REVIEW
Childhood-Onset Schizophrenia: Rare but Worth
Studying
Rob Nicolson and Judith L. Rapoport
Childhood-onset schizophrenia (defined by an onset of
psychosis by age 12) is a rare and severe form of the
disorder that is clinically and neurobiologically continu-
ous with the adult-onset disorder. There is growing
evidence for more salient risk or etiologic factors, partic-
ularly familial, in this possibly more homogenous patient
population. For the 49 patients with very early onset
schizophrenia studied to date at the National Institute of
Mental Health, there were more severe premorbid neuro-
developmental abnormalities, a higher rate of cytogenetic
anomalies, and a seemingly higher rate of familial schizo-
phrenia and spectrum disorders than later onset cases.
There was no evidence for increased obstetric complica-
tions or environmental stress. These data, while prelimi-
nary, suggest that a very early age of onset of schizophre-
nia may be secondary to greater familial vulnerability.
Consequently, genetic studies of these patients may be
particularly informative and may provide important etiologic
information. Biol Psychiatry 1999;46:1418 –1428
Key Words: Schizophrenia, genetics, family studies
Introduction
A ge of onset of illness has provided an avenue to the
understanding of disease across all of medicine, with
earlier onset cases often having more striking genetic and
environmental influence, differing pathophysiologies, or
both (Childs and Scriver 1986). In some cases, the early
onset disorder may be physiologically and etiologically
different from the later onset illness. For example, the
study of early onset disease led to a description of different
and important mechanisms of illness in insulin-dependent
diabetes mellitus (Weiss 1993). Moreover, important mo-
lecular genetic discoveries in human diseases as diverse as
breast cancer (FitzGerald et al 1996) and Alzheimer’s
disease (St. George-Hyslop et al 1996) have been tied to
an earlier age of onset of illness, attesting to the impor-
tance of the present topic. Studies of patients with depres-
sion and anxiety disorders with an onset in childhood
From the Child Psychiatry Branch, National Institute of Mental Health, Bethesda,
Maryland.
Address reprint requests to Rob Nicolson, Building 10, Room 3N202, 10 Center
Drive MSC 1600, Bethesda, MD 20892-1600.
Received June 17, 1999; revised August 6, 1999; accepted August 10, 1999.
Published 1999 by Elsevier Science Inc.
suggest these conditions may be more homogenous and
etiologically unique subgroups (Rapoport, in press).
Although most cases of schizophrenia have their onset
in late adolescence and early adulthood (Hafner et al
1993), the disorder has been identified in children since
early in the 20th century (Bleuler 1911/1950; DeSanctis
1906; Kraepelin 1899). Despite this identification, the
nosological status of schizophrenia in children was con-
troversial for many years, and the DSM-II category
“childhood schizophrenia” included a variety of psychotic
disorders in children as well as autistic disorder (American
Psychiatric Association 1968), limiting the usefulness of
early studies. By 1971, however, the landmark studies by
Kolvin (1971) clearly differentiated schizophrenia with
onset in childhood from the pervasive developmental
disorders.
Since 1990, a study of childhood-onset schizophrenia
has been ongoing at the National Institute of Mental
Health (NIMH) (Gordon et al 1994; Jacobsen and Rap-
oport 1998). The study first addressed the continuity of
childhood- and adult-onset schizophrenia. It is now exam-
ining the association between this early onset form of the
disorder and familial and proband risk factors. These
results, indicating potent familial factors as the basis for
this rare subgroup of patients, suggest that future studies of
these patients may provide important information about
the etiology of the disorder.
Is Childhood-Onset Schizophrenia
Continuous with Adult-Onset
Schizophrenia?
The question of continuity between early and later onset
schizophrenia is fundamental to other aspects of research
on very early onset schizophrenia. If the illness is the same
as the adult-onset disorder, childhood-onset schizophrenia
may provide important etiologic clues. If continuity cannot
be demonstrated, then any findings from studies of
childhood-onset schizophrenia would have limited
generalization.
The NIMH study first addressed the continuity question
comprehensively (Gordon et al 1994; Jacobsen and Rap-
oport 1998; McKenna et al 1994). Examination of the
phenomenology, neuropsychology, and neurobiology of
these patients has provided strong evidence that child-
0006-3223/99/$20.00
PII S0006-3223(99)00231-0
Childhood-Onset Schizophrenia BIOL PSYCHIATRY 1419
1999;46:1418 –1428

Table 1. Childhood-Onset Schizophrenia: Continuity with Adult-Onset Schizophrenia

Continuity with Resemblance to
adult-onset adults with poor
Measure schizophrenia outcome Reference
Clinical presentation ⫹ (by definition) ⫹ Gordon et al 1994
McKenna et al 1994
Premorbid function ⫹ ⫹ Alaghband-Rad et al 1995
Hollis 1995
Neuropsychology ⫹ ⫹ Asarnow RF et al 1994
Kumra et al, in press
Autonomic functioning ⫹ ⫹ Zahn et al 1997
SPEM abnormalities ⫹ ⫹ Jacobsen et al 1996b
Kumra et al 1998
Anatomic brain MRI ⫹ ⫹ Frazier et al 1996a
Jacobsen et al 1997a, 1997b
PET ⫹ ⫺ Jacobsen et al 1997d
MRS ⫹ ⫺ Bertolino et al 1998
SPEM, smooth pursuit eye movement; MRI, magnetic resonance imaging; PET, positron emission tomography; MRS,
magnetic resonance spectroscopy.

hood-onset schizophrenia is clinically and biologically
continuous with later onset forms of the disorder. As the
data supporting continuity have been reviewed in detail
elsewhere (Jacobsen and Rapoport 1998), these studies are
briefly summarized below and in Table 1.
Clinical Features
Whereas early studies of children with schizophrenia were
plagued by problems of diagnostic heterogeneity (Werry
1996), recent studies have demonstrated that schizophre-
nia can be diagnosed reliably in children with the use of
the same criteria as those applied to adults (Gordon et al
1994; Green et al 1992; Russell 1994; Spencer and
Campbell 1994). Although male patients constitute 60% of
the NIMH sample, there have been few gender differences
in clinical or biological parameters. In keeping with
gender differences in other childhood developmental dis-
orders, however, 21 of the 29 male patients but only six of
the 19 female patients (␹2 ⫽ 7.8, df ⫽ 1, p ⫽ .005) had
premorbid motor abnormalities, including delayed mile-
stones, abnormal movements, and clumsiness or poor
coordination (Nicolson et al 1998). There was no excess of
undifferentiated and disorganized subtypes, and, surpris-
ingly, the paranoid subtype was as frequent as seen in
adult disorders. As patients in the NIMH study were all
treatment refractory, it is not surprising that they resemble
adult patients with poor outcome in various ways. How-
ever, others, using unselected series of patients, have also
found childhood-onset schizophrenia to be a severe disor-
der with a generally poor outcome (Asarnow JR et al
1994). A preliminary analysis of 4-year outcome data on
the NIMH cohort has similarly found that a systematic
diagnosis of childhood-onset schizophrenia is stable over
time, with a chronic illness being the rule (Lenane M
unpublished data).
