Appendix 1: Outline of Included Studies by Author reference.
Further information
Date of sample: refers to birth year unless otherwise specified.
Quality Control Assessment Scale used : Wells, Shea, O’Connell, Peterson, Welch, Losos&Tugwell (2013) : The Newcastle-Ottawa Scale (NOS) for
assessing the quality of nonrandomised studies in meta-analyses.
Maximum score of 8 for Cohort Study, 9 for Case Control. For further detail on quality assessment score please refer to appendix 3 and 4.
Further notes on study method: Additional notes were added from the paper if deemed as helpful in adding to the evaluation of the study method, or in the
interpretation of the authors’ findings.
1
Author reference
Date of
Sample
Participant
Detail(Cases
& Controls)
Diagnostic
scale used
to assess
case-ness.
Aetiological factors
measured
Quality
Control
Assessment(
QAR)
Abel, Wicks,
Susser, Dalman,
Pedersen,
Mortensen& Webb
(2010)
1973-1984
Follow
up:2002.
Total of
cohort:1, 077
,393 from
singleton live
births in
Sweden.
5445 cases of
schizophrenia
and other
related
disorders
within this
sample.
ICD
9&101
Low birth weight
(<2500 g and low for
gestational age)
5.5/8
Further notes
on study
methods (not
within QAR)
e.g. how did
they recruit?_
•”Low weight”
was defined by
the World Health
Organisation but
arbitrary cut off;
not categorical.
Stratifying into
500g cut offs is
questionable re.
utility of it.
•Useful that the
study used only
term births over
37 weeks. So can
more reliably
measure birth
Summary of study
findings
An association
between birth
weight and adult
mental disorder was
found, but with
no indication the
effect was specific
to a birth weight less
than 2500 g or to
Schizophrenia.
Low birth weight
may represent a
mechanism for a
general psychiatric
vulnerability rather
than one specific to
1
ICD: International Classification of diseases: Codification/Classification of Diseases from the World Health Organisation
1
2
2
Allebeck, Adamsson
,Engstrom&Rydber
g (1993)
1971-1983:
112 cases of
schizophrenia
(Stockholm
County
Only:populatio
n around 1.5
million)
ICD 8 &
DSM III2
Cannabis Use
5/8
weight with less
confounding by
abnormal
development.
• Birth weight of
an Infant
provides little
information
about the path of
its growth in
utero in either an
adverse or
favourable
maternal
environment
• The study
included a large
enough sample to
detect small
effects that may
occur across the
normal birth
weight range.
•Cannabis may
be used for selfmedication
during a prodromal phase of
psychosis.
However within
the study
temporal findings
make this less
likely and give
strength to
causality.
Schizophrenia.
Equally low birth
weight may be a
marker of risk for
another variable.
69% of the cases
had a record of
heavy cannabis
abuse at least 1 year
before onset of
psychotic
symptoms.
Cannabis use shown
to be linked to
positive symptoms
only.
The Diagnostic and Statistical Manual of Mental Disorders (DSM):Codification/classification from the American Psychiatric Association
2
3
Andreasson,
Engstrom,
Allebeck&
Rydebeck(1987)
Majority
born:19491951.
Surveyed
1969/1970.
Follow up
1983.
45570 men,
246 cases of
Schizophrenia
ICD8
-Cannabis Use
(Category of usage:
None, 1-10,1150,50+).
6/8
•Difficulties of
non-anonymous
questionnaire and
response bias.
•Asked about
other drug and
alcohol use.
•Controlled for
other social
adjustment
variables.
Relative risk of
schizophrenia in
cannabis users was
found to be 6 x
higher than nonusers.
(1-10 uses: 1.3x
risk; 11-50 uses: 3x,
50+ uses: 6x).
However cannabis
may be a stressor for
those vulnerable to
developing
schizophrenia rather
than a necessary or
sufficient factor. Of
274 schizophrenics
only 21 were in the
high consuming
group and only 49
had ever tried
cannabis.
Additionally the use
of cannabis for selfmedication for
previous psychiatric
symptoms cannot be
ruled out within the
study methodology.
4
Andreasson,
Allebeck
&Rydebeck(1989)
Born 19491951
conscripted
1969-1970
8483 men, 42
cases of
schizophrenia.
ICD 8
-Cannabis
Use(Category of
usage: None, 1-10,1150,50+).
6.5/8
•Importantly
controlled for
Hereditary
presence of
schizophrenia,
other drug and
alcohol use,
negative social
background
There was no
evidence of mental
disorder prior to
cannabis abuse
within the study,
even if the role of
personality traits
could not be fully
assessed. The
3
factors.
5
Andréasson &
Allebeck, (1991).
Conscripted
in 1969/70.
Follow up
1983.
49,464 Young
Swedish
males who
were
conscripted for
compulsory
military
service.
ICD 8
Alcohol (more than
250 g alcohol per
week)
6/8
•Considerable
underreporting of
alcohol
consumption has
been shown in
several previous
studies which
leads to
suggestions it
may also have
authors concluded a
different pattern
of mental
deterioration was
found among
cannabis users, with
a more abrupt onset
of schizophrenic
symptoms than
nonusers. There was
no major difference
between
users and nonusers
in heredity for
schizophrenia (or
other psychiatric
disorders). Negative
social background
factors were more
common among
cannabis abusers.
Although the
number of cases in
this study was small,
the findings support
the hypothesis that
cannabis does play
an aetiological role
in schizophrenia.
Although a dose
response
relationship between
alcohol and
Schizophrenia was
found within the
study, as abstainers
also had an
increased risk
further research is
4
6
Cederlof, Bergen,
Langstrom, Larsson
,Boman, Craddock
,Ostberg ,Lundstrom
Sjolander, Nordlind,
Landen&
Lichtenstein (2014).
Total
population
register
used:those
registered as
Swedish
residents 1968
onwards.
Definitive
dates not
discussed.
A total
of 788
individuals
with Darier
disease and
3,228 of
their firstdegree
relatives were
identified. 770
cases were
used in the
final analysis.
ICD
8,9&10
Darier Disease
7/8
been
underestimated
in this study.
needed to clarify the
findings and
whether any
underlying
moderators can
explain the results.
What emerges is a
group with multiple
hardship in
which high alcohol
consumption may be
one factor among
many influencing
the aetiology of
schizophrenia.
