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Schizophrenia Research 99 (2008) 38 – 47

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Pathways to psychosis: A comparison of the pervasive

developmental disorder subtype Multiple Complex Developmental
Disorder and the “At Risk Mental State”
M. Sprong a,⁎, H.E. Becker b , P.F. Schothorst a , H. Swaab c , T.B. Ziermans a ,
P.M. Dingemans b , D. Linszen b , H. van Engeland a
a
Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, The Netherlands
b
Department of Psychiatry, Academic Medical Center De Meren in Amsterdam, The Netherlands
c
Department of Clinical Child and Adolescent Studies, University of Leiden, The Netherlands
Received 13 July 2007; received in revised form 11 October 2007; accepted 25 October 2007
Available online 4 December 2007

Abstract

Background: The comparison of high-risk populations with different developmental pathways to psychosis may lend more insight
into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways.
Aim: To compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents
presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple
Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect
regulation, anxieties, disturbed social relationships, and thought disorder.
Method: 80 ARMS- and 32 MCDD-adolescents (12–18 years) were compared on prodromal symptoms (Structured Interview of
Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social
Communication Questionnaire). In addition, both high-risk groups were compared with 82 healthy controls on schizotypal traits
(Schizotypal Personality Questionnaire-Revised).
Results: Although the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they
did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There
were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD
met criteria for ARMS.
Conclusion: These findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and
support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates
of transition to psychosis in both high-risk groups.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Prodromal; Psychosis; Multiple Complex Developmental Disorder

