Schizophrenia Bulletin vol. 41 no. 4 pp.

801816, 2015
doi:10.1093/schbul/sbv047
Advance Access publication April 22, 2015

Perinatal Risks and Childhood Premorbid Indicators of Later Psychosis: Next Steps
for Early Psychosocial Interventions

Cindy H.Liu*,1,2, Matcheri S.Keshavan1, EdTronick2,3, and Larry J.Seidman1,4

Department of Psychiatry, Harvard Medical School, Massachusetts Mental Health Center Division of Public Psychiatry, Beth Israel
1

Deaconess Medical Center, Boston, MA; 2Department of Psychology, University of Massachusetts, Boston, MA; 3Department of
Newborn Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA; 4Department of Psychiatry, Harvard
Medical School, Massachusetts General Hospital, Boston, MA
*To whom correspondence should be addressed; 75 Fenwood Road, Boston, MA 02115, US; tel:617-754-1227, fax: 617-754-1250,
e-mail: cliu@bidmc.harvard.edu

Schizophrenia and affective psychoses are debilitating dis-
orders that together affect 2%3% of the adult population.
Approximately 50%70% of the offspring of parents with
schizophrenia manifest a range of observable difficulties
including socioemotional, cognitive, neuromotor, speech-
language problems, and psychopathology, and roughly 10%
will develop psychosis. Despite the voluminous work on pre-
morbid vulnerabilities to psychosis, especially on schizo-
phrenia, the work on premorbid intervention approaches is
scarce. While later interventions during the clinical high-
risk (CHR) phase of psychosis, characterized primarily
by attenuated positive symptoms, are promising, the CHR
period is a relatively late phase of developmental derail-
ment. This article reviews and proposes potential targets
for psychosocial interventions during the premorbid period,
complementing biological interventions described by oth-
ers in this Special Theme issue. Beginning with pregnancy,
parents with psychoses may benefit from enhanced prenatal
care, social support, parenting skills, reduction of symp-
toms, and programs that are family-centered. For children
at risk, we propose preemptive early intervention and cog-
nitive remediation. Empirical research is needed to evalu-
ate these interventions for parents and determine whether
interventions for parents and children positively influence
the developmental course of the offspring.
Key words: psychosis/schizophrenia/early intervention/
prevention/stress/psychological/parenting
Introduction
We briefly summarize an extensive literature on premor-
bid vulnerabilities of later psychosis,1 focusing on the
period from pregnancy through the elementary school
years. Our goal is to identify potential treatment tar-
gets for even earlier intervention than those currently
The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
All rights reserved. For permissions, please email: journals.permissions@oup.com
emerging from the clinical high-risk (CHR) field,2 (also
called prodromal, ultra high-risk, or at risk men-
tal state) which typically address attenuated psychotic
symptoms in teenagers and young adults. We also present
a conceptual framework linking early psychosocial inter-
ventions with robustly identified developmental deficits.
This article complements the 2 treatment articles in this
Special Theme Issue that focus on potential biological
preventive interventions.
Study Designs for Identifying PremorbidRisks
Given that we focus here on leveraging knowledge of
premorbid deficits to develop a program of early psy-
chosocial interventions, this article is not a compre-
hensive review. Indeed, literature on premorbid deficits
has been reviewed from many angles previously.38 Our
review incorporates a number of study designs including
prospective cohort studies, which can provide potential
population-level causal inferences regarding the expo-
sure to environmental risks for those who later develop
psychosis; follow-back designs, which examine childhood
premorbid characteristics of adults with psychoses; and
familial (genetic) high-risk (FHR) studies, which eval-
uate the offspring of parents with psychosis at different
ages. The FHR approach enables researchers to study
development deficits in individuals not necessarily iden-
tified for treatment, in contrast to youth at CHR, who
are already suffering from attenuated positive psychotic
symptoms and significant functional impairments, and
are often seeking treatment.
The CHR field, focusing on the period just prior to
the emergence of psychosis typically in adolescence, has
rejuvenated the early intervention field in psychiatry.9
CHR research has focused on delaying the emergence
of psychosis or reduction of liabilities, with promising

