Early Intervention in Psychiatry 2009; 3: 213–220 doi:10.1111/j.1751-7893.2009.00135.

Original Article
Do premorbid impairments predict emergent
‘prodromal’ symptoms in young relatives at risk
for schizophrenia? eip_135 213..220

Matcheri S. Keshavan,1,2,3 Shaun M. Eack,2,4 Debra M. Montrose,2 Michelle M. Abela,1

Srihari S. Bangalore,2 Vaibhav A. Diwadkar,1 Konasale M. R. Prasad2 and
Rajaprabhakaran Rajarethinam1

Abstract as measured by the Scale of ‘Prodro-

1
Department of Psychiatry and Behavioral
Neurosciences, Wayne State University
School of Medicine, Detroit, Michigan;
2
Department of Psychiatry, University of
Pittsburgh School of Medicine, and
4
School of Social Work, University of
Pittsburgh, Pittsburgh, Pennsylvania, and
3 lems in premorbid social adjustment
Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston,
Massachusetts, USA
Corresponding author: Dr Matcheri S.
Keshavan, 2P12, landmark building, 401
Park Drive, Boston, MA 02215, USA.
Email: mkeshava@bidmc.harvard.edu
Aims: Individuals at risk for deve-
loping schizophrenia (SZ) in the
future frequently exhibit subtle
behavioural and neurobiological
abnormalities in their childhood. A
better understanding of the role of
these abnormalities in predicting
later onset of ‘prodromal’ symptoms
or psychosis may help in early identi-
fication of SZ.
Methods: In an ongoing prospective
follow-up study of young genetically
at-risk relatives of patients with SZ,
we studied the prevalence of prob-
and childhood psychopathology and
examined their relationship with the
presence and progression of ‘prodro-
mal’ symptoms of SZ.
Results: Growth curve analyses
showed that ‘prodromal’ symptoms,
mal’ Symptoms, increased during
follow-up. Premorbid maladjustment
and childhood behavioural distur-
bances were cross-sectionally
correlated broadly with ‘prodromal’
symptomatology scores. Longitudinal
analyses revealed that behavioural
disturbances, but not childhood mal-
adjustment at baseline, significantly
predicted increases in ‘prodromal’
symptomatology during the 2-year
study period.
Conclusion: Premorbid behavioural
disturbance and maladjustment
may predict the later emergence of
‘prodromal’ symptoms. ‘Prodromal’
symptoms in young at-risk relatives
may define a subgroup worthy of
follow-up into the age of risk for
psychosis in order to cost-effectively
characterize the predictors of psy-
chotic symptoms and SZ.

Received 13 February 2009; accepted 14 Key words: predictor, premorbid, prodrome, schizophrenia,
June 2009 schizotypy.

INTRODUCTION and functional decline) and psychotic phases (i.e.

Schizophrenia (SZ) is a leading cause of lifetime
disability.1 Effective treatments are available, but
mainly palliative. The illness runs a chronic, phasic
course characterized by a sequential emergence of
premorbid (i.e. years prior to the onset of psychotic
symptoms, often with trait-like deficits in psychopa-
thology, behaviour and function), prodromal (i.e.
immediately preceding the onset of psychotic
symptoms with sub-threshold positive symptoms
the frank emergence of psychotic symptoms with
hallucinations, delusions and thought disorder
emerging in late adolescence or early adulthood).2
We want to clarify at the outset the uncertainties in
the use of the term ‘prodrome’ that incorrectly
implies that these symptoms always precede the
onset of psychotic disorder; most studies indicate a
high false-positive rate in those with ‘prodromal’
symptoms deemed at risk for psychosis. Thus, we
will refer to the term ‘prodrome’ in inverted commas

