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Schizophr Bull. 2009 May; 35(3): 603–623.
Published online 2008 July 24. doi:  10.1093/schbul/sbn084
PMCID: PMC2669575

The Antecedents of Schizophrenia: A Review of Birth Cohort Studies

Abstract

Background: Birth cohort (BC) studies demonstrate that individuals who develop schizophrenia differ from the general population on a range of developmental indices. The aims of this article were to summarize key findings from BC studies in order to identify areas of convergence and to outline areas requiring further research. Method: We define BC studies as studies based on general population BCs where data are collected prospectively from birth or childhood and which identify schizophrenia or related disorders as an outcome. To identify such studies, we searched various electronic databases using the search parameters (schizo* OR psych*) AND (birth cohort). We also checked the references of relevant articles and previous reviews. Results: We identified 11 BCs from 7 countries that have examined schizophrenia as an outcome in adulthood. There is relatively consistent evidence that, as a group, children who later develop schizophrenia have behavioral disturbances and psychopathology, intellectual and language deficits, and early motor delays. Evidence with respect to alterations in language, educational performance, and physical growth has also been identified in some studies. BC studies have also contributed evidence about a wide range of putative risk factors for schizophrenia. Conclusions: BC studies have provided important, convergent insights into how the developmental trajectory of individuals who develop schizophrenia differs from their peers. The combination of new paradigms and larger cohorts, with the tools of modern epidemiology and biomedical science, is advancing our understanding of the developmental pathways to schizophrenia.

Keywords: schizophrenia, birth cohort, epidemiology

Introduction

Subtle deviations in various developmental trajectories during childhood and adolescence can foreshadow the later development of schizophrenia. Studies exploring the antecedents of schizophrenia have used research designs ranging from narrative case studies based on clinical observation, through case control studies, to population-based cohort studies. The latter have included genetic high-risk studies,1 reconstructed cohorts from archival data,2,3 military conscript records,4 and prospectively assessed birth cohorts (BCs). The BC studies were originally designed to explore early health outcomes, but as the cohort members matured a range of adult-onset disorders could also be studied. Thus, over recent decades there has been a shift from retrospective toward prospective studies, from clinical samples toward population-based studies, and from narrowly focussed cross-sectional studies toward detailed longitudinal studies.

The different types of population-based cohort studies, while providing valuable insights into the antecedents of schizophrenia, have various strengths and limitations. For example, young, unaffected individuals have been recruited who are at increased genetic risk of developing schizophrenia (eg, the presence of an affected parent).5,6 These “high-risk” studies are more economical than general population studies in terms of power (ie, the number of expected cases in the sample) and duration of follow-up (ie, subjects can be recruited in the years prior to maximum risk during early adulthood). However, most people with schizophrenia do not have affected family members79; thus, results from high-risk studies may not be generalizable.

Studies based on representative, population-based samples provide the ideal sampling frame to quantify the attributable risk associated with various exposures. Studies of military conscripts provide a convenient way to access population-based data, and when linked to mental health registers, such studies can provide insight into the precursors of treated schizophrenia.1012 However, these studies are limited with respect to time points (ie, usually one assessment on intake related to fitness for military service in adolescence) and coverage (ie, some conscription-based studies only examine males).

Ideally, population-based cohorts are recruited prior to or soon after birth. Their ability to examine various unbiased domains of interest from birth through childhood and adolescence to adulthood can provide unique insights into the changes in developmental trajectories associated with schizophrenia.

The main aim of this article is to summarize key findings from BC studies that have examined the antecedents of schizophrenia. To achieve this, we systematically collated data from the various domains of interest (eg, behavioral, cognitive, etc) to identify areas of consistency and areas lacking in data. We were particularly interested in studies of longitudinal development covering multiple domains. In the second part of the article, we will also provide a concise summary of instances where BC studies had been used to explore putative risk factors for schizophrenia. We conclude by discussing the role of BC studies and developmental epidemiology in informing an integrated model of schizophrenia etiology.