1. Introduction
⁎ Corresponding author. Department of Child and Adolescent
Psychiatry, University Medical Center, Heidelberglaan 100, HP Psychotic symptoms are not only part of the
A01.468, 3508 GA Utrecht, The Netherlands. Tel.: +31 30 250 9839. syndromes of schizophrenia and other psychotic
E-mail address: m.sprong-2@umcutrecht.nl (M. Sprong). disorders, but may also arise in other psychiatric
0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2007.10.031
 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47
disorders, in particular the affective disorders (American
Psychiatric Association, 1994). In addition, certain
personality disorders (Benvenuti et al., 2005; Dowson
et al., 2002; Rodriguez Solano and Gonzalez, 2000), and
genetic syndromes such as Klinefelter (DeLisi et al.,
1994; Kunugi et al., 1999; Van Rijn et al., 2006) and
22q11-deletion syndrome (Baker and Skuse, 2005;
Debbane et al., 2006; Murphy et al., 1999; Vorstman
et al., 2006) have been associated with elevated risks of
psychotic symptoms and schizophrenia spectrum
disorders.
Retrospective studies have shown that the onset of
overt psychosis is often preceded by prodromal signs
and symptoms, including functional decline, subtle
deviations in thought, emotion and perception, and
subthreshold psychotic symptoms (e.g. Häfner et al.,
1999; Schothorst et al., 2006). Over the past decade, the
focus of attention in schizophrenia research has been
widened to also include the prodromal phase. Projects are
being set up all over the world to identify and offer
treatment to prodromal individuals in the hope of
preventing or delaying psychotic outbreak (e.g. Adding-
ton, 2004; Bechdolf et al., 2006; Chong et al., 2004;
Klosterkötter et al., 2005; McGlashan et al., 2003;
McGorry et al., 2002; Ruhrmann et al., 2005). However,
because the term “prodrome” can only be used in
retrospect, the terms “ultra high-risk” or “clinical high-
risk” or “At Risk Mental State” (ARMS) are used. The
first results of these projects have indicated that ARMS
individuals are indeed at imminent risk of psychosis, with
transition rates ranging from 15% to 54% after 6 months
to 1 year (e.g. Haroun et al., 2006; Miller et al., 2002).
Another population at risk for psychosis consists of
subjects with Multiple Complex Developmental Dis-
order (MCDD), a subtype of pervasive developmental
disorder not otherwise specified (PDD-NOS) which is
characterized by early childhood-onset affect dysregula-
tion, high levels of anxiety, social impairment, and
thought disorder. This combination of symptoms has
received various labels in the past, including borderline
syndrome of childhood, multiplex developmental dis-
order, schizoid disorder, and schizotypal disorder (Ad-
Dab'bagh and Greenfield, 2001; Cohen et al., 1986).
Cohen et al. (1986, 1994) proposed a set of diagnostic
criteria for MCDD (Table 1), which have been refined
by Towbin et al. (1993), and Buitelaar and Van der Gaag
(1998). Follow-up of 55 children with MCDD revealed
a considerably elevated risk of psychosis; 22% that had
been followed until adolescence, and 64% that had been
followed until young adulthood had developed schizo-
phrenia spectrum disorders (Van Engeland and Van der
Gaag, 1994).
39
Table 1
Diagnostic criteria for Multiple Complex Developmental Disorder
(MCDD; Cohen et al., 1994)
1) Regulation of affective state and anxiety is impaired beyond that
seen in children of comparable age, as exemplified by several of the
following:
a. intense generalized anxiety or tension
b. fears and phobias (often unusual or peculiar)
c. recurrent panic episodes or flooding with anxiety
d. episodes of behavioral disorganization punctuated by markedly
immature, primitive or violent behaviors
e. significant and wide emotional variability with or without
environmental precipitants
f. frequent idiosyncratic or bizarre anxiety reactions
2) Consistently impaired social behavior/sensitivity, as exemplified by
the following types of disturbances:
a. social disinterest, detachment, avoidance or withdrawal despite
evident competence
b. severely impaired peer relationships
c. markedly disturbed attachments; high degree of ambivalence to
adults (especially parents/caregivers)
d. profound limitations in the capacity for empathy or understanding
others affects accurately
3) Impaired cognitive processing (thinking disorder), as exemplified
by some of the following difficulties:
a. irrationality, sudden intrusions on normal thought process,
magical thinking, neologism or repetition of nonsense words,
desultory thinking, blatantly illogical, and bizarre ideas
b. confusion between reality and inner fantasy life
c. perplexity and easy confusability (trouble understanding social
processes or keeping thoughts ‘straight’)
d. delusions, overvalued ideas including fantasies of omnipotence,
paranoid preoccupations, over-engagement with fantasy figures,
grandiose fantasies of special powers, and referential ideation
4) The syndrome appears during the first several years of life
5) The child is not suffering from autism or schizophrenia
The notion that some psychotic patients show
premorbid behavioral abnormalities dates back to
Bleuler (1911), and since then it has often been
confirmed (e.g. Isohanni et al. 2000; Niemi et al.
2003). Furthermore, the fact that subjects with MCDD
have severe impairments from early childhood, whereas