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Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd
Premorbid impairment and ‘prodromal’ symptoms
in the rest of the paper. Despite significant advances
in our understanding of the neurobiology of the
early course of SZ, we know relatively little about the
predictors of susceptibility to SZ, a better under-
standing of which is critical for prevention and early
intervention.
The question of what might be the best predictors
for later psychosis must be guided by hypothesis-
driven indicators of risk that stem from extant
pathophysiological models. The view that SZ is a
neurodevelopmental disorder suggests that behav-
ioural and neurobiological alterations may be
detectable in the premorbid phase before the typical
onset of the features of the illness (e.g. psychosis)
during childhood, adolescence or early adulthood.
It is also unclear who among the predisposed indi-
viduals might be at a heightened risk for ‘prodromal’
symptoms. Genetic factors are among the best-
established aetiological risk factors in SZ.3–5 Pro-
spectively studying young relatives of SZ patients
with high genetic risk (HR-S subjects) is instructive
in our search of markers that predict the onset of the
symptomatic manifestations of the illness.6–8
Premorbid behavioural deficits are more frequent
in HR-S subjects relative to the general population;
HR-S subjects have increased the prevalence of trait-
related measures of SZ spectrum psychopathology,
such as schizotypy,9 premorbid social and scholastic
impairment,10,11 and childhood behavioural distur-
bances as measured by the Childhood Behaviour
Check List (CBCL) scores.12 Longitudinal studies of
HR-S subjects have shown that schizotypy13 and
CBCL score elevations13 may be predictive of psycho-
sis during follow-up. Problems in social adjustment
beginning in childhood have also been found in sub-
jects who eventually convert to psychosis.14 It is not
clear whether HR-S subjects with one or more of
these premorbid impairments are more at risk for
developing the ‘prodromal’ symptoms and eventu-
ally SZ spectrum disorders. This is an important
question to address because the emergence of ‘pro-
dromal’ symptoms are more proximal to the premor-
bid phase, and appear before the full psychotic
manifestations emerge several years later. However,
to our knowledge, few studies have examined the
relation between premorbid impairments and the
‘prodromal’ symptoms that emerge during adoles-
cence in individuals predisposed to SZ.
In an ongoing prospective study of HR-S subjects,
we examined the relationship between indices of
premorbid impairment at baseline (behavioural dis-
turbance and premorbid social adjustment) and the
occurrence of, and increase in, ‘prodromal’ symp-
toms as seen during adolescence or early adulthood.
Specifically, we hypothesized that premorbid
214
dysfunction would predict ‘prodromal’ psychopa-
thology both cross-sectionally and their emergence
or worsening during follow-up up to 2 years.
METHODS
Subjects
A group of 102 adolescent and young adult high risk
relatives were recruited. Of these, 85 participants
(average age = 15.98 (standard deviation (SD) =
3.57) years; 43 (51%) males) had at least one ‘prodro-
mal’ assessment and were included in the analysis.
Fifty-eight HR-S (41 offspring, 6 siblings and 11
second-degree relatives) were recruited at the Uni-
versity of Pittsburgh site, and 27 HR-S (18 offspring,
4 siblings and 5 second-degree relatives) were
recruited at the Wayne State University site, Detroit.
HR-S subjects were required to have at least one
first- or second-degree family member with a Diag-
nostic and Statistical Manual of Mental Disorders-
Fourth Edition (DSM-IV) diagnosis of an SZ or
schizoaffective disorder. Affected family members
were ascertained by Structured Clinical Interview
for DSM-IV Axis I Disorders (SCID) verified by clini-
cal consensus diagnosis. Clinical evaluation of the
HR-S subjects was conducted by using the Struc-
tured Clinical Interview for DSM-IV Axis I Disorders
(SCID-I), supplemented by the Behavioral Disorders
sections of the Kiddie-Schedule for Affective Disor-
ders and schizophrenia (K-SADS).15
HR-S subjects with a DSM-IV diagnosis of an SZ
spectrum disorder, mental retardation, significant
head injury, current substance use disorder, signifi-
cant history of or current medical or neurological
illness were excluded from the study. All subjects,
following a description of the study, provided
written informed consent approved by the institu-
tional review board and Departments of Psychiatry
at University of Pittsburgh and at the Wayne State
University, Detroit. Subjects less than 18 years of age
were required to have a parent or guardian provide
informed written consent for the study.
Assessments
To assess the childhood/adolescent behavioural
disturbances, we administered the Child Behaviour
Checklist16 to the parents/primary caregivers of sub-
jects, the youth self-report (YSR) to subjects and the
Teacher Rating Form to the teachers of subjects.
Collectively, these scales have been widely adopted
for research and clinical purposes, have com-
plete, detailed normative data, and outstanding
© 2009 The Authors
Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd

psychometric properties. Relations between youth
and teacher reports in this sample was not high
(r = 0.19, not significant for internalizing and
r = 0.51, P < 0.01 for externalizing). In this study, we
have used the YSR data because previous studies
have suggested this to be more sensitive and reliable
in detecting psychopathology in adolescents.17
Premorbid adjustment was assessed by the
Cannon-Spoor Premorbid Adjustment Scale.18 The
scale examines four areas of development: (i) socia-
bility and withdrawal; (ii) peer relationships; (iii)
ability to function outside of the nuclear family; and
(iv) capacity to form intimate socio-sexual ties
at each of the four developmental stages (i.e.
childhood (up to age 11), early adolescence
(12–15 years), late adolescence (16–18 years) and
adulthood (19 years of age and older). In this study
we used the childhood subscale as a measure of
premorbid functioning.
‘Prodromal’ symptoms were assessed using the
Structured Interview for Prodromal Syndromes
(SIPS), and Scale of ‘Prodromal’ Symptoms (SOPS).19
SIPS is a structured diagnostic interview used for
diagnosis of the ‘prodromal’ syndromes and is
thought to be analogous to the SCID or other struc-
tured diagnostic interviews. The predictive validity,
reliability and training procedures have been well
documented in the literature.19 The SIPS/SOPS mea-
sures, on a 6-point severity scale, a group of five
psychotic symptoms (unusual thought content/
delusional ideas; suspiciousness/persecutory
ideas; grandiosity; perceptual abnormalities/
hallucinations; and disorganized communication);
a group of six negative symptoms (social anhedonia;
avolition; expression of emotion; experience of
emotions and self; ideational richness; and occupa-
tional functioning); a group of four disorganization
symptoms (odd behaviour and appearance; bizarre
thinking; trouble with focus and attention; and poor
personal hygiene); and a group of four general
symptoms (sleep disturbance; dysphoric mood;
motor disturbances; and impaired tolerance to
normal stress). The interviewers were trained in
using the SIPS/SOPS interviews using teaching vid-
eotapes supplied by Jean Addington, PhD; adequate
inter-rater reliability was established between raters
on five videotaped interviews (kappa > 0.7). There
were no significant differences in SOPS ratings
between first- and second-degree relatives at base-
line, all t(83) < 1.37, all P > 0.173.
Statistical analyses
Analysis of the relations between premorbid
factors and ‘prodromal’ symptoms proceeded
© 2009 The Authors
Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd
M. S. Keshavan et al.
by first computing correlation matrices among
premorbid social adjustment, externalizing/
internalizing behaviour during childhood and ‘pro-
dromal’ symptom scores at study baseline. Partial
correlation analyses were used to examine these
relations after adjusting for age and sex effects. Sub-
sequently, longitudinal analyses were conducted
using individual growth curve analyses20 to examine
the relations between premorbid predictors and
change in ‘prodromal’ symptoms over time. Growth
curve analysis is a method of hierarchical linear
modelling that is particularly powerful for analysing
longitudinal data. It is a special case of a two-level
hierarchical linear model where repeated measure-
ment occasions are nested within individuals.
The typical unconditional growth curve model is
illustrated in Equations 1–3:
Level-1:
Yti = β0 i + β1i ( Time )ti + rti (1)
Level-2:
β0 i = γ 00 + μ 0 i (2)
β1i = γ 10 + μ1i (3)
The level-1 equation represents scores on Y for
individual i at time t as a function of his or her inter-
cept b0i, and rate of change, b1i, plus error, rti. When
Time is coded such that 0 = the initial or baseline
score for individuals, the intercept parameter, b0i,
can be interpreted as the person’s initial status on Y.
Level-2 equations represent individual intercept
and rate of change parameters as a function of the
average intercept, g00, and rate of change, g10, across
the entire sample, plus error or random individual
variation in these parameters (i.e. m0i and m1i). The
variability in intercept and rate of change, or growth
parameters, across the study sample is captured
by the variance components of m0i and m1i, which
includes t00 and t11 representing the variance of b0i
and b1i, or intercept and rate of change parameters,
respectively; and t10 representing the relationship or
covariance between intercept and rate of change
parameters across individuals.
As can be seen by the interpretation of the param-
eters in Equations 1–3, unlike traditional repeated-
measures or general linear modelling approaches,
growth curve analysis allows each individual in the
study to have his or her own starting point (inter-
cept) and rate of change (slope) in a particular
construct tracked longitudinally. The average
and variance of these individual trajectories then
become the metrics for assessing longitudinal
215
Premorbid impairment and ‘prodromal’ symptoms

