160  Review article
Offspring of parents with schizophrenia, bipolar disorder,
and depression: a review of familial high-risk and molecular
genetics studies
Andrea Sandstroma,b, Qendresa Sahitib,c, Barbara Pavlovaa,b and
Rudolf Uhera,b,c
Offspring of parents with severe mental illness, including
schizophrenia, bipolar disorder, and major depressive
disorder, have a one-in-three risk of developing severe
mental illness themselves. Over the last 60 years,
three waves of familial high-risk studies examined
Downloaded from http://journals.lww.com/psychgenetics by BhDMf5ePHKbH4TTImqenVAaoM33QR5KTFkk7E55VmCBgjKUPR5y1bmdTiTiqXilTatTyfC21yos= on 12/08/2019
the development of severe mental illness in offspring
of affected parents. The first two waves established
familial nature of schizophrenia, and demonstrated
early impairment in offspring of affected parents. The
most recent wave has added a focus on mood disorders
and examined the transdiagnostic nature of familial
risk. A synthesis of current knowledge on individuals at
familial risk points to psychopathology, neurocognitive,
neuroanatomical, and environmental factors involved
in the familial transmission of severe mental illness.
Although family history remains the single strongest
predictor of illness, molecular genetic tools are becoming
Introduction
Major depressive disorder (MDD), bipolar disorder, and
schizophrenia share common genetic and environmental
risk factors as well as typical age of onset in late adolescence
or early adulthood (Uher and Zwicker, 2017). After an early
onset, these disorders tend to cause lifelong impairment
(Kessler et al., 2005; Harvey, 2011). Consequently, the cost of
these disorders to society is higher than the cost of physical
diseases, which typically have a later onset (Ratnasingham
et  al., 2012). Because of their shared features and signifi-
cant impact, these disorders are often jointly referred to as
severe mental illness (SMI). Understanding the development
of SMI is essential for designing effective prevention and
treatment strategies, which may help alleviate the burden
of SMI for both the individual and society.
Understanding the developmental precursors of SMI is
particularly important. We use the term antecedents to
describe early manifestations of psychopathology that
do not meet diagnostic criteria for SMI but are known
to precede and predict disease onset. Suspected ante-
cedents of SMI are often retrospectively identified in
individuals who are already affected with SMI; this does
not allow distinguishing between precursors and conse-
quences of SMI (Thapar and Rutter, 2019). For exam-
ple, are the cognitive deficits observed in patients with
schizophrenia a risk factor for the disorder or do they
0955-8829 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
increasingly informative. The next decade may see family
history and molecular genetics complementing each
other to facilitate a transdiagnostic approach to early risk
identification and prevention. Psychiatr Genet 29:160–169
Copyright © 2019 Wolters Kluwer Health, Inc. All rights
reserved.
Psychiatric Genetics 2019, 29:160–169
Keywords: bipolar disorder, familial high-risk, major depressive disorder,
offspring, review, schizophrenia, youth
a
Department of Psychiatry, Dalhousie University,  bDepartment of Psychiatry,
Nova Scotia Health Authority and  cDepartment of Psychology & Neuroscience,
Dalhousie University, Halifax, Nova Scotia, Canada
Correspondence to Rudolf Uher, MD, PhD, Dalhousie University, 5909 Veterans
Memorial Lane, Halifax, Nova Scotia B3H 2E2, Canada
Tel: +902 473- 2585; fax: +902 473 4887; e-mail: uher@dal.ca
Received 3 June 2019 Accepted 1 August 2019
develop as a result of the illness? The way to establish
whether a risk factor actually precedes SMI is to pro-
spectively study individuals before the onset of SMI
(Thapar and Rutter, 2019). Large prospective studies
of the general population are informative regarding
risk factors which precede common mental disorders,
including anxiety disorders and attention-deficit/hyper-
activity disorder (ADHD). However, general popula-
tion studies may be less suited to detect antecedents
to SMI, because only a small proportion of participants
will end up developing truly severe illness and individu-
als at highest risk for SMI may actually be less likely to
participate (Martin et al., 2016). Therefore, researchers
aiming to prospectively study developmental anteced-
ents to SMI may need to specifically target high-risk
individuals.
