Just The Facts Epidemiology and Etology

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Schizophrenia Research 102 (2008) 1 – 18

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Schizophrenia, “Just the Facts” What we know in 2008.

2. Epidemiology and etiology
Rajiv Tandon a , Matcheri S. Keshavan b , Henry A. Nasrallah c
a
University of Florida, 3706 Glin Circle, Tallahassee, FL 32309, United States
b
Wayne State University, Detroit, Michigan, United States
c
University of Cinncinnatti, Cinncinnatti, Ohio, United States
Received 15 February 2008; received in revised form 31 March 2008; accepted 2 April 2008
Abstract
Although we have studied schizophrenia as a major disease entity over the past century, its causes and pathogenesis remain obscure.
In this article, we critically review genetic and other epidemiological findings and discuss the insights they provide into the causes of
schizophrenia. The annual incidence of schizophrenia averages 15 per 100,000, the point prevalence averages approximately 4.5 per
population of 1000, and the risk of developing the illness over one's lifetime averages 0.7%. Schizophrenia runs in families and there are
significant variations in the incidence of schizophrenia, with urbanicity, male gender, and a history of migration being associated with a
higher risk for developing the illness. Genetic factors and gene-environment interactions together contribute over 80% of the liability for
developing schizophrenia and a number of chromosomal regions and genes have been “linked” to the risk for developing the disease.
Despite intensive research and spectacular advances in molecular biology, however, no single gene variation has been consistently
associated with a greater likelihood of developing the illness and the precise nature of the genetic contribution remains obscure at this
time. Environmental factors linked to a higher likelihood of developing schizophrenia include cannabis use, prenatal infection or
malnutrition, perinatal complications, and a history of winter birth; the exact relevance or nature of these contributions is, however,
unclear. How various genetic and environmental factors interact to cause schizophrenia and via which precise neurobiological
mechanisms they mediate this effect is not understood. Etiological heterogeneity, complex patterns of gene–gene and gene–environment
interaction, and inadequately elucidated schizophrenia pathophysiology are among the explanations invoked to explain our inadequate
understanding of the etio-pathogenesis of schizophrenia. The ability to question some of our basic assumptions about the etiology and
nature of schizophrenia and greater rigor in its study appear critical to improving our understanding about its causation.
© 2008 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia; Facts; Epidemiology; Genetics; Environmental risk factors; Incidence; Chromosomes; Genes; Prevalence; Linkage;
Association; Pregnancy; Etiology; Causes
1. Introduction essence of epidemiology; with reference to schizophrenia,

this includes both genetic and environmental risk factors
Epidemiology is the study of distribution and which need to be considered together since both are
determinants of disease (MacMahon and Pugh, 1970). important in the etiology of schizophrenia and neither
Distinguishing characteristics and experiences of persons appears to operate in isolation (Tsuang et al., 2004).
who develop a disease from those of individuals who do In this paper, we summarize major epidemiological
not allows one to identify factors related to causation of findings in schizophrenia and discuss what they tell us
that disease. Determinants of disease constitute the about genetic and environmental factors involved in its
0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2008.04.011
2 R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18
causation. We first summarize current knowledge about ability to precisely demarcate those with disease from
variations in the occurrence of schizophrenia across those without it. In the absence of any pathognomonic
populations, socio-demographic characteristics and feature and several impediments to constructing a fully
time. We then briefly review key genetic findings and reliable patient clinical profile, it becomes a greater art to
environmental risk factors linked to the development of diagnose schizophrenia than most other diseases (Eaton et
schizophrenia and critically discuss our state of under- al., 2007). Additionally, consistent case definition (when
standing about the etiology of schizophrenia. We does a possible case become a case — e.g., persons with
highlight key conceptual issues, outline approaches to prodromal symptoms) and identification (e.g., a person
dissecting genetic and environmental contributions to its may not seek treatment/s and is thereby missed as a case)
causation, and consider major challenges towards can be problematic. Furthermore, although we have made
elucidating the etio-pathogenesis of this disease. substantial advances over the past two decades in being
able to diagnose schizophrenia with greater reliability, it is
2. Incidence and prevalence unclear if we have made any progress with regard to
validity (McCormick and Flaum, 2005).
The distribution of a disease is generally expressed in These challenges have contributed, in significant part,
terms of incidence (new cases), and prevalence (total to varying estimates of incidence obtained across the
number of cases: existing + new). Incidence rate refers to multitude of studies. In the only global study that directly
the number of new cases of the disease that develop over a generated incidence data (WHO 10-nation study, Sartorius
specific period of time among people who are at risk for et al., 1986; Jablensky et al., 1992), the annual incidence
developing the disease. Instead of a rate (new cases per was found to range from 16–40/100,000/year using broad
population at risk per time), incidence can also be expressed criteria (ICD-9; World Health Organization, 1978) and 7–
as the probability that an individual will develop a particular 14/100,000 using narrow criteria (CATEGO class S+
disease (e.g., lifetime risk). Differences between the identifying nuclear schizophrenia; Wing et al., 1974) for
characteristics of people who develop versus do not diagnosing schizophrenia. A 10-fold higher incidence rate
develop the disease help to define the risk and protective was detected in the U.S.A.-based five community site
factors for and against development of the disease, National Institute of Mental Health Epidemiological
respectively. Thus knowledge about the distribution of Catchment Area (ECA) program (Tien and Eaton,
new disease development (incidence) over time, place, and 1992), but these results were derived from community
person points to etiological factors (determinants) for surveys conducted by individuals with minimal or no
developing the disease. Prevalence refers to the proportion clinical experience rather than on the basis of service
of people in a community who have a particular disease at a provision and clinician diagnosis, which is how most
given time (point prevalence) or over a given time-span other studies derived their data; this likely resulted in
(period prevalence) including both people with pre-existing several false positives (Anthony et al., 1985; Regier et al.,
disease and those who newly develop the disease over this 1998). Studies based on service provision, on the other
specified time period. hand, might underestimate rates of schizophrenia because
some affected individuals may not seek treatment. A
2.1. Incidence and lifetime risk recent meta-analysis of all published studies between
1965 through 2001 obtained a median incidence rate of
Since incidence is a measure of the number of new 15.2/100,000/year with 80% confidence interval rates
cases of a disease occurring among people who are at risk (10th–90th decile) ranging from 8–43 per 100,000 per
for developing the disease over a specified period of time year (McGrath et al., 2004). Data were derived from 55
(generally one year), it requires knowing who is a case at studies conducted across 33 countries. Rates were not
the beginning (and excluding them from both the found to vary by broad world regions or economic status
numerator and denominator), the number of people at of the country (Saha et al., 2006). Contrary to prior
risk for newly developing the disease (denominator), and assumptions of uniform rates of schizophrenia across the
the number of people who newly develop the disease world, however, this meta-analysis revealed robust
(numerator) over this specified period of time. The number variations in incidence of schizophrenia, with urbanicity,
of new cases can be determined by community surveys or migration, and male gender found to be associated with
by identifying them as they seek services (first contact a higher risk for developing schizophrenia.