Method

BCs can be defined retrospectively by linking routine administrative datasets. However, for this review, we required that information about cohort members was augmented by additional direct assessments. Thus, to be included in this review, we required that BC studies were based on (a) general population BCs; (b) detailed data collected prospectively from birth, infancy, or childhood; and (c) schizophrenia and related disorders as an outcome.

A broad search string “(schizo* OR psych*) AND (birth cohort)” was applied in MEDLINE (PubMed), PsychINFO, Google Scholar, and Web of Science (including the “Cited Reference Search” system). These databases were searched at the end of May 2008 (details are available from the authors). Potentially relevant articles (in all languages) were reviewed. Citations from relevant articles and review articles were also scrutinized to locate additional relevant articles, book chapters, and conference articles. Additional searches were undertaken based on the names of included BCs.

The results from the BC studies were sorted into 3 primary domains: behavior and psychopathology, cognition (cognitive, language, motor, education), and physical growth. Key features of the included studies were extracted and presented in tabular format.

Results

We identified 11 BCs from 7 countries (see table 1). There were 2 BCs from the United Kingdom, the National Survey of Health and Development (NSHD)1315 and National Child Development Survey (NCDS).16,17 We identified 2 BCs from the United States; the National Collaborative Perinated Project (NCPP) (the New England cohorts18,19 and the NCPP Philadelphia cohort20) and the Perinatal Determinants of Schizophrenia (PDS).21,22 BCs were also identified from Denmark (Danish Longitudinal Study [DLS],23,24 and the Copenhagen Perinatal Cohort [CPC],25,26 Finland (North Finland 1966 Birth Cohort [NFBC_1966]),27,28 Israel (Jerusalem Perinatal Study [JPS]),29,30 Dunedin, New Zealand (Multidisciplinary Health and Development Study [MHDS]),31,32 and Australia (Mater University Study of Pregnancy [MUSP]).33

Table 1.
Characteristics of Birth Cohorts
Table 2.
Birth Cohort Studies of the Behavioral and Psychopathological Antecedents of Schizophrenia
Table 3.
Birth Cohort Studies of Intellectual Functioning as an Antecedent of Schizophrenia
Table 4.
Birth Cohort Studies of Speech and Language Functioning as Antecedents of Schizophrenia?
Table 5.
Birth Cohort Studies of Neuromotor Dysfunction as an Antecedent of Schizophrenia
Table 6.
Birth Cohort Studies of Educational Performance as an Antecedent of Schizophrenia
Table 7.
Birth Cohort Studies of Physical Growth and Pubertal Maturation as an Antecedent of Schizophrenia

The BCs, which were all based in developed countries, ranged in size from 1037 (the Dunedin cohort) to 68794 (Jerusalem BC). Based on the most recent follow-up with respect to schizophrenia outcomes, we estimate that these studies were based on 2 079 534 person/years.

Most cohorts recruited subjects antenatally of from birth, with the Dunedin MHDS34 and the Danish DLS23 prospectively collecting data from later childhood. All used standard but often different diagnostic criteria (table 1); however, there were differences in the definition of the outcome. Some studies defined the outcome as “schizophrenia,”15,35,36 while other studies used “psychotic symptoms” (NCPP-Providence,37) “schizophreniform disorder” (Dunedin MHDS34,38), or “screen-positive nonaffective psychosis” (MUSP).39 Given the differences in the size of the cohorts and the different diagnostic criteria used, the number of cases by last assessment varied from 12 cases of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, broad schizophrenia in the Providence cohort from the NCPP40 to 520 cases of International Classification of Diseases, Ninth Revision, broad schizophrenia from the JPS.41 Most studies relied on mental health registers to initially identify cases. Exceptions were the Dunedin BC where a psychiatrist ascertained diagnosis directly by interview and the MUSP which used a questionnaire and the Composite International Diagnostic Interview, computerized version. Some BC studies followed-up with a diagnostic interview of a proportion of the cases (eg, PDS, Susser et al21).