801
C. H.Liu etal
early findings.9 The idea of staging highlights the CHR
period as a relatively late phase in the development of
psychosis and provides a framework for even earlier
intervention.10 Indeed, the relative success of early inter-
vention has given support to the idea that transition to
psychosis can be prevented in some CHR individuals.
The FHR approach provides opportunities for devel-
opmentally sensitive, earlier interventions. While the
FHR paradigm allows the study of offspring, where
approximately 10% go on to develop psychosis, it yields
a much larger percentage (~50%) that have nonpsychotic
problems. These problems could be targets for early inter-
vention and could be addressed as a potential part of the
trajectory to psychosis.
Early Developmental Signs in Prepsychotic Individuals
and Children atFHR
Prepsychotic and FHR children show more neuromo-
tor and minor physical anomalies (MPAs), speech and
language, socioemotional, and cognitive abnormalities,
in families with parental schizophrenia than preaffective
psychosis (see table1 for major studies).
Neuromotor and Minor Physical Anomalies
Neuromotor deviations may be the most common child-
hood abnormality for individuals that develop psycho-
sis.42 Birth cohorts have documented developmental
delays in sitting, standing, and walking alone at 2years
of age.11,14,54 Through a follow-back approach, archi-
valobservational studies of home movies showed pre-
schizophrenia children to have greater clumsiness or
odd movements and slower reactions compared to their
healthy siblings by age 2.55 Premorbid abnormalities
such as unbalanced, involuntary, or unusual movements
like heel-to-toe standing have been observed in develop-
ment beyond toddlerhood.12,19 MPAs are a heterogeneous
group of morphologic markers (eg, wider skull bases,
shorter lower facial heights) potentially resulting from
genetic or gestational insults that occur during craniofa-
cial and brain development.56 MPAs are more prevalent
in those with schizophrenia and those at high-risk neuro-
developmental disorders.57,58
Speech, Language, and Hearing
Compared to controls, speech delays (ie, saying words
other than calling parents) in toddlers, non-structural
speech problems from toddlerhood to 16 years,11 and
mispronunciation of words at ages 7 and 1119 were more
frequent among preschizophrenia children than compari-
sons. Unusual speech (eg, echolalia, meaningless laugh-
ter) at ages 4 and 7 significantly predicted children who
later developed schizophrenia,21 and poorer speech per-
formance at ages 5 and 14 was associated with later psy-
chosis among males.6 Hearing impairments at age 4 have
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also been found to be associated with an increased risk
for later nonaffective psychotic illness.15 Because speech,
language, and hearing are central to social engagement
and cognitive functioning, early deficits may derail trajec-
tories in these functional domains.
Cognition
Cognitive impairments that typically characterize
schizophrenia5961 have been observed in milder forms
before the onset of psychosis62 (see figure 1 and the
accompanying article by Agnew-Blais et al). FHR7,63
and cohort studies evaluating children who later
develop schizophrenia demonstrate persuasive evi-
dence of impairments in children as early as 4 years
of age.38,6466 In crystallized verbal intelligence, devel-
opmental impairments were relatively stable, but
increased developmental lag in fluid intelligence from
ages 7 to 13 was observed in children with later schizo-
phrenia.67 Although verbal, psychomotor, receptive
language, attention, and memory deficits have been
observed,18,66,68,69 the most robust evidence comes from
IQ measures,70 which demonstrate greater impairments
among preschizophrenia children compared to those
developing affective psychoses.38,64
The relatively stable verbal deficits of the preteenage
years begin to lag increasingly behind that of healthy
comparisons during the teen years among those who
develop schizophrenia.74,75 The cohort studies do not
identify whether these belong to a CHR subgroup; how-
ever, CHR studies clearly demonstrate greater impair-
ment in those who go on to develop psychosis than those
who do not.73,76
In considering targeted interventions, a focus on indi-
vidual rather than group differences is essential. Seidman77
and others proposed that substantial premorbid, neuro-
cognitive heterogeneity is present in early childhood.78,79
In a cohort study, approximately 45% of preschizophre-
nia children were cognitively impaired at the age of 7.38
Thus, only a subgroup of individuals with schizophrenia
may be appropriate for cognitive remediation.
Socioemotional
A review of 19 studies reported poor childhood social
functioning as a sensitive predictor of later schizophre-
nia, but the effect was dependent on the specific devel-
opmental time point and aspect of social functioning.5
While social functioning within infancy or preschool was
not predictive, antisocial-externalizing behavior was a
sensitive and specific predictor for schizophrenia relative
to other nonpsychotic disorders, as early as 5 years of
age. Socialwithdrawal internalizing behavior was a sen-
sitive predictor for schizophrenia at the age of11.
Using an archival-observational approach, one fol-
low-back study evaluated the interpersonal experiences
 Early Psychosis Risks to Inform Intervention

Table1. Overview of Early Developmental Impairments in Prepsychotic and FHR Offspring up to Age12