with health worker, hospitalization, etc.). Correctly Recent findings confirm and clarify longstanding
determining the distribution of a disease depends upon suggestions of a link between urbanicity and schizo-
having a reliable and valid diagnosis of the disease and the phrenia (Faris and Dunham, 1939). For many decades,
R. Tandon et al. / Schizophrenia Research 102 (2008) 1–18 3
there was controversy about whether this association the population is predominantly white; similarly, migrat-
meant that urban dwelling caused schizophrenia (“breeder ing to areas with a lower density of people with a similar
hypothesis”) or whether persons with schizophrenia ethnic background has been found to be associated with a
migrated to urban settings (“selection hypothesis”). For higher liability for psychotic illness (Kirkbride et al.,
the past half-century, this argument was seemingly 2007; Veling et al., 2008). What factor/s then might
resolved in favor of the later perspective and the observed mediate the link between migration and schizophrenia?
association was ascribed to the “social drift” of persons Social adversity associated with being a migrant (social
with schizophrenia to inner city areas with cheaper ac- isolation, discrimination and “racism”, experience of
commodation and relative anonymity (Dohrenwend et al., “social defeat”, etc.) has been cited as the major factor
1992). Even as the social drift phenomenon has been (Boydell et al., 2001; Cooper et al., 2008), although
corroborated, well designed recent studies have also “biological” explanations such as vitamin D insufficiency
confirmed an association between urban birth and and epigenetic mechanisms have also been suggested
upbringing (upto the age of 15) and an increased risk of (Dealberto, 2007). The association between migration and
developing schizophrenia (Lewis et al., 1992; Mortensen increased risk of developing schizophrenia provides
et al., 1999; Kirkbride et al., 2006). The finding of a dose– compelling evidence supporting a role for social factors
response relationship between degree of urbanicity and in its etiology (Cantor-Graae, 2007); the specific risk-
risk of schizophrenia strongly supports the proposition mediating factor (social or biological), however, remains
that some factor associated with urbanicity may be causally to be elucidated.
related to schizophrenia (Pedersen and Mortensen, 2001). Estimates of the risk of developing schizophrenia over
What that specific risk-modifying factor linked to one's lifetime range from 0.3–2.0% with an average of
urbanicity might be, however, is unclear. Several approximately 0.7% (Saha et al., 2005). Although gender
candidates have been proposed — these include urban– differences in the clinical expression and outcome of
rural differences in rates of cannabis and other substance schizophrenia have long been recognized (Seeman,
use, prenatal and perinatal health, degree of social stress 1982), it has generally been believed that the risk of
and social connectedness, poverty, rates and nature of developing schizophrenia over one's lifetime is similar
migration, environmental toxins, various infectious dis- among males and females (e.g., Wyatt et al., 1988). More
eases, or vitamin D deficiency. Whereas some of these recent studies have undermined this assumption and two
factors have independently been linked to schizophrenia recent meta-analyses revealed that males have a higher
(e.g., migration) and others to urbanicity (e.g., vitamin D lifetime risk of developing schizophrenia with a male–
deficiency), none has been convincingly linked to both or female relative risk of about 1.4 (Aleman et al., 2003;
established as the schizophrenia risk-modifying factor McGrath et al., 2004). The male–female ratio in
that satisfactorily explains the urbanicity–schizophrenia morbid risk for schizophrenia is found to increase as
connection. more stringent current diagnostic criteria are utilized
Ever since Odegaard (1932) documented a higher (Beauchamp and Gagnon, 2004). Studies from develop-
occurrence of “schizophrenic breakdown” among Nor- ing countries have not found such a difference and study
wegians who had migrated to Minnesota than among samples obtained prior to 1980 were much less likely
those who remained in Norway, several studies have to reveal a gender difference in the risk of schizo-
confirmed an association between migration and an phrenia (Aleman et al., 2003). This observed discrepancy
increased risk of developing schizophrenia (Malzberg, between findings of studies conducted in the past two
1964; Bhugra, 2004). A meta-analysis of 18 studies decades and those conducted earlier is of obvious
published between 1977 through 2003 identified a importance but poorly understood, although proposed
personal or family history of migration as a significant explanations include differences between the two time
risk factor for schizophrenia (Cantor-Graae and Selten, periods with regard to diagnostic criteria, case-ascertain-
2005); the relative risk for developing schizophrenia was ment methods, or differential changes in a variety of
found to be 2.7 for first-generation immigrants and 4.5 for physical and/or social environment risk factors among the
second-generation immigrants. Both selective migration two genders (Hambrecht et al., 1992; Aleman et al.,
(Odegaard, 1932) and diagnostic bias (Sashidharan, 2003).
1993) have been cited as explanations; neither of them
appears to adequately account for the association. The 2.1.1. Incidence of schizophrenia over time: is schizo-
migration–schizophrenia link has been found to be more phrenia a new disease?
robust among individuals migrating from a country where Schizophrenia has been more consistently and
the population is predominantly black to a country where frequently described over the past two centuries
(Bleuler, 1950; Kraepelin, 1971). Although loose Logically, estimates of period prevalence should equal
descriptions resembling schizophrenia are obtained in or exceed those of point prevalence and estimates of
texts dating back several thousand years (Jeste et al., lifetime prevalence should equal or exceed those of
1985; Ellard, 1987), easily recognizable descriptions of period prevalence. The prevalence of any condition in a
schizophrenia are much less common than those of other community is influenced by several factors including
psychiatric or neurological disorders (Evans et al., rates of new case development (incidence), duration of
2003). This has led some to suggest that schizophrenia is the condition, and differential mortality or migration
a disease that has afflicted humans only over the past patterns associated with the condition (Fig. 1). Although
two centuries and that some factor related to indus- variable degrees of “recovery” do occur (Harding et al.,
trialization, urbanization, or increasing population 1987), complete cures are uncommon and the average
density may have contributed to the emergence of this duration that an affected person lives with schizophrenia
disease (Torrey, 1980; Hare, 1988). The broadly even is approximately 30 years. Based on a median incidence
distribution of schizophrenia across the world in the rate of 15.2/100,000/year, one would roughly predict a
context of its strong genetic underpinnings (Crow, median point prevalence of about 456/100,000 or 4.56/
1995), however, argues against the proposition that it is 1000 population.