the ARMS-symptoms are identified in adolescents and
young-adults who in most cases have been relatively
inconspicuous as a child, suggests that there are
different developmental pathways to psychosis. This is
supported by a retrospective study in schizophrenia
patients by Rossi et al. (2000) who identified two
subgroups. The first displayed only minor behavioral
abnormalities during childhood, which increased pro-
gressively over the years. The other already displayed
severe behavioral abnormalities during childhood,
which remained relatively stable over time. Corcoran
et al. (2003), who retrospectively studied the evolution
of symptoms in ARMS-adolescents, also identified two
40 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47
subgroups. The largest subgroup had had an essentially
normal development throughout childhood but dis-
played behavioral and personality changes in adoles-
cence. The smaller subgroup was described as never
normal.
Research into precursors of psychosis leads to a
better understanding of the pathogenesis, and a more
accurate identification of those at high-risk. The
comparison of these precursors in populations with
different pathways to psychosis is of particular interest,
because it may additionally lend more insight into the
heterogeneity of the manifestation of the psychotic
syndrome (Schmael et al., 2007). The aim of the present
study is to explore whether ARMS-adolescents and
adolescents with prepubertal diagnoses of MCDD can
be differentiated based on prodromal symptoms, and
autism and schizotypal traits. First, because the ARMS-
group is defined by the presence of prodromal
symptoms and the MCDD-group is not, higher levels
of these symptoms are hypothesized in the first group
than in the latter. Second, because MCDD is considered
a subtype of PDD-NOS, more autism traits are expected
in MCDD-adolescents than in ARMS-adolescents.
Third, since schizotypal traits have been shown to
reflect a biological-genetic vulnerability to schizophre-
nia or psychosis-proneness (Vollema et al., 2002), it is
hypothesized that both high-risk groups differ from
healthy controls regarding these traits.
2. Method
This study is part of the Dutch Prediction of
Psychosis Study, a longitudinal research project that
has been approved by the Dutch Central Committee on
Research Involving Human Subjects. It is a cooperation
between the Child and Adolescent Psychiatry Depart-
ment of the University Medical Center (UMC), and the
Psychiatry Department of the Academic Medical Center
(AMC). The latter is part of the European Prediction of
Psychosis Study (EPOS; Klosterkötter et al., 2005).
2.1. Subjects
The ARMS-group consisted of help-seeking adoles-
cents who met one or more of the four EPOS inclusion
criteria (Klosterkötter et al., 2005): 1) attenuated
positive symptoms, 2) brief, limited, or intermittent
psychotic symptoms, 3) a 30% reduction in overall level
of social, occupational/school, and psychological func-
tioning in the past year, combined with a genetic risk of
psychosis, and 4) two or more of a selection of nine
basic symptoms, i.e. subjective deficits in cognitive,
perceptual, and motor functioning. The first three
inclusion criteria were assessed with the Structured
Interview for Prodromal Syndromes (SIPS; McGlashan
et al., 2001). The fourth inclusion criterion was assessed
with the Bonn Scale for the Assessment of Basic
Symptoms-Prediction List (BSABS-P; Schultze-Lutter
and Klosterkötter, 2002).
The MCDD-group consisted of adolescents with
prepubertal DSM-IV diagnoses of PDD-NOS (Amer-
ican Psychiatric Association, 1994), with the additional
qualification of “meeting the criteria for MCDD”,
implying early childhood-onset impairments in affect
regulation, social behavior/sensitivity, and cognition
(Cohen et al., 1994). Diagnoses were confirmed by
expert clinical opinion (HvE, PS) after psychiatric
examination including the Autism Diagnostic Inter-
view-Revised (Lord et al., 1994), as well as a parent
interview based on the diagnostic criteria for MCDD
(Table 1), which was developed for internal use at the
UMC. Consecutively, the MCDD-criteria were rated
using the information present in the medical records of
the patients (PS, MS). The mean number of criteria met
was 8.46 (SD = 2.60).
Healthy controls (HCs) were recruited from second-
ary schools in the region of Utrecht. They were excluded
if they had MCDD, met one of the ARMS-criteria, or if
they had a history of any psychiatric illness themselves,
or in a first-degree relative, or a second-degree relative
with a psychotic disorder.
All participants were aged between 12 and 18 years.
They all signed an informed consent, and for those
younger than 16, parents co-signed. None of them had
ever experienced a psychotic episode lasting N week,
defined as the presence of positive symptoms that are
seriously disorganizing, i.e. a score of 6 on any of the
items of the SIPS-Positive Symptoms subscale, or on the
SIPS-item “Odd behavior or appearance”. All had a
level of verbal intellectual functioning (VIQ) ≥ 75. At
the UMC, VIQ was assessed with the Wechsler
Intelligence Scales (Wechsler, 1997, 2002). At the
AMC, VIQ was estimated using the Dutch adaptation of
the National Adult Reading Test (Nelson, 1982;
Schmand et al., 1992). Since there was no relationship