The strongest known risk factors for SMI is having a parent
with SMI, as one-in-three offspring of affected parents will
develop MDD, bipolar disorder, or schizophrenia by early
adulthood (Rasic et  al., 2014). Therefore, studies in off-
spring of parents with SMI provide an opportunity to exam-
ine early manifestations of risk that are relevant to SMI.
The first familial high-risk studies were launched in the
1950s and 1960s. The rationale behind this design was
the need to study individuals at genetic risk for SMI in
DOI: 10.1097/YPG.0000000000000240

order to identify antecedents that occurred before dis-
ease onset (Mednick and McNeil, 1968). At this point,
family history was the only way to index genetic risk.
Thus, studies in offspring of parents with SMI allowed
researchers to disentangle the etiological factors of SMI
from consequences which occur after the development of
the disorder (Mednick et al., 1987). Significant advance-
ments in molecular genetics over the past few decades
now allow genetic risk for SMI to be assessed directly
using polygenic risk scores (PRS) based on genome-
wide association studies (Martin et al., 2018). PRS is the
sum of alleles associated with a particular phenotype
and provides an estimate of the likelihood of a specific
trait based on multiple genetic variants. Thus, genetic
vulnerability can now be estimated without knowing
family history and separated from environmental factors
that may also be shared within families and passed on
from generation to generation. This development raises
questions about the relative roles of familial high-risk
studies and molecular genetic studies in further research
on the causation, prediction, and prevention of mental
illness. In this review, we provide a synthesis of familial
Fig. 1
Studies of offspring of parents with schizophrenia, bipolar disorder and major depressive disorder.
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Review of familial high-risk studies Sandstrom et al.  161
high-risk studies, with the aim to inform future research
in this field. We review completed and ongoing familial
high-risk studies to provide a synthesis of current knowl-
edge regarding psychopathology, cognitive, neuroim-
aging, genetics, and environmental factors in high-risk
offspring. We then summarize research on interventions
for offspring of parents with SMI, and finish by outlining
future directions for the field.
Historical perspective
As the efforts invested in familial high-risk studies have
waxed and waned over the decades and each period of
renewed interest brought new topics, we summarize
familial high-risk studies as occurring in three waves
(Fig. 1).
Wave one
The trail-blazers of familial high-risk research launched
the first studies in the 1950s and 1960s with a focus on
schizophrenia. These longitudinal studies followed
offspring of parents with schizophrenia beginning in
infancy (Fish, 1987), childhood (Worland et  al., 1984),
162  Psychiatric Genetics  2019, Vol 29 No 5
or adolescence (Mednick et al., 1987). The Copenhagen
high-risk project, initiated in 1962, followed more than
200 offspring of parents with schizophrenia and con-
trols over 20 years (Mednick et  al., 1987). The findings
from these projects have transformed the understanding
of schizophrenia. In addition to demonstrating that off-
spring of affected parents were at high risk for schizo-
phrenia, they showed early impairments across a number
of domains, including social problems and neurological
difficulties (Fish, 1959; Mednick et al., 1987). These find-
ings led to the realization that schizophrenia is a neurode-
velopmental condition rather than a neurodegenerative
condition, as previously believed (Murray and Lewis
1988).
Wave two
A second generation of familial high-risk studies began
in the 1970s and 1980s, and some of these studies have
only recently completed the final rounds of data collec-
tion. Although the primary focus remained on schizo-
phrenia, some of these studies also included offspring of
parents with mood disorders. Notably, the three-gener-
ation project initiated in 1982 assessed depression and
continued to track familial risk across three generations
(Weissman et  al., 2016). The Stony Brook High-Risk
Project and the Emory University Project also included
offspring of parents with depression and bipolar disorder
as additional comparison groups to offspring of parents
with schizophrenia (Goodman, 1987; Weintraub, 1987).
These studies also found early impairment in offspring of
parents with mood disorders, raising questions about the
specificity of developmental precursors to schizophrenia
(Goodman, 1987; Weintraub, 1987; Egeland et al., 2003).