a recent disease and most experts believe that schizo- Although findings from the approximately 200 studies
phrenia, like many other diseases, had been present for a are found to vary several-fold, the average is very close to
long time before its first lucid description in the early this predicted estimate. Saha et al. (2005) conducted a
19th century. Resolution of this controversy is unlikely systematic review of 188 studies from 46 countries and
until we have a better understanding of the etio- derived a range of different prevalence estimates in
pathophysiology of the illness. schizophrenia. Based on a meta-analysis of 21 studies,
What is less controversial is the fact that descriptions they obtained a median point prevalence estimate of 4.6
of schizophrenia have been fairly consistent over the per 1000 persons with 80% confidence interval estimates
past two centuries and that its occurrence has been (10th–90th decile) ranging from 1.9–10/1000. Based on a
relatively stable over this period even though specific meta-analysis of 34 studies, they obtained a median
diagnostic criteria have changed. Its presentation has, period (upto 1 year) prevalence estimate of 3.3 per 1000
however, evolved over the past century with a modest persons with 80% confidence interval estimates (10th–
improvement in the overall prognosis (Bleuler, 1972; 90th decile) ranging from 1.3–8.2/1000. Based on a meta-
Hegarty et al., 1994) and reduced occurrence of more analysis of 24 studies, they obtained a median lifetime
severe forms of the disease such as hebephrenia and prevalence estimate of 4.0 per 1000 persons with 80%
catatonia (Morrison, 1974; Stompe et al., 2002). Some confidence interval estimates (10th–90th decile) ranging
studies suggest a decline in the incidence of schizo- from 1.6–12.1/1000. Sixty-seven distinct studies pro-
phrenia (Eagles et al., 1988; Woogh, 2001) whereas vided data towards these three estimates: two studies for
others suggest an increase (Tsuchiya and Munk- all three meta-analyses, 8 for two of the estimates, and the
Jorgensen, 2002; Bray et al., 2006); changing diagnostic remainder for just one of these analyses.
criteria and case detection methods make such compar- Although these estimates of prevalence were some-
isons difficult (Stromgren, 1987; Kendell et al., 1993). what lower than previously believed (e.g., Kessler et al.,
1994) and more recently reported (e.g., Perala et al.,
2.2. Prevalence 2007), this systematic review confirmed our notions of
worldwide prevalence with pockets of low and high
Prevalence is a measure of the proportion of prevalence. Similar to the observed higher incidence of
individuals in a defined population who either are schizophrenia among migrants, this comprehensive
manifesting a given disease at a particular time (point or review also found the prevalence of schizophrenia to
period prevalence) or have manifested the disease at any be higher among this group. In contrast to observed
time during their life (lifetime prevalence). Point differences in incidence across gender and urban–rural
prevalence thus refers to the proportion of the popula- settings, however, no such differences in prevalence
tion with the disease on a given day, period prevalence were observed. Prevalence was found to be similar
to the proportion with the disease during a particular among males and females as also among urban and rural
time-frame (generally 6 months or one year), and dwellers. In comparison to the similar incidence across
lifetime prevalence to the proportion that ever had the less developed and more developed countries, on the
disease at any time during their life regardless of other hand, a significantly higher prevalence of schizo-
whether they currently do or do not have the disease. phrenia was observed in more developed versus less
Fig. 1. Relation between incidence and prevalence in a given population.
developed countries. A higher prevalence of schizo- and environmental risk factors related to its causation
phrenia among lower versus higher socio-economic and the neurobiological mechanisms that might mediate
classes within communities has also been consistently these effects?
documented over the past century.
The combinations of incidence-prevalence findings 3. The genetic basis for schizophrenia
observed in schizophrenia are not easily explained.
Variables linked to both higher incidence and prevalence It is well known that schizophrenia aggregates in
are likely relevant to the etiology and possibly to families. Although over two-thirds of the cases occur
persistence of the disease. Factors associated with sporadically, having an affected family member sub-
higher incidence but equal prevalence of schizophrenia stantially increases the risk of developing schizophrenia.
may be related in complex ways to both etiology and This risk increases as the degree of genetic affinity with
outcome differences (e.g., hypothetically, a greater risk the affected family member increases (Kendler et al.,
of developing the illness along with greater illness- 1993). Although a genetic basis for schizophrenia has
related mortality in males versus females might explain long been suggested (Kallman, 1946), family dynamic
the higher incidence but equal prevalence of schizo- and interactional explanations were commonly invoked
phrenia among males versus females; alternatively, this to explain this familiality until the 1960s (Bateson et al.,
set of gender findings could hypothetically also be 1956; Lidz et al., 1965). To differentiate between these
explained by a greater risk of development but higher explanations, a series of seminal studies (Heston, 1966;
rate of “cure” among males versus females, Fig. 1). Kety et al., 1968) examined the risk of schizophrenia in
Variables associated with equal incidence but higher the adopted-away offspring of parents with schizophre-
prevalence are probably unrelated to etiology but nia raised by parents without the illness and adopted-
relevant to outcome. Although the basis of these away offspring of parents without schizophrenia raised
incidence-lifetime risk-prevalence findings is not well by parents with the illness; they found that the risk of
understood, they do provide a rich substrate for schizophrenia was related to the presence of the illness
developing and testing hypotheses about what causes in biological parents but not in the adoptive parents.
schizophrenia (McGrath, 2007): we need to better In keeping with the genetic basis for schizophrenia
understand what these patterns of distribution of implied by this finding, twin studies have consistently
schizophrenia are telling us about the specific genetic found more than a three-fold greater concordance for the
disease among monozygotic twins than among dizygo- knock-out and related studies about what specific brain
tic twins (Gottesman et al., 1987; Sullivan et al., 2003) processes may be affected by such genetic variations and
(Table 1). Dizygotic twins share 50% of their genetic how this may result in schizophrenia. Gottesman et al.
material and if one twin has schizophrenia the risk of the (1987) had subtitled their review “A decade of modest
other having the illness is 10–15% (similar to that in gains while playing for time”. Despite phenomenal
siblings of a person with schizophrenia — who also advances in the science and technology of molecular
share 50% of their genes). In contrast, monozygotic biology over the past two decades highlighted by the
twins share 100% of their genetic material and if one mapping of the human genome seven years ago, it could
twin has schizophrenia, the risk of schizophrenia in the be argued that we have not learned very much more and
other is about 40–50%. that we are still playing for time (Sullivan, 2008);
Twin concordance rates are also utilized to estimate although a genetic basis for schizophrenia is now clearly
the heritability of a disease. Heritability refers to the established, the precise mechanism of inheritance still
proportion of variance in liability for an illness in the remains obscure.
general population that is accounted for by genetic
effects — by themselves and through interactions with 3.1. Chromosomal abnormalities and linkage studies:
environmental factors, they contribute about 80% of the Where on the human genome are the risk genes for
liability for schizophrenia (Cannon et al., 1998; Cardno schizophrenia?
et al., 1999; Sullivan et al., 2003).