Neuromotor and Minor Speech/Language/

Physical Anomalies Hearing Socioemotional Behavior Cognition

(a) Impairments predicting later psychosis

Newborn period
<3months
Infancy 312months Sitting, walking, and
standing delays1113
Toddler and Potty training delays13,14
preschool 14years
Elementary school Poor coordination and
512years clumsiness, unusual
movements (walking
backward, heel-to-toe
standing)12,13,19
(b) Impairments among HR offspring
Newborn period Neuromotor deviations
<3months at birth2527; motor
weakness (ie, pull-to-sit)
and elevated muscle tone
at 3 and 14days old28;
broad neuromuscular and
perceptual developmental
delays29
Infancy 312months Pandysmaturation,
including motor
milestones3133; poor
motor and sensorimotor
coordination28,29,34; broad
neuromuscular and
developmental delays
including grasping29
Toddler and Pandysmaturation*33;
preschool 14years low reactivity, termed as
behaviorally quiet33;
broad neuromuscular and
perceptual developmental
delays29; delayed reflex
maturation29
Elementary school Neuromotor deviation:
512years poor coordination,39
involuntary
movements,25,40,41
balance40,42,43; autonomic
hyperresponse44
Delays in speech11,13; and Preference for solitary
in receptive language,13 play11; fewer joy16; and
hearing impairments15 more negative affect17
Poor abnormal speech More externalizing
acquisition and behaviors20; higher
quality19,20; abnormal aggression, inattention,19
language including delinquency for males,22
echolalia, meaningless social maladjustment and
laughter21 deviant behaviors21; more
internalizing20: social
anxiety,11 withdrawn19;
depressed19; self-reported
psychosis at 11years20;
positive psychosis screen
at 14years6
Poorer IQ scores30
Unusual language35; Low levels of stranger
less communicative wariness37; lower reactivity
competence36 in response to assessor34;
less affection, hostility,
and negative affect,
higher activity levels,36
psychosocial delays, and
irritability29;
Low verbal productivity, Less socially competent46;
inadequate cohesion greater interpersonal
between ideas45 problems,39 socially
isolated40,47; disturbed or
aggressive behavior33,44;
poor affective control;
greater schizoid
behaviors48
Poorer IQ scores13,18
Poorer IQ scores13
declines in IQ
scores from 4 to
7years23; lower
verbal and nonverbal
scores18; poorer
spatial reasoning,
verbal knowledge,
perceptual-motor
speed, and speed
processes of working
memory24;
Poorer IQ scores30
Lower IQ38
Poorer intellectual
functioning39; Lower
IQ49,50; attentional
dysfunction42,46,47,51,52;
poor
concentration49,53;
poorer memory42

Note: Please refer to published reviews for detailed findings.38

of the affective displays in 510-year-old schizophrenia of joy expressions throughout childhood was observed
and sibling controls, showing that those with schizo- in another study comparing schizophrenia and nonpsy-
phrenia had greater negative affect at 57 years.17 Lack chotic sibling controls, particularly for females.16