Premorbid Course
Patients with schizophrenia have been shown to have
subtle but demonstrable impairments in their premorbid
language as well as in their motor and social development
(Done et al 1994; Jones et al 1994), and a poor outcome in
schizophrenia is correlated with more pronounced early
developmental abnormalities (Gupta et al 1995). Several
independent studies have found that very early onset
schizophrenia is associated with similar but more pro-
nounced abnormalities (Alaghband-Rad et al 1995; Asar-
now and Ben-Meir 1988; Hollis 1995; Russell et al 1989;
Watkins et al 1988). Hollis (1995), for example, reported
that patients with an onset of schizophrenia before age 13
had significantly more premorbid language delays and
difficulties than did patients with onset later in
adolescence.
The prepsychotic developmental data from the 49
NIMH patients confirms and extends these findings. To
date, 55% had language abnormalities, 57% had motor
abnormalities, and 55% had social abnormalities years
before the onset of psychotic symptoms. There was an
exceedingly high rate of failed grades and special educa-
tion placement. Thirty-one patients (63.3%) had either
failed a grade or required placement in a special education
setting before the onset of their illness (Nicolson et al
1998).
These findings argue for a more severe early disruption
of brain development in childhood-onset schizophrenia
than for adult-onset cases. Evidence from our study and
parallel ones at other centers (reviewed below) suggests
1420 BIOL PSYCHIATRY R. Nicolson and J.L. Rapoport
1999;46:1418 –1428

Table 2. MRI Brain Anatomy in Childhood-Onset Schizophrenia

ANOVA ANCOVAa
Measure F p F p Commentb
Total cerebral volume 4.3 .04
White matter 0.4 .5 29.5 .0001 COS ⬎ NC
Gray matter 13.0 .0005 44.7 .0001 COS ⬍ NC
Prefrontal 6.9 .01 2.5 .1
Temporal lobe 0.01 .9 4.5 .04 COS ⬎ NC
● Subdivisions not significantly
different
● Planum temporale asymmetry
not different between COS
and NC
Cerebellum 10.3 .003 7.8 .008 COS ⬍ NC
● COS had decreased midsagittal
vermal area and inferior
posterior lobe (VIII–X)
Lateral ventricles 10.9 .001 13.5 .0004 COS ⬎ NC
Hippocampus 0.7 .4 0.3 .6 NC: L ⬎ R; COS: L ⫽ R
Amygdala 0.01 .9 0.7 .4 NC: L ⬎ R; COS: L ⬎⬎ R
Thalamus (area) 20.3 .0001 15.3 .0002 COS ⬍ NC
a
ANCOVA covaried for total brain volume; all p values are 2-tailed.
b
COS, childhood-onset schizophrenia (n ⫽ 41); NC, healhy control subjects (n ⫽ 63).

that this group of patients with greater disruptions of
premorbid development also has a greater familial vulner-
ability for schizophrenia, indicating that their earlier age of
onset may be due, in part, to more aberrant neurodevel-
opment secondary to a higher level of familial loading for
schizophrenia.
Neuropsychology
Adults with schizophrenia have particularly poor neuro-
psychological functioning in the areas of attention, work-
ing memory, and executive function (Goldberg and Gold
1995). Several studies in patients with childhood-onset
schizophrenia (Asarnow RF et al 1994), including studies
with the NIMH cohort (Kumra et al, in press), have
obtained similar findings.
Brain Morphology
Magnetic resonance imaging abnormalities of brain mor-
phology have been observed in most studies of adults with
schizophrenia (McCarley et al 1999), and childhood-onset
schizophrenics have similar abnormalities (Frazier et al
1996a; Jacobsen et al 1997a, 1997b). Initial scans of 41
childhood-onset schizophrenia patients and 63 matched
control subjects (see Table 2) showed the expected in-
crease in lateral ventricular volume with decreased cere-
bellar volume and midsagittal thalamic area. Whereas
reductions in the volumes of the anterior frontal and
medial temporal lobe structures were not found (Frazier et
al 1996a; Jacobsen et al 1996a, 1997c) on initial scans,
there was evidence for progression during adolescence
such that by late adolescence their scans resembled those
of adult patients with respect to these structures (Giedd et
al 1999; Jacobsen et al 1998a; Rapoport et al 1997, 1999).
While brain changes have been noted after treatment with
atypical antipsychotics (Chakos et al 1995; Frazier et al
1996b), the differential progression for the NIMH patients
does not appear to be accounted for by such confounds as
it is time limited (chiefly between ages 13 and 18) and
occurs independent of the dose and type of antipsychotic
as well as clinical condition. Most intriguing is the finding
that the hippocampal decrease seen during this period is
related to the decreased ability of these patients to learn
new information (Bedwell et al, in press).
Although the role of medication in these changes appears
to be insignificant, it cannot be excluded completely. How-
ever, another group of patients with transient psychotic
symptoms and behavioral dyscontrol have also been fol-
lowed clinically and with longitudinal magnetic resonance
imaging scans at the NIMH (Kumra et al 1988). An analysis
of the brain changes of these patients, the majority of whom
take antipsychotics because of their disruptive behavior, is
under way and may permit a greater understanding of the role
of antipsychotics in the progressive brain changes seen in
patients with childhood-onset schizophrenia.
Functional and Metabolic Brain Imaging
Although studies of resting brain metabolism in adults
with schizophrenia have produced conflicting results,
Childhood-Onset Schizophrenia
studies of cerebral metabolism during activation tasks
have more consistently revealed frontal hypometabolism
(Swanson et al 1997). Patients with childhood-onset
schizophrenia were noted to have somewhat similar ab-
normalities in a positron emission tomography (PET)
study. Although interpretation of hypofrontality in these
patients is limited as they could not adequately perform
the activation task, hypofrontality was not more salient for
these early onset cases (Jacobsen et al 1997d).
Magnetic resonance spectroscopy study of childhood-
onset schizophrenic patients revealed decreases in the ratio
of NAA to creatine (a putative marker of neuronal density)
in the frontal cortex and hippocampus (Bertolino et al
1998; Thomas et al 1998). These results are similar in
direction and extent to those seen in adult patients (Keg-
eles et al 1998).