In reviewing the role of genetic factors in schizo- Although a number of “structural” chromosomal
phrenia twenty years ago, Gottesman et al. (1987) abnormalities have been described in schizophrenia
suggested that the above clinical genetic data merely (MacIntyre et al., 2003), the three most often noted are
provided clues to the “real” genetics of schizophrenia deletion of 22q11, a balanced reciprocal translocation of
which would be elucidated by the thousands of 1q42/11q14, and involving the X chromosome (DeLisi
molecular genetic studies (linkage, association, gene et al., 1994; Blackwood et al., 2001; Williams et al.,
knock-out, etc.) that were to follow in the next two 2006b) implicating them as chromosomal regions which
decades. In assessing the genetic underpinnings of a might harbor a risk gene or genes for schizophrenia. The
disease, clinical genetic studies provide information complete mapping of the human genome in the past
about the presence and extent of genetic contributions to decade (Lander et al., 2001; Venter et al., 2001) has
its development, chromosomal and linkage studies about allowed a more detailed assessment of the linkage of
where in the genome relevant risk genes for the disease specific chromosomal segments to differences in
may exist, association studies about which particular liability for schizophrenia. Linkage analysis utilizes
gene variation modifies the risk for the disease, and gene genetic information from families with multiply affected
Table 1
Estimates of relative risk for schizophrenia due to various genetic and environmental risk factors
Risk factor Average relative risk of schizophrenia References
if risk factor present (approximate)
Family history of schizophrenia 2–70 Gottesman et al. (1987); Kendler et al.
Monozygotic twin 50–70 (1993); Sullivan et al. (2003)
Both parents affected 40–60
Dizygotic twin or 1st degree relative 9–18
2nd degree relative (e.g., grandparent) 3–6
3rd degree relative (e.g., 1st. cousin) 2–3
Any specific single gene variant 1.1–1.5 Allen et al. (2008)
Urbanicity 2–3 Pedersen and Mortensen (2001)
Migration 2–3 Cantor-Graae and Selten (2005)
1st or 2nd trimester maternal infection or malnutrition 2–3 Penner and Brown (2007)
Winter birth 1.1 Davies et al. (2003)
Obstetric and perinatal complications 2–3 Geddes and Lawrie (1995); Geddes et al.
(1999); Byrne et al. (2007)
Cannabis or stimulant use 2–3 Semple et al. (2005)
Paternal age N35 years 1.5–3 Wohl and Gorwood (2007)
Male gender 1.4 Aleman et al. (2003)
individuals with schizophrenia and seeks to identify relatively small effect but require careful attention to the
regions of the genome linked to the illness; i.e., which possibility of false positive (type 1 error) and false
chromosomal segments are shared among affected re- negative (type 2 error) results in view of the large
latives but not among unaffected relatives. More than number of gene variants that can potentially be eva-
thirty genome-wide scans have been conducted in schi- luated (Hunter and Kraft, 2007). Publication of an
zophrenia and two meta-analyses (Badner and Gershon, extensive catalogue of common human DNA variants
2002; Lewis et al., 2003) both pinpointed chromosomal (International HapMap Consortium, 2005), develop-
regions 8p21–22 and 22q11–12 as harboring schizo- ment of sophisticated data-analytic tools, ready avail-
phrenia risk genes. Lewis and co-workers meta-an- ability of high-throughput methods of genomic analysis,
alyzed results from 20 genome scans and in descending increased sharing of genetic materials across research
likelihood identified chromosomal regions 2p12–q22, groups, and broad international collaboration have
5q23–q34, 3p25–p22, 11q22–q24, 6pter–p22, 2q22– significantly facilitated the search for the association
q23, 1p13–q23, 22pter–q12, 8p22–p21, 6p22–p21, between specific variations of defined genes and the risk
20p20–p11, 14pter–q13, 16p13–q12, 18q22–qter, for developing schizophrenia. Variations in specific
10pter–p14, 1q23–q31, 15q21–q26, 6q15–q23, and gene sequences are compared between individuals with
17q21–q24 as containing susceptibility genes for schi- and without schizophrenia and variants found with sig-
zophrenia. A genome-wide scan for linkage in sibling nificantly different frequency among those with schizo-
pairs (DeLisi et al., 2002) also identified chromosomal phrenia considered to confer susceptibility to the
regions 10p15–p13, 2 centromere, and 22q12. disease. As such associations may also be detected
Linkage analysis does not, however, identify the due to numerous artifacts, replication is a critical sine
particular susceptibility genes themselves and the total qua non (Hunter and Kraft, 2007). After case–control
number of genes in chromosomal regions linked to comparisons of the gene variant, the next steps are
schizophrenia suggested by the above meta-analyses assessment of whether the protein product of the gene is
approximates 4000 genes (about one-quarter of all expressed in the brain and its function, if the different
known genes), which indicates the extreme lack of forms of the gene yield functionally different proteins,
precision of this approach by itself. The power to detect whether there is differential expression of the gene pro-
linkage depends on the available samples; unfortunately, duct in persons with schizophrenia, and if the gene
the samples currently available worldwide may be product may plausibly be relevant in terms of the
insufficient to detect genes of relatively small effect hypothesized pathophysiology of the illness.