TABLE 1. Relations between baseline premorbid alterations and ‘prodromal’

symptomatology

Baseline characteristic Baseline ‘prodromal’ symptomatology

Total Positive Negative Disorganized General

Age 0.18 0.07 0.07 0.09 0.27*

Sex (1 = male; 2 = female) -0.05 -0.12 -0.11 -0.08 0.10
Total ‘prodromal’ – 0.79** 0.87** 0.82** 0.84**
symptoms
Childhood maladjustment 0.46** 0.22* 0.48** 0.47** 0.38**
Childhood internalizing 0.29** 0.27* 0.26* 0.27* 0.20
problems
Childhood externalizing 0.14 0.11 0.08 0.05 0.13
problems

*P < 0.05; **P < 0.01.

change and its correlates. Significant variability in
growth parameters suggests non-uniformity in
change over time, which then becomes the subject
of targeted predictors. Also, unlike traditional
repeated-measures approaches, when data are
missing at random, growth curve analysis has the
advantage of providing accurate estimates of indi-
vidual trajectories even in the presence of incom-
plete data.20 Together, this provides a powerful
method for investigating two key questions regard-
ing ‘prodromal’ symptomatology: (i) whether there
is variability among HR-S individuals in their longi-
tudinal course of ‘prodromal’ symptoms; and (ii)
whether premorbid factors might contribute to this
variability.
These two questions were the focus of uncondi-
tional and conditional (predicted by premorbid
factors) growth curve models in this research, all of
which used restricted maximum likelihood estima-
tion and an autoregressive error structure most
appropriate to longitudinal data.20 Growth curve
analyses proceeded by first estimating uncondi-
tional growth models to examine the characteristics
of change in ‘prodromal’ symptoms in this sample,
and then moved to examine the degree to which
premorbid factors predicted different rates of ‘pro-
dromal’ change after adjusting for age, sex and base-
line ‘prodromal’ symptoms. Primary predictor and
outcome variables were placed on a standardized
z-metric to ease the interpretation and compar-
ability of regression coefficients and missing data
were handled using the expectation-maximization
approach.21 SOPS data were logarithmically trans-
formed because of skewness. All analyses were
conducted on the combined sample of first- and
second-degree relatives. Secondary analyses (not
shown) were restricted to only first-degree relatives
and showed the same pattern of results.
RESULTS
Are premorbid factors associated with
‘prodromal’ symptomatology in
high-risk subjects?
Strong and highly significant relations between
childhood maladjustment, internalizing problems
and ‘prodromal’ symptomatology were observed
when examining the relationships between premor-
bid characteristics and ‘prodromal’ symptoms
in HR-S subjects at baseline (Table 1). Relations
between these childhood adjustment factors were
most strongly related to negative ‘prodromal’ symp-
tomatology, although all relations were statistically
significant and persisted after adjusting for the age
and sex of participants. Interestingly, externalizing
problem behaviours during childhood were not cor-
related with baseline ‘prodromal’ characteristics.
After adjusting for multiple tests of statistical
inference using Hochberg’s procedure, childhood
adjustment problems remained the only significant
cross-sectional predictor of ‘prodromal’ symptoms.
These findings suggest that premorbid adjustment
factors make a significant contribution to all
the domains of ‘prodromal’ symptoms in HR-S
participants.
Do premorbid factors predict the progression
of ‘prodromal’ symptomatology over time?
After demonstrating significant relations between
several premorbid adjustment factors and broad

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 M. S. Keshavan et al.