Behavioral and Psychopathological Antecedents

We identified 7 articles based on 5 BCs that examined behavioral functioning.15,3436,38,39,42 These studies as a group demonstrate that, for many, schizophrenia is associated with a range of behavioral problems during childhood and adolescence.15,35,36,39,42

There have been few studies of antecedent psychopathology using BC studies. Important exceptions are the 2 studies from the Dunedin MHDS cohort which identified that responding positively to psychosis-related items can precede schizophrenia34,38 and a recent study from the MUSP which found that self-reported hallucinations at age 14 can precede nonaffective psychosis.39

The exact nature of the behavioral antecedents varies between studies (in keeping with the differences in the measures used in the different cohort studies), but several broad themes have emerged from this literature. The behavioral antecedents of schizophrenia are subtle. Individuals who later develop schizophrenia are not marked by extreme deviations in behaviors. Also most cohort members with a behavioral feature associated with later schizophrenia do not develop the disorder. In other words, behavioral features have poor positive predictive value.

An advantage of BCs over cross-sectional designs is their ability to report on behavioral changes over time—including sex by age differences. For example, a NSHD study15 found that schizophrenia was predicted by solitary play preference in childhood and social anxiety by adolescence, while the 2 NCDS studies36,42 found sex differences in behavioral changes over time. However it appears that, with the exception of the NCPP study35 and the MUSP study,39 most studies used mean group differences rather than within-individual change measures to assess behavioral change through childhood and adolescence. For example, the MUSP study,39 when comparing behavioral measures within the same individual at 5 and 14 years, found a relatively strong association between change measures of “thought disorder” and subsequent nonaffective psychosis. Exploring comparable measures within the same individual over time is better able to describe the direction and “velocity” of trajectories. This information that can be masked when comparing cross-sectional group means. Furthermore, relying on mean group difference may not be the best way to summarize data (eg, if the association is U shaped).

A study of the Dunedin BC was the first to identify that psychotic symptoms at age 11 were strongly predictive of later schizophreniform disorder.34 A subsequent study of this cohort showed that self-reported psychotic symptoms appeared specific to schizophreniform disorder; they did not predict mania or depression.38 They concluded that this suggested continuity of psychotic symptoms from childhood to adulthood, rather than adult psychotic symptoms simply being the result of general childhood psychopathology. The MUSP study39 has also found that self-reported hallucinations (as assessed on the Youth Self Report)43 during adolescence were significantly associated with increased risk of nonaffective psychosis in young adulthood.

In sum, BC studies have provided relatively consistent evidence that individuals who develop schizophrenia are more likely to have subtle, nonspecific behavioral features compared with their well peers. There is also evidence from 2 cohorts that psychotic-like experiences (particularly hallucinations) may precede schizophrenia by many years.

Cognitive Antecedents

Schizophrenia patients, when considered as a group, show a range of cognitive impairments, some of which predate the onset of psychotic symptoms. BC studies have helped to establish that, for many, schizophrenia is associated with subtle differences in cognitive development during childhood and adolescence. These studies are presented under 4 main headings, intelligence, language and speech, neuromotor, and educational antecedents of schizophrenia.

Cognitive Antecedents: Intelligence

We identified 8 articles based on 6 BCs that examined the issue of intellectual functioning. These studies uniformly found that individuals who develop adult schizophrenia (or schizoaffective disorder, or psychotic symptoms), as a group, achieved lower scores on intelligence tests in childhood and adolescence than their peers,15,37,44 with some identifying a linear effect rather than subgroup differences.15,44 BC studies have also generally identified deficits in a range of intellectual impairments covering verbal, nonverbal, and mathematical abilities.15,37,38,42,44 And in terms of neuropsychological functioning, one study45 found that schizophreniform disorder was associated with attentional, executive, and motor impairments (but not memory and learning) in early adolescence.

