 |
|
Schizophrenia and Schizophrenia-Spectrum Personality Disorders in the First-Degree Relatives of Children With Schizophrenia
The UCLA Family Study
Robert F. Asarnow, PhD;
Keith H. Nuechterlein, PhD;
David Fogelson, MD;
Kenneth L. Subotnik, PhD;
Diana A. Payne, PhD;
Andrew T. Russell, MD;
Joy Asamen, PhD;
Heidi Kuppinger, PhD;
Kenneth S. Kendler, MD
Arch Gen Psychiatry. 2001;58:581-588.
ABSTRACT
| |
Background This study tested the hypothesis that childhood-onset schizophrenia
(COS) is a variant of adult-onset schizophrenia (AOS) by determining if first-degree
relatives of COS probands have an increased risk for schizophrenia and schizotypal
and paranoid personality disorders.
Methods Relatives of COS probands (n = 148) were compared with relatives of
attention-deficit/hyperactivity disorder (ADHD) (n = 368) and community control
(n = 206) probands. Age-appropriate structured diagnostic interviews were
used to assign DSM-III-R diagnoses to probands and
their relatives. Family psychiatric history was elicited from multiple informants.
Diagnoses of relatives were made blind to information about probands' diagnoses.
Final consensus diagnoses, which integrated family history, direct interview
information, and medical records, are reported in this article.
Results There was an increased lifetime morbid risk for schizophrenia (4.95%
± 2.16%) and schizotypal personality disorder (4.20% ± 2.06%)
in the parents of COS probands compared with parents of ADHD (0.45% ±
0.45%, 0.91% ± 0.63%) and community control (0%) probands. The parents
of COS probands diagnosed as having schizophrenia had an early age of first
onset of schizophrenia. Risk for avoidant personality disorder (9.41% ±
3.17%) was increased in the parents of COS probands compared with parents
of community controls (1.67% ± 1.17%).
Conclusions The psychiatric disorders that do and do not aggregate in the parents
of COS probands are remarkably similar to the disorders that do and do not
aggregate in the parents of adults with schizophrenia in modern family studies.
These findings provide compelling support for the hypothesis of etiological
continuity between COS and AOS.
INTRODUCTION
RECENT INTEREST in childhood-onset schizophrenia (COS) is sparked by
the belief that COS may be a more homogeneous, severe form of schizophrenia
than adult-onset schizophrenia (AOS).1, 2
Many neurocognitive, linguistic, and psychophysiological impairments and changes
in brain structure observed in AOS are present in COS, suggesting that COS
and AOS may have a common neurobiological substrate.1, 2, 3, 4
The present study provides an important further test of the hypothesis that
COS is a variant of AOS.
Schizophrenia strongly aggregates in families. Twin and adoption studies
suggest that genetic factors play a major role in the etiology of AOS.5 This study tested the hypothesis that first-degree
relatives of COS probands, like relatives of AOS probands, have an increased
risk for schizophrenia and schizophrenia-related personality disorders. If
so, this would be further evidence for etiological continuity with AOS.
Two early studies6, 7 found
an aggregation of schizophrenia in relatives of COS probands comparable with
that reported in relatives of AOS probands. In addition, in COS twins the
concordance rates for schizophrenia were significantly higher in monozygotic
than in dyzygotic twins, suggesting genetic transmission of COS.7
While these results are intriguing, neither study meets modern methodological
standards. We employed modern family study methods to determine if there is
an increased aggregation of schizophrenia in first-degree relatives of COS
probands compared with first-degree relatives of community controls.
With only 1 exception,8 10 prior studies
that compared the prevalence of schizotypal personality disorder (SPD) in
relatives of AOS probands with matched controls found substantial evidence
for a familial relationship between schizophrenia and SPD.5, 9, 10, 11, 12
Familial relationships of schizophrenia to paranoid, schizoid, and avoidant
personality disorders is limited or mixed in studies of AOS probands.10, 11, 12, 13 The present
study tested the hypothesis that there is an increased aggregation of SPD,
and of paranoid, schizoid, and avoidant personality disorders in relatives
of COS probands. We examined the specificity of this familial relationship
by determining if there was an increased risk of schizophrenia, SPD, paranoid,
schizoid, and avoidant personality disorders in relatives of attention-deficit/hyperactivity
disorder (ADHD) probands, another disorder with prominent cognitive features.
We attempted to establish the outer boundaries of schizophrenia-spectrum personality
disorders by examining one personality disorder, borderline personality disorder,
which prior research5 suggested does not tend
to aggregate in families of AOS probands.
Eliminating control probands with any psychiatric disorder ("supernormal
controls") may produce spurious evidence for coaggregation.14, 15
Therefore, we used a case-control design in which community control probands
with the index disorders (schizophrenia or ADHD) were excluded, but community
control probands were allowed to have any other psychiatric disorder.