An excellent overview of this wave of studies in a special
issue of Schizophrenia Bulletin (Asarnow, 1988) in 1988
was followed by a lull decade when few new studies were
initiated.
Wave three
Over the past two decades, familial high-risk research
has regained momentum with a new focus on offspring
of parents with bipolar disorder and on transdiagnostic
approaches to SMI. Several large-scale projects include
offspring of parents with different types of SMI, opening
an opportunity to map both shared and disorder-specific
antecedents for MDD, bipolar disorder and schizophre-
nia. The routine application of neuroimaging and molec-
ular genetics in these studies expands the range of
questions that can be answered.
Among the first to take a transdiagnostic approach was a
study by Maziade et al. (2008) which followed relatives of
people with schizophrenia or bipolar disorder over twenty
years. Findings indicated that there was significant over-
lap in early risk factors and later mental disorder diagno-
ses between offspring of parents with schizophrenia and
offspring of parents with bipolar disorder (Paccalet et al.,
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
2016). Further evidence for a general rather than specific
vulnerability associated with familial risk was established
through a meta-analysis (Rasic et  al., 2014), which has
shown that offspring of parents with SMI are at increased
risk for all psychiatric disorders.
There are currently at least three ongoing transdiag-
nostic familial high-risk studies; the Danish High Risk
and Resilience Study-VIA (Ellersgaard et  al., 2018),
the Bipolar and Schizophrenia Young Offspring Study
(Sanchez-Gistau et  al., 2015) and Families Overcoming
Risks and Building Opportunities for Wellbeing (Uher
et al., 2014). In addition to furthering the study of etiol-
ogy through direct examination of specificity and overlap
between diagnoses, these studies are combining familial
high-risk design with molecular genetic methodology and
examining the potential of early interventions to reduce
the risk of SMI among offspring of affected parents. More
offspring of parents with SMI are being followed up in
research studies at present than at any previous time
point (Fig. 1).
Synthesis of current knowledge
Antecedent psychopathology and childhood-onset
disorders in offspring of affected parents
Years before the typical age of onset for major mood and
psychotic disorders, antecedents of SMI are elevated in
offspring of parents with SMI, including higher scores on
parent-, teacher-, and observer-reports of psychopathol-
ogy and increased rates of emotional and behavioral dis-
orders (Ellersgaard et  al., 2018; Sandstrom et  al., 2019a).
As familial risk is associated with both general and spe-
cific psychiatric liabilities, certain antecedents are shared
across offspring of parents with MDD, bipolar disorder,
and schizophrenia, whereas others are preferentially
related to one type of parental illness.
The rates of childhood-onset mental and behavioral dis-
orders are elevated in high-risk offspring from a young
age. Increased rates of ADHD, anxiety, and disruptive
behavior disorders are shared by offspring of parents
with bipolar disorder and offspring of parents with schiz-
ophrenia (Rasic et  al., 2014; Sanchez-Gistau et  al., 2015;
Ellersgaard et al., 2018). As these same disorders also pre-
dict later onset of both major mood disorders and of schiz-
ophrenia (Hans et al., 2004; Nurnberger et al., 2011; Rice
et  al., 2017; Duffy et  al., 2018; Meier et  al., 2018), child-
hood-onset ADHD and anxiety disorders may represent
transdiagnostic antecedents of SMI. Unusual experiences
including basic symptoms and psychotic-like experi-
ences are also strong predictors of SMI (Poulton et  al.,
2000; Schultze-Lutter et  al., 2012) and are elevated in
offspring of parents with all types of SMI (Noguera et al.,
2018; Aylott et  al., 2019; Zwicker et  al., 2019a). Certain
aspects of temperament may also represent early man-
ifestations of risk for SMI, as offspring of parents with
SMI display less positive mood dimensions, adaptability
 Review of familial high-risk studies Sandstrom et al.  163

(Díaz-Caneja et  al., 2018) and greater behavioral inhi-
bition (Rosenbaum et  al., 2000; Hirshfeld-Becker et  al.,
2006a). As inhibited temperament is a strong risk factor
for anxiety (Sandstrom et al., 2019b), which in turn pre-
dict SMI (Duffy et al., 2018; Meier et al., 2018), behavioral
inhibition may also be an early antecedent for SMI.