•Limitation:
Those that
receive one
diagnosis may be
more be more
likely to receive
another due to
bias from
clinicians.
An increased risk
was found for later
Schizophrenia in
individuals with
Darrier Disease.
However the
increase was greater
for bipolar
suggesting any
association may
reflect a general
psychiatric
vulnerability rather
than a direct
temporal link. The
authors suggest this
underlying
vulnerability is
likely to be genetic
but further research
is needed.
5
7
Class, Abel,
Khashan, Rickert,
Dalman, Larsson,
Hultman,
Långström,
Lichtenstein &
D‘Onofrio(2014)
1992-2000 for
childhood
outcomes
1973-1997
adulthood
outcomes
8
Dalman &Allebeck
(2002)
1960-1977
9
Dalman,Allebeck,
Cullberg,
Grunewald&Koster(
1999)
1973-1977
(Diagnosis
follow up
1987-1995)
Total Sample:
738144
children &
2155221
adults.
ICD
8,9&10
Maternal Stress: death
of a first-degree
relative
during (a) the 6 months
before conception, (b)
pregnancy or (c) the
first two postnatal
years.
6/8
1043 matched
controls. 524
subjects with
schizophrenia
ICD 9&10
Paternal Age
8/8
507516
children. 238
with
schizophrenia.
ICD 8&9
Obstetric
complications and
characteristics of
neonate.
5.5/8
2400 with
schizophrenia.
•Childhood
outcomes could
not include
schizophrenia
only Austism
Spectrum
Disorder and
Asperger
Disorder.
•Schizophrenia
diagnosis was up
to 35
•Importantly
controlled for
maternal age,
parity, marital
status,
socioeconomic
status, maternal
psychotic illness,
and obstetric
complications.
•Controlled for
differences
between gender.
No association was
found for
schizophrenia but
associations were
found for other
psychiatric
morbidities.
The odds of
schizophrenia in
offspring of fathers
45 years old or older
were 2.8 times as
great as in offspring
of fathers aged 20–
24 years
An association
between Obstetric
complications and
Schizophrenia was
found with
preeclampsia (an
indicator of foetal
malnutrition)
This was shown to
be the strongest
individual risk
factor for later
development of
Schizophrenia
within the study.
6
10
11
Dalman, Thomas,
David, Gentz, Lewis
& Allebeck (2001)
David, ,Malmberg,
Brandt, Allebeck
&Lewis (1997)
Born since
1969 Follow
up 1971-1994
1969/1970
(Follow up
1983)
Swedish
conscripts
524 cases of
schizophrenia,
1043 controls
49968 male
conscripts. 195
Cases of
schizophrenia.
ICD 8&9
ICD8&DSMIII
Asphyxia at
Birth/Obstetric
complications
Low IQ
6/8
5/8
•Controlled for
maternal age,
parity, marital
status,
socioeconomic
status, maternal
psychotic illness,
and obstetric
complications.
•Men only and
all aged 18.
•Reasons why
low IQ
associated still
unknown.
•Controlled for
age factors(older
may mean more
cognitively
impaired)
Signs of asphyxia
are independently
associated with
Schizophrenia.
Other factors
showed significance
but this disappeared
after confounders
and other obstetric
complications were
taken into account.
Low scores on
verbal tasks and
mechanical
knowledge led to
increased risk of
Schizophrenia.
The effect of IQ and
later psychotic
illness was highly
significant for
psychotic disorder
and Schizophrenia
specifically.
But low IQ had low
predictive power
predicting only
3.1% of cases.
Within this study
risk for
Schizophrenia was
also attenuated in
comparison to risk
for other psychoses
7
12
David, Malmberg
Lewis,Brandt&
Allebeck (1995)
1969-1970
conscripts.
1970-1983
psychiatric
admission
50087 Swedish
male
conscripts, 203
with
Schizophrenia.
ICD 8
Left-handedness,
epilepsy,
hearing impairment
3/8
13
Ek,
Wicks,Magnusson
&Dalman(2012)
1955-1985
Adoptive
children, total:
31 188,
131 with
schizophrenia.
ICD 8&9
Adoptive paternal
age(Psychosocial
influence)
7/8
•Hearing may be
a proxy for
something else;
possibility it
exposes
individual to
perceptual
abnormalities.
•Reporting/recall
bias on past
behaviour may
be present from
self-report;
handedness also
based on selfreport.
•Limitation we
don’t know when
the sensory
deficit occurred.
•Excluded were
individuals living
with a biological
parent at any 5
year point when
they were 1–15
years old (n =
1337), not living
in a family
household (n =
257), or adopted
by grandparents
or siblings (n =
230).
Schizophrenia was
1.81 times higher
amongst those with
severe hearing loss,
but epilepsy and
left-handedness did
not prove
significant.
Authors conclude
previous results
suggesting
neurodevelopmental
anomalies may be
result of bias and
that hearing
impairment is the
only variable of true
influence here.
This study shows
that advancing
adoptive paternal
age did not increase
adopted children’s
risk of developing
schizophrenia or
non-affective
psychosis
suggesting any
previous association
shown with
advancing paternal
age in familial
studies is likely to
have a stronger
genetic
aetiology.Further
studies are needed
8
to confirm this
finding.
14
Ek, Wicks,
Svensson, Idring,&
Dalman(2014)
Born between
1955 and
1985
1 294 063
individuals
3447 cases of
Schizophrenia.
ICD 8,9,10
Delayed
Fatherhood(rather than
advancing paternal age
per se)
7/8
1973-2006
(diagnosis)
15
Ekeus, Olausson
&Hjern (2005)
1973–1979
follow up
1987-2002.
292 129
First born
children .
366 cases of
Schizophrenia.
ICD 9&10
Advancing parental
age(maternal and
paternal)
6/8
•Paternal age was
divide into <20,
20–24, 25–29,
30–34, 35–39,
40–44, and ≥45
years. But may
have benefited if
over 45 was
categorised
further.
•Level of
urbanicity was
chosen to
represent an
indicator of
cultural factors of
late parenthood
and
environmental
factors such as
toxins. Paternal
unemployment
was used an
indicator of
socioeconomic
status.
The association
between advancing
paternal age and
increased risk of
schizophrenia in
offspring
disappeared after
controlling
for delayed
fatherhood
•Obstetric
complications,
such as
instrumental
deliveries and
abnormal
positions,
increased
with increasing
Considerable risks
for psychiatric
disorders such as
schizophrenia
remained after
adjustments
for social factors.