SUBJECTS AND METHODS
SUBJECTS
Ascertainment and Diagnosis of Probands
The UCLA Family Study involves parallel studies of the relatives of
3 child (principal investigator: R.F.A.) and 3 adult proband groups (principal
investigator: K.H.N.). This report concerns the relatives of the 3 child proband
groups: COS, ADHD, and community controls. We ascertained COS probands by
identifying 12 Los Angeles County facilities that treated substantial numbers
of these children. We screened 9 facilities by periodically reviewing cases
with site clinicians to identify potential COS probands. Child-onset schizophrenia
probands were also ascertained through the University of California, Los Angeles
Neuropsychiatric Hospital and school-based programs for seriously emotionally
disturbed children in Los Angeles County. Attention-deficit/hyperactivity
disorder probands were ascertained through outpatient pediatric clinics and
support groups for the families of children with ADHD (particularly the Children
and Adults With Attention-Deficit/Hyperactivity Disorder group) located in
Los Angeles County.
Lists of potential community controls living in the same ZIP codes as
COS probands were obtained from a scientific survey research firm (Survey
Sampling Inc, Fairfield, Conn). Parents of potential community control probands
were contacted by telephone to explain the purpose of the study and to screen
probands for schizophrenia and ADHD or placement in special classes for either
exceptionally bright or learning-disabled children.
All participants in this study provided informed consent or assent (if
a minor).
An experienced child clinical psychologist used the Schedule for Affective
Disorder and Schizophrenia for School-Aged Children: Epidemiologic Version
(K-SADS-E)16 to interview the best-informed
parent about the proband's history of psychiatric symptoms and then interviewed
the proband. The K-SADS-E was used to diagnose schizophrenia, ADHD, and other
Axis I disorders in COS, ADHD, and community control probands. Medical and
school records were obtained. The clinician interviewing the parent and proband
reviewed diagnostic interviews and ancillary information with an experienced
child psychiatrist to reach a consensus diagnosis.17
Our earlier formal study17 of diagnostic reliability
on 35 children with schizophrenia revealed satisfactory agreement (
= 0.88). Our goal was to enroll 120 ADHD and 60 COS and community control
families. Because a few proband diagnoses changed when additional diagnostic
information became available and some families declined toparticipate in family
interviews after the parents consented to diagnostic interviews of the proband,
118 ADHD probands, 51 COS, and 61 families of community control probands were
entered into this study. Children with consensus diagnoses of DSM-III-R18 schizophrenia with first
onset of psychosis before 13 years of age were the schizophrenia probands.
Children with consensus diagnoses of DSM-III-R ADHD
(at least 8 ADHD symptoms rated as definitely or probably present) were the
ADHD probands. Of these, 106 had at least 8 ADHD symptoms rated as definitely
present, while 12 children had at least 6 ADHD symptoms rated as definitely
present.
Children were excluded from these proband groups if they had a full-scale
IQ less than 70, had a history of central nervous system disease (eg, temporal
lobe epilepsy), or had taken drugs that could have produced psychotic episodes.
Children were excluded from the community control group for personal diagnoses
of either schizophrenia or ADHD, but not for any other psychiatric diagnosis.
More than 31% of the community control probands received at least 1 DSM-III-R diagnosis. The most frequent diagnoses were separation
anxiety disorder (n = 5), adjustment disorder (n = 4), oppositional defiant
disorder (n = 3), overanxious disorder (n = 3), and simple phobia (n = 3).
Diagnosis of First-Degree Relatives
The diagnoses of 566 first-degree relatives were based on direct interview,
family history, and ancillary information. The diagnoses of 156 additional
first-degree relatives, who were not directly interviewed, were based on family
history interviews and, when available, medical records.
First-degree relatives 16 years and older were interviewed to assess DSM-III-R Axis I diagnoses using the Diagnostic Interview
Schedule,19 to which a time line for affective
and psychotic symptoms was added. When subjects reported any experiences suggesting
the presence of psychotic symptoms, the psychosis section of the Present State
Examination20 was administered. Although the
Diagnostic Interview Schedule has good reliability and validity,21, 22
the modifications were designed to mitigate concerns about its sensitivity
to schizophrenia. The structured Diagnostic Interview Schedule ensured that
no areas of psychopathology were overlooked, while the additional semistructured
Present State Examination probes and syndrome time line facilitated differential
diagnosis of schizophrenia, schizoaffective disorder, and mood disorders.
Siblings aged 7 to 15 years were directly interviewed using the K-SADS-E,
and the best-informed parent was also interviewed about the sibling. For children
aged 5 to 6 years, diagnostic information was collected solely through parental
interview with the K-SADS-E.