Although some antecedents may be transdiagnostic, other
precursors show disorder specificity. Mood instability and
irritability are a cluster of related symptoms that are com-
mon in mood disorders (Balbuena et al., 2016). Propensity
to sudden rapid changes in mood, referred to as mood
instability or affective lability, is elevated in offspring of
parents with mood disorders, but not offspring of parents
with schizophrenia (Zwicker et al., 2019b). Mood instabil-
ity and irritability also predict the onset of mood disorders
in offspring of parents with MDD and bipolar disorder
(Hafeman et al., 2016; Rice et al., 2017). Taken together,
previous investigations suggest that mood instability and
irritability may be antecedents that are relatively spe-
cific to mood disorders. Childhood sleep problems have
also been implicated in offspring of parents with mood
disorders (Wescott et al., 2019), and are associated with a
two-fold increased risk for future bipolar disorder in off-
spring of parents with bipolar disorder (Levenson et al.,
2015). Evidence for an association between sleep prob-
lems and family history of schizophrenia has not yet been
established.
Antecedents often develop in childhood and adolescence
and maybe the first indicators of risk for SMI in high-
risk offspring beyond family history. In the coming years,
transdiagnostic longitudinal studies of high-risk offspring
will probe the relative specificity or transdiagnostic char-
acter of further antecedents and associated biomarkers.
With accumulation of longitudinal data and assessment
of various risk factors concurrently, we can also start
examining how multiple antecedents and biomarkers
Fig. 2
may be combined to optimize the early identification of
risk for SMI.
Onsets of severe mental illness in offspring of affected
parents
The rates of major mood and psychotic disorders among
offspring of parents with SMI have been summarized in
a meta-analysis (Rasic et al., 2014). Of offspring of parents
with SMI who have been followed-up into adulthood,
32% have a diagnosis of MDD, bipolar disorder, or schiz-
ophrenia compared to 14% of control offspring of parents
without SMI. Across age-groups, offspring of parents
with SMI are at 2.5-fold increased risk for any SMI com-
pared to offspring of parents with no SMI (Rasic et  al.,
2014). In addition, offspring of parents with SMI are also
at a greater risk for almost all other psychiatric disorders
including substance use and disruptive behavior disorder
(Rasic et al., 2014). Since it is relatively rare for both bio-
logical parents to be affected with SMI and some high-
risk studies have excluded families with two affected
parents, the above rates apply primarily to children who
have one biological parent with SMI and the other bio-
logical parent without mental illness. A Danish registry
study shows that risk of SMI is further increased when
both parents are affected (Gottesman et al., 2010). Future
research on the risk for MDD, bipolar disorder, and schiz-
ophrenia when both parents have SMI is warranted.
Staging model of severe mental illness
The progression to SMI is a complex and multistage pro-
cess with early manifestations of illness emerging before
disease onset. Thus, it is helpful to conceptualize SMI on
a continuum with phases that differ in severity and spec-
ificity. The staging model (Fig.  2; McGorry & Nelson,
2016; Fusar-Poli et  al., 2017), presents a framework for
the trajectory of SMI occurring along this continuum.
Stage 0 is the period when individuals are asymptomatic.

Staging model of severe mental illness in offspring of parents with major depressive disorder, bipolar disorder, and schizophrenia matched with
possible interventions in the absence and presence of family history.

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164  Psychiatric Genetics  2019, Vol 29 No 5
Stage 1a occurs when distress disorders develop, which
may include ADHD and oppositional defiant disorder.
In some cases, manifestation of SMI risk will become
increasingly specific and form a clinical at-risk state/pro-
drome for a mood or psychotic disorder (stage 1b). Stage 2
is marked by first episode onset of SMI. In some individ-
uals, illness may progress and SMI may become recurrent
(stage 3). Stage 4 occurs when the illness is chronic, treat-
ment resistant, and causes severe impairment. Staging
in offspring of parents with SMI is similar to individuals
with no family history of major mental illness from stage
1a onwards. However, in the context of positive family
history, antecedents that fall short of distress disorder
diagnoses are also important predictors for future SMI.