The association
between paternal
age and
schizophrenia is not
due to paternal age
per se, but rather
to an unknown
factor associated
with both delayed
fatherhood
and schizophrenia.
9
16
17
Fors, Abel, Wicks,
Magnusson
&Dalman (2013)
Frans ,McGrath ,
Sandin, Lichtenstein
Reichenberg
Långström &
Hultman (2011)
1975-1985.
Within
inpatient care
1973-2004
20 cases of
Schizophrenia.
213 controls.
Complete data
for both
grandparents
and parents:
2511 cases
15619
controls.
ICD-10:
Inpatient
admissions
in hospital
since 1987.
ICD 8,9,10
Abnormal physical and
behavioural
development (in
childhood): Hearing
and speech impairment
aged 4.
Advancing paternal
and grand-paternal age.
6/9
6/8
maternal age. So
unclear whether
maternal age or
the complication
itself that is the
issue.
•Excluded acute
schizophrenia
episode=useful
•Schizophrenia
and psychoses
cases together
•Difficulties of
participant
recruitment
highlighted here.
Majority didn’t
reply. Don’t’
know those with
the largest
impairments
weren’t the most
socially isolated.
•Sample
population
between 18-28.
•Looked at
gender
separately.
Both hearing and
speech impairment
in childhood linked
to increased risk of
early onset
schizophrenia.
The study shows
that hearing
impairment is likely
to be important in
more than just
elderly populations
for psychosis
development.
.
Offspring of older
fathers at greater
risk of
schizophrenia was
confirmed.
First study to find
association with
grandparent age (but
maternal side only).
Having a maternal
grandfather over age
55 led to an
10
18
Fouskakis, Gunnell
Rasmussen,
Tynelius,Sipos&
Harrison (2004)
1973-1980
Continued
follow up to
1999 at aged
16.
Sample of
696025,
506 developed
schizophrenia.
ICD 9&10
Season of
Birth(alternative
explanations)
4/8
•Possibility that
sample lacked
statistical power
to capture
differences
19
Giordano, Ohlsson,
Sundquist,
Sundquist and
Kendler(2015)
Diagnosis
2000-2010
5456
individuals
with an initial
diagnosis of
schizophrenia,
matched with
five
schizophreniafree controls.
ICD 10
Cannabis
7/9
•To consider
potential
prodromal
effects,
investigated the
time between
Cannabis and
schizophrenia
diagnosis at 1-,
3-, 5- and 7-year
intervals.
increased risk in
offspring; however
further clarification
with regards to the
mechanisms behind
this is needed.
A moderate
increased risk of
schizophrenia was
shown amongst
winter births,
but this did not
reach conventional
levels of statistical
significance. There
was also no
association shown
with non-affective
psychoses. Finally,
there was no
evidence that these
associations were
confounded by
measures of foetal
growth or maternal
socioeconomic
position.
The authors
concluded that
Cannabis abuse has
an appreciable
causal impact on
future risk for
schizophrenia.
However,
population-based
estimates of
cannabis–
schizophrenia co-
11
20
Gunawardana,
Davey Smith,
Zammit, Whitley,
Gunnell,Lewis&Ras
mussen(2011)
1973–1980
183 921 born
in Sweden and
still resident
there at aged
16 included in
the final
analysis,
164 with
schizophrenia
ICD 9&10
Pre-conception interpregnancy interval
6.5/8
•Causality issue:
Not cannabis use
but the legal
consequences of
its
use/environment
you may find
yourself in.
morbidity
substantially
overestimate their
causal association.
•A shorter
pregnancy
interval is more
commonly found
in male offspring
and may explain
the findings.
Those born with
shorter
inter-pregnancy
intervals(where
maternal folate
stores are being
replenished) had a
higher risk of
schizophrenia.
However findings
may be largely
explained by women
who conceive
following a short
inter-pregnancy
interval
differing on a
number of
characteristics that
could subsequently
influence risk of
schizophrenia,
(compared with
women with longer
intervals.)
Adjustment
for confounders
attenuated the
associations we
observed by
12
approximately 30%.
21
22
Gunnell, Harrison,
Rasmussen,
Fouskakis&Tynelius
(2002)
Born 19731980
Conscripted
before 1994
109 643
subjects with a
mean 5-year
follow-up,
60 of these
developed
schizophrenia.
ICD 9&10
Prenatal and early
childhood exposures
on intellectual
development (and then
later schizophrenia)
5.5/8
•Information on
family history of
psychosis was
not available for
all individuals.
Gunnell, Harrison, 2
Whitley, Lewis,
Tynelius&
Rasmussen(2005)
Birth Register
(1973–1980),
Inpatient and
Discharge
Register
(1988–2002),
Military
Service
Conscription
Register
(1990–
1997), and the
Population
and Housing
Censuses
(1970
&1990).
719,476
followed up
from 16 for a
mean of 9.9
years.
ICD9&ICD 10
Birth weight
Ponderal
Index(Birthweight/birt
h length)
Birth length(Foetal and
childhood growth)
5/8
•Restricted to
term babies.
•No evidence that
birth length,
ponderal index or
gestational age
differed between
genders.
•Large numbers
of schizophrenia
cases gives
adequate power
to sample.
736 of these
developed
schizophrenia.
Poor scores for each
of the five tests were
Associated with a 3to14foldincreasedrisk
of psychosis,
particularly
schizophrenia.
Poor intellectual
performance at18
years of age was
also shown to be
associated with
early-onset
psychotic
disorder.
Some evidence was
provided by the
study to suggest that
patterns
of risk, in relation to
foetal growth, differ
depending on postnatal growth
patterns. Within the
study the increased
risk associated with
low body mass
index was restricted
to long babies who
became light adults.
However, the
exposures
underlying these
associations and the
13
23
Gunnell Rasmussen
Fouskakis Tynelius,
&Harrison(2003)
1973-1980
246,655
Swedish male
conscripts.
80 cases of
Schizophrenia
within this.
ICD 9&10
Three markers of foetal
growth: birth weight,
birth length, and
ponderal index (birth
weight (kg)/birth
length (m)3)
; and 2) two markers of
later
childhood growth: the
subject’s height and
body mass index
(weight (kg)/height
(m)2)
5/8
•Controlled for
selection bias(for
details see paper)
•Family history
of psychosis was
not available for
all individuals.