Autonomic Functioning
Abnormalities in peripheral indicators of autonomic activ-
ity (such as skin conductance and heart rate) have been
noted in adult-onset schizophrenia. A study of autonomic
functioning in patients with childhood-onset schizophrenia
found them to be similar on this measure to adults with
chronic, poor outcome schizophrenia (Zahn et al 1997).
Smooth Pursuit Eye Movements
From 40% to 80% of patients with adult-onset schizophre-
nia have abnormalities in smooth pursuit eye movements,
and the finding of similar abnormalities in their relatives
suggests that this abnormality may be a genetic marker of
vulnerability to the illness (Levy et al 1993). Patients with
childhood-onset schizophrenia have abnormalities similar
to those reported in adult patients: decreased gain (ratio of
eye speed to target speed), increased root mean square
error (global level of aberrant tracking), and increased
anticipatory saccades (Jacobsen et al 1996b; Kumra et al
1998). Additionally, 67% of childhood-onset schizophren-
ics had qualitatively poor eye tracking. While these results
are similar to those of adult patients, Ross et al (1999)
have reported an increased rate of anticipatory saccades in
a small group of childhood-onset probands when com-
pared with adult-onset patients.
In sum, independent studies show clinical and biologi-
cal continuity between childhood- and adult-onset schizo-
phrenia. As the patients in the NIMH study were selected
for a poor treatment response, comparison with unselected
adult-onset schizophrenic patients may not be entirely
appropriate. However, this treatment refractory group
resembled refractory, chronically ill adult patients with
schizophrenia. The clear continuity has allowed us to turn
to the more intriguing and potentially more important
question of which risk factors are increased in patients that
BIOL PSYCHIATRY 1421
1999;46:1418 –1428
develop schizophrenia at such an early age when com-
pared with community control subjects and adult-onset
patients.
Is Childhood-Onset Schizophrenia
Associated with More Salient Risk Factors?
Virtually all models of schizophrenia include genetic and
environmental components. The earlier age of onset in
childhood-onset schizophrenia, as Kallmann and Roth
(1956) noted, may be because of a “factor or combination
of factors which in some cases leads to clinically recog-
nizable symptoms at an unusually young age” (p 599).
These “factors” may include a greater genetic diathesis,
more potent environmental insults, or a combination of
both.
A number of environmental factors, including prenatal
maternal infections and perinatal complications, have been
implicated in the pathogenesis of schizophrenia. As well,
the correlation of less than 1.0 for age of onset in
monozygotic twins concordant for schizophrenia suggests
that nongenetic factors may play a role in determining the
age of onset (Kendler et al 1987, 1996). A greater
frequency or severity of these factors could result in an
earlier onset of schizophrenia, and, indeed, at least for
adult-onset patients, obstetric complications have been
associated with an earlier age of onset (O’Callaghan et al
1993; Verdoux et al 1997).
Alternatively, the earlier age of onset may be related to
a greater genetic vulnerability. As discussed previously,
increased familiality has been observed in a number of
early onset disorders (Childs and Scriver 1986). Familial
illness reported for childhood-onset schizophrenic patients
in a very early study (Kallmann and Roth 1956) was not
higher than that for adult patients, but this study undoubt-
edly included a number of patients with pervasive devel-
opmental disorders. More notably, Kolvin et al (1971),
using more modern diagnostic criteria, found a high rate of
introversion (50%) and sensitive or suspicious (42%)
personalities among the parents of their childhood-onset
schizophrenic patients, suggesting the possibility of a high
rate of spectrum personality disorders and a greater ge-
netic diathesis in this population.
Risk factors potentially associated with the earlier age of
onset in childhood-onset schizophrenia are discussed below.
Obstetric Complications
Patients with adult-onset schizophrenia have been reported
to have an increased rate of obstetric complications when
compared with sibling (Eagles et al 1990; Gunther-Genta
et al 1994) or community (O’Callaghan et al 1993) control
subjects, although not all studies have found similar results
1422 BIOL PSYCHIATRY
1999;46:1418 –1428
Table 3. Prenatal and Perinatal Events in Childhood-Onset Schizophrenia
Childhood-Onset
Schizophrenia
Measurea (n ⫽ 36)
Buka Scale 10 (28%)
Lewis Scale 13 (36%)
a
Only definite complications were rated on both scales. No significant differences between childhood-onset schizophrenics
and siblings on either scale.
(Done et al 1991). A meta-analysis also demonstrated an
increased rate of obstetric complications in patients with
adult-onset schizophrenia (Geddes and Lawrie 1995), and
a reanalysis of the original data from a number of studies
found that birth complications were greater in patients
with an earlier onset of illness (Verdoux et al 1997).
Blinded scoring of the birth records of 36 patients with
childhood-onset schizophrenia and 35 sibling control sub-
jects found no significant differences between the groups
(Nicolson et al in press-a). Moreover, the rate of compli-
cations in the early onset patients of the NIMH study was
similar to that seen in adult-onset patients (see Table 3).
These preliminary results, as well as the work of others
(Frangou 1999), suggest that, while obstetric complica-
tions may play a role in the development of schizophrenia
in some patients, they are not, as previously hypothesized
(Lewis et al 1989), more salient in childhood-onset cases.
Other environmental factors, such as socioeconomic
status and unusual psychological trauma, do not appear
clinically to account for the earlier age of onset in this
cohort, although, as with all studies of rare disorders, an
inevitable ascertainment bias exists. Similarly, there is no
evidence that the earlier age of onset is due to early
puberty (Frazier et al 1997).
In summary, investigation of some nongenetic factors
for our very early onset cohort have not revealed more
salient features than in adult-onset schizophrenia. These
investigations complement other data suggesting that more
potent familial factors may be related to the earlier age of
onset in childhood-onset schizophrenia.
Familial Factors
Genetic factors play a significant role in the pathogenesis
of schizophrenia (Kendler and Diehl 1993), and the notion
that such factors may be more salient in very early onset
cases, as noted above, has fueled two classic family
studies of childhood-onset schizophrenia (Kallmann and
Roth 1956; Kolvin et al 1971).
In studies of adult patients, age of onset in schizophre-
nia has a lower correlation between affected siblings
R. Nicolson and J.L. Rapoport
Siblings Adult-Onset
(n ⫽ 35) Schizophrenia References
16 (46%) 50%– 67% Buka et al 1993
Jones et al 1998
Nicolson et al, in press-a
12 (34%) 21%–32% Nicolson et al, in press-a
O’Callaghan et al 1993
Verdoux et al 1997
(approximately 0.26) and concordant dizygotic twins (ap-
proximately 0.30) than between concordant monozygotic
twins (mean r ⫽ .68) (Kendler et al 1987), suggesting
genetic influences on age of onset. Although some studies
find a relationship between pedigree density and age of
onset (Pulver and Liang 1991; Suvisaari et al 1998), others
have not (Kendler et al 1987, 1996). This inconsistency, in
combination with the higher correlation between age of
onset in concordant monozygotic twins when compared
with dizygotic twins, suggests that age of onset may be
influenced by genetic factors unrelated to the disease
liability. However, there are to date no published studies
of the relationship between age of onset and family
loading in childhood-onset samples, and the possibility
remains that very early onset cases may reveal more
unique or potent genetic factors.