Thus, in Fig.  2 we present an adapted staging model
for SMI in familial high-risk offspring, where we high-
light the antecedent stage (stage 0.5) as a distinct phase
from stage 0 and stage 1a. The inclusion of this stage has
important implications for the timing of early interven-
tion strategies in offspring of parents with SMI.
Neurocognitive functioning
On average, offspring of parents with SMI perform less
well on measures of cognitive functions than do control
offspring. Lower intelligence quotient (IQ) has been
found in offspring of parents with schizophrenia and
bipolar disorder compared to controls (Klimes-Dougan
et al., 2017; de Zwarte et al., 2018). Offspring of parents
with schizophrenia also perform substantially lower than
offspring of parents with bipolar disorder on IQ tests
(Hemager et  al., 2018). Thus, on average IQ decreases
from offspring of parents with no SMI to offspring of
parents with bipolar disorder to offspring of parents with
schizophrenia. Offspring of parents with depression also
perform less well on cognitive tests than offspring of par-
ents without mental illness (MacKenzie et al., 2019). As
IQ in childhood predicts psychiatric disorders (Mollon
et  al., 2018), lower IQ in high-risk offspring may be an
early indicator of risk for SMI. Specific domains of cog-
nition may index familial risk of SMI better than general
cognitive ability. Offspring of parents with schizophrenia
show greatest difficulties in verbal ability, visual mem-
ory, and attention (Hameed and Lewis, 2016). Offspring
of parents with bipolar disorder also show on average
lower cognitive functioning in processing speed, and
visual memory (Klimes-Dougan et al., 2006; de la Serna
et  al., 2017). Out of tests of various cognitive functions,
offspring of parents with MDD perform worst in tasks
that depend on language and verbal ability (MacKenzie
et al., 2019).
The usefulness of neurocognitive measures in predict-
ing the onset of SMI in high-risk offspring has not yet
been established. However, preliminary findings sug-
gest cognitive deficits defined as impairment in verbal
episodic memory, processing speed or visual episodic
memory, may be associated with major affective and
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non-affective disorders in high-risk offspring (Berthelot
et al., 2015). ‘Hot’ cognition that involves reasoning and
thinking in emotionally-salient context may also index
risk of mental illness independently of general cognitive
ability. Emotional decision-making scores in offspring of
parents with SMI may represent an early indicator of pro-
pensity to psychotic symptoms (McCormack et al., 2016;
MacKenzie et  al., 2017). Finally, low reward-seeking
measured using the Cambridge Gambling Task from the
Cambridge Neuropsychological Test Automated Battery
has been found to predict depressive symptoms and
depressive disorders in offspring of parents with MDD
(Rawal et al., 2013).
The evidence from familial high-risk studies suggests that
early cognitive deficits in high-risk offspring may repre-
sent antecedents to SMI. Future longitudinal research in
high-risk offspring may indicate which cognitive domains
may improve the prediction of SMI when used alone or
in combination with other types of predictors.
Neuroimaging
Brain imagining in high-risk offspring aims to identify
deviations in brain structure and function, which may
indicate biomarkers for SMI. The findings include both
biomarkers that are specific to offspring of parents with a
particular diagnosis and those that generalize to offspring
of parents with different types of mental illness.
Studies of brain structure found cortical thinning in off-
spring of parents with all types SMI (Prasad et al., 2010;
Talati et  al., 2013; Hanford et  al., 2016) suggesting that
thinner cortex may be a transdiagnostic marker of familial
risk. In contrast, increased volume and surface of the right
inferior frontal gyrus has been reported as a replicable
biomarker of familial risk for bipolar disorder (Hajek et al.