24
Harrison, Fouskakis,
Rasmussen,
Tynelius,
Sipos&Gunnell (
2003)
1973-1980
696025
363 with
schizophrenia
590 non
affective
ICD-9
Urbanicity
7/8
Parental
Education data
missing in 10%
of cases.
Difficulties can
biological
mechanisms
mediating them,
require further
clarification
Evidence was found
to suggest birth
weight was
associated with
schizophrenia but
not other nonaffective psychoses..
Higher risks existed
for males who
remained small as
adults. The
associations with
birth weight indicate
that foetal
exposures, including
possible effects of
gestational diabetes
were concluded to
be important in the
aetiology of
schizophrenia by the
authors. The role of
childhood
exposures, as
indexed
by adult height and
body mass index,
were concluded to
be less strong.
Urbanisation of
birthplace was
associated with
general psychoses
but was not shown
14
psychosis.
occur with
generalisation
between studies
due to differing
definitions of
“rural” and
“urban” areas.
25
Harrison, Whitley,
Rasmussen,Lewis,
Dalman &Gunnell
(2006)
1973-1980
748 cases
Of
schizophrenia
with 14,960
matched
controls.
ICD-10
Head injury
8/9
•Unable to
exclude
association
between head
injury and less
severe psychotic
illness.
•Excluded minor
concussive and
other injuries
assessed in
Accident
and Emergency
departments.)
26
Hjern, Wicks
&Dalman (2004)
Adult sample:
1929-1965
Child sample:
1968-1975
Hospital
discharge
1.47 million
adults
1.16 million
children
1268 cases of
Schizophrenia
ICD 9&10
Migration(and the
socio-economic
variables that surround
it).
6/8
•First Generation
immigrants= The
latter category
was defined as
foreign-born who
had settled in
to be specific to
schizophrenia. This
effect was smaller
than has been seen
in previous research.
This was not
reduced by control
for parental
educational status or
obstetric
complications.
The authors
conclude that it is
unlikely that head
injury causes
schizophrenia.
A small but
significant risk of
non-schizophrenic
psychotic disorders
and head injury was
shown; this was not
associated with
early age of injury
or family history of
psychosis. The
authors stated that
further research is
needed to clarify the
potential roles of
social and biological
intermediary factors.
A higher risk of
schizophrenia and
psychoses was
found in two
generations of
immigrants
15
data: 19912000
within the
adult group.
27
Hultman, Sparén,
Takei, Murray&
Cnattingius (1999)
1973-1979
Sample aged
15-21
years with a
main diagnosis
of
Schizophrenia
167 cases
835 controls.
ICD-8&9
28
Johansson,
Lundholm, Hillert,
Masterman,
Lichtenstein,
Landén & Hultman
Born between
1969-1991
Analysed
when
Multiple
Comorbidty
cohort:
Patients with
multiple
sclerosis
ICD
8,9&10
General Overview
Pregnancy and
DeliveryHypertensive Diabetes,
bleeding during
pregnancy, uterine
autonomy.
Child
Characteristics: Birth
weight for gestational
age, Ponderal Index,
Apgar score at 1
minute, season of
birth.
Maternal Factors: age
at delivery, and parity
or number of previous
births.
x Late winter birth
was associated with
increased
risk of both
schizophrenia and
affective psychosis
Multiple
Sclerosis(MS)
7/9
7/8
Sweden after
their twentieth
birthday.
•Useful that
looked at
children and
adults separately
as timing of
stressor may also
be important.
•Did not include
late onset cases.
of diverse ethnicity.
The results indicate
that social adversity
contributes to the
higher risk.
•Shared familial
risk between MS
and psychiatric
disorders
was estimated by
The risk of
developing
schizophrenia was
lower following
MS. The association
A few specific
pregnancy and
perinatal
factors were
associated with the
subsequent
development of
psychotic disorder,
particularly
schizophrenia, in
early adult life. The
association of
small size for
gestational age and
bleeding during
pregnancy with
increased risk of
early onset
schizophrenia
among males could
reflect placental
in-sufficiency.
16
(2014)
Sclerosis was
the event until
2009.
N=16,467)
36 cases of
Schizophrenia
sibling
comparison.
between having a
sibling with a
psychiatric disorder
and developing MS
was also not
significant. Previous
research where an
association has been
shown may be
specific to an
affective subtype of
psychosis rather
than schizophrenia
•Levels of
IgG directed at
gliadin (a
component of
gluten) and
casein (a milk
protein) were
analyzed in
eluates from
dried blood
spots by enzymelinked
immunosorbent
assay.
High levels of antigliadin IgG in the
maternal circulation
were associated
with an elevated risk
for the development
of non-affective
psychosis in
offspring.
Matched
Control group
(N=164,670)
29
Karlsson,
Blomström,
Wicks,
Yang,Yolken&
Dalman, (2012)
1975 to1985
Diagnosis:
1987 to 2003
Sibling cohort
Multiple
sclerosis after
matching
(N=26,506)
93 cases of
Schizophrenia.
553 controls
and
51 cases of
Schizophrenia
born in
Sweden.
ICD 9&10
Mechanisms behind
maternal malnutrition
or infections
and complications of
pregnancy and birth)>
Maternal antibodies to
dietary antigens.
8/9
However, further
research is needed
to identify the
mechanisms
underlying this
association
and in order to
develop preventive
strategies.
No association was
additionally found
between Caesarean
section and non-
17
30
Larsson, Ryde´n,
Marcus Langstrom,
Lichtenstein&Lande
(2013)
1973-2009
Sample aged
3-65 at time of
ADHD
diagnosis.
467 cases of
Schizophrenia
715 controls.
ICD
8,9&10
ADHD
5/8
•Majority of
those in Sweden
with ADHD
measured due to
strengths of
National Register
Method
31
Leao, Sundquist,
Frank,
Johansson,
Johansson&Sundqui
st (2006)
1992-1999
Follow up
period.
2,243,546
individuals
followed
for first
hospital
admission for
schizophrenia
from 1992 to
1999.
ICD 9&10
Immigration
5.5/8
•Would have
been useful to
have looked at
presence of
psychotic
phenomena and
its interaction
with what could
be protective
factors.