The evolution of intellectual functioning, however, is unclear. While most studies included assessments at a number of ages (thus providing longitudinal assessments of intellectual functioning),15,37,38,42,44 several areas require further clarification. It is unclear if the longitudinal deficit associated with later schizophrenia is best characterized as stable or declining. For example, while the NCPP Providence study found an IQ decline between ages 4 and 7 years specifically predicted those who developed psychotic symptoms,37 the NCPP Philadelphia study found IQ lower yet stable between these ages (ie, no intraindividual decline).44 Examining change at a later age, a CPC study24 found that both low cognitive function at 12 and 18 years and cognitive decline between these ages increased the risk of schizophrenic disorders. Secondly, it appears that, with the exception of the NCCP Philadelphia study,44 studies used mean groups differences to assess change over time, rather than assessing intraindividual changes. This may partly explain the differences in findings.

Interestingly, the study by Niendam et al46 found subtle differences between probands and their unaffected sibs. While probands and their siblings had similar patterns of deficits involving spatial reasoning, verbal knowledge, perceptual-motor speed, and speeded processes of working memory, probands had more severe deficits in perceptual-motor speed and speeded processes of working memory than their unaffected sibs.

Cognitive Antecedents: Speech and Language

Early language dysfunctions have been identified in 4 articles based on 4 BCs. In the British NHSD, preschizophrenia children were found to have subtle speech differences by the age of 2, and up to age 15, they had more speech problems.15 In the NCDS study, parents rated pre-schizophrenia speech as normal at age 7, while teachers’ rated their oral and reading ability at age 7 and speech at age 14 as poor.42 It is less clear if expressive or receptive language is most disordered. For example, the NCPP study35 found childhood poor speech and expressive language predicted schizophrenia-schizoaffective disorder, whereas in the Dunedin cohort, Cannon et al38 found that throughout childhood receptive rather than expressive language predicted schizophreniform disorder. Several studies had repeated measures of speech and language at various ages and were able to report on continuity. For example, the NSHD study found that preschizophrenia was not associated with grossly abnormal speech in adolescence; they had apparently caught up.15

Cognitive Antecedents: Neuromotor Dysfunction

We found 6 articles based on 5 BCs that examined neuromotor functioning. These studies uniformly found that deficits in infant motor development (IMD) and/or motor coordination were associated with schizophrenia in adulthood. Some studies examined age at attaining motor milestones in infancy.15,47 For example, the NFBC_1966 study found a linear effect where earlier milestones attainment reduced and later milestones attainment increased the risk.47 Other BC studies covered IMD and/or motor coordination in later childhood, adolescence, or adulthood.15,38,42,48,49 Interestingly, the NFBC_1966 study48 which found that early developmental deviation capacity in the first year of life was associated with lower school performance at age 16 also found that developmental continuity in children who developed psychoses was stronger, ie, less flexible, than among normal. However, Rosso et al49 found that motor coordination deviance at age 7 predicted both adult schizophrenia and unaffected sib status, while unusual movements at ages 4 and 7 predicted adult schizophrenia but not unaffected sib status (perhaps then specific to the clinical phenotype). Also preschizophrenia children did not show expected developmental decline in unusual movements, which the authors thought may reflect aberrant functional maturation of cortical-subcortical pathways.

All studies included multiple premorbid assessments and found evidence of a continuity of motor deficits in schizophrenia—and between differing measures of motor function—infant developmental milestones (ie IMD), and later childhood motor functioning. For example, in the early UK study15 probands did not show grossly abnormal motor behavior in adolescence, they had largely caught up. Further studies based on the NFBC_1966 found continuity between IMD and poor adolescent school performance in motor domains, while the pattern of association between development and adult cognition was broadly similar in schizophrenia and the general population.50 Similarly in the Dunedin cohort, children who subsequently developed schizophreniform disorder had persistently poor motor function over repeated measurements in childhood.38 Interestingly, 2 other BC studies (not included in the table) have found similar associations between IMD and cognitive performance/brain morphology in the adult nonpsychosis cohort.45,51 The latter study51 also found that the normal relationship between infant development at age 1 and adult brain structure 34 years later is disturbed in schizophrenia (“developmental dysmetria”).