803
C. H.Liu etal
Fig.1. Effect sizes from 4 meta-analyses on cross-sectional IQ
impairment in individuals with psychosis or at risk for psychosis
compared to controls (Cohens d), from L.Seidman. CSZ,
chronic schizophrenia71; FE, first-episode schizophrenia72; PRE,
premorbid70; PRO-C, prodrome converter73.
Refined observational measures may be an important
next step for detecting the subtle socioemotional deficits
among infants and toddlers. Behavioral coding schemes
may be used to differentiate socioemotional displays
among controls and children from other neurodevelop-
mental disorders (eg, autism spectrum) or from FHR
offspring of other disorders (eg, affective disorders, per-
sonality disorders, or children with siblings who have
autism).80,81
Summary
Socioemotional abnormalities are predictive of who will
develop psychosis.20,67 Uncovering abnormalities in early
development is promising for interventions, given the
sensitive period in which childrens regulatory systems
may repair and resume a normally developing trajectory.
However, the reliance on these signs for detecting psycho-
sis is immensely challenging because many are not spe-
cific to psychosis.11,82 Rather, it would be advantageous
if the earlier and specific roots of these developmental
deficits could be identified. For instance, a novel study by
Gamma etal83 examining intermodal integration, the abil-
ity to relate perception across senses, found greater early
impairments among the 8-month-old infants of parents
with psychosis, especially in offspring of parents with
schizophrenia. Comparing these early impairments in
relation to those of other developmental disorders may
provide greater insights into the developmental origins of
psychosis.
Etiological Mechanisms in the Development of
Psychosis Across Childhood
Identification of the biological origins of psychosis has
been advanced by recent, large-scale genetic studies.84
Additionally, a large body of epidemiological research
has contributed to our understanding of the prena-
tal and obstetric risks for later psychosis at a popula-
tion level, along with more refined laboratory studies
804
assessing the stressful experiences of parents and preg-
nant women in determining later risk for psychosis in
their offspring.
Genetic Etiology and Biological Mechanisms
Schizophrenia is highly heritable; genetic factors may
account for about 80% of the variation in risk.85 Many
common genes of small effect and some rare mutations
of larger effect may be associated with increased risk,
such as genes involved in brain development, cell mem-
brane functions, and immune mechanisms.8688 Similar to
disorders with many early impairments, genes underlying
risk for schizophrenia cut across diagnostic boundaries,
overlapping with those for bipolar disorder, autism, and
attention deficit disorders.89
Pathophysiological Mechanisms: Neurodevelopmental
Abnormalities Underlying Risk for Schizophrenia. The
longstanding theory that increased dopaminergic activity
in the striatal and limbic systems is core to schizophrenia
has not been examined directly in children at risk. Recent
work points to an excess of presynaptic dopamine in the
ventral striatum in CHR individuals.90 Other neurotrans-
mitters, such as gamma-aminobutyric acid (GABA) and
glutamate, have also been implicated in schizophrenia.
Given the major role these neurotransmitter systems play
in brain development and plasticity, it would be impor-
tant to determine if such alterations are actually observed
in early development since the adult brain is the outcome
of gene by environment sculpting.
Timing of Pathophysiology. Previously reviewed stud-
ies suggest that the premorbid developmental anom-
alies originate at or before birth. For example, the
evidence of increased prevalence of MPAs in schizo-
phrenia suggests abnormal intrauterine development.57
Neuropathological studies also suggest early develop-
mental derailments, such as a maldistribution of inter-
stitial neurons in white matter regions, reflecting a failure
of normal processes of neuronal migration.91 Imaging
studies suggest abnormal cortical gyrification in schizo-
phrenia.92 Gyrificationexpansion of the surface area
of the brainbegins early in development; thus, reduced
gyrification could suggest early developmental origins.
Arecent review demonstrated structural abnormalities,
especially in prefrontal cortex and hippocampus in FHR
for schizophrenia children studied as young as 7 years
of age.93
Such alterations in early brain development may
underlie the observed premorbid cognitive, social, and
neuromotor difficulties seen in childhood but may not
explain why psychotic symptoms do not usually begin
until adolescence. Instead, early developmental abnor-
malities may interact with later developmental processes
such as synaptic pruning and myelination or particular