Schizophrenia and spectrum disorders (schizoaffective
disorder and schizotypal and paranoid personality disor-
ders) are increased in the relatives of patients with schizo-
phrenia (Kendler et al 1993a, 1993b, 1993c), and adoption
studies (Kendler et al 1994; Kety et al 1994) document the
genetic basis for these spectrum disorders. First-degree
relatives of the NIMH cohort 18 years of age and over
were administered the Schedule for Affective Disorders
and Schizophrenia and the Structured Interview for
DSM-IV Personality Disorders (n ⫽ 114). With the use of
a hierarchical method to assign diagnoses (Kendler 1988),
29 (25.4%) first-degree relatives met criteria for schizo-
phrenia or a spectrum disorder: two for schizophrenia,
another for schizoaffective disorder; 13 met criteria for
schizotypal personality disorder; and a further 13 met
criteria for paranoid personality disorder. Twenty-two
(44.9%) of the probands had at least one relative with a
spectrum disorder (Lenane et al 1999).
As shown in Table 4, the rates of the more disabling
disorders (schizophrenia and schizoaffective disorder) in
relatives of the childhood-onset patients were similar to
those seen in relatives of adult-onset patients. This rate
may be because of an ascertainment bias inherent in a
national study of a rare disorder, which involves long
Childhood-Onset Schizophrenia
Table 4. Ratesa of Schizophrenia Spectrum Disorders in First-Degree Relatives of Childhood-
Onset Schizophrenics
Relatives of
Childhood-Onset
Diagnosis Schizophrenics
Schizophrenia 2/114 (1.8%)
Schizoaffective disorder 1/112 (0.9%)
Schizotypal personality disorder 13/111 (11.7%)
Paranoid personality disorder 13/98 (13.3%)
Any schizophrenia spectrum disorder 29/114 (25.4%)
a
Rates determined using hierarchical method (Kendler 1988).
b
Kendler et al 1993a, 1993b, 1993c.
distance travel and parental participation. As such, parents
who were severely ill and their children could not partic-
ipate. However, there appears to be a striking excess of
schizotypal and paranoid personality disorders in the
relatives of these patients. Although these data are prelim-
inary and based on unblinded interviews, they are in
accordance with results from the ongoing University of
California at Los Angeles study of childhood-onset
schizophrenia (Asarnow 1999) in which significant eleva-
tions of schizophrenia spectrum disorders in the relatives
of childhood-onset schizophrenics when compared with
control subjects and previous family studies of adult-onset
schizophrenic patients have also been found with the use
of carefully blinded interviews. Together, these studies
suggest a more striking role for familial factors in these
very early onset patients.
In the NIMH study, a family history of schizophrenia
spectrum disorders was related to premorbid impairments
in the proband. Seventeen of the 22 patients (77.3%) with
relatives with schizophrenia spectrum disorders had pre-
morbid language abnormalities, whereas only 10 of the 26
subjects (38.5%) without a similar family history had early
speech and language difficulties (␹2 ⫽ 7.3, df ⫽ 1, p ⫽
.007) (Nicolson et al 1998). This relationship is intriguing
as British and American birth cohort studies (Bearden et al
1999; Done et al 1994; Jones et al 1994) have found
aberrant speech and language development in infancy and
childhood to be significantly increased in those who later
developed schizophrenia. Early language impairments also
appear to be predictive of schizophrenia as well as other
disorders: Rutter and Mawhood (1991) reported that three
of 25 children with severe receptive language disorders
developed schizophrenia, all during adolescence. Our
finding of an association with spectrum disorders in
relatives supports a model in which specific disease-
related factors interact with a more general liability or,
more interestingly, could indicate that genes involved in
the etiology of schizophrenia also interfere with the
neurodevelopment of language-related brain regions.
Another indirect measure of familial risk for schizo-
BIOL PSYCHIATRY 1423
1999;46:1418 –1428
Relatives of Adult- Relatives of
Onset Schizophrenic Normal Control
Patientsb Subjectsb
6.5% 0.5%
2.3% 0.7%
6.9% 1.4%
1.4% 0.4%
~17.1% ~3.0%
phrenia is smooth pursuit eye movements, which have
been proposed as a marker of liability to schizophrenia in
unaffected relatives of probands (Levy et al 1993). To
date, 56 relatives (age 14 years and over) of our probands
have been examined, and, with the use of qualitative
ratings, 8 (14.3%) were determined to have abnormal eye
tracking, whereas only one of 42 control subjects (2.4%)
had similar results (p ⫽ .04). The relatives also had greater
root mean square errors (p ⫽ .02) (Nicolson et al 1999). In
the NIMH study, therefore, these abnormalities do not
appear to be increased in comparison with the relatives of
adult-onset patients. However, Ross et al (1999) have
reported that anticipatory saccades are greater in the
relatives of childhood-onset patients than in those of
adult-onset patients, and childhood-onset patients also
have a greater likelihood of having both parents demon-
strate this abnormality.
Other Genetic Studies
An increased rate of sex chromosome abnormalities has
been reported in adult-onset schizophrenia (DeLisi et al
1994), and other chromosomal abnormalities have also
been found (Bassett 1992; Karayiorgou and Gogos 1997).
Cytogenetic abnormalities have been examined in the
NIMH childhood-onset schizophrenia cohort. Five of our
49 patients had cytogenetic abnormalities (a girl with
Turner’s syndrome, a boy with a balanced translocation of
chromosomes 1 and 7, and two girls and a boy with
velocardiofacial syndrome [deletion 22q11]) (Nicolson et
al, in press-b), a rate that appears to be higher than that
seen in adult-onset schizophrenia. However, all five of
these patients had other risk factors for schizophrenia (a
family history of schizophrenia spectrum disorder, familial
eye-tracking dysfunction, or obstetric complications),
which is consistent with most models of schizophrenia that
implicate several genes (Risch 1990). Rather than suggest-
ing a specific association between gross chromosomal
disruptions and a very early onset of schizophrenia, these
data may be more compatible with a model in which the
1424 BIOL PSYCHIATRY R. Nicolson and J.L. Rapoport
1999;46:1418 –1428

Table 5. Childhood-Onset Schizophrenia: Association with Risk and Etiologic Factors

Measure
Cytogenetic abnormalities
Schizophrenia spectrum
disorders in relatives
SPEM abnormalities in
relatives
Birth complications
Early language and motor
abnormalities
Pubertal timing
SPEM, smooth pursuit eye movement.