between site and VIQ (F(1,70) = 0.001; p = 0.972), the
VIQ-data of the two sites were combined.
2.2. Prodromal symptoms
The semi-structured SIPS-interview was designed to
assess a broad spectrum of prodromal signs and symp-
toms. It has 4 subscales: Positive (5 items), Negative
(6 items), Disorganization (4 items), and General
 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47
symptoms (4 items), and also includes a Global Assess-
ment of Functioning (GAF-) scale with well-defined
anchor points (McGlashan et al., 2001). Symptoms are
scored on a 7-point scale from 0 (absent) through 6
(extreme/psychotic intensity). The distinction between a
score of 5 (severe) and a score of 6 (psychotic) for the
positive symptoms is mainly determined by “the lack of
conviction regarding the externally generated, “real”
nature of the symptom as well as the maintenance of
insight regarding the sense that the experience is, in fact, a
symptom” (Miller et al., 2003).
The semi-structured BSABS-P interview was used to
rate subjective disturbances, that have been found to be
predictive for psychosis (Schultze-Lutter and Klosterköt-
ter, 2002). The 33 items are summarized in three sub-
scales, i.e. Cognitive (11 items), Perceptual (19 items),
and Motor disturbances (3 items). In line with the SIPS, a
7-point scoring scale has been developed to rate the
presence and severity of the symptoms (0 = absent, 6 =
frequent/extreme).
2.3. Schizotypal traits
The revised self-report Schizotypal Personality
Questionnaire (SPQ-R) was used to assess schizotypal
personality traits (Raine, 1991; Vollema and Hoijtink,
2000). Factor analyses have shown that the 74 items can
be reduced to three latent variables corresponding with
the positive, negative and disorganization dimensions of
schizotypy (Raine et al., 1994; Vollema and Hoijtink,
2000). In the UMC, the SPQ-R was slightly modified to
better accommodate a young population (e.g. items
referring to work were changed into school).
2.4. Autism traits
At the UMC, the parent-completed Social Commu-
nication Questionnaire-lifetime version, formerly
known as the Autism Screening Questionnaire, was
used to assess the presence of autism traits in both high-
risk groups (SCQ; Rutter et al., 2003; Warreyn and
Roeyers, 2001). It is a 40-item screening questionnaire
for autism spectrum disorders, with a possible total
score of 0–39 for verbal children. The items refer to core
autistic behaviors, covering the areas of communication,
reciprocal social interaction, and restricted and repetitive
behaviors, with many of the items specifically referencing
to behaviors between the fourth and fifth birthdays.
Berument et al. (1999) showed that a cut-off of 15 dis-
criminates PDD and non-PDD diagnoses well. Ques-
tionnaires with more than 4 omitted items were excluded
from the analyses.
41
2.5. Data analysis
Data distributions were checked for normality using
the Kolmogorov–Smirnov test, and homogeneity of the
variances using the Levene's test, supplemented by
visual inspections of the data distributions and residual
plots. Hypotheses were tested using χ 2 -tests and
nonparametric tests. Possible confounding of age and
gender was explored by nonparametric bivariate corre-
lations. All analyses were two-tailed, and to reduce the
risk of making Type I errors due to multiple testing, α
was set at 0.01, and a Bonferroni-correction was applied
to all post hoc comparisons. Effect sizes were calculated
as Rosenthal's r (Field, 2005). Following the widely
used convention for appraising effect sizes in behavioral
research, effect sizes of 0.10 were considered small, of
0.30 medium, and above 0.50 large (Cohen 1988).
3. Results
3.1. Baseline characteristics
During the two-year recruitment phase, 327 young
patients were referred to the project. After consultation
with the referring persons, 53 patients were considered
ineligible for screening: 19 did not have “prodromal”
signs or MCDD, 19 were outside the age range, 9 had
already experienced a psychotic episode lasting more than
1 week, 4 had a VIQ b 75, 1 only had symptoms after the
use of drugs, and 1 lived in a youth penitentiary facility. Of
the remaining 274 patients, 132 were interviewed, of
whom 80 met ARMS-criteria and 32 had a diagnosis of
MCDD. The other 142 were not interviewed: 88 refused
to participate, in 29 cases the case manager requested not
to approach the patient because of clinical considerations,
and in 26 cases there were other reasons (e.g. change of
case manager, not able to contact patient).
Statistical comparisons revealed group differences
regarding age, gender and VIQ (Table 2). The two high-
risk groups had similar GAF-scores. As expected, the
MCDD-group had more early-onset behavioral problems
than the ARMS-group, exemplified by a larger proportion
of subjects with a first mental health contact before age 6,
which was broadly defined and included contacts with
social workers, psychologists, and psychiatrists. Also, a
large proportion of MCDD-subjects had received special
primary education, whereas the percentage of ARMS-
subjects receiving special primary education compared
well with the general population. About 3% of all school-
going children in the Netherlands received special
education in 2005/2006 according to the Centre for
Policy Related Statistics (2007).
42 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47