Cognitive Antecedents: Educational Performance

We found that 5 articles based on 2 BCs have examined the issue of educational performance as an antecedent of schizophrenia. While a number of school-related risk factors for developing schizophrenia have been identified (repeating a grade, difficulties completing the final school level, and school marks), results have produced mixed or unreplicated findings. In the early NCDS study, poor educational performance had a linear association with schizophrenia. This effect was not confined to those with lowest IQ and was independent of behavior, apparent by age 8 as a general dysfunction, and possibly increased thereafter.15 However, in the NFBC_1966, 14-year-olds who were below their expected normal grade (as predicted by age) had a higher risk of developing schizophrenia, but low school marks did not predict schizophrenia.52 Interestingly, good school performance may also be associated with later schizophrenia. A NFBC_1966 study found that 11% of boys with premorbid symptoms had excellent school marks compared with 3% in the healthy population.53 Also, Alaräisänen et al54 found that good school performance at age 16 was associated with increased risk of suicide (before age 35) in persons who develop psychosis, while for those who do not develop psychosis, it is associated with lower suicide risk. Interestingly, studies of the general population of the NFBC_1966 have also identified developmental continuity between age of IMD and educational performance at age 16 and 3155,56: (ie, those who develop faster during their first year of life tend to attain higher levels of education in adolescence and adulthood).

In sum, BC studies have provided relatively robust evidence that individuals who later develop schizophrenia show early deviation on a range of cognitive measures related to intelligence, motor development, speech and language, and educational outcomes. The importance of examining the longitudinal course of cognition in schizophrenia has been highlighted by a recent meta-analysis.57

Physical Growth and Puberty

We identified 9 studies based on 7 BCs that examined physical growth, with 2 including pubertal maturation. Low birth weight and/or being small for gestational age (SGA) can be conceptualized as indices of fetal growth retardation (which may be a proxy marker for more widespread impairment of physical development) or independent risk-modifying factors. Measures related to birth anthropometry were reported in 8 studies from 6 countries. Results were mixed with 3 reporting that low birth weight or being SGA increased the risk for adult schizophrenia, while 4 failed to find such an effect. Interestingly, a BC study based on the NCPP58 found that low birth weight (along with hypoxia) was associated with poorer cognitive functioning of cohort members at age 7. Other variables related to possible fetal growth retardation, such as birth length and head circumference, have received little attention. However, the UK NCDS study42 found that head circumference at birth did not predict later schizophrenia.

Concerning anthropometric measures during childhood and adolescence, studies based on the 2 UK BCs, the NHSD and NCDS, found no association between childhood height, weight, and future schizophrenia.15 Similarly, in the NHSD, head circumference at age 7 did not predict schizophrenia.42 However, a male-only study from the CPC59 found that body mass index rather than height at age 18 predicted subsequent schizophrenia. A recent PDS study60 is the first BC study to examine the growth trajectory in schizophrenia. They found that early growth in schizophrenia spectrum disorder was slower during early life for females but not for males.

Two BC studies have reported on pubertal maturation (NSHD15; NCDS42). Neither study found an association between pubertal maturation and later schizophrenia. In sum, there is a relative paucity of BC studies of growth and maturation from infancy to adulthood, with only one study examining a growth trajectory.60

BCs and the Exploration of Risk Factors for Schizophrenia

The first section provided a systematic review of neurodevelopmental processes from the perspective of antecedents of schizophrenia. By studying the progression of the preclinical “phenotype” associated with schizophrenia, researchers hope that deviations in the expected trajectory of development may reveal vulnerability mechanisms that impact on these pathways. The second part of the article provides selected examples of studies that use BCs to explore more specific research questions (eg, risk factors related to susceptibility, risk factors that impact on the subsequent course of the illness, etc). The taxonomy of BC studies is by no means distinct, and studies in both sections share common conceptual frameworks.