(&Whether having
one parent born in
Sweden has a
protective effect
among
second-generation
immigrants.)
affective
psychoses(including
schizophrenia)
within the study.
An increased risk of
Schizophrenia in
those with ADHD
was found. Firstdegree
relatives of probands with ADHD
were more likely to
have
schizophrenia than
relatives of controls
The risk of
schizophrenia was
similar among
maternal and
paternal halfsiblings(who are
likely to share the
same environment)
and substantially
lower than for full
siblings
Second-generation
immigrants with one
parent born in
Sweden and secondgeneration Finns
had a higher risk of
being
hospitalised for
psychotic disorders,
comparatively to
the Swedish
majority population.
Second-generation
18
32
Lewis, David,
Malmberg&
Allebeck (2000)
Conscripted
in 1970
Total: 50, 087
195 cases of
schizophrenia
ICD-8,
DSM III
Somatic symptoms:
(Headache, difficulty
sleeping, stomach
ache, feeling nervous,
feeling
down/depressed, angry
easily, troubled
restless, upset when
things go wrong
Other diagnosis:
Neurosis, Personality
disorder, alcohol
misuse, substance
misuse.)
6/8
•Schizophrenia
cases were until
age 31 only.
Male sample.
33
Li, Sundquist,
Hemminki
&Sundquist (2009)
Diagnosis
between
1987-2004.
Birth dates of
individuals
included not
listed within
paper,
Males: 21,199
hospitalized
cases of
psychotic
disorders
(43.7%
Schizophrenia9,264)
Females:
19,029
hospitalized
ICD 9&10
Age difference and
hereditary risk.
7.5/8
•Patients younger
than 72 years
were included;
this cut off may
present issues for
those in the later
end of the age
bracket.
refugees had a
higher risk of being
hospitalised for
psychotic disorders
than the
Swedish majority
population. All
results remained
significant even
after adjustment
for socio-economic
status (income and
education).
Nearly 40% of those
that develop
Schizophrenia had a
previous non
Psychotic
Psychiatric
diagnosis. However
the authors
concluded that other
than for Personality
Disorder, other
disorders are likely
to reflect a prodromal phase of the
illness.
Age difference
between siblings
had no effect on the
magnitude of the
SIRs.
The higher familial
risks in singleton
siblings and
twins compared
with spouses
provide strong
19
cases of
psychotic
disorders
(29.6%
schizophrenia:
5,633)
genetic
epidemiological
evidence for the
overall heritable
effects
with regard to
psychotic disorders
including
schizophrenia.
Total sample
of psychotic
disorders:
3006 affected
sibling pairs.
2838 singleton
siblings
34
Lichtenstein, Bjork,
, Hultman, Scolnick,
Sklar
&Sullivan(2006)
1932-2002
7 739 202
sample of
which 32536
had
Schizophrenia
ICD
8,9&10
Familial risk:
recurrence
7.5/9
•Study analysed
both first(e.g
parent)
second(e.g
grandparent) and
third(e.g cousin)
relatives,
The lifetime
prevalence of the
narrow definition of
schizophrenia
was 0.407%; it was
estimated that one in
every 79 extended
Swedish families
had been impacted
by
schizophrenia. The
proportion of
affected families
with multiple
affected members
was 3.81%.
Recurrence risk
estimates for all
relative types were
similar to those
reported in smaller
and older studies.
20
35
Lichtenstein, Yip,
Björk, Pawitan,
Cannon, Sullivan&
Hultman (2009)
Families
identified
within
Multigenerati
on register:
1973-2004
9,009,202 total
sample.
35 985 cases
of
Schizophrenia
ICD
8,9&10.
Familial risk: (Non
shared environment,
environment, pure
genetic, in common
with Bipolar.)
6.5/9
•Some diagnoses
may overlap; so
results may be
partially due to
problems with
classification.
The study provided
evidence of a
substantial genetic
association
Between
schizophrenia and
bipolar disorder.
Additionally
adopted children
whose biological
parents had
Schizophrenia had a
significantly
increased
risk for bipolar
disorder suggesting
an underlying
shared aetiology.
When relatives of
probands with
bipolar
disorder were
analysed, increased
risks for
schizophrenia
existed for all
relationships,
including adopted
children to
biological parents
with bipolar
disorder.
Non-shared
environmental
effects contributed
to
comorbidity by
around 30%
21
36
Ludvigsson, Osby,
Ekbom&
Montgomery(2007)
Diagnosis in
inpatient
register:
1973-2003
14,003
individuals
with Coeliac
disease
68,125
controls.
14 with
Coeliac
disease and
Schizophrenia.
ICD –
7,8,9,10
Coeliac Disease
5/8
•Number of
individuals with
schizophrenia
may have been
too low to detect
an association
37
MacCabe , Lambe ,
Cnattingius, Torrång
,Björk , Sham ,
David , Murray &
Hultman (2008)
1973-1983
907011
individuals
born in
Sweden.
493 cases of
ICD 9&10
Scholastic achievement
at age 15-16.
6/8
•Important to
consider whether
functioning was
poor in all areas,
or whether
Grade E as predictor of
schizophrenia in every
suggesting both an
environmental and
genetic aetiology is
involved in the
development of
schizophrenia
Individuals with
Coeliac Disease
may be at increased
risk of non-affective
psychosis but not
schizophrenia.
However numbers
of schizophrenia
cases within the
study were low so
an association can
not yet be ruled out.
The authors suggest
the association with
non affective
psychosis may be
mediated through
nutritional factors
in
early life or other
exposures
influencing
neurological
development;
further research is
needed to explore
such mechanisms.
Poor school
performance across
all domains
associated with
schizophrenia(and
22
Schizophrenia.
subject
38
MacCabe, Wicks,
Lofving, David,
Berndtsson,
Gustafsoon, Allbeck
&Dalman (2013)
1953, 1967,
1972, 1977
Follow up
2006.
Adolescent
boys and
young men
(n=10717)
Schizophrenia(
or
Schizoaffectiv
e cases:50)
ICD-8,9,10
dependent
on cohort.
Cog performance 1318 : Scores on tests of
verbal, spatial and
inductive ability at age
13 &18.
8/8
39
Malmberg, Lewis,
David&Allbeck(199
8)
Born 19491950
50,054
Swedish male
conscripts.