The Structured Clinical Interview for DSM-III-R:
Personality Disorders23 was used to assess 2
"narrow" schizophrenia-spectrum disorders (paranoid and SPD), and schizoid,
avoidant, and borderline personality disorders. We modified the Structured
Clinical Interview for DSM-III-R: Personality Disorders
so that it could be used with adolescents.
Nine family interviewers were doctorate- or master's degree–level
clinicians, while 1 family interviewer had a bachelor's degree and 4 years
of experience in clinical interviewing. All interviewers were trained to criterion
levels on the Diagnostic Interview Schedule by the person who trained the
Los Angeles staff of the Epidemiologic Catchment Area project and on the Present
State Examination by the diagnosis and psychopathology core of the University
of California, Los Angeles, Clinical Research Center for Schizophrenia. One
of us (R.F.A.) conducted K-SADS-E training. Our training procedures for the
Structured Clinical Interview for DSM-III-R: Personality
Disorders and its adequate reliability in the current study have been described
elsewhere.24 Every family interviewer rated
gold standard videotapes of each diagnostic interview, conducted "mock" interviews
of other staff, and finally carried out at least 5 videotaped interviews of
patient volunteers that were co-rated by training staff.
Family history information on all first- and second-degree relatives
(including directly interviewed relatives) was typically obtained from 2 adult
informants, the proband's parents whenever possible. After the systematic
generation of a genealogy, family history of major psychiatric illness was
elicited using the National Institute of Mental Health Relative Psychiatric
History25 interview format. Personality disorders
were assessed using the Structured Clinical Interview for DSM-III-R: Personality Disorders adapted to a third-person format.
DIAGNOSTIC PROCEDURES FOR FIRST-DEGREE RELATIVES
To keep family interviewers blind to the proband's diagnosis, diagnostic
evaluations of probands and first-degree relatives were conducted by entirely
different diagnostic teams, housed in separate buildings. Whenever feasible,
first-degree relatives were directly interviewed by staff members who had
not interviewed any other relatives within the same family. Information regarding
other family members' psychiatric histories was not considered in making a
relative's psychiatric diagnosis.
A 2-stage diagnostic process was used. In the first stage, interviewers
made independent diagnoses for each first-degree relative based on 1 source
of information (either direct interview or family history information). Two
interviewers for each relative then met to make consensus diagnoses that integrated
family history and direct interview information and medical records, if available.
To further minimize any potential bias, cases with psychotic symptoms or potential
schizophrenia-spectrum personality disorders were reviewed at a weekly project
meeting by senior clinicians (D.F., K.L.S., K.H.N., and R.F.A.) blind at all
stages of the diagnostic process to the diagnosis of probands and all other
family members. For each diagnosis, interviewers assigned a confidence level
(definite, probable, and possible). In this report, only definite diagnoses
are considered.
The second stage of the diagnostic process was carried out immediately
before data analysis. To ensure uniform application of DSM-III-R criteria over time, all cases with possible psychotic symptoms
and/or with diagnoses of SPD or paranoid personality disorder (or who were
1 symptom short of receiving these diagnoses) were reviewed. Senior clinicians
reached final consensus diagnoses after case presentation of all symptom and
illness course information. The net effect of this final diagnostic review
was to downrate the diagnoses of paranoid and SPD from definite to probable
for a number of cases lacking clear examples of certain symptoms.
To permit the comparison of the results of this study to prior studies,
the primary data analyses used a minor modification of the hierarchy employed
by Kendler et al.26 That hierarchy was (1) schizophrenia;
(2) schizoaffective disorder; (3) SPD; and (4) nonaffective psychoses (schizophreniform
disorder and atypical psychosis). We placed paranoid personality disorder
fifth in our hierarchy. When a relative received multiple diagnoses, the diagnosis
highest in the hierarchy was used for analyses.
STATISTICAL ANALYSES
The Kaplan-Meier method of analyzing life tables, as operationalized
in the LIFETEST procedure in SAS27 was used
to calculate lifetime morbid risks. The age of onset for personality disorders
was set at 18 years, except for relatives younger than 18 years at the time
of the evaluation. In these instances, the age of onset was considered to
be the age at evaluation. We tested for differences in life table curves between
various groups using the log-rank  2 statistic. We used 2-tailed
tests for all comparisons between groups for morbid risk. The  level
was P<.05 for all analyses. Analyses of variance,
followed up by Bonferroni protected post hoc t tests,
were used to test between group differences on continuous demographic variables,
while 2 analyses were used on dichotomous demographic variables.