(odds ratio ~ 1.8, as is believed to be the case in Over the past decade, several genetic associations for
schizophrenia) (Risch and Merinkangas, 1996; Moldin, schizophrenia (Owen et al., 2005; Gogos and Gerber,
1997). Genetic heterogeneity, or the presence of several 2006; Straub and Weinberger, 2006) have been reported
independent risk genes, further reduces the sensitivity of and these have been supported by varying amounts of
linkage analysis (Sawa and Snyder, 2002; Fanous and evidence. There are several ongoing efforts to collate
Kendler, 2005). Finally, the difficulties in finding large and update these data (e.g., Becker et al., 2004; Lin
multiplex families for such analyses and technological et al., 2006; Allen et al., 2008); despite these resources,
advances that allow relatively inexpensive rapid staying on top of these association findings can be
throughput genome-wide scanning have diminished challenging in view of the sheer volume and discre-
interest in this approach to locating likely schizophrenia pancies. In addition to data suggesting an association
susceptibility genes. between gene variants and risk for schizophrenia,
messenger RNA of many of these genes is expressed in
3.2. Association studies and susceptibility genes: Which the brain and varying amounts of data suggest that they
genes cause schizophrenia? may be differentially expressed in individuals with the
illness. Furthermore, neurobiological data plausibly link
Linkage analysis (which requires family samples) many of these genes to pathophysiological processes
and association studies (which can be conducted on considered relevant in schizophrenia (Harrison and
samples of related or unrelated individuals) are two Weinberger, 2005; Law et al., 2006; Lang et al., 2007;
complementary molecular approaches to connecting O'Tuathaigh et al., 2007; Tan et al., 2007a; Talkowski
genes to disease. Genetic association studies evaluate et al., 2008). Some of the genes (with their protein
the relationship between specific gene variants and the products) that are currently of etio-pathogenetic interest in
risk of developing schizophrenia. Such studies are more schizophrenia include NRG1 (neuroregulin 1), DTNBP1
suitable than linkage analysis for detecting genes of (dysbindin), DRD1-4 (dopamine receptors D1–D4),
DISC1 (disrupted in schizophrenia 1), COMT (catechol- genes of small effect (Owen et al., 2005) that might vary
O-methyl-transferase) and GRM3 (metabotropic gluta- across populations with different genetic ancestry, and
mate receptor), (Duan et al., 2007; Lewandowski, 2007; that the allelic diversity (leading to discrepant findings)
Li and He, 2007; Nicodemus et al., 2007; Tan et al., being observed in schizophrenia is no different from that
2007b; Chubb et al., 2008; Hanninen et al., 2008; Munafo seen in other complex genetic disorders (Straub and
et al., 2008; Schwab et al., 2008; Talkowski et al., 2008). Weinberger, 2006); these experts caution against an
Even for these “most promising” genes, however, there is overly rigid “nihilistic” approach and argue for the need
a remarkable failure to replicate exactly the same markers to pursue each “promising lead” in order to avoid type 2
and haplotypes across studies and a lack of consistency in errors in our difficult search for the precise genetic basis
implicating particular alleles in liability for schizophrenia for schizophrenia. Other experts suggest, however, that
(Alkelai et al., 2008; Sanders et al., 2008; Sullivan, 2008). more consistent genetic findings have been noted in
There are findings that do not easily fit and although there other complex genetic diseases (Welcome Trust Case
are ways to explain discrepancies, the veracity of these Control Consortium, 2007) and there is no obvious
explanations has not been adequately tested. reason why schizophrenia should be considered more
Therefore, we cannot as yet assert with certainty that complex (Sullivan, 2007); they provide a strong case for
any particular gene variant increases the risk for schizo- “hard” replication in order to avoid type 1 errors
phrenia and we have considerable work to do before we (Ioannidis, 2005; DeLisi and Faraone, 2006). Both
will be able to precisely define the pathogenetic me- concerns merit attention and a balanced “middle-of-the-
chanisms mediating the effects of various risk genes to road” approach would entail vigorous pursuit of all leads
“cause” schizophrenia. The several large case-controlled in a rigorous manner in conjunction with explicit testing
whole genome association studies (e.g., GAIN, 2008; of explanations offered for discrepant findings. In any
Kingsmore et al., 2008) currently underway will hope- event, a key concern should be the power of a particular
fully provide useful insights. study to replicate prior reports.
How has schizophrenia persisted across world
3.3. The genetic basis of schizophrenia, Circa 2008. populations at a relatively stable rate despite its obvious
The promise and the challenge evolutionary disadvantages such as decreased repro-
ductivity and increased mortality (Svensson et al., 2007;
Is the glass half-full or half-empty? Genetic factors are Tandon et al., 2008)? While some may question the
critically important and our increasingly powerful premise that incidence rates of schizophrenia have been
technological tools are enabling us to better study the stable over time, this assertion appears to be well-
nature of these genetic contributions to the etiology of founded at least over the past two centuries (see section
schizophrenia. But failures of clear and consistent on incidence above). Although we do not have
replication need to be considered in the context of our definitive explanations, it has been suggested that the
history of previous highly publicized “solid” genetic genes for schizophrenia may also be relevant to adaptive
findings in schizophrenia that could subsequently not be human evolution and thereby confer evolutionary
confirmed (e.g., Sherrington et al., 1988; Brzustowicz advantages to unaffected family members (Crow,
et al., 2000). Four broad issues that warrant specific 1995; Williams et al., 2006a; Crespi et al., 2007).
consideration include the desirability of adopting stan- There has also been much debate about other models to
dards for interpretation of future genetic studies, explain- explain the persistence of schizophrenia in the context of
ing the evolutionary-genetic paradox of the relatively the plausibility of mutation rates that such models
constant incidence of schizophrenia over the past century invoke (Doi and Hoshi, 2007).
despite its evolutionary disadvantages, suitability of our Currently, the predominant genetic view of schizo-
current genetic framework of schizophrenia, and whether phrenia is that it is a heterogeneous, polygenic/multi-
schizophrenia is the appropriate phenotype for us to be factorial disease (Risch, 1990; Lichtermann et al., 2000)
conducting these genetic studies on. with multiple common genetic polymorphisms, each of
There is considerable disagreement in our field about which contributes a small effect to disease susceptibility.
the degree of appropriate concern about our failure to This “common disease-common alleles with multiple
consistently and unambiguously replicate findings genes of small effect” (Chakravarti, 1999) model of
implicating a particular gene variant as a risk factor schizophrenia is the basis for the large-scale genetic
for schizophrenia (DeLisi, 2000). Some experts suggest association studies conducted around the world in the
that this is only to be expected in view of the fact that past decade and the current emphasis on population
schizophrenia is a heterogeneous disease with multiple case–control genome-wide association studies. Some
experts suggest that our genetic conceptualization of thereby reduce the problem of nonreplication in genetic
schizophrenia is wrong and this flawed model is the association studies is being advocated (Gottesman and
reason for our difficulties in elucidating the precise Gold, 2003; Bearden et al., 2007; Braff et al., 2007;
nature of the genetic basis for schizophrenia (McClellan Glahn et al., 2007; Gur et al., 2007; Owen et al., 2007;
et al., 2007; Crow, 2007a). They instead provide two Tan et al., 2008). Although this approach is being found
alternate genetic models for schizophrenia that they to be useful (Greenwood et al., 2007), the extent to
suggest are more appropriate. McClellan et al. (2007) which it will facilitate the elucidation of the genetic
suggest that instead of viewing schizophrenia as basis of schizophrenia is still an open question. Another
resulting from the combined effects of multiple common approach towards reducing etiological heterogeneity is
and weakly penetrant genetic polymorphisms, it is better to utilize subtypes or dimensions of schizophrenia as the
conceptualized as a highly heterogeneous genetic entity phenotype for genetic association studies (Jablensky,
caused by multiple, highly penetrant and individually 2006). Even if such approaches lead to more consistent
very rare mutations that may be specific to single cases genetic findings, the question of how and why different
or individual families. This model points to a very dimensions or endophenotypes co-occur in schizophre-
different approach towards elucidating the genetic basis nia would still need to be answered.