Table 2
Demographic and sample characteristics
ARMS MCDD HC Statistic df p Post hoc comparisons,
(n = 80) (n = 32) (n = 82) Bonferroni corrected
Mean age in years (SD) 16.4 (1.6) 13.9 (1.8) 15.1 (1.5) F = 30.43 2, 191 b0.001a ARMS N HC N MCDD
(all comparisons: p b0.001a)
n male (%) 43/80 (53.8%) 24/32 (75.0%) 40/82 (48.8%) χ2 = 6.51 2 0.038 –
Median GAF-score 53 (29–100) 53 (21–87) 95 (60–100) H = 133.61 2 b0.001a ARMS = MCDD (p = 1.000);
(lowest–highest) ARMS b HC ( p b 0.001a);
MCDD b HC ( p b 0.001a)
Mean verbal intelligence 100.9 (11.3) 102.1 (14.2) 108.4 (13.4) F = 7.38 2, 183 0.001a ARMS b HC ( p = 0.001a);
(SD) MCDD b HC ( p = 0.055);
ARMS b MCDD ( p = 1.000)

Psychopharmaca use in the past 3 months:

Any psychopharmaca (%) 36/80 (45.0%) 20/32 (62.5%) NA – – –
• Antipsychotic (%) 20/80 (25.0%) 16/32 (50.0%) NA – – –
• Antidepressant (%) 18/80 (22.5%) 4/32 (12.5%) NA – – –
• Anxiolytic (%) 9/80 (11.3%) 0/32 (0.0%) NA – – –
• Psychostimulant (%) 2/80 (2.5%) 5/32 (15.6%) NA – – –
• Other (%) 3/80 (3.8%) 2/32 (6.3%) NA – – –

Early developmental problems:

Special primary education (%) 2/49b (4.1%) 14/31 (45.2%) NA – – –
Mental health contact 3/75 (4.0%) 21/32 (65.6%) NA – – –
before age 6 (%)
Mental health contact 20/75 (26.7%) 31/32 (96.9%) NA – – –
before age 12 (%)
ARMS = At Risk Mental State; MCDD = Multiple Complex Developmental Disorder; HC = healthy controls; GAF = General Assessment of
Functioning; NA = not applicable.
a
Statistically significant at α = 0.01; bOnly data for the UMC site were available.

3.2. At Risk Mental State criteria
The rates of subjects meeting each of the four subsets
of ARMS-criteria are reported in Table 3. Of the ARMS-
group, 43.8% met one, 45.0% met two, and 11.3% met
three criteria. Although different inclusion criteria were
used, i.e. having a childhood MCDD-diagnosis, now in
their adolescence 78.1% of the MCDD-group also met
at least one of the ARMS-criteria; 50.0% met one,
25.0% met two, and 3.1% met three.
The rate of first- or second-degree relatives with a
psychotic disorder in the MCDD-group was comparable
to that in the ARMS-group (12.9% and 13.0% res-
pectively), but the genetic risk and drop in GAF-score
criterion was met in none of the MCDD-subjects.

3.3. Prodromal symptoms

Table 3
Distribution of putatively prodromal state criteria in two groups of The ARMS-group reported higher levels of SIPS-
adolescents at high-risk for psychosis Positive and Negative symptoms than the MCDD-group
ARMS MCDD (Table 4), representing medium effect sizes. Further
n meeting Attenuated Positive 73/80 23/32 analyses revealed that relatively more ARMS-adolescents
Symptoms (%) (91.3%) (71.9%) than MCDD-adolescents reported at least one elevated
n meeting Brief Limited Intermittent 8/80 1/32 score (i.e. ≥3) on any of the items of the SIPS-Positive
Psychotic Symptoms (%) (10.0%) (3.1%)
scale (93.8% and 65.6% respectively, χ2(1) = 14.77,
n meeting Genetic Risk plus Reduced 9/80 0/32
Functioning (%) (11.3%) (0.0%) p b 0.001). There were no differences between the two
n meeting Basic Symptoms(%) 44/79 11/30 high-risk groups regarding the SIPS-Disorganization and
(55.7%) (36.7%) General symptoms, the BSABS-P summary scales, nor
ARMS = At Risk Mental State; MCDD = Multiple Complex Develop- the percentages of subjects with elevated (i.e. ≥3) scores
mental Disorder. on any of the items of the BSABS-P scales.
 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47 43