RESULTS
CHARACTERISTICS OF SUBJECTS
There were no significant group differences in the mean age of parents
at evaluation (Table 1). The 3
groups of siblings differed in age (F2,272 = 17.29, P<.0001). The siblings of the schizophrenic probands were significantly
older than the siblings of the ADHD (t272
= 4.74, P = .00001) and community control probands
(t272 = 5.80, P
= .00001), who did not differ from each other. The 3 groups of parents differed
in education level (F2,221 = 6.86, P<.001).
Parents of COS probands completed significantly fewer years of school than
parents of community control (t221 = 3.56, P = .0007) and ADHD probands (t221 = 2.97, P = .005), who did not differ from
each other. More mothers than fathers were directly interviewed in all 3 groups
(2 = 15.35, P<.0001). The 3 groups
did not, however, differ significantly in the percentage of parents directly
interviewed who were mothers.
|
|
|
|
Table 1. Demographic Characteristics of Subjects*
|
|
|
There were significant differences in ethnic backgrounds (2 = 7.33, P = .02) between the proband groups.
The COS group contained relatively fewer white and relatively more Hispanic
and African American children than the other 2 groups.
RISK FOR SCHIZOPHRENIA AND NARROW SCHIZOPHRENIA-SPECTRUM DISORDER
Parents
Risks of schizophrenia and schizophrenia-spectrum personality disorders
are presented separately for parents and siblings because the vast majority
of siblings have not yet entered the typical age of risk for schizophrenia
(Table 1). The first set of analyses
used the diagnostic hierarchy described above to ensure that no relative received
more than 1 diagnosis.
There were no cases of schizophrenia or DSM-III-R Axis I diagnoses closely related to schizophrenia (schizophreniform,
schizoaffective disorder [depressed type], or atypical psychosis) among the
parents of community control probands. The risk for schizophrenia in parents
of COS probands (Table 2) was significantly
greater than in parents of community control (2 = 6.15, P = .01) and ADHD probands (2 = 7.69, P = .006). The parents of ADHD and community control probands
did not differ in the risk for schizophrenia or schizophrenia-related Axis
I disorders.
|
|
|
Table 2. Morbid Risk for Schizophrenia-Spectrum Disorders and 3 Other
Personality Disorders as Determined by Life Table Analysis, in Parents and
Siblings of 3 Groups of Child Probands*
|
|
|
There were 5 cases of schizophrenia and 1 case of schizoaffective disorder
(depressed type) in the parents of COS probands. These parents have a rather
early age of first onset of schizophrenia (mean [SD], 20.8 [4.5]
years).
The risk for SPD was significantly greater in the parents of COS probands
compared with parents of community control (2 = 5.21, P = .02) and ADHD probands (2 = 3.91, P = .05). There were no significant differences in risk
for paranoid personality disorder between the 3 groups of parents. The parents
of ADHD and community control probands did not differ significantly in risk
for SPD or paranoid personality disorder.
Combining diagnoses of schizophrenia, schizoaffective, schizotypal,
and paranoid personality disorders, the risk for narrow schizophrenia-spectrum
disorders was significantly greater in parents of COS probands compared with
parents of community control (2 = 14.96, P = .0001) and ADHD probands (2 = 6.76, P = .009). A greater risk for narrow schizophrenia-spectrum disorders
in parents of ADHD probands compared with parents of community control probands
(2 = 4.52, P = .03) was almost entirely
caused by paranoid personality disorder.
Siblings
No cases of schizophrenia were identified among siblings of COS, ADHD,
or community control probands. One sibling of a COS proband received a diagnosis
of schizoaffective disorder (mainly depressed type). The differences between
3 groups of siblings in risk for schizotypal or paranoid personality disorder
were not significant.
RISK FOR OTHER PERSONALITY DISORDERS
Parents
These analyses concern the risk for other personality disorders when
they occur outside of the presence of narrow schizophrenia-spectrum disorders.
Consistent with prior practice, we did not hierarchically organize avoidant,
schizoid, and borderline personality disorders. The risk for avoidant personality
disorder was significantly increased (2 = 6.40, P = .01) in parents of COS probands compared with parents of community
controls (Table 2). Consistent
with prior research, there was no increased risk for borderline personality
disorder in parents of COS probands compared with parents of community controls.
The risk for schizoid personality disorder was quite low in all 3 groups,
and group differences were not significant. Parents of COS and ADHD probands
did not differ in risk for avoidant, schizoid, or borderline personality disorder.
Parents receiving personality disorder diagnoses typically received
at least 1 other diagnosis (10 of 11 cases of borderline, 5 of 6 of cases
of schizotypal, and 5 of 7 of cases of paranoid personality disorder). Avoidant
personality disorder, however, appears 64% of the time (7 of 11 cases) outside
the presence of narrow schizophrenia-spectrum disorders.