for schizophrenia emphasizing intensive study of What is the status of our understanding of the nature
individual cases or single families. While recent of genetic contributions to the etio-pathogenesis of
findings of increased runs of homozygosity that reveal schizophrenia in 2008? To the best of our knowledge,
highly penetrant recessive loci in schizophrenia (Lencz this is what we do know:
et al., 2007) are suggestive, there are several limitations
to this idea (Craddock et al., 2007; Crow, 2007b). (i) Heritability is high and genetic factors contribute
Another genetic model proposed for schizophrenia is about 80% of the liability for the illness.
that it is not DNA sequence variation but heritable (ii) There is no ‘major’ gene locus that could explain
changes in gene expression that explain its genetic a substantial portion of the heritability and a large
origins (DeLisi et al., 2002; Costa et al., 2006; Crow, number of candidate susceptibility genes may con-
2007a). Such epigenetic factors exert their effect on tribute to the liability for the illness.
genomic functions principally through DNA methyla- (iii) No gene appears to be either sufficient or ne-
tion and histone remodeling of chromatin structure. cessary for the development of schizophrenia.
Although epigenetic explanations for the genetic basis (iv) Although there are many “findings” of genetic
for schizophrenia bear much promise, our understanding variations being linked to differential risk for devel-
of the role of epigenetic factors in the etio-pathogenesis oping the illness, inconsistent replication prevents the
of complex diseases such as schizophrenia is still in its consideration of any single allelic variant as a gene for
infancy. While it is conceivable that epigenetic mechan- schizophrenia with absolute certainty at this time.
isms are relevant in schizophrenia (Mill et al., 2008), the
extent and precise nature of their contributions remain 4. Environmental risk factors
unclear. Copy number variations account for a sub-
stantial proportion of human genomic variation and A variety of specific environmental exposures have
have been found to be relevant to the expression of been implicated in the etiology of schizophrenia
various neurodevelopmental disorders; their specific (Table 1). These include both biological and psychoso-
role in risk for schizophrenia remains to be clarified cial risk factors during the antenatal and perinatal
(Sutrala et al., 2007; Kirov et al., 2008; Mulle, 2008). periods, early and late childhood, adolescence and early
The phenotypic heterogeneity of schizophrenia has adulthood (Maki et al., 2005).
been cited as another reason for the difficulties in precise In the antenatal period, maternal infections and
delineation of its genetic basis and it has been suggested nutritional deficiency during the first and early second
that the “schizophrenia genes” do not code for schi- trimesters of pregnancy have been linked to an increased
zophrenia per se, but for some broader clinical construct liability for developing schizophrenia (Penner and
such as psychosis (Kendler et al., 1998; Weiser et al., Brown, 2007; Meyer et al., 2007); these associations
2005; Craddock and Owen, 2007) or neurocognitive have not, however, been consistently detected (Crow and
deficits that occur in schizophrenia and other conditions Done, 1992). Although maternal influenza is the infection
(Whalley et al., 2005; Toulopoulou et al., 2007). In- most frequently linked to an increased risk of developing
creasingly, the use of intermediate phenotypes (endo- schizophrenia (Mednick et al., 1988), other maternal in-
phenotypes) to improve etiological homogeneity and fections (e.g., rubella, toxoplasmosis, etc.) during this
period have been associated with an increased liability for confidence in any of these associations is limited by
developing schizophrenia as well (Brown et al., 2001, discrepancies in findings and several methodological
2002). Although the precise neurobiological mechanism constraints. Such factors include childhood trauma (Read
whereby this increased risk might be mediated is not et al., 2005; Morgan and Fisher, 2007), head injury (Wilcox
clearly understood, a role for cytokines and an aberrant and Nasrallah, 1987; David and Prince, 2005), parental
immune response to these infections that interfere with separation or death (Morgan et al., 2006), adverse child
normal fetal brain development during this period is rearing (Tienari et al., 2004), and infection (Dalman et al.,
commonly invoked (Ashdown et al., 2006). Severe 2008). As earlier discussed in the section on incidence,
nutritional deficiency (Susser et al., 1996; St Clair et al., urbanicity during the childhood years and migration are
2005) and severe adverse life events (Khashan et al., important risk factors for developing schizophrenia.
2008) experienced by the mother during the first trimester During adolescence, cannabis use has been linked to
of pregnancy have been linked to an increased risk for an increased risk of developing schizophrenia (Semple
developing schizophrenia; these effects are hypothesized et al., 2005; Moore et al., 2007). Although an etiological
to be mediated by “stress sensitization” (Koenig et al., role is probable, some experts question this cause–effect
2005; Yuii et al., 2007) and a predisposition to subsequent relationship and suggest instead that cannabis use might
hyperdopaminergia (Lipska et al., 1993). precipitate schizophrenia in vulnerable individuals or
A range of obstetric and perinatal complications have otherwise modify the expression of schizophrenia but
been linked to an approximate doubling of the risk of not the risk for developing it (Degenhardt and Hall,
developing schizophrenia in the offspring (Geddes and 2006; Barnes et al., 2006). Although social adversity
Lawrie, 1995; Cannon et al., 2002b; Byrne et al., 2007); and stressful life events have long been linked to the
there are, however, some discrepant findings (Done et precipitation of schizophrenia (Norman and Malla,
al., 1991). Although the precise mechanism whereby 1993); some suggest that these might actually increase
exposure to obstetric/perinatal complications might the liability for developing the illness (Harrison, 2004;
increase the risk for developing schizophrenia has not Allardayce and Boydell, 2006).