Abnormality More Striking
Relative to than Adult-
Control Subjects Onset Patients
⫹ ⫹
⫹ ⫹ (?)
⫹ ⫺ (?)
⫺ ⫺
⫹ ⫹
⫺ ⫺
Comment/Reference
Nicolson et al, in press-b
Possible ascertainment bias,
data not examined in blind
fashion (Lenane et al 1999)
Nicolson et al 1999
Nicolson et al, in press-a
Significant association with
schizophrenia spectrum
disorders in relatives
(Nicolson et al 1998)
Frazier et al 1997

interaction of a greater level of aberrant neurodevelopment cytogenetic abnormalities. As summarized in Table 5, a

(because of, among other things, cytogenetic abnormali-
ties) and more specific risk factors for schizophrenia
(familial eye-tracking dysfunction and a family history of
schizophrenia spectrum disorders) results in an unusually
early age of onset of the disorder.
Trinucleotide repeats, human leukocyte antigen (HLA),
and apolipoprotein (APO) E4 have been investigated as
possible etiologic factors in adult-onset schizophrenia with
conflicting results (Karayiorgou and Gogos 1997). In the
NIMH childhood-onset patients, no association was seen
for APO E4 (Fernandez et al 1999), HLA (Jacobsen et al
1998b), or trinucleotide repeats (Sidransky et al 1998).
Thus, whereas these factors might play a role in schizo-
phrenia (and the literature generally does not support this),
they are not more salient in patients with childhood-onset
schizophrenia.
The possibility remains that other genetic protective or
liability factors unrelated to the illness itself will be
important for childhood-onset cases. Several examples
exist of “protective” genes affecting the expression or
inheritance of disorders, including acquired immunodefi-
ciency syndrome (Picchio et al 1997), Alzheimer’s disease
(Corder et al 1994), and diabetes (Wicker et al 1994).
Recently, Ginns et al (1998) have reported protective
genes in bipolar disorder that seem to prevent or modify
the clinical manifestations of the disorder.
In summary, patients with childhood-onset schizophre-
nia have more significant premorbid abnormalities than
adult-onset schizophrenic patients and appear to have a
greater history of schizophrenia spectrum disorders in
their first-degree relatives. Although eye movement ab-
normalities are also increased in the families, the rates of
eye-tracking dysfunction do not appear to be higher than
those for relatives of adult-onset schizophrenics (Nicolson
et al 1999). Additionally, there may be a greater rate of
range of genetic factors may account for the early age of
onset in childhood-onset schizophrenia.
Summary and Discussion
The initial phase of the NIMH childhood-onset schizo-
phrenia study, in addition to results from other studies, has
provided strong and consistent evidence for clinical and
biological continuity between very early onset and adult-
onset schizophrenia, permitting an examination of the
potentially more important question of why such an earlier
age of onset might occur. A wide range of possible risks
are under investigation. Our subjects have more severe
premorbid abnormalities, more cytogenetic abnormalities,
and greater rates of family illness than later onset cases.
Additionally, they do not have a greater rate of obstetric
complications.
The data from the NIMH cohort have several limita-
tions, including a probable recruitment and selection bias,
skewing the sample for a higher level of functioning
among the families of these patients and, at the same time,
a greater severity of illness in the probands. Nonetheless,
the pattern of the findings is suggestive of a greater genetic
vulnerability in these patients and is consistent with
growing evidence from other sources (Asarnow 1999;
Frangou 1999). If confirmed, these results indicate that
genetic studies of these patients may be particularly
informative in uncovering the genes involved in the
etiology of schizophrenia, although such studies will likely
require the use of intermediate phenotypes (schizophrenia
spectrum disorders, neuropsychological deficits, and eye-
tracking dysfunction) to take into account the previously
mentioned ascertainment bias and the fact that the major-
ity of relatives have not passed through the age of risk for
schizophrenia. As childhood-onset patients are more likely
Childhood-Onset Schizophrenia
to have a greater rate of available relatives, genetic studies
in which family members provide control subjects may
eventually permit a whole genome screen with the use of,
for example, linkage disequilibrium. Although difficult
and time consuming, it would seem that such a study
would be of significant benefit in untangling the complex
genetics of schizophrenia. Future studies of our cohort of
childhood-onset schizophrenic patients and their relatives
will be devoted to exploring and determining the genetic
basis for the earlier age of onset in childhood-onset
schizophrenia. It is anticipated that DNA from a multisite
collection of a large cohort will be of great value as
molecular and cytogenetic methods evolve for mapping
and scanning the human genome.
References
Alaghband-Rad J, McKenna K, Gordon CT, Albus KE, Ham-
burger SD, Rumsey JM, et al (1995): Childhood-onset schizo-
phrenia: The severity of premorbid course. J Am Acad Child
Adolesc Psychiatry 34:1273–1283.
American Psychiatric Association (1968): Diagnostic and Sta-
tistical Manual of Mental Disorders, 2nd Edition. Washing-
ton, D.C.: American Psychiatric Association.
Asarnow JR, Ben-Meir S (1988): Children with schizophrenia
spectrum and depressive disorders: A comparative study of
premorbid adjustment, onset pattern and severity of impair-
ment. J Child Psychol Psychiatry 29:477– 488.
Asarnow JR, Tompson MC, Goldstein MJ (1994): Childhood-
onset schizophrenia: A followup study. Schizophr Bull 20:
599 – 617.
Asarnow RF (1999): What are the boundaries of the schizophre-
nia phenotype? [Abstract]. Biol Psychiatry 45:12S.
Asarnow RF, Asamen J, Granholm E, Sherman T, Watkins JM,
Williams ME (1994): Cognitive/neuropsychological studies
of children with a schizophrenic disorder. Schizophr Bull
20:647– 669.
Bassett AS (1992): Chromosomal aberrations and schizophrenia.
Autosomes. Br J Psychiatry 161:323–334.
Bearden CE, Cannon TD, Hollister JM, Gasperoni TL, Hadley T
(1999): A prospective cohort study of childhood behavioral
deviance and language abnormalities as predictors of adult
schizophrenia [Abstract]. Schizophr Res 36:37.
Bedwell JS, Keller B, Smith AK, Hamburger S, Kumra S,
Rapoport JL (in press): Childhood-onset schizophrenia:
Why does post-psychotic full-scale IQ decline. Am J
Psychiatry.
Bertolino A, Kumra S, Callicott JH, Mattay VS, Lestz RM,
Jacobsen L, et al (1998): Common pattern of cortical pathol-
ogy in childhood-onset and adult-onset schizophrenia as
identified by proton magnetic resonance spectroscopic imag-
ing. Am J Psychiatry 155:1376 –1383.
