JN, Lenane M, et al. Clinical and neurobiological correlates of
cytogenetic abnormalities in childhood-onset schizophrenia. Am J Psychiatry
1999;156(10):1575–9.
12. De Hert M, Dobbelaere M, Sheridan EM, et al. Metabolic and endocrine adverse
effects of second-generation antipsychotics in children and adolescents: a sys-
tematic review of randomized, placebo controlled trials and guidelines for clin-
ical practice. Eur Psychiatry 2011;26(3):144–58.
13. Large M, Nielssen O, Slade T, et al. Measurement and reporting of the duration
of untreated psychosis. Early Interv Psychiatry 2008;2(4):201–11.
14. Singh SP. Outcome measures in early psychosis; relevance of duration of un-
treated psychosis. Br J Psychiatry Suppl 2007;50:s58–63.
15. Schimmelman BG, Conus P, Cotton SM, et al. Pre-treatment, baseline, and
outcome differences between early-onset and adult-onset psychosis in an
epidemiological cohort of 636 first-episode patients. Schizophr Res 2017;
95:1–8.
16. Stentebjerg-Olesen M, Pagsberg AK, Fink-Jensen A, et al. Clinical characteris-
tics and predictors of outcome of schizophrenia-spectrum psychosis in children
and adolescents: a systematic review. J Child Adolesc Psychopharmacol 2016;
26(5):410–27.
17. Jones HJ, Stergiakouli E, Tansey KE, et al. Phenotypic manifestation of genetic
risk for schizophrenia during adolescence in the general population. JAMA Psy-
chiatry 2016;73:221–8.
18. Riglin L, Collishaw S, Richards A, et al. Schizophrenia risk alleles and neurode-
velopmental outcomes in childhood: a population-based cohort study. Lancet
Psychiatry 2017;4(1):57–62.
19. Black K, Peters L, Rui Q, et al. Duration of untreated psychosis predicts treat-
ment outcome in an early psychosis program. Schizophr Res 2001;47(2–3):
215–22.
20. Done DJ, Crow TJ, Johnstone EC, et al. Childhood antecedents of schizo- phre-
nia and affective illness: social adjustment at ages 7 and 11. BMJ 1994;
309(6956):699–703.
21. Jones P, Rodgers B, Murray R, et al. Child development risk factors for adult
schizophrenia in the British 1946 birth cohort. Lancet 1994;344(8934):
1398–402.
22. Rapoport J, Chavez A, Greenstein D, et al. Autism spectrum disorders and
childhood-onset schizophrenia: clinical and biological contributions to a relation
revisited. J Am Acad Child Adolesc Psychiatry 2009;48(1):10–8.
Descargado para Anonymous User (n/a) en Universidad Libre de ClinicalKey.es por Elsevier en octubre 10, 2023. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
84 Driver et al
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exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
Childhood-Onset Schizophrenia 85
41. Cohen DJ, Paul R, Volkmar FR. Issues in the classification of pervasive and other
developmental disorders: toward DSM-IV. J Am Acad Child Psychiatry 1986;
25(2):213–20.
42. Ad-Dab’bagh Y, Greenfield B. Multiple complex developmental disorder: the
“multiple and complex” evolution of the “childhood borderline syndrome”
construct. J Am Acad Child Adolesc Psychiatry 2001;40(8):954–64.
43. Nicolson R, Lenane M, Brookner F, et al. Children and adolescents with psy-
chotic disorder not otherwise specified: a 2- to 8-year follow-up study. Compr
Psychiatry 2001;42(4):319–25.
44. Gogtay N, Ordonez A, Herman DH, et al. Dynamic mapping of cortical develop-
ment before and after the onset of pediatric bipolar illness. J Child Psychol Psy-
chiatry 2007;48(9):852–62.
45. Lukianowicz N. Hallucinations in non-psychotic children. Psychiatr Clin (Basel)
1969;2(6):321–37.
46. Caplan R. Thought disorder in childhood. J Am Acad Child Adolesc Psychiatry
1994;33(5):605–15.
47. Rothstein A. Hallucinatory phenomena in childhood. A critique of the literature.
J Am Acad Child Psychiatry 1981;20(3):623–35.
48. Abramowicz M. Drugs that cause psychiatric symptoms. Med Lett Drugs Ther
1993;35:65–70.
49. Davison K. Schizophrenia-like psychoses associated with organic cerebral dis-
orders: a review. Psychiatr Dev 1983;1(1):1–33.
50. McGee R, Williams S, Poulton R. Hallucinations in nonpsychotic children. J Am
Acad Child Adolesc Psychiatry 2000;39(1):12–3.
51. Lambert TJ, Velakoulis D, Pantelis C. Medical comorbidity in schizophrenia.
Med J Aust 2003;178(Suppl):S67–70.
52. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years
of potential life lost, and causes of death among public mental health clients in
eight states. Prev Chronic Dis 2006;3(2):A42.
53. Goff DC, Cather C, Evins AE, et al. Medical morbidity and mortality in schizo-
phrenia: guidelines for psychiatrists. J Clin Psychiatry 2005;66(2):183–94
[quiz: 147]. 273–4.
54. Ahn K, An SS, Shugart YY, et al. Common polygenic variation and risk for
childhood-onset schizophrenia. Mol Psychiatry 2016;21(1):94–6.
55. Zhou D, Gochman P, Broadnax DD, et al. 15q13.3 duplication in two patients
with childhood-onset schizophrenia. Am J Med Genet B Neuropsychiatr Genet
2016;171(6):777–83.
56. Hoffmann A, Ziller M, Spengler D. Childhood-onset schizophrenia: insights from
induced pluripotent stem cells. Int J Mol Sci 2018;19(12) [pii:E3829].
57. Curie A, Lesca G, Bussy G, et al. Asperger syndrome and early-onset schizo-
phrenia associated with a novel MECP2 deleterious missense variant. Psychiatr
Genet 2017;27(3):105–9.
58. Jolly LA, Homan CC, Jacob R, et al. The UPF3B gene, implicated in intellectual
disability, autism, ADHD and childhood onset schizophrenia regulates neural
progenitor cell behaviour and neuronal outgrowth. Hum Mol Genet 2013;
22(23):4673–87.
59. Ambalavanan A, Girard SL, Ahn K, et al. De novo variants in sporadic cases of
childhood onset schizophrenia. Eur J Hum Genet 2016;24(6):944–8.
60. Arinami T, Ohtsuki T, Takase K, et al. Screening for 22q11 deletions in a schizo-
phrenia population. Schizophr Res 2001;52(3):167–70.
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exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
86 Driver et al
61. Green T, Gothelf D, Glaser B, et al. Psychiatric disorders and intellectual func-
tioning throughout development in velocardiofacial (22q11.2 deletion) syn-
drome. J Am Acad Child Adolesc Psychiatry 2009;48(11):1060–8.
62. Monteiro FP, Vieira TP, Sgardioli IC, et al. Defining new guidelines for screening
the 22q11.2 deletion based on a clinical and dysmorphologic evaluation of 194
individuals and review of the literature. Eur J Pediatr 2013;172(7):927–45.
63. Ahn K, Gotay N, Andersen TM, et al. High rate of disease-related copy number
variations in childhood onset schizophrenia. Mol Psychiatry 2014;19(5):568–72.
64. McClellan J, Stock S, American Academy of Child and Adolescent Psychiatry
(AACAP) Committee on Quality Issues (CQI). Practice parameter for the assess-
ment and treatment of children and adolescents with schizophrenia. J Am Acad
Child Adolesc Psychiatry 2013;52(9):976–90.
65. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-
cardio-facial syndrome. Arch Gen Psychiatry 1999;56(10):940–5.
66. Gochman P, Miller R, Rapoport JL. Childhood-onset schizophrenia: the chal-
lenge of diagnosis. Curr Psychiatry Rep 2011;13(5):321–2.
67. Giedd JN, Jeffries NO, Blumenthal J, et al. Childhood-onset schizophrenia: pro-
gressive brain changes during adolescence. Biol Psychiatry 1999;46(7):892–8.
68. Giedd JN, Raznahan A, Alexander-Bloch A, et al. Child psychiatry branch of the
National Institute of Mental Health longitudinal structural magnetic resonance
imaging study of human brain development. Neuropsychopharmacology
2015;40(1):43–9.
69. Rapoport JL, Giedd J, Kumra S, et al. Childhood-onset schizophrenia. progres-
sive ventricular change during adolescence. Arch Gen Psychiatry 1997;54(10):
897–903.
70. Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia. A systematic and
quantitative review of volumetric magnetic resonance imaging studies. Br J Psy-
chiatry 1998;172:110–20.
71. Wright IC, Rabe-Hesketh S, Woodruff PW, et al. Meta-analysis of regional brain
volumes in schizophrenia. Am J Psychiatry 2000;157(1):16–25.
72. Shenton ME, Dickey CC, Frumin M, et al. A review of MRI findings in schizo-
phrenia. Schizophr Res 2001;49(1–2):1–52.
73. Anvari AA, Friedman LA, Greenstein D, et al. Hippocampal volume change re-
lates to clinical outcome in childhood-onset schizophrenia. Psychol Med 2015;
45(12):2667–74.
74. Weisinger B, Greenstein D, Mattai A, et al. Lack of gender influence on cortical
and subcortical gray matter development in childhood-onset schizophrenia.