kinds of experience (eg, poor parenting, abuse), leading
to the emergence of psychotic symptoms.9496
Prenatal Environmental Risks and Mechanisms
While knowledge of genetic susceptibility for psychotic
disorders has become robust,84,97,98 the role of the earliest
(eg, fetal) adverse environmental risks is also important.
Environmental factors contribute to risks for neurode-
velopmental disorders in offspring99 and an intervention
within environmental factors may be more feasible than
within genetic mechanisms.
Prenatal Risks. Maternally acquired infections that
have been positively associated with schizophrenia100106
are consistent with studies of exposures to viral patho-
gens via the maternal placenta,107 resulting in disruption
of fetal brain development and abnormal neurodevel-
opmental outcomes. Researchers have identified several
key nutrients, including vitamin D and folate, involved in
DNA repair and methylation, and iron, where low levels
may lead to dopaminergic dysfunction,108115 with related
structural and functional brain deficits characteristic of
those with schizophrenia.113 Early socioeconomic fac-
tors, including housing in an urban environment, low-
income status, or ethnic minority status, are also risks
for the development of psychosis. Of additional concern
is that lower socioeconomic status may be associated
with increased health risk behaviors (eg, smoking, sub-
stance use),116 which may increase a childs susceptibility
to cognitive impairments and thus increase the risk for
psychosis.117
Another concern is that a mothers stress response
during pregnancy contributes to her offsprings neuro-
developmental problems.118,119 For instance, children of
mothers that experienced major life stress (ie, death or
severe illness in family members, catastrophic events) dur-
ing pregnancy were at higher risk for schizophrenia.120123
These risks strongly indicate the need to prioritize the
protection of women by ensuring that they have a sta-
ble and healthy lifestyle, preventing maternal infections
during gestation or even preconception,124 and ensuring
proper nutrition during pregnancy for optimal fetal brain
development.
Obstetric Complications. Those at risk for schizophre-
nia tend to experience more obstetric complications
(OCs),125 which can increase offspring risk for schizophre-
nia.125130 This includes hypoxia,119,120 which is significantly
associated with structural brain abnormalities.66 Children
with low birth weight were also found to be more likely
to develop schizophrenia.131133 Other OCs such as preg-
nancy bleeding, preeclampsia, diabetes, delivery compli-
cations such as asphyxia or Cesarean section, or birth
abnormalities including congenital malformations or
small head circumference, have all been implicated as risk
Early Psychosis Risks to Inform Intervention
factors for schizophrenia.134,135 These complications can
be reduced or mitigated through improved prenatal care.
Postpartum and Childhood Environmental Risks and
Mechanisms
Stress and Adversity. Recent findings suggest that
adverse life events may produce greater emotional reac-
tivity to subsequent stressors, in turn contributing to
the vulnerability for psychotic disorders.5,136 An asso-
ciation between childhood adversity and psychosis has
been documented through prospective, case-control, and
cross-sectional designs. In a meta-analysis, trauma (eg,
sexual abuse, physical abuse, emotional/psychological
abuse, neglect, parental death, and bullying) was found
to increase the risk of psychosis, regardless of the specific
nature of the exposure.137
Proposed biological mechanisms to explain the rela-
tionship between adversity on childrens neurodevelop-
ment have suggested that persistent exposure to stressors
and chronic heightened glucocorticoid activity in early
development can produce permanent changes in the
hypothalamic-pituitary-adrenal (HPA) axis, impair-
ing the negative feedback system in dampening HPA
activation.138 Early stress hypersensitivity may increase
the risk for psychosis for those later developing schizo-
phrenia.139142 Furthermore, the pattern of socioemo-
tional impairments among FHR children and those who
later develop psychosis may reflect these HPA system
alterations.
Stress exposure and childhood trauma may also affect
dopaminergic transmission, which has been linked to
psychosis.143 Chronic adverse exposures may produce
sensitization and hyperreactivity of the dopaminergic
system at high levels,144146 even in moderate stress.147,148
Dopamine may be involved in the formation of particular
psychotic experiences (eg, persecutory delusions that act
as responses to threat-related stimuli).149 Altogether, these
findings suggest that individual vulnerability in reactivity
may be altered by prolonged or severe exposure to stress.
Parents Wth Psychosis. In addition to being at greater
genetic risk for psychosis, children with parents that
have psychosis are more likely than healthy peers to be
exposed to stress, including financial and social chal-
lenges and stigma.150152 Women with schizophrenia tend
to have higher rates of unplanned pregnancy, exposure
to violence during pregnancy, less partner support,153,154
and household instability, altogether posing risks to chil-
drens socio-emotional and cognitive development.155159
Indeed, household stability, social support, and high IQ
have been shown to be protective for children with moth-
ers with schizophrenia.160162
Problematic parenting and issues with the parent-child
relationship among parents with schizophrenia may
impede optimal development in their children.152,163166
805
C. H.Liu etal
Caretaking responsibilities may be affected by delusions
or hallucinations, negative symptoms, or by dysregu-