Siblings
Differences between the 3 groups of siblings in the risk for avoidant,
schizoid, and borderline personality disorders were not significant. However,
a substantial percentage of siblings of COS probands received diagnoses of
avoidant personality disorder.
ANALYSES BY ETHNICITY, FAMILY DENSITY, AND DIAGNOSTIC METHODS
There were no significant differences between white and nonwhite parents
of COS in morbid risk for schizophrenia or schizophrenia-spectrum disorders.
The increased risk for schizophrenia and schizophrenia-spectrum disorders
in parents of COS probands is not caused by an increased percentage of nonwhites,
since the risk for schizophrenia-spectrum disorders tends to be slightly less
in nonwhite than white parents of COS probands.
A few densely loaded families might have contributed disproportionately
to the elevated risk of schizophrenia-spectrum disorders in parents of COS
probands. Thus, we conducted analyses in which the family was the unit of
analysis by comparing the percentage of families containing 1 or more relatives
with schizophrenia-spectrum diagnoses (Table
3). More than 33% of the families of COS probands had at least 1
first-degree relative with either a diagnosis of schizophrenia, or schizotypal
or paranoid personality disorder. Consistent with studies of AOS families26 the percentage of families with at least 1 relative
receiving a narrow schizophrenia-spectrum disorder was significantly greater
for families of COS probands than for families of ADHD (2
= 9.87, P<.001) and community control probands
(2 = 17.8, P<.001).
|
|
|
|
Table 3. Percentage of Families in Which at Least 1 First-Degree Relative
Received a Schizophrenia-Spectrum Diagnosis
|
|
|
Because diagnoses based on informants and medical history are less sensitive
and may be more biased than diagnoses based on direct interviews,28, 29, 30, 31 we compared
morbid risks for diagnoses based on direct interview with diagnoses from family
history interviews. Within each proband group, there were no significant differences
in risk for schizophrenia, schizoaffective, schizophreniform, and schizotypal
disorders, and borderline and avoidant personality disorders for those relatives
who were directly interviewed vs those who were not. In contrast, the relatives
of community control and ADHD probands who were not directly interviewed had
a significantly greater risk (2 = 3.75, P<.05, and 2 = 17.1, P<.0001,
respectively) for paranoid and schizoid personality disorders (2 = 3.89, P<.05, and 2 =
6.25, P<.01) than did relatives of community control
and ADHD probands who were directly interviewed. This may reflect a selection
bias (more suspicious relatives not agreeing to be interviewed).
The surprising sensitivity of family history diagnoses may be attributable
to the fact that diagnoses of relatives not directly interviewed were almost
always based on information from 2 informants and sometimes included information
from medical records. When information from multiple sources and specific
diagnostic criteria are employed, the family history method can detect schizophrenia
and schizophrenia-related personality disorders in relatives of schizophrenic
patients.29, 30, 32
COMMENT
The results of the present study are consistent with recent AOS family
studies,5, 9, 12 which
indicate a clear familial aggregation of schizophrenia-spectrum disorders.
There was an increased risk of schizophrenia in parents of COS compared with
parents of community control probands. These findings replicate with a larger
sample and more rigorous methods the results of 2 earlier family studies of
COS probands.6, 7 An interesting,
but unexpected, finding was that the mean (SD) age of first onset of schizophrenia
in parents of COS probands was 20.8 (4.5) years. This is considerably younger
than the median age of onset of 24 to 28 years for males and 28 to 31 years
for females.33, 34 Age of onset is
typically older in schizophrenic patients who are parents.34
Methodological differences, of course, might account for these differences
in the estimates of age of onset.
None of the siblings of COS probands had developed schizophrenia. This
is not surprising since the mean (SD) age of the siblings of COS probands
is only 15.1 (6.0) years. Only 17.4% of these siblings were older than 20
years.
Consistent with 11 of the 12 most recent, methodologically rigorous
AOS family studies, there was a significantly greater risk of SPD in parents
of COS probands compared with parents of community control probands.9, 10 These results extend support for a familial
relationship between schizophrenia and SPD to instances in which the schizophrenic
proband has an onset in childhood.
There was also an increased risk of avoidant personality disorder in
parents of COS probands compared with parents of community control probands.
This supports the hypothesis that the schizophrenia spectrum may include avoidant
personality disorder, and underscores the importance of recent suggestions13, 35 that avoidant personality disorder
be evaluated in future family genetic studies of schizophrenia.
The parents of COS and community control probands did not significantly
differ in their risk for borderline and schizoid personality disorders. Again,
these findings are consistent with the results of most modern family genetic
studies10, 11 of AOS probands that
have failed to find a consistent familial aggregation of borderline and, with
1 exception,13 schizoid personality disorders
among relatives of AOS probands.