Schizophr Bull 2013;39(1):52–8.
75. Johnson SL, Wang L, Alpert KI, et al. Hippocampal shape abnormalities of pa-
tients with childhood-onset schizophrenia and their unaffected siblings. J Am
Acad Child Adolesc Psychiatry 2013;52(5):527–36.e2.
76. Johnson SL, Greenstein D, Clasen L, et al. Absence of anatomic corpus callosal
abnormalities in childhood-onset schizophrenia patients and healthy siblings.
Psychiatry Res 2013;211(1):11–6.
77. Mattai A, Hosanagar A, Weisinger B, et al. Hippocampal volume development in
healthy siblings of childhood-onset schizophrenia patients. Am J Psychiatry
2011;168(4):427–35.
78. Ordóñez AE, Luscher ZI, Gogtay N. Neuroimaging findings from childhood
onset schizophrenia patients and their non-psychotic siblings. Schizophr Res
2016;173(3):124–31.
Descargado para Anonymous User (n/a) en Universidad Libre de ClinicalKey.es por Elsevier en octubre 10, 2023. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
Childhood-Onset Schizophrenia 87
79. Jacobsen LK, Giedd JN, Berquin PC, et al. Quantitative morphology of the cer-
ebellum and fourth ventricle in childhood onset schizophrenia. Am J Psychiatry
1997;154(12):1663–9.
80. Greenstein D, Lenroot R, Clasen L, et al. Cerebellar development in childhood
onset schizophrenia and non-psychotic siblings. Psychiatry Res 2011;193(3):
131–7.
81. Jardri R, Pouchet A, Pins D, et al. Cortical activations during auditory verbal hal-
lucinations in schizophrenia: a coordinate based meta-analysis. Am J Psychiatry
2011;168:73–81.
82. Moran ME, Weisinger B, Ludovici K, et al. At the boundary of the self: the insular
cortex in patients with childhood-onset schizophrenia, their healthy siblings, and
normal volunteers. Int J Dev Neurosci 2014;32:58–63.
83. Pantelis C, Yucel M, Wood SJ, et al. Structural brain imaging evidence for mul-
tiple pathological processes at different stages of brain development in schizo-
phrenia. Schizophr Bull 2005;31(3):672–96.
84. Mathalon DH, Sullivan EV, Lim KO, et al. Progressive brain volume changes and
the clinical course of schizophrenia in men: a longitudinal magnetic resonance
imaging study. Arch Gen Psychiatry 2001;58(2):148–57.
85. Gur RE, Cowell P, Turetsky BI, et al. A follow-up magnetic resonance imaging
study of schizophrenia. Relationship of neuroanatomical changes to clinical
and neurobehavioral measures. Arch Gen Psychiatry 1998;55(2):145–52.
86. Lieberman J, Chakos M, Wu H, et al. Longitudinal study of brain morphology in
first episode schizophrenia. Biol Psychiatry 2001;49(6):487–99.
87. DeLisi LE. Regional brain volume change over the life-time course of schizo-
phrenia. J Psychiatr Res 1999;33(6):535–41.
88. Berman RA, Gotts SJ, McAdams HM, et al. Disrupted sensorimotor and social-
cognitive networks underlie symptoms in childhood-onset schizophrenia. Brain
2016;139(Pt 1):276–91.
89. Jacobson S, Kelleher I, Harley M, et al. Structural and functional brain correlates
of subclinical psychotic symptoms in 11-13 year old school children. Neuro-
image 2010;49:1875–88.
90. Gogtay N. Cortical brain development in schizophrenia: insights from neuroi-
maging studies in childhood-onset schizophrenia. Schizophr Bull 2008;
34(1):30–6.
91. Luders E, Narr KL, Thompson PM, et al. Mapping cortical gray matter in the
young adult brain: effects of gender. Neuroimage 2005;26(2):493–501.
92. Thompson PM, Mega MS, Vidal C, et al. Detecting disease specific patterns of
brain structure using cortical pattern matching and a population-based probabi-
listic brain Atlas, IEEE conference on information processing in medical imaging
(IPMI), UC Davis 2001. In: Insana M, Leahy RM, editors. Lecture notes in Com-
puter Science (LNCS), vol. 2082. Berlin: Springer-Verlag; 2001. p. 488–501.
93. Thompson PM, Giedd JN, Woods RP, et al. Growth patterns in the developing
brain detected by using continuum mechanical tensor maps. Nature 2000;
404(6774):190–3.
94. Gogtay N, Giedd JN, Lusk L, et al. Dynamic mapping of human cortical devel-
opment during childhood through early adulthood. Proc Natl Acad Sci U S A
2004;101(21):8174–9.