Bleuler (1911/1950): Dementia Praecox or the Group of Schizo-
phrenias. Zinkin J, translator. New York: International Uni-
versities Press.
Buka SL, Tsuang MT, Lipsitt LP (1993): Pregnancy/delivery
BIOL PSYCHIATRY 1425
1999;46:1418 –1428
complications and psychiatric diagnosis. A prospective study.
Arch Gen Psychiatry 50:151–156.
Chakos MH, Lieberman JA, Alvir J, Bilder R, Ashtari M
(1995): Caudate nuclei volumes in schizophrenic patients
treated with typical antipsychotics or clozapine. Lancet
345:456 – 457.
Childs B, Scriver CR (1986): Age at onset and causes of disease.
Perspect Biol Med 29:437– 460.
Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel
DE, Gaskell PC Jr, et al (1994): Protective effect of apolipo-
protein E type 2 allele for late onset Alzheimer disease. Nat
Genet 7:180 –184.
DeLisi LE, Friedrich U, Wahlstrom J, Boccio-Smith A, Forsman
A, Eklund K, et al (1994): Schizophrenia and sex chromo-
some anomalies. Schizophr Bull 20:495–505.
DeSanctis S (1906): On some varieties of dementia praecox. In:
Szurek SA, Berlin IN, editors (1973): Clinical Studies in
Childhood Psychosis: 25 years in Collaborative Treatment
and Research. New York: Bruner/Mazel, 31– 47.
Done DJ, Johnstone EC, Frith CD, Golding J, Shepherd PM,
Crow TJ (1991): Complications of pregnancy and delivery
in relation to psychosis in adult life: Data from the British
perinatal mortality survey sample. BMJ 302:1576 –1580.
Done DJ, Crowe TJ, Johnstone EC, Sacker A (1994): Childhood
antecedents of schizophrenia and affective illness: Social
adjustment at ages 7 and 11. BMJ 309:699 –703.
Eagles JM, Gibson I, Bremner MH, Clunie F, Ebmeier KP, Smith
NC (1990): Obstetric complications in DSM-III schizophren-
ics and their siblings. Lancet 335:1139 –1141.
Fernandez T, Yan WL, Hamburger S, Rapoport JL, Saunders
AM, Schapiro M, et al (1999): Apolipoprotein E alleles in
childhood-onset schizophrenia. Am J Med Genet 88:211–
213.
FitzGerald MG, MacDonald DJ, Krainer M, Hoover I, O’Neil E,
Unsal H, et al (1996): Germ-line BRCA1 mutations in Jewish
and non-Jewish women with early-onset breast cancer.
N Engl J Med 334:143–149.
Frangou S (1999): The Maudsley early onset schizophrenia
study: Abnormal genes, abnormal brains, abnormal families
[Abstract]. Biol Psychiatry 45:12S.
Frazier JA, Giedd JN, Hamburger SD, Albus KE, Kaysen D,
Vaituzis AC, et al (1996a): Brain anatomic magnetic reso-
nance imaging in childhood-onset schizophrenia. Arch Gen
Psychiatry 53:617– 624.
Frazier JA, Giedd JN, Kaysen D, Albus K, Hamburger S,
Alaghband-Rad J, Lenane MC, McKenna K, Breier A,
Rapoport JL (1996b): Childhood-onset schizophrenia: Brain
MRI rescan after 2 years of clozapine maintenance treatment.
Am J Psychiatry 153:564 –566.
Frazier JA, Alaghband-Rad J, Jacobsen L, Lenane MC, Ham-
burger S, Albus K, et al (1997): Pubertal development and
onset of psychosis in childhood onset schizophrenia. Psychi-
atry Res 70:1–7.
Geddes JR, Lawrie SM (1995): Obstetric complications and
schizophrenia: a meta-analysis. Br J Psychiatry 167:786 –
793.
Giedd JN, Jeffries NO, Blumenthal J, Castellanos FX, Vaituzis
AC, Fernandez T, et al (in press): Childhood-onset schizo-
phrenia: Progressive brain changes during adolescence. Biol
Psychiatry 46:892– 898.
1426 BIOL PSYCHIATRY
1999;46:1418 –1428
Ginns EI, St Jean P, Philibert RA, Galdzicka M, Damschroder-
Williams P, Thiel B, et al (1998): A genome-wide search for
chromosomal loci linked to mental health wellness in rela-
tives at high risk for bipolar affective disorder among the Old
Order Amish. Proc Natl Acad Sci U S A 95:15531–15536.
Goldberg TE, Gold JM (1995): Neurocognitive functioning in
patients with schizophrenia: An overview. In: Bloom FE,
Kupfer DJ, editors. Psychopharmacology: The Fourth Gen-
eration of Progress. New York: Raven Press, 1245–1257.
Gordon CT, Frazier JA, McKenna K, Giedd J, Zametkin A, Zahn
T, et al (1994): Childhood-onset schizophrenia: An NIMH
study in progress. Schizophr Bull 20:697–712.
Green WH, Padron-Gayol M, Hardesty AS, Bassiri M (1992):
Schizophrenia with childhood onset: A phenomenological
study of 38 cases. J Am Acad Child Adolesc Psychiatry
31:968 –976.
Gunther-Genta F, Bovet P, Hohlfeld P (1994): Obstetric compli-
cations and schizophrenia. A case– control study. Br J Psy-
chiatry 164:165–170.
Gupta S, Rajaprabhakaran R, Arndt S, Flaum M, Andreasen NC
(1995): Premorbid adjustment as a predictor of phenomeno-
logical and neurobiological indices in schizophrenia. Schizo-
phr Res 16:189 –197.
Hafner H, Maurer K, Loffler W, Riecher-Rossler A (1993): The
influence of age and sex on the onset and early course of
schizophrenia. Br J Psychiatry 162:80 – 86.
Hollis C (1995): Child and adolescent (juvenile onset) schizo-
phrenia: A case– control study of premorbid developmental
impairments. Br J Psychiatry 166:489 – 495.
Jacobsen LK, Giedd JN, Vaituzis AC, Hamburger SD, Rajapakse
JC, Frazier JA, et al (1996a): Temporal lobe morphology in
childhood-onset schizophrenia. Am J Psychiatry 153:355–
361.
Jacobsen LK, Hong WL, Hommer DW, Hamburger SD, Castel-
lanos FX, Frazier JA, et al (1996b): Smooth pursuit eye
movements in childhood-onset schizophrenia: Comparison
with attention-deficit hyperactivity disorder and normal con-
trols. Biol Psychiatry 40:1144 –1154.