ICD-8
Schizoid
Personality(Premorbid
personality)
Social adjustment
5/8
1973-1983
(time of
conscription)
Follow up 15
years later.
195 cases of
Schizophrenia
impairment was
specific. This
may help target
future treatment
and prevention
strategies.
•Excluded those
who had already
experience a
psychotic
disorder at time
of
conscription/aged
18/ before 25.
Results less
likely to
represent a
capturing of a
pro-dromal
phase.
•Schizoaffective
disorder
combined with
schizophrenia
data
•Examined wide
variety of
variables both of
an interpersonal
and intrapersonal
nature.
other psychoses)
Repeating a year
was also a
significant predictor
of schizophrenia.
Relative decline in
verbal ability
between 13&18
associated with
increased risk for
schizophrenia. A
cognitive decline
was shown to more
important than
initial score at 18.
Four variables
reflecting
early problems with
interpersonal
relationships were
strongly associated
with later
schizophrenia and,
to a lesser
extent, nonschizophrenic
psychoses,
but also occurred
commonly in the
23
40
Manrique-Garcia,
Zammit, Dalman,
Hemmingsson,
Andreasson&Allebe
ck (2012)
Conscripted
1969-1970
Follow up
1970-2007
50 087
military
conscripts
41943 on
follow up
322 cases of
schizophrenia.
ICD8,9&10
Cannabis use
4.5/8
•Men only.
•Controlled for
other substance
use and alcohol,
IQ and
urbanicity.
cohort as a whole.
These associations
with schizophrenia
persisted after early
onset
cases were
excluded, though
their predictive
value was low
Psychotic
outcomes(schizophr
enia specifically)
among frequent
cannabis users
compared with nonusers were 3.7
greater.
24
41
Manrique-Garcia,.
Zammit, Dalman,
Hemmingsson,Andr
easson &
Allebeck(2014)
Conscripted
1969-1970
Follow up
1973-2007.
50087 Swedish
men
Cannabis use
Aged 18-20.
ICD
8,9&10
Cannabis Use
7/8
•Divided into
sub-types of
schizophrenia,
not necessarily
helpful.
•Do
not know to what
extent subjects
continued
cannabis
use into
adulthood.
Results of this longterm (34 years)
follow-up show
that schizophrenia
patients with a
history of cannabis
use had a
significantly higher
burden of in-patient
care, with regard to
hospital readmission
and hospital
duration, compared
with those without a
history of
cannabis use.
ICD 8&9
Obstetric Records:
maternal age, maternal
complications
during pregnancy, birth
order (first- or second
born twin), birth year,
birth place (at home or
at hospital), sex of the
child, gestational age
(in completed
gestational weeks
based on the last
menstrual period),
birth weight, head
circumference and
complications of the
infant in the neonatal
period.
6.5/8
•Results conflict
some of the
results of
previous studies.
Individuals with a
birth-weight of less
than 2300 grams
faced an almost
doubled risk of
developing
schizophrenia
compared to
individuals with
higher
birth-weight.
Children with a
small head
circumference
(31.5 cm or less)
had a 60% higher
risk of developing
schizophrenia
compared to
children with a
larger head
357 cases of
schizophrenia
from inpatient
care
42
Nilsson, Stålberg,
Lichtenstein,
Cnattingius,
Olausson&
Hultman(2005)
Born: 19261958
Approached
in 1972
Cohort
analysis of
11,360 samesexed twins,
and
within–twin
pair analyses
were
conducted on
90
twin pairs
discordant for
schizophrenia
25
circumference.
Compared to
children born at
term
(37 gestational
weeks or more),
children born
preterm
(36 weeks or less)
had a 70% increased
risk of developing
schizophrenia.
43
Nosarti,
Reichenberg,
Murray,
Cnattingius, Lambe,
Yin, MacCabe,
Rifkin& Hultman
(2012)
Live-born
individuals
registered in
the
nationwide
Swedish
Medical Birth
Register
between 1973
and 1985 and
living in
Sweden at age
16 years by
December
2002
Total:1 301,
522
699 non
affective
psychoses.
Schizophrenia
cases not listed
individually.
ICD 8, 9,
10
Preterm Birth
(Gestational age at
birth, birth weight for
gestational age, and
Apgar score at
5minutes)
5.5/8
•Maternal
smoking could
have impacted
and wasn’t
controlled for,
but appropriate
records did not
exist at time to
measure.
The vulnerability for
hospitalization with
a range of
psychiatric
diagnoses (including
Schizophrenia) was
shown to increase
with younger
gestational age.
•Age of onset
only to 29; so
later onset cases
not included.
Similar associations
were not observed
for non-optimal
foetal growth and
low Apgar score
within this study.
26
44
Sariaslan, Larsson,
D’Onofrio,
Långström, Fazel,&
Lichtenstein(2014)
1967-1989
Children: 2
361 585
Cousins:1 715
059
Siblings:1 667
894
4952 cases of
Schizophrenia
within sample.
ICD 9&10
Population density
Neighbourhood
Deprivation
7/8
•Sex, birth year
(categorized into
5-year intervals),
and
birth order
(categorized as
first, second,
third, and fourth
or more).
Excess risks of
schizophrenia, in
densely populated
and
socioeconomically
deprived Swedish
neighbourhoods
appear to
result primarily
from unobserved
familial selection
factors, within the
study.
Previous studies
may have
overemphasized the
aetiological
importance of these
environmental
factors.
Neighbourhood
level effects only
account for 2-3% of
variance
27
45
Sipos, Rasmussen,
Harrison, Tynelius,
Lewis, Leon&
Gunnell(2004)
Born 19731980
754 330
individuals.
639 cases of
schizophrenia.
ICD 9&10
Advancing paternal
age
7.5/8
•Individuals
followed up from
16 for 9 years
only.
After adjustment for
birth related
exposures,
socioeconomic
factors, family
history of psychosis,
and early
parental death the
overall hazard ratio
for each 10 year
increase
in paternal age was
1.47 (95%
confidence interval
1.23 to 1.76)
for schizophrenia
and 1.12 (0.98 to
1.29) for nonschizophrenic
non-affective
psychosis. This
association between
paternal age
and schizophrenia
was present in those
with no family
history of the
disorder, but not in
those with a family
history .