BCs play an important role in exploring candidate risk factors associated with schizophrenia and thus have complemented data from other research designs. The potential effect of various pregnancy and delivery complications has been the topic of 6 studies based on 5 BCs (the NCDS 195817,61; the NFBC_196662; cohorts from the NCPP40,44; and the Dunedin MHDS38). Two of these studies,61,62 along with other population-based studies, were subject to a meta-analysis resulting in a modest effect size of about 2.63 However, the NFBC_1966 study found that a stringent definition of severe delivery complications led to a larger effect: schizophrenia was 7 times as common in those exposed to perinatal brain damage.62

Paternal age has been examined in 2 BC studies (JPS41 and PDS),64 with both finding that older paternal age at the birth of the offspring increases the risk of schizophrenia; while Kimhy et al30 in the JPS study found that much of an association between maternal household crowding during pregnancy and the offspring's risk of schizophrenia was explainable by the impact of paternal age. BC studies have also examined the effect of the mothers’ behavior during pregnancy. For example, 2 BCs have reported on the effects of the mother's mental health and lifestyle as a risk for schizophrenia: while studies of the NFBC_196665 and NCDS15 found an increased risk for schizophrenia in the offspring of antenatally depressed mothers. Significantly, an early study of the NCDS61 found that increased risk of OCs in schizophrenia may result from maternal physique/lifestyle rather than environmental factors or delivery complications. Two related findings are studies from the CPC (Sorensen et al26) where offspring of mothers having hypertension and/or having diuretic treatment during pregnancy had a 4-fold increased risk of developing schizophrenia (maternal schizophrenia led to a 11-fold increase) and where early weaning was associated with an increased risk of schizophrenia (adjusted odds ratio [OR] = 1.73 with 95% confidence interval = 1.13–2.67).66

A surprisingly wide range of early life exposures have been examined in BCs, which range from dry cleaning fluid67 and analgesics68 to nutritional deficiencies and infectious agents. With respect to prenatal nutrition, homocysteine, a marker of folate of metabolism, was found to be significantly elevated in the third trimester sera from mothers of individuals with schizophrenia.69,70 Developmental vitamin D deficiency, a candidate risk factor that might underlie the season of birth effect71 has been examined in 2 BCs. Absence of vitamin D supplementation was associated with an increased risk of schizophrenia in males in the NFBC_1966,72 and a trend level association between very low maternal vitamin D and an increased risk of schizophrenia was identified in NCPP-Providence sample.73 With respect to prenatal infection, studies based on the PDS have reported an association between schizophrenia and (a) rubella74 and (b) various respiratory infections (including influenza).75 Archived biological samples from BCs have also helped to clarify the ambiguous associations between prenatal infection and schizophrenia found at ecological studies (reviewed by Brown and Susser76). Based on banked sera, increased risk of schizophrenia/psychosis has been associated with prenatal exposure to influenza,77 genital and reproductive infections (PDS),78 Toxoplasma gondii,70 and herpes simplex virus type 2.79 However, a subsequent PDS study failed to confirm the specific finding on IgG and herpes simplex virus type 2.80 While most studies have focus of prenatal exposure, cerebral infection in childhood may also be a risk for later schizophrenia.81,82

With respect to psychosocial risks factors, a study based on the NFBC_1966 reported that the risk of later schizophrenia among “unwanted children” showed a 2.4-fold increase compared with wanted or mistimed children.83 This finding has received some support from a PDS study.84 However, there is mixed evidence on whether separation from parents presents a risk. In the NCDS,42 preschizophrenia children were more likely to have been in care, experienced parental separation, or loss or been referred to a specialist for emotional problems.

Similarly there is mixed evidence from cohort studies based on various designs on whether low, medium, or high socioeconomic status (SES) in the family of origin presents an increased risk of schizophrenia (reviewed by Bresnahan et al85). Studies of BC have produced some interestingly findings. For example, an early study from the NSHD UK194615 found no association between schizophrenia and low social class (or urban/rural birth or population size of place of birth). A later NFBC_1966 study86 found that schizophrenia was associated with the father's higher social class (interestingly, these fathers often also showed serious psychopathology, especially alcoholism). Consistent findings of higher rates of schizophrenia in migrants and urban areas have highlighted that social risk is more complex than SES per se.87 Curiously, Bresnahan et al88 have recently examined the relationship between ethnicity and the incidence of schizophrenia in the PDS—a higher incidence of schizophrenia was found in the African American cohort members, which was still significant after controlling for family SES.