lated or unusual affect.151,158,167 Social cognitive deficits
including mental attribution errors may affect the way
parents interact with their children.168171 Such subtle
social and cognitive deficits from schizophrenia possibly
affect parental sensitivity more so than other illness fea-
tures.172 Reduced parenting capacity may lead parents to
be less responsive, sensitive or energetic, remote, intru-
sive, or overprotective with their child.4,36,152,159,167,173176
Importantly, adoptees at FHR for schizophrenia spec-
trum disorder, when exposed to parental communication
deviance of adoptive parents were more likely to show
psychiatric disorders, including schizophrenia spectrum
disorders.165,177 Altogether, this may explain the greater
rates of insecure or disorganized attachment relation-
ships associated with parental psychosis.178180
Developmental Models Integrating Stress and Psychosis
Risk. The traumagenic-neurodevelopmental model
posits that adversity or trauma in conditions where
stress is prolonged, severe, or within crucial time points
may contribute to the vulnerability for psychosis.181
Models that include familial risk may also explain
how 1114-year-old children who either showed mul-
tiple risks for schizophrenia (motor or speech abnor-
malities, socioemotional problems, and endorsement
of psychotic-like symptoms) or had a family history of
schizophrenia were more frequently exposed to negative
life stress and daily stressors and were more distressed
by these experiences, compared to typically developing
children.182 Furthermore, other models that incorpo-
rate psychosocial experiences in early development and
reflect the multicausality of psychosis should be consid-
ered. For instance, childhood bullying is a risk factor for
psychosis among nonclinical and clinical samples.183185
Of interest is the attachment-developmental-cognitive
hypothesis, which proposes that specific disturbances in
childhood attachment, perhaps emanating from trauma,
lead to altered neural representation of the self and the
formation of other psychosis symptoms. Additionally,
the model of mutual regulationalthough not specific
to psychosisargues that normal development is a pro-
cess of effective reciprocal social emotional communica-
tion and that chronic reiterated daily stressors can lead
to poor social-emotional functioning in both the child
and the parent, ultimately spiraling in derailed develop-
ment.186 Confirming these theories would provide evi-
dence for early interventions involving the parent-child
relationship.187
Epigenetic Mechanisms
Given the broad array of environmental perinatal risks
for psychosis,188 specific environmental risks at certain
developmental time points may induce changes in gene
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expressionepigenetic effectsthat influence the emer-
gence of psychosis. Animal and human studies have
shown the effect of postnatal factors on the gene regula-
tion implicated in human psychosis.189 Of note is the role
of environmental adversity, including lack of maternal
care and chronic maternal separation, which approxi-
mates the childhood experiences of many children with
parents suffering from psychosis. Early life maternal
separation among mice have showed increased HPA-
axis activity associated with phosophrylation of methyl
CpG-binding protein 2 and hypomethylation of arginine
vasopressin, which are genes involved in the expression
of parvocellular division in hypothalamic paraventricular
nucleus, an area implicated in psychosis.190
Environmental factors, several of which may operate
early during brain development, are likely to interact
with risk genes to increase the liability of schizophrenia.
Examples include interactions between fetal hypoxia and
hypoxia-related genes on hippocampal structure and the
effect of interactions between serotonin transporter and
COMT gene polymorphisms and childhood trauma on
cognitive functioning.191,192
Recommendations for Earlier Intervention Targets
We argue that the knowledge of early developmental
signs observed in prepsychotic and individuals at FHR
for schizophrenia and the known etiological mechanisms
in the development of psychosis across childhood is suf-
ficient to identify plausible therapeutic targets for inter-
vention. The conceptual model in figure 2 highlights
promising and practical strategies that ameliorate stress
and address early environmental risks and impairments
across development.
Targeting FHR children and their families may be the
most practical strategy for early intervention at this time.
Parents with psychosis are an underserved population;
the majority of mothers with psychosis serve as primary
caretakers for their children who wish for a healthy family
relationship.193195 The implementation of enhanced care
for parents is a public health strategy, because its effects
would likely generalize to children. Conceivably, one
could also target preteen children at CHR for treatment,
and some investigators are studying such children.196
Of course, there may be some differences in the specific
deficits between children at FHR versus CHR, with both
types of risks exerting independent effects.197 Nevertheless,
because our focus is conceptualized as a potential pri-
mary prevention of psychosis strategy, and because many
of these children develop a wide range of nonpsychotic
mental disorders and functional impairments,198 we chose
to focus on a FHR population. Interventions may be bet-
ter framed in terms that promote resilience and oppor-
tunities for improved development. We believe that such
interventions could treat current difficulties and may pre-
vent adverse outcomes including psychosis.