The psychiatric disorders that do and do not aggregate in parents of
COS probands are remarkably similar to the disorders that do and do not aggregate
in parents of AOS probands in modern family studies. These findings provide
compelling support for the hypothesis of etiological continuity between COS
and AOS.
Childhood onset of a disorder is frequently associated with increased
familial aggregation compared with adult onset of a disorder.36
To determine if this is the case for COS, we compared the risk for schizophrenia
in the current study with rates observed in prior AOS family studies by comparing
risk to relatives of schizophrenia probands with risk to relatives of community
controls (relative risk [RR]). Relative risk is less affected by variations
in interview methods, diagnostic practices, and criteria across studies than
raw prevalence. However, a limitation of RR ratios is that they often have
very large confidence intervals37 so the comparisons
below are qualitative only and may not be statistically significant. Both
classic38 and "second-generation"5, 39
family studies found significant differences in RR for schizophrenia between
the siblings and parents of probands with AOS. Therefore, we examined the
data from parents and siblings separately. The RR for schizophrenia in parents
of COS probands is 17. This is considerably greater than the 6-fold and 3-fold,
respectively, RR for schizophrenia observed in parents in "classic"38 and second-generation5, 9, 12
AOS family studies.
Prior studies40, 41 produced
conflicting results about the relationship between age at onset of schizophrenia
in the proband and degree of familial liability to schizophrenia. None of
the prior family studies, however, examined probands with onsets of schizophrenia
before 15 years of age. Collectively, the present and prior studies suggest
that an increase in familial liability to schizophrenia may be associated
with very early (ie, preadolescent) onset of schizophrenia.
The only 2 prior studies26, 35
that compared the risk for schizophrenia-spectrum personality disorders separately
for parents and siblings of AOS probands found RRs for SPD and/or paranoid
personality disorder of 6.626 and 3.035 in parents compared with 3.826
and 2.535 in siblings. The RR for SPD and/or
paranoid personality disorder was 10.5 in parents of COS probands and 3.8
in siblings of COS probands. The RR for SPD and paranoid personality disorder
is somewhat increased in parents and comparable in the siblings of COS probands
compared with the parents of AOS probands. In the Roscommon Family Study,13, 26 the RR of schizophrenia, SPD, or paranoid
personality disorders in parents of AOS probands was 5.8% compared with 15.1%
in parents of COS probands in this study.
Our blind diagnostic procedures yielded quite low rates of narrow schizophrenia-spectrum
disorders in relatives of community control probands. The greater RR of schizophrenia-spectrum
disorder in the parents and siblings of COS probands, however, is probably
not attributable to our community control group being a "supernormal control
group." As noted above, 31% of the community control probands received a psychiatric
diagnosis. Moreover, the rates of unipolar and bipolar disorder in the parents
of the community control group are within the range reported in prior community
samples.
The aggregation of schizophrenia-spectrum disorders in relatives of
COS probands shows a considerable degree of diagnostic specificity when compared
with relatives of ADHD probands. Schizophrenia occurs in parents of ADHD probands
at the population base rate, and at a significantly lower rate than in the
parents of COS probands. These findings are consistent with prior family studies
of ADHD probands.42, 43 Similarly,
there were no significant differences between parents of ADHD and community
control probands in risk for schizotypal and paranoid personality disorders.
The limitations of this study include the fact that the sample size
in the COS group, while much larger than in prior COS family studies, was
still relatively small. In addition, we cannot determine the extent to which
the current sample is representative of children with a schizophrenia-spectrum
disorder. Clearly, the current findings need to be replicated in another family
study of children with schizophrenia.
The increase in RR of narrow schizophrenia-spectrum disorders in parents
of COS probands compared with the rates observed in prior studies of AOS probands
is based on studies that did not use wholly comparable interview methods and
diagnostic procedures. While the result of this comparison is quite intriguing,
a direct comparison of rates of disorder in relatives of COS and AOS probands
diagnosed by identical methods is required before firm conclusions about differential
aggregation can be reached.
AUTHOR INFORMATION
Accepted for publication January 22, 2001.
Supported by research grants MH45112 (Dr Asarnow), MH 49716 (Dr Nuechterlein),
MH46981 (Dr Asarnow), MH30911 (Dr Nuechterlein), and MH14584 (Dr Nuechterlein)
from the National Institute of Mental Health, Bethesda, Md, and by the Della
Martin Foundation, Los Angeles, Calif (Dr Asarnow).