been delineated, fetal hypoxia is most commonly cited Delayed attainment of various developmental mile-
as the mediating factor (Geddes et al., 1999; Byrne et al., stones (e.g., language) and a range of “premorbid”
2007). impairments during childhood and adolescence (cogni-
Although maternal risk factors for schizophrenia tive — e.g., specific impairments and poor academic
during the prenatal–perinatal period receive the most achievement, physical — “minor physical anomalies”
attention (Patterson, 2007), older paternal age at and “soft neurological signs”, and social — e.g.,
conception has been linked to an approximate doubling “schizotaxia” and poor social adjustment) have been
of the risk for developing schizophrenia (Malaspina linked to an increased likelihood of developing schizo-
et al., 2001; Byrne et al., 2003; Wohl and Gorwood, phrenia (Walker and Lewine, 1990; Fish et al., 1992;
2007). While we do not understand the precise Jones et al., 1994; Cornblatt et al., 1999; Cannon et al.,
mechanism whereby this increased risk is mediated, 2002a; Keshavan et al., 2005). It is unclear, however,
impaired spermatogenesis leading to an increased whether such impairments represent risk factors for
likelihood of de novo mutation and aberrant epigenetic developing schizophrenia or are instead early manifesta-
regulation have been advanced as explanations (Byrne tions of the disease itself.
et al., 2003; Perrin et al., 2007; Cheng et al., 2008). A range of environmental risk exposures have thus
Birth during late winter or early spring has been been linked to liability to develop schizophrenia, but
associated with a 5–10% greater likelihood of developing their exact relevance remains unclear. Many associa-
schizophrenia (Torrey et al., 1997; McGrath and Welham, tions have been suggested by less reliable observational
1999; Davies et al., 2003), although some statistical studies and several putative environmental factors (e.g.,
artifacts are inadequately explained (Lewis, 1989). This urbanicity, migration, and ethnicity) are proxies for
season of birth effect appears to become stronger with some other specific risk exposure whose nature remains
increasing latitude and increasing severity of winter. How obscure. None of the environmental risk factors appear
this season of birth effect might be mediated is not fully sufficient or necessary to cause schizophrenia and no
understood, but it is suggested that it represents a proxy single factor fully satisfies the nine epidemiological
for one of the above three factors (prenatal infection, criteria for an exposure-disease cause–effect relation-
prenatal malnutrition, or risk of mutation). ship (Hill, 1965).
Although a range of risk factors in childhood have Although a role for both genetic and environmental
been suggested as increasing the risk for schizophrenia, risk factors in the etiology of schizophrenia has long
been proposed, previously these were considered environmental elements interact to cause schizophrenia”
dichotomously and questions such as “is it genetic or (Tienari et al., 2004; Caspi et al., 2005; Krabbendam and
environmental in origin” and “what is different about the van Os, 2005; Benzel et al., 2007; Cougnard et al., 2007;
schizophrenia caused by genetic versus environmental Mathew et al., 2007; Nicodemus et al., 2007; Sei et al.,
factors” focused upon. It is only in the past couple of 2007; Zammit et al., 2007; Cheng et al., 2008; Hanninen
decades that investigators have instead seriously begun et al., 2008). How these factors might interact to cause
to explore issues such as “exactly how do genetic and schizophrenia and what neurobiological processes
Table 2
Epidemiological “facts” Reproducibility Whether Durability Key questions
primary of finding
to illness? over time
Annual incidence = 8–40 per 100,000 per year with *** ** *** What specific causal factors — social or
relatively similar incidence across broad regions biological — explain differences in incidence?
and countries.
Higher incidence associated with urbanicity. ** ** ** Does a dose–response relationship exist for
specific factors?
Higher incidence associated with migration. ** ** **
Lifetime risk = approximately 0.7% ** ** ** What specific factors explain sex differences?
Greater lifetime risk in males ** ** *
Point prevalence = 2–10/1000 with pockets of *** * *** To what extent do variations in diagnostic
high and low prevalence. criteria/case-ascertainment methods explain
variations?
Higher prevalence among lower socio-economic classes. *** * ***
Schizophrenia is highly heritable and genetic factors *** ** *** What genetic model best explains these genetic
contribute to approximately 80% of the liability for the contributions?
illness.
There is genetic heterogeneity, with multiple genes ** ** ** Why is consistent identification of any single
(no single one of which is necessary or sufficient susceptibility gene variant proving so difficult?
by itself) related to risk of illness.
Multiple chromosomal regions across the genome are ** ** * What do the risk genes code for —
linked to illness liability. schizophrenia, psychosis, cognitive deficit,
physiological abnormality, endophenotype?
Specific gene variants of small effect in several genes * * *
have been linked to illness liability and/or illness
expression.
Several environmental factors of small effect have been ** ** ** What neurobiological mechanisms mediate
associated with an increased risk of developing these effects?
schizophrenia.
– To *** SCALE to be used to score reproducibility, specificity, and durability of each “fact”
1. Replicability
–: very few studies OR Few–Fair number of studies with contradictory findings
*: Few studies with consistent replication OR Fair–Many studies with inconsistent replication
**: Fair number of studies with consistent replication OR Many studies with fairly consistent replication
***:Many independent studies with consistent replication and no contradictory findings
2. Whether primary to schizophrenia
–: finding certainly because of some other confounding variable and definitely not related to schizophrenia.
*: finding possibly because of some other confounding variable but may be related to schizophrenia.
**: finding probably not because of some other confounding variable and likely related to schizophrenia.
***: finding certainly not because of some other confounding variable and definitely related to schizophrenia.
3. Long-term durability
–: very new finding (b5 years) not in previous 2 versions of “FACTS” in 1998 and 1999.
*: relatively new finding (5–15 years). Not in 1988 version, but may have been noted in 1999 version
**: fairly established finding (15–30 years). Listed in 1999 and may have been noted in 1988 versions
***: long established finding, well known for over 30 years. Listed in both 1988 and 1999 versions
From Table 1, Tandon et al., 2008. “Schizophrenia, Just the Facts, Circa 2008”.
might mediate such gene–gene, gene–environment, and Table 3

environment–environment interactive effects is not Critical issues that need to be addressed for all putative etiological
factors linked to schizophrenia
understood at this time.
Substantial specific questions
1. Is this the “real” risk-modifying factor or merely a surrogate marker
5. Etiology: what do genetic and environmental for some other etiological factor?
“facts” tell us about the causes of schizophrenia 2. Does a dose–response relationship exist between intensity of
exposure to this risk factor (genetic or environmental) AND risk of
Although it appears that our understanding of the developing the illness?
causation of schizophrenia has substantially increased 3. Does this factor modify the risk of developing schizophrenia,
moderate the risk of some other etiological factor, or mediate the
over the past two decades, what we can confidently effect of some other risk factor?
assert is essentially the same — both genetic and 4. Is the risk factor necessary or sufficient to cause schizophrenia? [No
environmental factors are important, but exactly which factor can be both necessary and sufficient to cause schizophrenia as
specific exposures and exactly how they cause schizo- that would mean that it is the sole cause for the disease and we know
phrenia is still unknown (Table 2). For the past twenty multiple etiological factors are relevant].