Fig.2. Risk-based targets for psychosocial interventions. Risks and sources of stress are in blue and proposed interventions are in red. Numbers
correspond to text subsections. Interventions may interact and promote other intervention effects.
Parent-, Dyadic-, and Family- Oriented Targets
1. Elevate the importance of prenatal care. Prenatal care
may buffer the nutritional, obstetrical, and stress risks
for psychosis. Adverse birth outcomes (prematurity,
low birth weight) among offspring of women with
psychosis may be attributable to inadequate prena-
tal care.199202 Unfortunately, women with psychosis
are less likely to receive adequate prenatal care than
healthy women, even accounting for sociodemo-
graphic backgrounds.153,203207 Treatment adherence
may not be maintained during pregnancy, due either
to parental or provider concerns regarding the poten-
tial medication effects on the fetus. Some studies show
high rates of relapse during pregnancy for women with
schizophrenia,208 which can adversely affect self-care
and generate additional risks for the developing fetus.
Lack of prenatal care is also associated with service
utilization, including decreased pediatric care.209,210
A multidisciplinary team (eg, obstetricians, psychia-
trists, adult- and infant-parent-trained psychologists,
neonatologists, nutritionists, and social workers) could
address problematic prenatal issues including nutri-
tional deficiencies such as food or vitamins, lifestyle
concerns such as the use of tobacco, alcohol or other
drug substances, or life stresses including psychotic
denial of pregnancy, unintended pregnancy, unstable
housing or violence in the home.
2. Increase social support. Support may be one way to
reduce stress among parents with psychosis, and in
turn, increase their parenting capacities and buffer the
Early Psychosis Risks to Inform Intervention
risks on their children.153,193,211 Support groups,212 non-
directive counseling,213 and home visits by nurses,214
have demonstrated improvement in mother-infant
interaction and maternal mood for depressed mothers.
Family therapy may be effective in addressing family
burdens.215
3. Enhance parenting skills. Schizophrenia patients
in recovery still experience parenting challenges.152
Parenting classes and coaching have been effective for
mothers with schizophrenia.216 Interventions aimed
at improving maternal sensitivity include observation
and modeling through video-based feedback,217219
although empirical evaluation of these approaches
with this population is needed.193,216
4. Reduce cognitive deficits and symptoms in parents.
Parents with psychosis have cognitive problems that
can affect the parent-child relationship including
second-order Theory of Mind, speed of processing,
cognitive flexibility, and motivation.172 Among the
psychosocial interventions for psychosis (cognitive
therapies, family therapy, life, and social skills train-
ing), cognitive behavioral therapy (CBT) seems best
suited to address social cognitive deficits symptomatic
of psychosis.220,221 Interventions to improve perspec-
tive taking interventions, including video feedback
or role play, may be useful.219,222,223 Cognitive remedia-
tion, which aims to improve processes such as memory,
attention, and problem solving,224 has demonstrated
improvements in emotion processing and social func-
tioning,225,226 and may be a useful tool for parents,
although little research has evaluated its effect on
807
C. H.Liu etal
parents and children.172 Furthermore, research on the
reduction of parental non-psychotic psychopathologi-
cal symptoms and its effects on the child is mixed.227,228
Integrating cognitive remediation with treatment con-
sidering the context of caretaking and the parent-child
relationship may help to enhance outcomes.
5. Instituting family-centered care across development.
Although not an intervention per se, wrap-around
care is crucial for healthy family functioning in fami-
lies affected by psychosis. This includes services that
support family health (prenatal, primary, psychiatric,
or pediatric care) and practical needs (financial, legal,
housing, transportation, vocational help, school)
through counseling or coaching (spiritual, parent-
ing), as well as crisis management.172,229,230 Moving the
parents into recovery, keeping their children safe, and
ensuring the health and stability of the family should
help protect against later psychosis or impairments
among children. Importantly, parent-child relation-
ship-based interventions may be more effective within
the context of other supports.217,231 Furthermore,
such care is practical because it addresses everyday
parenting challenges faced by parents with psychosis
(eg, sharing about their illness, worrying about their
childrens development, engaging in developmentally
appropriate family activities such as sport activities
or birthday parties). Psychoeducation for the child
regarding coping with their parents mental illness at
an appropriate age is important in raising the quality
of life for all affected family members.232
Additionally, the role of legal prevention is an
unexplored yet possible buffer to risk for psycho-
sis and related impairments. Families with psychosis
may interact with the legal system (eg, custody loss,
landlord-tenant disputes).233235 Custody loss or even
temporary separation (eg, hospitalization) from chil-
dren is a major fear among parents with mental illness,
and may explain their reluctance for service utiliza-
tion.150,236 It is worrisome that chronic separation
experiences could heighten the risks for psychosis and
other impairments in children. One recommendation
is that the care system includes a component by legal
professionals who specialize in mental illness.
Child-Oriented Targets
6. Regard early indicators of risk as treatment outcomes: A
preemptive early intervention strategy. With the excep-
tion of cognition, early intervention programs have
not specifically targeted early developmental risks.
Nonetheless, risk indicators yield a high rate of false
positives for later psychosis risk and often overlap with
other disorders;237,238 thus, understanding the combina-
tion of these risk indicators can improve the prediction
of individuals who later develop psychosis and serve as
targets for psychosocial intervention.
808
Evaluations and implementations of an intervention
at earlier stages [preemptive early interventions (PEI)]
are now taking place. Uher has proposed an interven-
tion beginning at 9 years of age among children at
high and low familial risk.239 The Skills for Wellness
program focuses on modifying early antecedents of
psychosis (developmental delays or experiences of
psychosis, anxiety, or affective lability) through cogni-
tive behavioral skills and parent training. Aside from
being a feasible target for psychosis intervention, the
amelioration of antecedents is also an important goal
in and of itself, as impairments are often distressing to
the child and family. It is a low-risk intervention rela-
tive to pharmacological treatments and probably less
stigmatizing.
7. Implement cognitive remediation in CHR children. Thus
far, there are no published studies of cognitive enhance-
ment in children at risk for schizophrenia. Promising
results have emerged from cognitive remediation tech-
niques in patients with schizophrenia,240,241 and pre-
liminary findings suggest that improvements may be
obtained during the CHR phase..242 Nevertheless,
while plasticity-based treatments have shown consider-
able promise and have few direct negative side effects,
research is needed to determine their impact and
durability on cognitive impairment in the premorbid
period. Specification is needed for the primary targets
(ie, executive functions, memory, attention, social cog-
nition), the intervention approach and its duration.
Other interventions can be used to treat premorbid
problems. Areview of the literature on improving execu-
tive functions (EFs) in 412-year-olds suggests different
ways to improve EFs, including computerized train-
ing, noncomputerized games, aerobics, martial arts,
yoga, mindfulness, and school curricula (p.959), with
benefits going to those most impaired.243 Integrating
social-emotional and physical training activities with
cognitive enhancing ones may maximize EF improve-
ment. Developing cognitive treatments that are effective
in the premorbid risk period might prevent the growing
adolescent achievement gaps affecting these children.67,74
How Treatment Milieus Support Both Early Prevention
and Ongoing Early Intervention Efforts
Given the developmental and intergenerational risks for
psychosis, integrated care for both children and fami-
lies is imperative. However, the US severely lacks such
services. Parents with psychosis generally receive psy-
chopharmacological and psychosocial treatments with-
out any specialized features that support their caregiver
role. Outpatient clinics or consultations within womens
health or perinatal psychiatry might provide care to par-
ents with psychosis (mostly mothers), although these
treatments may not incorporate parent skills training,
promote activities toward improving child development,