Aspects of early rearing may also present a risk for schizophrenia. For example, an effect has been found for birth order in the NFBC89 and for disturbances in parent-child relationships in the NSHD UK1946 BC15 and in the Dunedin MHDS BC.38 Other family-related factors have not shown an association with schizophrenia in NFBC_1966 studies, such as living in a single-parent family90 or being a member of a large family.91 While not necessarily arising from within the family, childhood abuse as a risk factor has recently received increased attention as a risk factor for schizophrenia.92,93 As far as we are aware, this topic has not been examined in a BC study.

Various exposures during later childhood or adolescence may also constitute risks for schizophrenia. For example, in the NFBC_1966, Riala et al94 found that initiation of smoking may signal the prodromal phase of schizophrenia. BC studies are also providing evidence that cannabis use is an independent risk factor for schizophrenia. A study based on the Dunedin cohort found cannabis use at age 15 and 18 increased the risk of psychotic symptoms or schizophreniform disorder at age 26 (with an OR = 11.4 for those using cannabis before age 15).95 No association was found for other substances. Importantly, they also assessed the presence of psychotic symptoms at age 11 and found that the cannabis use and increased psychosis-risk association was independent of preexisting psychotic symptoms. Another New Zealand–based BC (the Christchurch Health and Development, which has not yet included schizophrenia as an outcome measure) found daily users of cannabis had rates of psychotic symptoms that were between 2.3 and 3.3 times higher than those for nonusers.96 Although the evidence from the prospective cohort studies suggests a possible causal link between cannabis use and psychosis, most people who smoke cannabis do not develop schizophrenia. A gene-environment interaction has been proposed, with some individuals being genetically vulnerable to the effects of cannabis.97 A study using the Dunedin BC tested this hypothesis and found that a functional polymorphism of the catechol-O-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on adult psychosis.98

Finally, BCs can provide convenient platforms for the exploration of a range of factors related to schizophrenia outcomes and comorbidity. For example, one study found seasonality in schizophrenia admissions,99 and another associated duration of first hospitalization with risk of readmission.100 A number of NFBC_1966 studies have examined comorbid physical disorders101 and mortality risk.102 More recent studies have targeted lipid levels and medication,103 metabolic syndrome,104 and weight gain.105 Other studies have examined clinical and psychosocial sociodemographic correlates of schizophrenia.106,107 BC studies have also been involved in studying brain morphology and function in schizophrenia. For example, an early NSHD UK1946 study of laterality108 found that at age 11 preschizophrenia cohort members had excess left eye dominance. A later NFBC_1966 study109 found no differences between schizophrenia groups and controls in hippocampus and amygdala characteristics. The use of BCs to examine the course and outcome of schizophrenia will be the subject of a future review article.

Discussion

BC studies have identified subtle developmental deviances from infancy, through childhood and adolescence into adulthood in many individuals who develop schizophrenia. The behavioral, motor, and neurocognitive antecedents of schizophrenia have been documented in several independent studies. BC studies have also contributed evidence about a wide range of putative risk factors for schizophrenia. These studies generally support findings on antecedents made by studies based on other designs—such as high-risk studies.110,111

In general, the antecedents of schizophrenia are subtle in terms of the effects estimated from measures available in most BC studies. Those who develop schizophrenia do not form a readily identifiable subgroup but tend to have a slight shift in distribution of the variable of interest.15 Thus, these measures have weak positive predictive value.110 However, predictive value depends on prevalence; for rare disorders, such as schizophrenia, trying to distinguish early instances of premorbid symptoms from the general population is difficult.55 Nevertheless small, nonspecific effects are common to most genetic and environmental risk factors for complex diseases.112 Nonspecificity could mean that intervention to reduce childhood behavioral or neurocognitive dysfunction could avert a range of disorders—including schizophrenia.15 This is borne out by the Dunedin cohort finding that 75% of adults with a psychiatric disorder had a diagnosable disorder as children.113