Jacobsen LK, Giedd JN, Berquin PC, Krain AL, Hamburger SD,
Kumra S, et al (1997a): Quantitative morphology of the
cerebellum and fourth ventricle in childhood-onset schizo-
phrenia. Am J Psychiatry 154:1663–1669.
Jacobsen LK, Giedd JN, Rajapakse JC, Hamburger SD, Vaituzis
AC, Frazier JA, et al (1997b): Quantitative magnetic reso-
nance imaging of the corpus callosum in childhood onset
schizophrenia. Psychiatry Res 68:77– 86.
Jacobsen LK, Giedd JN, Tanrikut C, Brady DR, Donohue BC,
Hamburger SD, et al (1997c): Three-dimensional cortical
morphometry of the planum temporale in childhood-onset
schizophrenia. Am J Psychiatry 154:685– 687.
Jacobsen LK, Hamburger SD, Van Horn JD, Vaituzis AC,
McKenna K, Frazier JA, et al (1997d): Cerebral glucose
metabolism in childhood onset schizophrenia. Psychiatry Res
75:131–144.
Jacobsen LK, Giedd JN, Castellanos FS, Vaituzis AC, Ham-
burger SD, Kumra S, Lenane MC, Rapoport JL (1998a):
Progressive reduction of temporal lobe structures in child-
hood-onset schizophrenia. Am J Psychiatry 155:678 – 685.
Jacobsen LK, Mittleman BB, Kumra S, Lenane MC, Barracchini
R. Nicolson and J.L. Rapoport
KC, Adams S, et al (1998b): HLA antigens in childhood-
onset schizophrenia. Psychiatry Res 78:123–132.
Jacobsen LK, Rapoport JL (1998): Childhood-onset schizophre-
nia: implications of clinical and neurobiological research.
J Child Psychol Psychiat 38:697–712.
Jones P, Rodgers B, Murray R, Marmot M (1994): Child
development risk factors for schizophrenia in the British 1946
birth cohort. Lancet 344:1398 –1402.
Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P
(1998): Schizophrenia as a long-term outcome of pregnancy,
delivery, and perinatal complications: A 28-year follow-up of
the 1966 north Finland general population birth cohort. Am J
Psychiatry 155:355–364.
Kallmann FJ, Roth B (1956): Genetic aspects of preadolescent
schizophrenia. Am J Psychiatry 112:599 – 606.
Karayiorgou M, Gogos JA (1997): A turning point in schizo-
phrenia genetics. Neuron 19:967–979.
Kegeles LS, Humaran TJ, Mann JJ (1998):In vivo neurochem-
istry of the brain in schizophrenia as revealed by magnetic
resonance spectroscopy. Biol Psychiatry 44:382–398.
Kendler KS, Tsuang MT, Hays P (1987): Age at onset in
schizophrenia. A familial perspective. Arch Gen Psychiatry
44:881– 890.
Kendler KS (1988): The impact of diagnostic hierarchies on
prevalence estimates for psychiatric disorders. Compr Psy-
chiatry 29:218 –227.
Kendler KS, Diehl SR (1993): The genetics of schizophrenia: A
current, genetic-epidemiologic perspective. Schizophr Bull
19:261–285.
Kendler KS, McGuire M, Gruenberg AM, Spellman M, OHare
A, Walsh D (1993a): The Roscommon Family Study. II. The
risk of nonschizophrenic nonaffective psychoses in relatives.
Arch Gen Psychiatry 50:645– 652.
Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman
M, Walsh D (1993b): The Roscommon Family Study. I.
Methods, diagnosis of probands, and risk of schizophrenia in
relatives. Arch Gen Psychiatry 50:527–540.
Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman
M, Walsh D (1993c): The Roscommon Family Study. III.
Schizophrenia-related personality disorders in relatives. Arch
Gen Psychiatry 50:781–788.
Kendler KS, Gruenberg AM, Kinney DK (1994): Independent
diagnoses of adoptees and relatives as defined by DSM-III in
the provincial and national samples of the Danish Adoption
Study of Schizophrenia. Arch Gen Psychiatry 51:456 – 468.
Kendler KS, Karkowski-Shuman L, Walsh D (1996): Age at
onset in schizophrenia and risk of illness in relatives. Results
from the Roscommon Family Study. Br J Psychiatry 169:
213–218.
Kety SS, Wender PH, Jacobsen B, Ingraham LJ, Jansson L,
Faber B, et al (1994): Mental illness in the biological and
adoptive relatives of schizophrenic adoptees. Replication of
the Copenhagen Study in the rest of Denmark. Arch Gen
Psychiatry 51:442– 455.
Kolvin I (1971): Studies in the childhood psychoses. I. Diagnos-
tic criteria and classification. Br J Psychiatry 118:381–384.
Kolvin I, Garside RF, Kidd JS (1971): Studies in the childhood
psychoses. IV. Parental personality and attitude and child-
hood psychoses. Br J Psychiatry 118:403– 406.
Childhood-Onset Schizophrenia
Kraepelin E (1899/1919): Dementia Praecox and Paraphrenia,
8th ed. Edinburgh BR, translator. S Livingstone.
Kumra S, Jacobsen LK, Lenane M, Zahn TP, Wiggs E, Alagh-
band-Rad J, et al (1988): “Multidimensionally impaired
disorder”: Is it a variant of very early-onset schizophrenia?
J Am Acad Child Adolesc Psychiatry 37:91–99.
Kumra S, Bedwell J, Hommer D, Rapoport J (1998): Comparison
of smooth pursuit eye movements in pediatric patients with
childhood-onset schizophrenia and “multidimensionally im-
paired syndrome” [Abstract]. Biol Psychiatry 43:68S.
Kumra S, Wiggs E, Bedwell J, Smith AK, Arling E, Albus K, et
al (in press): Neuropsychological deficits in pediatric patients
with childhood-onset schizophrenia and psychotic disorder
not otherwise specified. Schizophr Res.
Lenane MC, Nicolson R, Bedwell J, Rapoport JL (1999):
Schizophrenia spectrum disorders in the relatives of patients
with childhood-onset schizophrenia [Abstract]. Schizophr Res
36:92.
Levy DL, Holzman PS, Matthysse S, Mendell NR (1993): Eye
tracking dysfunction and schizophrenia: a critical perspective.
Schizophr Bull 19:461–536.
Lewis SW, Owen MJ, Murray RM (1989): Obstetric complica-
tions and schizophrenia: Methodology and mechanisms. In:
Schulz SC, Tamminga CA, editors. Schizophrenia: Scientific
Progress. New York: Oxford University Press, 56 – 68.
McCarley RW, Wible CG, Frumin M, Hirayasu Y, Levitt JJ,
Fischer IA, et al (1999): MRI anatomy of schizophrenia. Biol
Psychiatry 45:1099 –1119.