We thank the families that participated in this study and the agencies
(Children and Adults With Attention-Deficit/Hyperactivity Disorder, Los Angeles
County Department of Mental Health, Desconso Pediatric Group, Pasadena, Calif,
and Leonard "Skip" Baker, MD) that referred families to this study. We also
thank Carol Giannini, MPH, Tampsen Thorpe, PhD, Heidi Kuppinger, PhD, Ann
Futternan, PhD, Kenneth Subotnik, PhD, Sharon Talouic, PhD, Diana Payne, PhD,
Laurie Post, PhD, Patricia Miller, BA, and Richard Torquato, MA, for assistance
in data collection, and Debbie Weissman for assisting in article preparation.
From the Neuropsychiatric
Institute and Departments of Psychiatry (Drs Asarnow, Nuechterlein,
Fogelson, Subotnik, Payne, Russell, and Kuppinger) and Psychology (Drs
Asarnow, Nuechterlein, and Asamen), University of California at Los
Angeles; Department of Psychology, Pepperdine University, Malibu, Calif
(Dr Asamen); Departments of Psychiatry and Human Genetics, Virginia
Commonwealth University, Richmond (Dr Kendler); and the Virginia
Institute of Psychiatric Genetics, Richmond (Dr Kendler).
Corresponding author: Robert F. Asarnow, PhD, Della Martin Professor
of Psychiatry and Biobehavioral Science, UCLA Department of Psychiatry, 48-240C
NPI, 760 Westwood Plaza, Los Angeles, CA 90024-1759.
REFERENCES
| |
1. Asarnow R, Asarnow J. Childhood-onset schizophrenia. Schizophr Bull. 1994;20:591-597.
2. Rapoport J, ed. Childhood-Onset of "Adult" Psychiatric Disorders. Washington, DC: American Psychiatric Press Inc; 1999.
3. Asarnow R, Karatekin C. Childhood-onset schizophrenia. In: Coffey CE, Brumback RA, eds. American Psychiatric
Press Textbook of Pediatric Neuropsychiatry. London, England: American
Psychiatric Press; 1998:617-648.
4. Jacobsen LK, Rapoport JL. Reseach update: childhood-onset schizophrenia: implications of clinical
and neurobiological research. J Child Psychol Psychiatry. 1998;39:101-113.
FULL TEXT
|
ISI
| PUBMED
5. Kendler KS, Diehl SR. The genetics of schizophrenia: a current, genetic epidemiologic perspective. Schizophr Bull. 1993;19:261-284.
6. Kolvin I, Ounstead C, Humphrey M, McNay A. Studies in the childhood psychoses, II: the phenomenology of childhood
psychoses. Br J Psychiatry. 1971;118:389-395.
7. Kallmann FJ, Roth M. Genetic aspects of preadolescent schizophrenia. Am J Psychiatry. 1956;112:599-606.
FREE FULL TEXT
8. Coryell W, Zimmerman M. Personality disorder in the families of depressed, schizophrenic, and
never ill probands. Am J Psychiatry. 1989;146:496-502.
FREE FULL TEXT
9. Kendler KS. The genetics of schizophrenia. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. Baltimore, Md: Williams & Wilkins; 1997:321-357.
10. Baron M, Gruen R, Asnis L, Lord S. Familial transmission of schizotypal and borderline personality disorders. Am J Psychiatry. 1985;142:927-934.
FREE FULL TEXT
11. Levinson DF, Mowry BJ. Defining the schizophrenia spectrum: issues for genetic linkage studies. Schizophr Bull. 1991;17:491-514.
12. Tsuang MT, Gilbertson MW, Faraone SV. The genetics of schizophrenia: current knowledge and future directions. Schizophr Res. 1991;4:157-171.
FULL TEXT
|
ISI
| PUBMED
13. Kendler KS, McGuire M, Gruenberg AM, O'Hare A, Spellman M, Walsh D. The Roscommon Family Study, III: schizophrenia-related personality
disorders in relatives. Arch Gen Psychiatry. 1993;50:781-788.
ABSTRACT
14. Kendler KS. The super-normal control group in psychiatric genetics: possible artifactual
evidence for co-aggregation. Psychiatr Genet. 1990;1:45-53.
15. Tsuang MT, Fleming JA, Kendler KS, Gruenberg AS. Selection of controls for family studies: biases and implications. Arch Gen Psychiatry. 1988;45:1006-1008.
ABSTRACT
16. Orvaschel E, Puig-Antich J. Schedule for Affective Disorder and Schizophrenia
for School-Aged Children: Epidemiologic Version (K-SADS-E). Philadelphia: Medical College of Pennsylvania; 1987.
17. Russell AT, Bott I, Sammons C. The phenomenology of schizophrenia occurring in childhood. J Am Acad Child Adolesc Psychiatry. 1989;28:399-407.