Table 4
Putatively prodromal symptoms in adolescents at high-risk for psychosis (median and lowest/highest values are reported)
ARMS MCDD Mann–Whitney U p and effect size Rosenthal's r
Structured Interview for Prodromal Symptoms:
Positive symptoms 9 6.5 686.5 b0.001 a
(max. = 30) (0–24) (0–19) r = 0.35
Negative symptoms 5 3 873.0 0.010 a
(max. = 36) (0–23) (0–14) r = 0.24
Disorganization symptoms 4 3 1208.0 0.793
(max. = 24) (0–22) (0–16) r = 0.03
General symptoms 7 5 980.0 0.064
(max. = 24) (0–15) (0–17) r = 0.18

Bonn Scale for the Assessment of Basic Symptoms-Prediction List:

Cognitive disturbances 12 10 927.0 0.211
(max. = 66) (0–40) (0–32) r = 0.12
Perceptual disturbances 8 4 872.0 0.072
(max. = 114) (0–33) (0–34) r = 0.18
Motor disturbances 0 0 1167.5 0.987
(max. = 18) (0–10) (0–8) r b 0.01
ARMS = At Risk Mental State; MCDD = Multiple Complex Developmental Disorder.
a
Statistically significant at α = 0.01.

3.4. Schizotypal traits 3.6. Possible confounding of age and gender on

Group differences were observed for all three
schizotypal factors (Table 5). Post hoc comparisons
showed that there were no differences between the two
high-risk groups. Both the ARMS- and the MCDD-
group scored higher than the HCs on all three factors,
representing medium to large effect sizes.
3.5. Autism traits
More autism traits were reported in the MCDD- than
in the ARMS-group (Mdns 18 and 6 respectively,
U = 112.0, p b 0.001). Using the experimental cut-off of
15 (Berument et al., 1999), 4.7% (n = 2) of the ARMS-
subjects and 71.4% (n = 20) of the MCDD-subjects
scored in the PDD-range.
symptomatology and traits
No significant correlations between age and gender
were observed when the two high-risk groups were
combined (r = 0.076, p = 0.427), nor when the two high-
risk groups were analyzed separately (ARMS: r = 0.038,
p = 0.739; MCDD: r = 0.048, p = 0.796).
In the combined high-risk sample, age was positively
related to SIPS-Positive symptoms (τ = 0.234, p b 0.001),
but not to the other SIPS-scales, the BSABS-P scales, nor
the schizotypy scales. When the two high-risk samples
were analyzed separately, the correlations between age
and SIPS-Positive symptoms no longer reached statistical
significance (ARMS: τ = 0.164, p b .040; MCDD:
τ = 0.069, p b .590), although the results suggest an in-
crease with age in the ARMS-group.