5. What specific neurobiological mechanisms mediate the effects of
years, we have been biding time and asserting that this risk factor to “cause” schizophrenia?
certain etiological information is just around the corner 6. Exactly what disease or group of diseases does the risk factor increase
(Gottesman et al., 1987); we still wait (Sullivan, 2008). the risk for (e.g., schizophrenia OR some psychotic disorder OR some
A reconsideration of our basic strategies and funda- disorder with specific cognitive impairment, etc.)?
mental assumptions may be in order. 7. Exactly how do different genetic risk factors interact with each other
and with environmental risk factors to modify risk of developing the
To make progress, we may need to exert substantially illness?
greater rigor in evaluating findings, better identifying a) is there a summing of risk factors that determines individual
and explaining discrepancies, developing clear and liability?
testable hypotheses (and then actually testing them!), b) are there interactions between specific sets of risk factors that lead
and explicitly discarding explanations or assumptions to development of schizophrenia?
c) are there windows of time (e.g., based on age or developmental
that are disproved by these efforts. We need to be more phase) when exposure to the factor (or to specific interactions between
precise in defining the contribution of each putative risk a set of factors) leads to increased risk of developing schizophrenia?
factor. Assuming that a particular risk factor is convin- 8. Are these effects similar across different populations and if not, why
cingly linked to liability for developing schizophrenia, not? Exactly how do these environmental and genetic risk factors
precisely what is the role of that risk factor and exactly interact in different populations?
how are its effects mediated? Does this factor itself General or methodological
modify the risk for developing schizophrenia or does it 1. Might variations in diagnostic criteria or case-ascertainment
moderate the effect of some other factor (Bauman et al., methods explain observed differences in incidence across different
2002; Fanous and Kendler, 2005). Alternatively, is this populations?
factor found to be linked to schizophrenia not because it 2. Can findings be replicated, exactly replicated? If not, are
explanations of failure to replicate explicitly tested?
is a risk modifier, but a risk mediator (Edwards and 3. What specific causal factors (genetic and/or environmental and/or
Lambert, 2007); if so whose effects does it mediate? interactional) explain differences in incidence across different
Finally, does this putative factor modify the risk for populations (e.g., differences based on gender, migration/ethnicity
developing schizophrenia or does it instead influence its status, urbanicity, etc.)?
expression (e.g., Cougnard et al., 2007; Shaner et al.,
2007)? Table 3 summarizes a set of critical questions of keeping up with new findings whose veracity we
that must be answered with regard to each risk factor cannot ascertain and whose significance we cannot
(genetic or environmental) in order for us to acquire a comprehend. This leads to different research groups
better understanding of its role in the etio-pathogenesis working in relative silos and ignoring large swaths of
of schizophrenia. established findings or worse misinterpreting and
There is also a clear need to effectively integrate the misrepresenting them. In addition to appreciating the
vast amounts of epidemiological data generated across need for and importance of meaningful integration, we
different fields of inquiry by research groups around the need to invest substantial effort and discipline in order to
world utilizing an assortment of paradigms and make this happen. In our individual research endeavors,
approaches. Otherwise, our field at large runs the risk greater rigor and healthy skepticism, a more inductive
of being buried under a plethora of unrelated and (“hypothesis-testing”) approach, in conjunction with
undigested findings (Tandon, 1999). As individual clear and precise explication of our findings would be
research groups, we are confronted with the challenge useful. In our areas of expertise, it would be helpful to
Fig. 2. Etiology to pathophysiology to illness: models of schizophrenia.
update what we know and don't know and how well we multiple etiological factors might interact to produce
know what we know. Furthermore, it would be crucial neurobiological aberrations that, in turn, lead to the
for us to regularly take stock of findings that survive expression of schizophrenia.
over time and those that don't (see Table 2); we often We have accumulated a significant amount of in-
hold on to untrue findings in our field and expend formation pertaining to the causes of schizophrenia, but
enormous and obviously unproductive effort in trying to our comprehension of its etiology remains limited. It is
“explain them” (e.g., McGrath, 2007). To paraphrase vital that we examine the reasons for this continuing gap
Mark Twain in this regard (Anonymous, 2003), “it ain't between “findings” and “understanding”.
what people don't know that hurts them it's what they
know that ain't so”. Role of funding source
Finally, we need to consider the possibility that there Independently prepared by authors. No external funding.
is no “one” schizophrenia, whose etiological basis we
are trying to define. Perhaps, schizophrenia includes Contributors
several (possibly hundreds) of different diseases whose Contributors to research and writing of manuscript. Rajiv Tandon,
Matcheri Keshavan, and Henry Nasrallah.
clinical manifestations are similar. Alternatively, schizo-
phrenia may represent a confluence of many distinct
dimensions (with different etiologies); but we then need Conflict of interest
This statement was independently developed by Rajiv Tandon,
to explain why they co-occur. Fig. 2 illustrates these Matcheri Keshavan, and Henry Nasrallah. The content of the article is
models along with the traditional “single common not part of the purview of Dr. Tandon's current employment by the
pathway” construct (Williamson, 2006) and depicts how State of Florida which bears no responsibility its contents.
Acknowledgement Boydell, J., van Os, J., McKenzie, K., et al., 2001. Incidence of
We acknowledge the mentorship of Richard J. Wyatt and guidance schizophrenia in ethnic minorities in London: ecological study into
of our many teachers and colleagues, whose collective efforts are interactions with the environment. B.M.J. 323, 1336–1338.
reflected in this manuscript. Braff, D.L., Freedman, R., Schork, N.J., Gottesman, I.I., 2007.
Deconstructing schizophrenia: an overview of the use of endophe-
notypes in order to understand a complex disorder. Schizophr. Bull.
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Schizophrenia Research 102 (2008) 1 – 18

Schizophrenia, “Just the Facts” What we know in 2008.

1. Introduction essence of epidemiology; with reference to schizophrenia,

Fig. 1. Relation between incidence and prevalence in a given population.

might mediate such gene–gene, gene–environment, and Table 3

Fig. 2. Etiology to pathophysiology to illness: models of schizophrenia.

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