70

Scale of ‘Prodromal’ Symptoms total

60

50

40

30

20
FIGURE 1. Two-year individual ‘prodromal’ symp-
tomatology growth trajectories for individuals at 10
risk for schizophrenia. Grey lines indicate indi-
vidual trajectories for the 85 individuals in the 0
study. The solid black line indicates the average
trajectory of ‘prodromal’ symptoms for the entire 0 1 2
sample during the 2 years of study. Year

domains of ‘prodromal’ symptomatology, we pro- TABLE 2. Growth curve models predicting 2-year longitudinal
ceeded to examine the second critical question of change in ‘prodromal’ symptoms from premorbid characteristics
this research by investigating the degree to which
Variable B SE t
premorbid characteristics would predict the longi-
tudinal development of the SZ ‘prodrome’ among Childhood maladjustment
HR-S subjects. As can be seen in Figure 1, on SOPS initial status
average there was a significant increase in total Childhood maladjustment 0.40 0.09 4.51**
SOPS scores over the course of the study (B = 0.46, SOPS growth
P < 0.001; baseline mean (M) (SD) = 4.57 (6.92); year SOPS initial status 0.11 0.10 1.08
Childhood maladjustment -0.09 0.10 -0.89
1 M (SD) = 9.50 (8.73); year 2 M (SD) = 14.43 (13.28)).
Childhood internalizing behaviours
However, there was also significant variability in the SOPS initial status
‘prodromal’ status of individuals entering the study, Internalizing behaviours 0.23 0.09 2.63*
t00 = 0.55, c2 (1, n = 85) = 13.81, P < 0.001, as well as SOPS growth
longitudinal change in ‘prodromal’ symptoms, SOPS initial status -0.08 0.09 -0.90
t11 = 0.11, c2 (1, n = 85) = 41.53, P < 0.001. Internalizing behaviours 0.23 0.09 2.57*
Conditional growth curve analyses adjusting for Childhood externalizing behaviours
the effects of age, sex and baseline ‘prodromal’ SOPS initial status
Externalizing behaviours 0.08 0.09 0.85
symptoms revealed that both childhood internaliz-
SOPS growth
ing and externalizing problematic behaviours at SOPS initial status -0.09 0.09 -1.02
baseline were significant predictors of increases in Externalizing behaviours 0.26 0.08 3.12**
‘prodromal’ symptoms over the course of the study
(see Table 2 and Fig. 2). Post hoc analyses of specific *P < 0.05; **P < 0.01.
Model estimates are adjusted for age and sex effects.
symptom domains indicated that internalizing SE, standard error; SOPS, Scale of ‘Prodromal’ Symptoms.
behaviours were significantly associated with
increases in general (B = 0.27, P = 0.005) and disor-
ganized ‘prodromal’ (B = 0.25, P = 0.011) symptoms, study (B = 0.17, P = 0.076). No significant relations
but not positive or negative symptoms (all P > 0.20). were observed between social adjustment during
Externalizing behaviours were, by contrast, broadly childhood and longitudinal change in overall ‘pro-
and significantly predictive of increased ‘prodromal’ dromal’ symptoms (see Table 2 and Fig. 2). Thus,
positive (B = 0.26, P = 0.010), general (B = 0.21, premorbid adjustment factors, particularly regard-
P = 0.031) and disorganized (B = 0.23, P = 0.018) ing problematic behaviours in childhood, are sig-
symptoms. Greater externalizing problems in child- nificant predictors of future increases in ‘prodromal’
hood showed a trend correlation with increased symptomatology among young individuals at
negative ‘prodromal’ symptoms over the 2 years of genetic risk for SZ.