Table 5
Schizotypal traits in adolescents at high-risk for psychosis and healthy controls (median and lowest/highest values are reported)
ARMS MCDD HC Kruskal–Wallis H p Mann–Whitney post hoc comparisons (Bonferroni
(n = 66) (n = 31) (n = 80) (df = 2) corrected p and effect size Rosenthal's r)
ARMS vs HC MCDD vs HC ARMS vs MCDD
Positive schizotypy 14 10 2 59.67 b0.001 a
b0.001 a
b0.001 a
0.407
(max. 38) (0–33) (0–36) (0–18) r = 0.60 r = 0.46 r = 0.15
Negative schizotypy 15 13 6 45.08 b0.001a b0.001a b0.001a 1.000
(max. 43) (1–38) (0–34) (0–24) r = 0.51 r = 0.44 r = 0.01
Disorganization 7 11 1 66.88 b0.001a b0.001a b0.001a 0.473
(max. 19) (0–19) (0–17) (0–8) r = 0.56 r = 0.65 r = 0.15
ARMS = At Risk Mental State; MCDD = Multiple Complex Developmental Disorder; HC = Healthy controls; aStatistically significant at α = 0.01.
44 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47
In the combined high-risk sample, significant
correlations were observed between gender and SIPS-
Positive symptoms (τ = 0.291, p b 0.001), SIPS-General
symptoms (τ = 0.269, p = 0.001), BSABS-P Perceptual
disturbances (τ = 0.232; p = 0.005), and SPQ-R Positive
schizotypy (τ = 0.287, p = 0.001). For all these scales,
higher levels were reported by girls than by boys (SIPS-
Positive: U = 874.5, p b 0.001; SIPS-General: U = 931.0,
p = 0.001; BSASB-P Perceptual: U = 892.5, p = 0.003;
SPQ-R Positive: U = 657.0, p b 0.001). When the two
high-risk groups were analyzed separately, none of these
correlations reached statistical significance.
Age was negatively related to autism traits (τ =
− 0.288, p = 0.001) in the two high-risk groups com-
bined. However, when the two high-risk groups were
analyzed separately, the correlations did not reach
statistical significance (ARMS: τ = 0.087, p = 0.423,
MCDD: τ = 0.133, p = 0.331).
Although the effects of gender on traits and symptoms
appeared to be small, to exclude the possibility that the
(lack of) group differences might be explained by gender
differences, the analyses of Sections 3.3 and 3.4 were
repeated for only the male subjects. Because there were
only 8 girls in the MCDD-group, girls were not analyzed
separately.
The results are completely in line with the results
when the girls were included. The difference between
ARMS-boys and MCDD-boys was significant only for
the SIPS-Positive and Negative scales (Positive:
U = 253.5, p = 0.001; Negative: U = 304.5, p = 0.008),
but not for the other SIPS- nor the BSABS-P-scales:
SIPS-Disorganized (U = 370.0, p = 0.092), SIPS-General
(U = 399.5, p = 0.166), BSABS-P-Cognitive (U = 374.0,
p = 0.173), BSABS-P-Perceptual (U = 340.5, p = 0.087),
BSABS-P-Motor (U = 437.0, p = 0.472). There were
group differences for all three SPQ-R-scales (all p's
b0.001). Two-by-two comparisons showed that boys of
the two high-risk groups differed significantly from HC-
boys on all three scales (all p's b0.001), and that ARMS-
and MCDD-boys did not differ on any of the scales
(Cognitive-perceptual: U = 360.5, p = 0.857; Interperso-
nal: U = 412.0; p = 1.000; Disorganized: U = 308.5;
p = 0.179).
4. Discussion
Contrary to the first hypothesis, ARMS- and MCDD-
adolescents did not differ regarding subjective distur-
bances in thought, perception, and motor functioning
(i.e. basic symptoms), nor regarding prodromal dis-
organization and general symptoms. In addition, the
majority (78.1%) of MCDD-adolescents unexpectedly
met the ARMS-criteria. However, as hypothesized, the
ARMS-group did report higher levels of positive and
negative prodromal symptoms, and elevated scores on at
least one of the positive prodromal symptoms were
more common in this group.
It has been suggested that in most psychotic
patients, the less specific basic symptoms develop
first, followed by positive, and later negative symp-
toms (Gross, 1997). The finding that higher levels of
positive and negative prodromal symptoms are re-
ported in the ARMS-group than the MCDD-group,
suggests that the former might be at more imminent
risk of developing psychosis than the latter. This could
perhaps be explained by the fact that the ARMS-sub-
jects were older. Consequently, a larger proportion
falls within the age-of-onset window for psychotic
disorders, which is from the late teens through early
twenties for non-affective psychoses (Kessler et al.,
2007). However, correlation-analysis showed that age
only had an effect on SIPS-positive symptoms in the
ARMS-sample, although this may be an artifact of
having few older MCDD-subjects in the sample, or
lack of power due to small sample size.
The high-risk groups were not gender-matched,
which is not surprising since PDDs are more prevalent
in males (Volkmar et al., 2004). In our study, boys
generally reported lower positive symptom levels than
girls. This is in line with evidence from a study on
subclinical psychotic symptoms in the general popula-
tion that showed that subclinical positive symptoms are
more prevalent in females (Maric et al., 2003). Post hoc
analyses of only the male subjects showed that gender
differences could not explain the observed results.
As hypothesized, the MCDD-group showed more
autism traits than the ARMS-group, and both high-risk
groups differed from HCs regarding schizotypal traits.
Schizotypy, and particularly the positive domain, is