ISI
| PUBMED
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
19. Robins LN, Helzer JE, Croughan J, Ratcliff KS. National Institute of Mental Health Diagnostic Interview Schedule:
its history, characteristics, and validity. Arch Gen Psychiatry. 1981;38:381-389.
ABSTRACT
20. Wing JK, Cooper JE, Sartorius N. The Measurement and Classification of Psychiatric
Symptoms: An Instruction Manual for the PSE and CATEGO Programs. London, England: Cambridge University Press; 1974.
21. Regier DA, Myers JK, Kramer M, Robins LN, Blazer DG, Hough RL, Eaton WW, Locke BZ. The NIMH Epidemiologic Catchment Area program: historical context,
major objectives, and study population characteristics. Arch Gen Psychiatry. 1984;41:934-941.
ABSTRACT
22. Robins LN, Helzer JE, Weissman MM, Orvaschel H, Gruenberg E, Burke JD, Regier DA. Lifetime prevalence of specific psychiatric disorders in three sites. Arch Gen Psychiatry. 1984;41:949-958.
ABSTRACT
23. Spitzer RL, Williams JBW. Structured Clinical Interview for DSM-III-R: Personality
Disorders. New York: Biometrics Research Dept, New York State Psychiatric Institute;
1986.
24. Fogelson DL, Nuechterlein KH, Asarnow RF, Subotnik KL, Talovic SA. Interrater reliability of the Structured Clinical Interview for DSM-III-R, Axis II: schizophrenic spectrum and affective
spectrum disorders. Psychiatry Res. 1991;39:55-63.
FULL TEXT
|
ISI
| PUBMED
25. Gershon ES. Relative Psychiatric History (RPH) Symptom Checklist
Interview. Bethesda, Md: National Institute of Mental Health; 1985.
26. Kendler KS, McGuire M, Gruenberg MD, O'Hare A, Spellman M, Walsh D. The Roscommon Family Study, I: methods, diagnosis of probands, and
risk of schizophrenia in relatives. Arch Gen Psychiatry. 1993;50:527-540.
ABSTRACT
27. SAS Institute. Software: changes and enhancements. In: SAS Technical Report. Cary, NC: SAS
Institute; 1992.
28. Roy MA, Walsh D, Kendler KS. Accuracies and inaccuracies of the family history method: a multivariate
approach. Acta Psychiatr Scand. 1996;93:224-234.
ISI
| PUBMED
29. Thompson WD, Orvaschel H, Prusoff BA, Kidd KK. An evaluation of the family history method for ascertaining psychiatric
disorders. Arch Gen Psychiatry. 1982;39:53-58.
ABSTRACT
30. Orvaschel H, Thompson WD, Belanger A, Prusoff BA, Kidd KK. Comparison of the family history method to direct interview: factors
affecting the diagnosis of depression. J Affect Disord. 1982;4:49-59.
FULL TEXT
|
ISI
| PUBMED
31. Gershon ES, Guroff JJ. Information from relatives: diagnosis of affective disorders. Arch Gen Psychiatry. 1984;41:173-180.
ABSTRACT
32. Andreasen NC, Rice J, Endicott J, Reich T, Coryell W. The family history approach to diagnosis: how useful is it? Arch Gen Psychiatry. 1986;43:421-429.
ABSTRACT
33. Ram R, Bromet EJ, Eaton W, Pato C, Schwartz JE. The natural course of schizophrenia: a review of first-admission studies. Schizophr Bull. 1992;18:185-207.
34. Maurer K, Hafner H. Methodological aspects of onset assessment in schizophrenia. Schizophr Res. 1995;15:265-276.
FULL TEXT
|
ISI
| PUBMED
35. Baron M, Gruen R, Rainier JD, Kane J, Asnis L, Lord A. A family study of schizophrenia and normal control probands: implications
for the spectrum concept of schizophrenia. Am J Psychiatry. 1985;142:447-455.
FREE FULL TEXT
36. Childs B, Scrivner CR. Age at onset and causes of disease. Perspect Biol Med. 1986;29:437-460.
ISI
| PUBMED
37. Kendler KS. Limitations of the ratio of concordance rates in monozygotic and dizygotic
twins. Arch Gen Psychiatry. 1989;46:477-478.
38. Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle. New York, NY: Cambridge University Press; 1982.
39. Maier W, Lichtermann D, Minges J, Hallmayer J, Heun R, Benkert O, Levinson DF. Continuity and discontinuity of affective disorders and schizophrenia:
results of a controlled family study. Arch Gen Psychiatry. 1993;50:871-883.
ABSTRACT
40. Kendler KS, Karkowski-Shuman L, Walsh D. Age at onset in schizophrenia and risk of illness in relatives. Br J Psychiatry. 1996;169:213-218.
|