95. Watsky RE, Pollard KL, Greenstein D, et al. Severity of cortical thinning corre-
lates with schizophrenia spectrum symptoms. J Am Acad Child Adolesc Psychi-
atry 2016;55(2):130–6.
Descargado para Anonymous User (n/a) en Universidad Libre de ClinicalKey.es por Elsevier en octubre 10, 2023. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
88 Driver et al
Descargado para Anonymous User (n/a) en Universidad Libre de ClinicalKey.es por Elsevier en octubre 10, 2023. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
Childhood-Onset Schizophrenia 89
116. Al-Dhaher Z, Kapoor S, Saito E, et al. Activating and tranquilizing effects of first-
time treatment with aripiprazole, olanzapine, quetiapine, and risperidone in
youth. J Child Adolesc Psychopharmacol 2016;26(5):458–70.
117. Ienciu M, Romosan F, Bredicean C, et al. First episode psychosis and treatment
delay–causes and consequences. Psychiatr Danub 2010;22(4):540–3.
118. Franz L, Carter T, Leiner AS, et al. Stigma and treatment delay in first-
episode psychosis: a grounded theory study. Early Interv Psychiatry 2010;
4(1):47–56.
119. Norman RM, Mallal AK, Manchanda R, et al. Does treatment delay predict occu-
pational functioning in first-episode psychosis? Schizophr Res 2007;91(1–3):
259–62.
120. Compton MT, Esterberg ML. Treatment delay in first-episode nonaffective psy-
chosis: a pilot study with African American family members and the theory of
planned behavior. Compr Psychiatry 2005;46(4):291–5.
121. Harrigan SM, McGorry PD, Krstev H. Does treatment delay in first-episode psy-
chosis really matter? Psychol Med 2003;33(1):97–110.
122. Vera I, Rezende L, Molina V, et al. Clozapine as treatment of first choice in first
psychotic episodes. What do we know? Actas Esp Psiquiatr 2012;40(5):281–9.
123. Pagsberg AK, Tarp S, Glintborg D, et al. Acute antipsychotic treatment of chil-
dren and adolescents with schizophrenia spectrum disorders: a systematic re-
view and network meta-analysis. J Am Acad Child Adolesc Psychiatry 2017;
56(3):191–202.
124. Lewis DA, Gonzalez-Burgos G. Neuroplasticity of neocortical circuits in schizo-
phrenia. Neuropsychopharmacology 2008;33(1):141–65.
125. Beneyto M, Lewis DA. Insights into the neurodevelopmental origin of schizo-
phrenia from postmortem studies of prefrontal cortical circuitry. Int J Dev Neuro-
sci 2011;29(3):295–304.
126. Howes OD, Bose SK, Turkheimer F, et al. Dopamine synthesis capacity before
onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am J Psychi-
atry 2011;168(12):1311–7.
127. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III–the
final common pathway. Schizophr Bull 2009;35(3):549–62.
128. Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, “just the facts” what
we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008;
102(1–3):1–18.
129. Tsuang MT, Faraone SV. The case for heterogeneity in the etiology of schizo-
phrenia. Schizophr Res 1995;17(2):161–75.
130. Walsh T, McClellan JM, McCarthy SE, et al. Rare structural variants disrupt mul-
tiple genes in neurodevelopmental pathways in schizophrenia. Science 2008;
320(5875):539–43.
131. Green WH, Padron-Gayol M, Hardesty AS, et al. Schizophrenia with childhood
onset: a phenomenological study of 38 cases. J Am Acad Child Adolesc Psychi-
atry 1992;31(5):968–76.
132. Garralda ME. Hallucinations in children with conduct and emotional disorders:II.
The follow-up study. Psychol Med 1984;14(3):597–604.
133. Garralda ME. Hallucinations in children with conduct and emotional disorders: I.
The clinical phenomena. Psychol Med 1984;14(3):589–96.
134. Calderoni D, Wudarsky M, Bhangoo R, et al. Differentiating childhood-onset
schizophrenia from psychotic mood disorders. J Am Acad Child Adolesc Psy-
chiatry 2001;40(10):1190–6.
Descargado para Anonymous User (n/a) en Universidad Libre de ClinicalKey.es por Elsevier en octubre 10, 2023. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
90 Driver et al
135. McKenna K, Gordon CT, Lenane M, et al. Looking for childhood-onset schizo-
phrenia: the first 71 cases screened. J Am Acad Child Adolesc Psychiatry
1994;33(5):636–44.
136. Kumra S, Briguglio C, Lenane M, et al. Including children and adolescents
with schizophrenia in medication-free research. Am J Psychiatry 1999;156(7):
1065–8.
Descargado para Anonymous User (n/a) en Universidad Libre de ClinicalKey.es por Elsevier en octubre 10, 2023. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.