McKenna K, Gordon CT, Rapoport JL (1994): Childhood-onset
schizophrenia: Timely neurobiological research. J Am Acad
Child Adolesc Psychiatry 33:771–781.
Nicolson R, Singaracharlu S, Lenane MC, Rapoport JL (1998,
December): Premorbid language and motor abnormalities in
childhood-onset schizophrenia: Association with genetic risk
factors. Presented at the American College of Neuropsycho-
pharmacology Annual Meeting, Puerto Rico.
Nicolson R, Hommer D, Thaker G, Brown M, Bedwell M,
Lenane M, et al (1999): Smooth pursuit eye movements in the
relatives of patients with childhood-onset schizophrenia [Ab-
stract]. Schizophr Res 36:93.
Nicolson R, Malaspina D, Giedd JN, Hamburger S, Lenane M,
Bedwell J, et al (in press-a): Obstetrical complications in
childhood-onset schizophrenia. Am J Psychiatry.
Nicolson R, Giedd JN, Lenane M, Hamburger S, Singaracharlu
S, Bedwell J, et al (in press-b): Clinical and neurobiological
correlates of cytogenetic abnormalities in childhood-onset
schizophrenia. Am J Psychiatry.
O’Callaghan E, Gibson T, Colohan HA, Buckley P, Walshe DG,
Larkin C, et al (1993): Risk of schizophrenia in adults born
after obstetric complications and their association with early
onset of illness: A controlled study. BMJ 305:1256 –1259.
Picchio GR, Gulizia RJ, Mosier DE (1997): Chemokine receptor
CCR5 genotype influences the kinetics of human immunode-
ficiency virus type 1 infection in human PBL-SCID mice.
J Virol 71:7124 –7127.
Pulver AE, Liang KY (1991): Estimating effects of proband
characteristics on familial risk: II. The association between
age at onset and familial risk in the Maryland schizophrenia
sample. Genet Epidemiol 8:339 –350.
BIOL PSYCHIATRY 1427
1999;46:1418 –1428
Rapoport JL, Giedd J, Kumra S, Jacobsen L, Smith A, Lee P, et
al (1997): Childhood-onset schizophrenia. Progressive ven-
tricular change during adolescence. Arch Gen Psychiatry
54:897–903.
Rapoport JL, Giedd J, Blumenthal J, Hamburger S, Jeffries N,
Fernandez T, et al (1999): Progressive cortical change during
adolescence in childhood-onset schizophrenic subjects: A
longitudinal study. Arch Gen Psychiatry 56:649 – 654.
Rapoport JL (in press): Childhood Onset of “Adult Psychopa-
thology”: Clinical and Research Advances. Washington DC:
American Psychiatric Press.
Risch N (1990): Linkage strategies for genetically complex traits.
I. Multilocus models. Am J Hum Genet 46:222–228.
Ross RG, Olincy A, Harris JG, Radant A, Hawkins M, Adler LE,
et al (1999): Evidence for bilineal inheritance of physiologi-
cal indicators of risk in childhood-onset schizophrenia. Am J
Med Genet 88:188 –199.
Russel AT (1994): The clinical presentation of childhood-onset
schizophrenia. Schizophr Bull 20:631– 646.
Russell AT, Bott L, Sammons C (1989): The phenomenology of
schizophrenia occurring in childhood. J Am Acad Child
Adolesc Psychiatry 28:399 – 407.
Rutter M, Mawhood L (1991): The long-term psychosocial
sequelae of specific developmental disorders of speech and
language. In: Rutter M, Cesar P, editors. Biological Risk
Factors for Psychosocial Disorders. Cambridge: Cambridge
University Press, 233–259.
St George-Hyslop PH, Levesque G, Levesque L, Rommens J,
Westaway D, Fraser PE (1996): Two homologous genes
causing early-onset familial Alzheimer’s disease. Cold Spring
Harb Symp Quant Biol 61:559 –564.
Sidransky E, Burgess C, Ikeuchi T, Lindblad K, Long RT,
Philibert RA, et al (1998): A triplet repeat on 17q accounts for
most expansions detected by the repeat-expansion-detection
technique. Am J Hum Genet 62:1548 –1551.
Spencer EK, Campbell M (1994): Children with schizophrenia:
Diagnosis, phenomenology, and pharmacotherapy. Schizophr
Bull 20:713–725.
Suvisaari JM, Haukka J, Tanskanen A, Lonnqvist JK (1998):
Age at onset and outcome in schizophrenia are related to the
degree of familial loading. Br J Psychiatry 173:494 –500.
Swanson CL, Mozley LMH, Gur RE (1997): Positron emission
tomography studies of cerebral metabolism and blood flow in
schizophrenia. In: Krishnan KRR, Doraiswamy PM, editors.
Brain Imaging in Clinical Psychiatry. New York: Marcel
Dekker, 401– 424.
Thomas MA, Ke Y, Levitt J, Caplan R, Curran J, Asarnow R, et
al (1998): Preliminary study of frontal lobe H-1 MR spec-
troscopy in childhood-onset schizophrenia. J Magn Reson
Imaging 8:841– 846.
Verdoux H, Geddes JR, Takei N, Lawrie SM, Bovet P, Eagles
JM, et al (1997): Obstetric complications and age at onset in
schizophrenia: An international collaborative meta-analysis
of individual patient data. Am J Psychiatry 154:1220 –1227.
Watkins JM, Asarnow RF, Tanguay PE (1988): Symptom
development in childhood-onset schizophrenia. J Child Psy-
chol Psychiatry 29:865– 878.
Weiss KM (1993): Genetic Variation and Human Disease:
Principles and Evolutionary Approaches. New York: Cam-
bridge University Press.
1428 BIOL PSYCHIATRY
1999;46:1418 –1428
Werry JS (1996): Childhood schizophrenia. In: Volkmar FR,
editor. Psychoses and Pervasive Developmental Disorders in
Childhood and Adolescence. Washington, DC: American
Psychiatric Press, 1– 48.
Wicker LS, Todd JA, Prins JB, Podolin PL, Renjilian RJ,
Peterson LB (1994): Resistance alleles at two non-major
histocompatibility complex-linked insulin-dependent dia-
R. Nicolson and J.L. Rapoport
betes loci on chromosome 3, Idd3 and Idd10, protect
nonobese diabetic mice from diabetes. J Exp Med 180:
1705–1713.
Zahn TP, Jacobsen LK, Gordon CT, McKenna K, Frazier JA,
Rapoport JL (1997): Autonomic nervous system markers of
psychopathology in childhood-onset schizophrenia. Arch Gen
Psychiatry 54:904 –912.