2013; Sarıçiçek et al., 2015; Roberts et al., 2017; Drobinin
et al., 2019). In addition, decreased volume in white mat-
ter across different brain regions has also been reported
in offspring of parents with mood disorders (Nery et al.,
2017; Ganzola et al., 2018; Versace et al., 2018).
Imaging of brain function has also demonstrated differ-
ences between offspring of parents with SMI and control
offspring. The variety of procedures used to index brain
function limits comparability of findings across studies.
Recent trends include the applications of vastly multivar-
iate methods, such as network analysis and graph theory,
to capture the complex patterns of co-variation in func-
tion across brain regions and time points. So, for exam-
ple, it has been reported that connectivity deficits in the
brain’s central rich club system (Collin et al., 2017) and in
the left basal ganglia resting-state network (Solé-Padullés
et al., 2016) distinguish offspring of parents with schizo-
phrenia from controls. Offspring of parents with MDD
show reduced resting-state activity in the right parietal
temporal hemisphere (Talati et al., 2013), and deficits in
prefrontal connectivity have been found in offspring of
 Review of familial high-risk studies Sandstrom et al.  165

parents with bipolar disorder (Singh et al., 2014; Roberts genome-wide genotyping will help test whether PRS
et  al., 2017; Roberts et  al., 2018). Taken together, these meaningfully complement family history in predicting
findings suggest that reduced connectivity in differ- the onsets of major mood and psychotic disorders. This
ent brain regions may represent a genetic liability for may be especially relevant in cases where family history
SMI. However, because of variation in methods, lack of is less informative because of small family size or missing
transdiagnostic comparisons and absence of replication information on biological relatives.
attempts, it is currently unclear whether any of these
functional features are specific to a particular parental Environment factors
diagnosis or are shared between different familial high- Exposures to an adverse environment, which occur across
risk groups. the life course, also contribute to the development of SMI
in high-risk offspring. Some of the earliest environmen-
Brain imaging in offspring of parents with SMI indicates
tal risk factors in offspring of parents with SMI include
that certain abnormalities in brain structure may repre-
birth complication and separation from family, which may
sent developmental markers of familial risk. Functional
occur more frequently for offspring of parents with men-
imagining techniques also suggest difference in brain
tal illness (Mednick et  al., 1987; Davidsen et  al., 2015).
connectivity in offspring of parents with SMI compared
Other family stressors including family conflict and insta-
to controls, although where these differences occur may
bility are also more common in high-risk offspring and
depend on the high-risk group. It remains to be deter-
may contribute to vulnerability for SMI (Beardslee et al.,
mined whether early abnormalities in brain structure and
1998; Ferreira et  al., 2013). In addition, parenting style
function may predict later onset of SMI.
may moderate risk, with warm and predictable parenting
being protective and criticism and rejection being asso-
Genetics
ciated with later onset of mood disorders (Kemner et al.,
The transmission of SMI from parent to child is to a large
2015). Other environmental exposures including socio-
degree due to genetic factors. This genetic risk contrib-
economic status, economic disadvantage, psychosocial
utes to offspring’s vulnerability to develop mental disor-
adversity, and stressful life events have all been found
ders and may also manifest in subtle deviations of brain
to predict SMI (Kemner et  al., 2015; Rice et  al., 2017;
structure and cognitive abilities. The heritable risk of
Noguera et al., 2018). Good-quality peer relationships act
SMI is due to hundreds or thousands of genetic variants,
as a protective factor for mental health problems in off-
of which each one contributes a small portion of liability
spring of parents with SMI (Collishaw et  al., 2016) and
to disease risk (Uher and Zwicker, 2017). PRS provides
poor social relationships and exposure to bullying may
a cumulative measure of this vulnerability across thou-
contribute to the development of SMI (Bowes et al., 2014;
sands of genetic variants (Torkamani et al., 2018). PRS for
Singham et al., 2017).
schizophrenia, depression and bipolar disorder correlate
with family history of SMI and distinguish offspring of Throughout development, children and youth experi-
parents with bipolar disorder or schizophrenia from con- ence a number of positive and negative environmental
trols (Fullerton et al., 2015; Neilson et al., 2018). influences, which may moderate the risk for SMI. It is
unlikely that one single exposure is enough to cause SMI.