regarded a biological-genetic vulnerability marker for
psychosis (Vollema et al., 2002). Our data support the
notion suggested by Jansen et al. (2000) that such a
vulnerability for psychosis may exist in subjects with
MCDD. An association between PDD(-NOS) and
psychosis has been reported elsewhere (e.g. Clarke
et al., 1989; Mouridsen et al., 2007; Nylander and
Gillberg, 2001; Sporn et al., 2004; Stahlberg et al.,
2004). However, whether having a PDD increases the
vulnerability for psychosis, or whether the childhood
developmental abnormalities that are observed in many
subjects with adult schizophrenia, including social
maladjustment and cognitive abnormalities (e.g. Iso-
hanni et al., 2000; Niemi et al., 2003), are sometimes
diagnosed as PDD is not clear.
 M. Sprong et al. / Schizophrenia Research 99 (2008) 38–47
Some comments need to be made on the association
between schizotypy and MCDD. First, when comparing
SPQ-R schizotypal traits with the diagnostic criteria for
MCDD (Towbin et al., 1993), one cannot overlook the
overlap regarding interpersonal (e.g. social disinterest,
withdrawal, anxiety) and cognitive traits (e.g. magical
thinking, delusional ideas, ideas of reference, paranoid
preoccupations). Also, the diagnostic criteria for
schizotypal personality disorder (American Psychiatric
Association, 1994) and MCDD overlap, as has been
pointed out by Cohen et al. (1986). Second, historically
there has been diagnostic confusion between (child-
hood) schizoid and schizotypal personality disorder and
PDD (Clarke et al. 1989; Parry-Jones 2001; Scheeringa
2001; Tantam 1988; Wolff 1991; 1996). It has been
argued that these disorders may lie on the same
continuum, or may be distinct disorders with some
amount of overlap. Third, as suggested by Scheeringa
(2001), schizoid and schizotypal personality disorder
may be underdiagnosed in children in favor of PDD, due
to negative associations with schizophrenia that clin-
icians may have.
One might argue that the two high-risk groups in this
study cannot truly be differentiated, since they did not
differ regarding schizotypal traits, and because the
majority of MCDD-adolescents met the ARMS-criteria.
Also, 26.7% of the ARMS-sample had a mental health
contact before the age of twelve, implying that at least
some of them had childhood-onset behavioral problems.
This percentage is in line with the study by Corcoran
et al. (2003) in which 25% of the ARMS-group was
reported to have early behavioral problems. However,
although there may be similarities between the two high-
risk samples now they are in adolescence, the data show
that MCDD-adolescents were much more impaired in
early childhood than the ARMS-adolescents. Most
importantly, the MCDD-subjects showed high levels
of autism traits, were often unable to attend regular
primary school, and in most cases started receiving
mental health care before the age of six. And of course,
there were no subjects with clinical diagnoses of MCDD
in the ARMS-group, because they would automatically
be included in the MCDD-group.
Limitations of this study include the relatively small
size of the MCDD-sample causing inequality of the
sample sizes, and the fact that statistical analyses were
nonparametric, and thus unifactorial, because ANCOVA-
assumptions were not met. Furthermore, only long-term
follow-up can determine whether both high-risk samples
are truly at elevated risk, i.e. whether the symptoms will
develop into psychosis or whether they will disappear
spontaneously or after treatment. Many of our patients
45
were already using psychopharmaca. This may affect
transition rates, current symptom reports, and compar-
ability with other high-risk studies.
In sum, this study contributes to the evidence for
different early developmental pathways to psychosis.
Future ultra high-risk research should focus on the
neurocognitive similarities and differences between
(diagnostic) subgroups within the “prodromal” samples,
as this may lead to better insight into the pathogenesis of
psychosis and the heterogeneity within the schizophrenia
spectrum. In addition, long-term follow-up of these
subgroups might also lead to a better distinction between
true and false positives within samples that present with
ARMS-symptoms.
Role of funding source
This study was supported by a grant from ZON-MW (ZorgOnder-
zoek Nederland/NWO-Medische Wetenschappen, project # 2630.0001).
This organization had no further role in the study design, in the collection,
analysis and interpretation of data, in the writing of the report, or in the
decision to submit the paper for publication.
Contributors
P.F. Schothorst, H.E. Becker, P.M. Dingemans, D. Linszen, and H.
van Engeland designed the study and wrote the protocol. M. Sprong, T.B.
Ziermans, P.F. Schothorst, H.E. Becker, and P.M. Dingemans managed
the data collection. M. Sprong managed the literature searches and
analyses. M. Sprong, H. Swaab, and P.F. Schothorst undertook the
statistical analysis, and M. Sprong wrote the first draft of the manuscript.
All authors contributed to and have approved the final manuscript.
Conflict of interest
None of the authors have any actual or potential conflicts of
interest.
Acknowledgement
None.
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