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Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd
 Premorbid impairment and ‘prodromal’ symptoms
Δ Prodomal symptoms (z)

3 3
2 2
1 1
0 0
–1 –1
–2 –2
–3 –2 –1 0 1 2 3 –3 –2 –1 0 1 2 3
Internalizing problems (z) Externalizing problems (z)
Δ Prodomal symptoms (z)

3
2 FIGURE 2. Longitudinal relations between pre-
morbid characteristics and increases in ‘prodro-
1
mal’ symptoms. Significant relations were found
0 between internalizing (B = 0.23, P = 0.012) and
externalizing (B = 0.26, P = 0.003) problem
–1
behaviours at baseline with longitudinal growth
–2 in ‘prodromal’ symptoms. Longitudinal relations
between baseline premorbid social adjustment
–3 –2 –1 0 1 2 3
and growth in ‘prodromal’ symptoms were not
Social adjustment (z) significant (B = -0.09, P = 0.377).

DISCUSSION to be better characterized in future studies, and cri-

teria to define this phase need to be developed.
One of the main findings in this study was that mild Premorbid adjustment and internalizing behav-
elevations in ‘prodromal’ symptoms are present in a iours, but not externalizing behaviours in child-
substantial proportion of adolescent and young hood, were broadly correlated with cross-sectional
adult relatives at risk for SZ. Additionally, we measures of ‘prodromal’ symptoms, including posi-
observed an increase in the severity of the ‘prodro- tive ‘prodromal’ symptoms. Interestingly, these
mal’ symptoms during follow-up. Although this is relationships were stronger for the negative, disor-
not surprising, few previous studies have character- ganized and general symptoms than for the positive
ized the frequency and trajectory of ‘prodromal’ symptoms. This observation is consistent with find-
symptoms in HR-S subjects. Despite the prevalence ings of non-specific and general psychopathological
of ‘prodromal’ symptoms, however, only one of the symptoms, such as anxiety, depression and social
participants met the Yale19 or Melbourne criteria for isolation, to be among the earliest ‘prodromal’
the genetic risk + deterioration subtype of the ‘pro- symptoms reported in retrospective studies of first-
drome’.22 This is likely because of the fact that the episode SZ patients.24,25 Impaired social functioning
majority of the HR-S subjects did not have Global has also been detected in children and adolescents
Assessment of Functioning (GAF) reductions of >30 who later developed SZ in large birth cohort
points within the past year, a required criterion. It studies.14,26 Cognitive impairments, including
may be that the HR-S subjects pass through an ‘early disorganization, social isolation and school failure,
prodromal’ phase of variable duration with sub- have also been thought to represent early manifes-
threshold general, negative and positive symptoms, tations of help-seeking subjects deemed to be clini-
with relatively gradual functional declines. Another cally at high risk (CHR) for SZ; this subgroup of
effort to characterize such early ‘prodromes’, utiliz- ‘prodromal’ patients has been termed the CHR-
ing sub-threshold psychotic-like (‘basic’) symptoms subgroup, by contrast to those who present
without functional declines, has yielded a high with sub-threshold positive symptoms (the CHR +
power to predict later psychosis.23 Current defini- group).27 It is possible that social and scholastic
tions of ‘prodrome’ are more likely to capture the impairments predispose to the early emergence
‘late prodromal’ phase with more marked func- of non-specific ‘prodromal’ symptoms, which in
tional declines. The early ‘prodromal’ phase needs turn may be followed by the later appearance of