The precise nature of the deviations is not always shifted toward impairment. Some researchers have suggested that deviations from the norm in either direction (ie, either inferior or superior performance) may be risk factor for schizophrenia.110 Furthermore, the division between antecedents as passive risk indicators vs active risk–modifying factors is somewhat artificial. They may be better conceptualized as interactive domains leading to a developmental cascade.114,115

BC studies have important limitations. For example, like any observational study, participants are not randomly assigned to exposures; thus, any observed associations may be confounded by an unmeasured factor (ie, residual confounding). Also, there is a lengthy lag between the initiation of the BC and the age when schizophrenia becomes clinical prominent.116 In fact, we found that many BCs are “young”—cohort members would not have passed through their full period of risk for schizophrenia. For example, while the UK BCs age at follow-up was 43 years, the MUSP age at follow-up was 21 years. This generally results in a limited number of cases and reduced power to detect associations particularly when stratified by sex and controlling for confounding effects. In addition, because the cohorts require decades of follow-up in order to examine schizophrenia, period (or secular) effects may limit the application of the results to more recently born groups. Also longitudinal studies are beset with some degree of attrition. Practically, BCs benefit from a relatively stable population, considerable financial support, and the ability to link records across population-based registers. For these reasons, BCs are currently restricted to developed countries. Furthermore, like studies using other design, BC studies have not examined protective factors that reduce to the risk of mental disorders, a need recently highlighted by Patel and Goodman.117

Thus, apart from focusing more on comparing developmental trajectories based on individual measures (rather than group means),39,45 future BC studies could play a pivotal role in identifying both protective and promotive factors influencing the transition from vulnerability to psychosis. This would complement the important work conducted in high-risk cohorts.110,111 Typically, BCs are rich with data, with a wide range of variables from many different domains collected over many years. The variables are usually selected to cover health and development in general, not psychotic disorders. Thus, BC lend themselves to more integrative and sweeping models and analyses. For example, Isohanni et al110 have proposed a lifespan model of causation which encompasses biological, social, and psychological elements and which can capture the interplay between multiple risk factors over time, mapping out of a life course. These models incorporate such elements as cumulative insults over the life course, critical periods of susceptibility throughout life, and interaction between early and late factors. Such models are transforming our understanding of chronic physical disorders118 and can enhance the discoveries emerging from genetics. The ability to examine both genetic factors and a wide range of environmental exposures prior to the onset of the illness provides a powerful discovery platform for gene by environment studies. For example, BCs have been able to link particular genetic susceptibilities (eg, polymorphism in the 5-HTT gene), with related exposures (stressful life events) and later depression.119

While some environmental risks can be modeled at the individual level (eg, exposure to an infectious agent), other factors are best examined at the level of the family, neighborhood, or society.120,121 Multilevel studies can capture both ecological level variables (eg, a neighborhood marker of social capital or poverty) and individual level variables (eg, experience-sampling methodology to assess changes in individual stress levels). Developments in statistical modeling may help this endeavor. For example, multilevel regression has been used to examine the effects of both individual and community socioeconomic variables on risk of schizophrenia in a BC study.122

We can expect more BC publications on schizophrenia in the decades to come. New BCs include the 1970 British BC Study,123 the Avon Longitudinal Study of Parents and Children study in Britain (commenced 1991–1992),124 the Danish National Birth Cohort (commenced 1996),125 the Northern Finland Cohort 1986,126 and the National Children's Study currently underway in vanguard centers across the United States.127

We have entered the new age of epidemiology of schizophrenia.21,128 The combination of new paradigms and larger cohorts, with the tools of modern epidemiology and biomedical science, is advancing our understanding of the developmental pathways to schizophrenia. BC studies provide important insights into how the developmental trajectory of individuals who develop schizophrenia differs from their peers. BC studies provide important temporal information related to various risk factors. However, their most important contribution may lie in providing both the epidemiological context and biological samples necessary to examine the interplay of genetic and environmental factors in the etiology of schizophrenia.

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