or target the parent-child relationship. Without a com-
prehensive program, maintaining a healthy level of sta-
bility and family functioning will remain a struggle for
most families, with variability in treatment engagement
and adherence.244 Community-based supports in and out
of the home that also integrate health and social services
would help comprehensively address the various needs of
parents affected by psychosis.
US parents with acute severe psychosis are often
separated from their children following hospital admis-
sion, causing enormous stress on the family. Yet, models
of comprehensive care for mothers and infants within
inpatient and partial programs exist. Mother-Baby
Units (MBUs), which began in the mid-1900s, exist in
Europe, Australia, and New Zealand as inpatient and
day treatment facilities with pharmacological and psy-
chosocial interventions that accommodate mothers and
infants.245,246 While this specific inpatient model has not
been adopted in the US it could be adapted for a compre-
hensive outpatient program for mothers and their infants.
Conclusions
Clearly, the multidisciplinary understanding of develop-
mental risks for schizophrenia has shaped a promising out-
look for early intervention. Research to date supports the
initiation of psychosocial interventions that target early
impairments and biological and psychosocial processes
involved in the trajectory for psychosis. Reducing prena-
tal risk exposures, including family stress, is an impor-
tant focus. Furthermore, the needs of families affected
by psychosis warrant accommodations to treat both par-
ents and infants through appropriate treatment settings
that also equip parents with practical parenting skills and
ways to improve the parent-child relationship. Because of
the chronicity and severity of schizophrenia, substantial
coordination to provide acute and long-term support is
needed for parents and children. Additionally, systematic
research is needed to examine the impact of such interven-
tions on preventing psychopathology and functional dis-
ability, as well as its cost-effectiveness. The impact of the
parent-child interactions and psychosocial adversity on
brain development and plasticity in at-risk children needs
to be understood to help identify therapeutic targets for
early intervention. Early interventions may be more effec-
tive with reliable identification of parents and children at
highest risk; ascertaining biomarkers of the early stages of
psychotic disorders will be valuable.247 Such investments
within early development, can improve the developmental
risk trajectory and intergenerational transmission of risk
of psychosis, and promote intact and healthy families.
Funding
Commonwealth Research Center (SCDMH82101008006)
and NIMH (R21 MH092840).
Early Psychosis Risks to Inform Intervention
Acknowledgments
The authors have declared that there are no conflicts of
interest in relation to the subject of this study.
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