Recent findings have established there is considerable
Instead, it is probable that a number of environmental risk
overlap in the genetic variants for different psychiat-
factors interact to influence disease onset (Padmanabhan
ric disorders, with approximately two-thirds of genetic
et al., 2017; Uher and Zwicker, 2017). Therefore, studying
influences shared across schizophrenia, bipolar disorder
the cumulative effect of environmental exposures across
and MDD (Cross-Disorder Group of the Psychiatric
development may be helpful to improve our understand-
Genomics Consortium, 2013). Thus, the genetic risk
ing of how vulnerability develops in youth at low and
for SMI may also be shared across offspring of parents
high familial risk (Oliver et al., 2019).
with different psychiatric disorders. For example, poly-
morphisms in CACNA1C and SYNE associated with the
Pre-emptive early interventions
risk of SMI are enriched in offspring of parents with both
Offspring of parents with SMI are more likely to experi-
schizophrenia and bipolar disorder (Gassó et al., 2016). It
ence impairment across a number of domains and are at
is becoming increasingly possible to predict the risk of
increased risk for all types of psychiatric disorders. Thus,
mental illness from PRS, and combining PRS for multi-
offspring of parents with SMI represent a population in
ple disorders may be the most powerful approach (Maier
need who may benefit from early intervention. In the last
et al., 2015; Taylor et al., 2018).
decade, several familial high-risk studies have focused on
At present, family history remains a more powerful pre- opportunities for early intervention aiming to reduce the
dictor of mental illness than PRS. However, as the sam- risk of developing mental illness. Some researchers have
ples of molecular genetic studies are growing, PRS are tested treatments typically used for acute mental illness.
becoming more accurate in predicting mental illness. A few small open-label studies have used mood stabiliz-
The combination of familial high-risk design with ers or antipsychotics in offspring of parents with bipolar

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166  Psychiatric Genetics  2019, Vol 29 No 5
disorder, but results have been mixed and not replicated
in randomized control trials (RCT) (Zalpuri and Singh,
2017). Furthermore, the use of medication in youth who
are not diagnosed with a disorder may cause more harm
than good. Consequently, most recent intervention stud-
ies in offspring of parents with SMI have focused on psy-
chological approaches.
The strongest evidence for the effectiveness of psycho-
logical intervention in high-risk offspring comes from an
RCT of cognitive-behavioral prevention in offspring of
parents with depression (Garber et al., 2009). This study
found that the intervention reduced the risk of depres-
sion onset over the initial short-term follow-up, and the
benefits were maintained on long-term follow-up 6 years
later (Brent et al., 2015). Other preliminary investigations
suggest that Interpersonal and Social Rhythm Therapy
(Goldstein et  al., 2018) and Family-Focused Therapy
(Miklowitz et  al., 2013) may be beneficial for symptom
reduction in offspring of parents with bipolar disorder.
However, due to small sample size and short-term fol-
low-up it is unclear whether either of these therapies may
be effective at preventing bipolar disorder.
Two ongoing intervention projects: Skills for Wellness
(SWELL; Uher et  al., 2014) and VIA-family (Müller
et al., 2019) have taken a transdiagnostic approach to pre-
vention. SWELL is  a multimodal antecedent-focused
cognitive-behavioral training intervention for offspring
of parents with MDD, schizophrenia, and bipolar disor-
der. The aim of SWELL is to reduce the risk of future
psychiatric disorders by targeting the early antecedents
of SMI (affective lability, anxiety, psychotic, and basic
symptoms). Initial experiences in SWELL suggest good
acceptability and short-term benefits. VIA-family is a
multidisciplinary intervention for offspring of parents
with SMI that provides intensive support and treatment
strategies for the entire family. Initial response to VIA-
family suggests that the intervention is acceptable and
valued by participating families (A. Thorup 2019, per-
sonal communication, 19 April).
The staging model of SMI may allow matching inter-
vention to each stage of illness (Fig. 2). In the absence
of familial risk, the interventions typically begin at stage
1a, after individuals seek treatment for their symptoms.