28
46
Song, Bergen, KujaHalkola, Larsson,
Landen&
Lichtenstein (2014)
Born 1958 to
1985 with
followup from 1973
to 2009.
A total of
54,723
individuals
with BPD
were
identified
among
8,141,033
offspring from
4,149,748
nuclear
families.
3320
additional
diagnosis of
schizophrenia.
ICD
8,9&10
Bipolar& Heritability
6/8
•May have been
useful to look at
the association
between Bipolar
and occurence of
negative or
positive
symptoms within
schizophrenia, in
addition to an
overall diagnosis.
The strong cooccurrence with
schizophrenia and
bipolar that was
shown within the
study suggests a
common aetiology.
Both may have a
stronger common
genetic aetiology,
than environmental.
The authors
estimated this at:
76% heritability and
24% for non-shared
environment.
29
47
Stålberg, Haglund,
Axelsson,
Cnattingius,
Hultman&
Kieler(2007)
Ultrasound:
1973-1978
Follow up
1987-2004
370,945 total
sample
13,212
exposed to
ultrasound.
Total with
Schizophrenia
exposed
group:27
Unexposed:49
9
ICD
9&ICD10
Peri-natal exposure to
ultrasound.
5.5/8
•Only singletons
included.
To increase the
homogeneity of
the study
population,
included only
children
of mothers who
themselves had
been born in one
of the Nordic
countries,
.
•All included
children were
alive and living
in Sweden at the
age of twelve
(data from the
Cause of Death
Register).
No evidence was
found for clear
associations
between pre-natal
ultrasound
exposure and
schizophrenia or
other psychoses.
Other
factors relating to
place of birth might
have influenced the
results particularly
hospital/location of
birth with higher
IRR shown for
Malmo hospital
along with male sex,
high maternal age,
preterm births, and
mother’s psychiatric
care.
30
48
Sundquist, Li,
Hemminki,&
Sundquist, (2008)
Follow up
1973-2004
10 101 cases
of
schizophrenia
in general
population
ICD
8,9&10
Rheumatic disorders
prior to Psychiatric
disorder.
5/8
•Stratified by
male and female.
Useful as
disorders differ
between genders.
Neither men nor
women had an
increased risk of
Schizophrenia
following rheumatic
conditions, however
associations were
shown for other
Psychiatric
disorders.
The results for
schizophrenia may
be due to the small
numbers of cases of
schizophrenia
within the study.
ICD
8,9&10
Age at onset,
Parental characteristics
Season of birth
(As moderators to
familiality in
schizophrenia)
7/8
•Highlights that
there may be
many different
pathways to
schizophrenia;
useful to look at
moderators.
What may appear to
be a strong genetic
aetiology to
Schizophrenia is in
fact reduced by
higher age of onset,
advancing paternal
age and immigrant
status.
6 males
developed
schizophrenia
after rheumatic
condition,
20 females.
49
Svensson,
Lichtenstetin,
Sandin O¨Berg,
Sullivan & Hultman
(2012)
1932-1990
5,075,998 full
siblings,
16,346 cases
of
schizophrenia
31
50
Svensson ,Rogvin,
Hultman, Reichborn
Kjennerud,Sandin &
Moger(2013)
Born between
1955 and
1989
15,340
schizophrenia
cases
examined.
ICD
8,9&10
Season of Birth
Paternal Age at birth
Place of birth(urban vs
rural)
Familial risk.
4.5/8
•Definition of
familial
Schizophrenia
only included
siblings as cases.
Would have been
more useful to
also have
included parents
or children, this
was however not
accessible within
the registers at
the time.
•Participants
aged 18.
For individuals
without familial
schizophrenia, a
protective effect was
seen across most
ages of diagnosis for
females, low
paternal age, born in
rural areas, and
being born in later
cohorts.
For individuals with
familial
schizophrenia, a
protective effect is
found for females
diagnosed between
ages 18 and 30
years, corresponding
values were 18-25
years for low
paternal age.
There was no
statistically
significant effect of
paternal age on the
proportion of
susceptible.
32
51
Thomas, Dalman,
David, Gentz,
Lewis& Allebeck
(2001)
Diagnosis
between
1971-1994
524 cases,
1043 controls
Stockholm
County
Population.
ICD8&9
Obstetric
Complications
8/9
•Controls
matched on year
of birth.
The study did not
find any large or
consistent effect of
gender, age at
diagnosis or
maternal history of
psychosis on the
risk of
schizophrenia
associated with
individual
complications.
52
Van der Ven.
Dalman, Wicks,
Allebeck,
Magnusson, van
Os& Selten (2014)
Conscripted
1969-1970
49321 Military
conscripts at
18
ICD 8&9
Migration as a proxy
for:
Cannabis use,
IQ, psychiatric
Diagnosis,
Social adjustment,
History of trauma,
Urbanicity
Place of upbringing.
6.5/8
•Measures may
differ over
time(cannabis
use etc): too
simple of a
design
Low IQ and poor
social adjustment
were significantly
less prevalent
among prospective
emigrants, whereas
a history of urban
upbringing was sig
different.
No differences in
cannabis use
Evidence opposes
selection hypothesis
(That the increased
rates of psychosis
observed among
migrants are due to
selective migration
of people who are
33
predisposed to
develop the
disorder.)
Greatest association
was non psychotic
psychiatric disorder
at conscription and
family history.
53
Westman,
Johansson&
Sundquist(2006)
Received a
diagnosis
19971998.
2315,461 men
and 2247,858
Women.
5233 cases of
Psychotic
disorder(of
which
schizophrenia
was included
but not
separated)
within all
included
countries.
DSM IV
ICD 9&10
Migration/Country of
Birth.
5.5/8
•Individuals were
aged 25-64.
• Marital status
was divided into:
single (including
never married,
divorced,
widowed and
cohabiting
people without
children)
and married
(including
cohabiting
people with
children
in common).
• Cultural
differences
in how symptoms
are presented
may have
resulted in
immigrants that
were
misdiagnosed
with mental
disorders.
The authors found
that several groups
of foreign-born men
and women
exhibited increased
risks of a first
hospital admission
(during the study
period) due to
psychotic disorders.
However the
increased risk of
psychotic disorders
decreased to some
extent after
adjustment for
demographic and
socioeconomic
factors suggesting
that social adversity
plays a role in the
aetiology of
Schizophrenia, with
the immigrant
population at least.