218 © 2009 The Authors

Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd

attenuated psychotic symptoms. The latter may be
at a high risk for conversion to psychotic disorders
and SZ. Ability to predict conversion to psychosis
may therefore be best achieved by characterizing
subgroups of HR-S subjects most likely to develop
early, and then the late ‘prodromal’ symptoms (the
‘close-in’ model). Such an approach is likely to be
cost-effective by comparison to the traditional high-
risk studies and birth cohort studies that suffer from
a lack of statistical power because of low base rates
of conversion to psychosis.28
When increases in ‘prodromal’ severity during
follow-up were investigated, both internalizing and
externalizing behaviours correlated with growth in
‘prodromal’ symptoms. In addition, it is interes-
ting that externalizing problem behaviours were
strongly predictive of increases in positive ‘prodro-
mal’ symptoms over time, whereas these behaviours
were not related to any ‘prodromal’ psychopathol-
ogy when examined cross-sectionally at baseline.
This observation is also consistent with our previous
observation of a relationship between externalizing
behaviours such as attention deficits and positive
schizotypal features in HR-S individuals.9 This
finding also illustrates the importance of long-term
longitudinal studies of at-risk individuals proximal
to the age range of typical SZ onset, where the
impact of initial markers of disorder are only likely
to be realized as the progression to psychosis
emerges, and sufficient variability in ‘prodromal’
symptoms begins to occur. The study of the progres-
sion of psychosis is inherently a longitudinal ques-
tion about dynamic change that is not completely
addressed by either cross-sectional investigations or
those examining premorbid predictors of end states
(e.g. the development of SZ). Longitudinal investi-
gations that capture the process of psychosis devel-
opment by examining associations with changes
in ‘prodromal’ characteristics, as was done in this
research, are likely to yield critical insights into the
factors that predispose individuals to psychosis,
which is currently most efficiently accomplished
when studying individuals at genetic risk for the
disorder.
The strengths of our study include the prospective
design and the fact that investigating untreated
youth at risk avoids the confounds of illness and
treatment effects. Previous studies examining the
predictive value of premorbid maladjustment have
largely focused on psychosis or SZ as the outcome
measures.29–31 To our knowledge, few studies have
examined the relation between premorbid variables
and ‘prodromal’ symptoms. One of the limitations
of this study is the lack of a healthy control dataset.
Because psychotic-like experiences are common in
© 2009 The Authors
Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd
M. S. Keshavan et al.
the general population, it would be important to
examine the question whether ‘prodromal’ symp-
toms in youths may be part of normal development;
if so, healthy controls would have shown increases
in these symptoms as well. A second limitation is the
fact that ascertainment of childhood premorbid
function and behavioural disturbance could suffer
from retrospective bias. However, the only way to
circumvent this limitation is to prospectively evalu-
ate at-risk children from childhood onwards, a
lengthy approach with prohibitive costs. In addi-
tion, because of the modest number of second-
degree relatives studied (n = 16), the effect of genetic
vulnerability on these results could not be investi-
gated. However, analyses including only first-degree
relatives yielded the same pattern of results. Future
studies will need to recruit larger samples of indi-
viduals with different genetic vulnerabilities to SZ to
more closely examine this issue.
In summary, our study provides characterization
of emergent ‘prodromal’ symptoms in young HR-S
relatives and evidence for the predictive value of
premorbid functional, behavioural and psycho-
pathological impairments for ‘prodromal’ symp-
toms. The presence of ‘prodromal’ symptoms in
HR-S subjects may define a subgroup worthy of
follow-up into the age of risk for psychosis in order
to cost-effectively characterize the predictors of
psychotic symptoms and SZ. The predictive ability
of the premorbid behavioural measures is likely to
be strengthened by comprehensive evaluation of
neurobiological, cognitive and clinical measures
and the use of integrated multivariate statistical
models to estimate their contribution to the pro-
spective emergence of psychopathology.32 Longitu-
dinal studies of such a cohort are also of substantial
importance to investigate the neurobiological pro-
cesses underlying the emergence of early ‘prodro-
mal’ symptoms.
ACKNOWLEDGEMENTS
This work was supported in part by NIMH grants
MH 64023, MH 01180 (MSK) and a NARSAD Inde-
pendent Investigator award (MSK). We are grateful
to Diana Dworakowski, Atefeh Jenrow and Usha
Rajan for conducting the assessments.
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