Knowledge of family history may allow moving the
intervention efforts to even earlier stages (Fig.  2). Due
to the increased risk associated with family history, pro-
active monitoring may present an alternative to restrict-
ing interventions to treatment-seeking individuals. Even
symptoms falling short of distress disorder diagnoses may
present an indication for early pre-emptive intervention
during the antecedent stage (stage 0.5).
To date, few interventions have been tested for offspring
of parents with SMI, and most of the existing studies are
limited by small sample size and short-term follow-up
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
periods. A broader transdiagnostic approach to preven-
tion may be an important step for addressing the risk fac-
tors associated with family history.
Conclusion
The earliest familial high-risk studies began because
researchers wanted to study SMI in individuals who
were known to have the genetic risk for these disorders.
Almost 60 years later, researchers now have the ability to
assess genetic risk without knowing family history. This
brings us back to the question raised at the beginning of
this review: what is the role of familial high-risk studies
now that we can measure genetic risk directly?
Among the various designs available to study the devel-
opment of mental illness, investigations in offspring of
parents with SMI continue to provide essential infor-
mation, due to concentration of risk, thoroughness of
assessments, completeness of follow-up, and severity
of outcomes. The familial high-risk design is powerful
because it enriches for both genetic and environmental
influences. However, for the same reason, it is less suited
to differentiating genetic and environmental influences.
The incorporation of genetic tools in studies of offspring
of parents with SMI may combine advantages of both
types of studies to provide a clearer picture of the causal
mechanisms of SMI and distinguish between the role of
environment and the role of genetics in the development
of psychiatric disorders.
A recent investigation (Rice et  al., 2019) in a popula-
tion-based cohort explored the predictive value of PRS
for neurodevelopmental disorders (ADHD and schiz-
ophrenia) and PRS for MDD on the age of onset of
depressive symptoms. The researchers found that PRS
for neurodevelopmental disorders was associated with
earlier age of onset of depressive symptoms, whereas PRS
of MDD predicted onset at typical age. These findings
suggest that there may be distinct depressive trajectories
based on genetic risk. These are intriguing findings with
implications for prevention and treatment. However, this
study is limited by high drop-out rate, which was not ran-
dom but rather predicted by high genetic risk for psychi-
atric disorders (Taylor et al., 2018). Thus, the individuals
we are most interested in studying are the ones who are
most likely to be missing from population-based studies.
As familial high-risk studies focus on exactly that seg-
ment of population and have better retention rates than
investigations in the general population, using familial
high-risk design will complement studies of general pop-
ulation and contribute to a better understanding of the
genetic and environmental factors which are involved in
the development of SMI.
Family history remains the most powerful predictor
for SMI, and offspring of parents with MDD, bipolar
disorder, and schizophrenia are at high risk for disease
onset. Thus, offspring of parents with SMI represent a

population in need and early interventions are essential.
With one notable exception (Garber et  al., 2009; Brent
et al., 2015), interventions to date have been limited by
small sample size and short-term follow-up. Recently
accumulated knowledge is converging to suggest that
taking a transdiagnostic approach to prevention may
yield the best outcomes (McGorry and Nelson, 2016;
Caspi and Moffitt, 2018).
Interventions have typically focused on targeting
high-risk offspring in later childhood and adolescence.
Prevention strategies which intervene at an earlier age
maybe even more effective at reducing risk for SMI.
Such interventions may take a parent-focused approach,
as young children are not able to fully engage and learn
from psychological intervention (Garber et  al., 2016).
Previous parent-focused interventions in mothers with
depression and mothers with anxiety have shown prom-
ising results (Goodman and Garber, 2017; Howes Vallis
et al., 2019). Another unexplored area is the use of genetic
technology in preventive interventions. It remains to
be determined whether the incorporation of genetic
tools in early interventions may be an effective way to
prevent SMI.
Acknowledgements
This work was supported by the Canada Research Chairs
Program (Grant number 231397), and the Nova Scotia
Health Research Foundation (Grant number 833).
Conflicts of interest
There are no conflicts of interest.
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