34
54
Wicks,
Hjern&Dalman
(2010)
1955-1984
13,163
children in
Sweden
followed up
until 2006
ICD 8,9,10
Wicks, Hjern,
Gunnell,Lewis and
Dalman (2005)
Born: 19631983
Diagnosis
1987-2002
ICD 9&10
Total sample:
2,130,376
Cases of
schizophrenia:
4,109
5/8
• Biological
fathers unknown
in 41% of
individuals.
6/8
•Didn’t adjust for
urbanicity,
immigration or
paternal age.
•Duration of
social adversity
may also be
important to
assess as well as
presence/frequen
cy.
Socioeconomic status
of household(social
liability)
91 cases of
schizophrenia.
55
Parental inpatient care
for psychosis (genetic
liability)
Social Adversity in
childhood
The results indicate
that
children reared in
families with a
disadvantaged
socioeconomic
position have
an increased risk for
psychosis. There
was
also some support
for an interaction
effect,
suggesting that
social disadvantage
increases this risk
more in children
with
genetic liability for
psychosis
A number of social
factors related to the
parental
socioeconomic
situation were
associated with an
increased risk of
schizophrenia .
Measured and found
significant: renting
apartments,
unemployment,
single-parent
households, and
households
receiving social
welfare benefits.
May be difficult to
generalise to the UK
35
population as
migration rules are a
lot stricter in
Sweden.
56
Zammit, Allebeck,
Andreasson,
Lundberg&
Lewis(2002)
1969-1970
50087
(male
conscripts 1820)
Schizophrenia
cases: 362.
ICD-8
&ICD 9
Cannabis Use.
7/8
•Cannabis use
was self reported.
•Cannabis may
have been used
to self-medicate
pro-dromal phase
of psychotic
symptoms; the
study still does
not rule this
explanation out.
•Males only; may
have different
interactions with
drug usage.
Cannabis use was
shown to be
associated with an
increased risk of
developing
schizophrenia(and
not psychiatric
illness in general),
consistent
with a causal
relation (dose
dependent). This
association was not
explained by use of
other psychoactive
drugs or
personality traits
relating to social
integration, within
the study.
36
57
Zammit, Allebeck, ,
Dalman,
Lundberg,
Hemmingson, Owen
&Lewis(2003)
Conscripted:
1969-1970.
Diagnosis:
1970
and1996.
50 087
adolescent
Males
362 with
schizophrenia.
DSM III
Paternal
age(advancing)
6.5/8
•Aimed to adjust
for personality
traits of fathers
by controlling for
social integration
in
subjects(Theory
the effect of
advancing
paternal age is
down to fathers
with an increase
in schizotypal
traits.)
Evidence was
provided for
advancing paternal
age to be an
independent risk
factor for
schizophrenia.
Adjusting for social
integration in
subjects made little
difference to this
association,
consistent
with the hypothesis
that advancing
paternal age may
increase liability to
schizophrenia owing
to accumulating
germ
cell mutations.
37
58
59
Zammit,
Allebeck,David;
Dalman,
Hemmingsson,
Lundberg&Lewis,
(2004)
Conscripted:
1969-1970
Zammit, Lewis,
Dalman&
Allebeck(2010)
1970-1996
50087 male
subjects.
ICD-8&9
Lower IQ
6.5/8
•May have
benefited from
using a different
cohort to
previous research
on the
relationship
between Low IQ
and psychosis.
•Also looked at
schizoaffective
disorder
separately(helps
us determine
specificity of
relationship)
Of the 4 intelligence
subtests, reduced
performance for
verbal IQ, visuospatial ability, and
mechanical ability
were associated with
increased risk of
Schizophrenia that
persisted after
adjusting for the
other subtest
measures. This may
represent an
increased risk for all
psychoses rather
than schizophrenia
in particular.
ICD 8&9
Additive and
Multiplicative models
examined on:
a) low IQ test score
(lowest 33% v. rest);
(b) poor social
adjustment
(c) disturbed behaviour
in childhood
(d) cannabis use (ever
used v. never used);
(e) non-psychotic
psychiatric diagnosis at
conscription (any v.
none).
5.5/8
•Poor social
adjustment
(lowest 30% on
composite
variable
(range 0–10)
derived from
questions
enquiring about
friendships,
girlfriends and
sensitivity to
others v. rest);
•Disturbed
behaviour in
childhood
(highest 20% on
composite
variable (range
0–9) derived
Although individual
variables such as
low IQ may
significantly
contribute to one’s
risk ,multiplicative
models describe the
joint effect of risk
factors more
adequately than
additive ones do.
362 with
schizophrenia
50 053
Swedish
conscripts (630
cases of
Schizophrenia)
Only two
combinations for
additive models
greater supported:
poor social
relationships and
disturbed behaviour;
disturbed behaviour
38
60
Zammit,Lewis,
Rasbash,Dalman,
Gustafsson&.Allebe
ck .(2010)
1972&1977
203,829
881 Cases of
Psychoses(Sch
izophrenia
included but
not separated).
Psychiatric
Admission
1973 &
ICD8-10
Urbanicity(as a proxy)
Minority ethnicity
Ethnic Density&social
fragmentation
Social deprivation
6/8
from questions
enquiring about
misconduct at
school, truancy,
running away
from home
and police
contact v. rest);
and other diagnosis;
rest largely
multiplicative.
•Social
fragmentation is
still a difficult
variable to
measure/capture.
The association
between urbanicity
and psychosis
appears to be a
reflection of
increased social
fragmentation
present within cities.
However the
majority of variation
was down to
individual level and
not neighbourhood
level factors.
•Not all
confounders
were included
e.g. cannabis use.
39
61
Zammit,
Rasmussen,
Farahmand ,
Gunnell , Lewis
Tynelius &Brobert
(2007)
1952 to 1982
Diagnosis:197
0-2002
1 347 520 men
born in
Sweden .
5,219 with
schizophrenia.
ICD 7,8&9
Height &BMI
7/8
•Association
with BMI
remained largely
unchanged when
the analysis was
restricted to
subjects first
admitted
with
schizophrenia
after the initial 5year period
following
conscription.
Both height and
BMI in early
adulthood are
strongly and
inversely associated
with risk of
schizophrenia.
Genetic and
nutritional
mechanisms are
argued to be the
causation behind
this, by the authors.
40