60464ournal ofNeurology, Neurosurgery, and Psychiatry 1996;61:604-613 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from NEUROEPIDEMIOLOGY

Schizophrenia

Mary Cannon, Peter Jones

Psychiatric epidemiology is the study of the studies of time trends and outcome in schizo- distribution and causes of in phrenia. Also, the commitment to a phenotype the population. Over the past 30 years based on symptoms in adult life may have progress in psychiatric epidemiology has been ignored an important developmental or life- slower than in other areas-for example, car- long dimension to the disorder. diovascular disease or cancer epidemiology, because of certain methodological problems AS A "RARE DISEASE" that are just now being overcome. In particular The low incidence (10-40 cases per 100 000 the epidemiology of schizophrenia has suffered per year) and relatively low lifetime prevalence from two major difficulties: uncertainty about (0 5%-1 %) of schizophrenia in the population how to define a case, and the relative rarity of have led to a reliance on case-control study schizophrenia in the population. designs in research. Chronic patients recruited from hospital wards are compared with volun- teer controls from the community and conse- Special methodological problems in quent problems of bias and confounding have schizophrenia epidemiology often led to unreplicated and contradictory WHAT IS A CASE findings. It seemed for a time that schizophre- The lack of physical signs or laboratory tests nia, already known as the "graveyard of neu- means that a diagnosis of schizophrenia is ropathologists",7 would also prove to be the based on evaluation of patients' self reported, undoing of epidemiologists. Over the past two subjective experiences. Until the late 1960s, decades, however, the application of advances there was a relatively loose definition of schizo- in case-control methodology to psychiatric phrenia and a good deal of diagnostic latitude epidemiology has led to more robust results.8 was allowed to individual psychiatrists. How- Also, cohort designs, for long thought too http://jnnp.bmj.com/ ever, a report published in 1972,' showed that costly and time consuming to use in schizo- the diagnostic habits of psychiatrists in the phrenia research, have made a "comeback". United States and United Kingdom differed to For the purposes of this review schizophre- an unacceptable degree, and led to the intro- nia refers to a recent, operational definition duction of strict operational diagnostic criteria such as CATEGO,9 ICD-10, DSM-III, DSM- for schizophrenia. The Diagnostic and III-R, or DSM-IV. Robust findings are those Statistical Manual DSM-III,2 published in from studies with an epidemiological design-

1980, reduced the reliance on symptoms alone that is, population based studies with well on September 29, 2021 by guest. Protected copyright. by incorporating an element of chronicity-six defined samples and appropriate controls. We months prior duration of symptoms and an aim to show how the findings from robust epi- upper age limit of 45 years for a first diagnosis demiological research can help to unravel the of schizophrenia. Since 1980 there have been complex aetiology of schizophrenia. two more restrictive revisions of this diagnostic system, DSM-III-R3 and DSM-IV,4 and the International Classification of Diseases, Geography Department of (ICD), the diagnostic system favoured by In 1978, a large multicentre study of schizo- Psychological European psychiatrists, has also undergone a phrenia was initiated by WHO the 10 country Medicine, Institute of similar "narrowing" process with the change study (also known as the Determinants of Psychiatry, Denmark Hill, London SE5 8AF, from ICD-9 to ICD-10.5 Outcome of Severe Mental Disorders Study), UK But has this process gone too far? Although to provide information about the incidence, M Cannon the restrictive diagnostic criteria have certainly course, and outcome of schizophrenia in dif- Department of increased the reliability of the diagnosis, they ferent cultures.10 Two case definitions of schiz- Psychiatry, University have not improved the validity of "DSM-IV" ophrenia were used: a clinical of Nottingham, broad, Duncan Macmillan or "ICD-10 schizophrenia".6 Recent family definition comprising ICD-9 schizophrenia House, Porchester studies indicate that a broader concept of and paranoid psychoses, and a narrow, restric- Road, Nottingham schizophrenia actually fits genetic models tive definition including only cases classified as NG3 6AA, UK P Jones more readily than a restrictive definition. In "nuclear" schizophrenia using the CATEGO 9 Correspondence to: addition, the frequent changes in diagnostic computer programme Figures 1A and B Dr Peter Jones. criteria have affected the comparability of show the incidence rates for both definitions. Cannon, _rones 605 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from Figure 1 (A) Incidence of 20 of non-affective was 0.7%.12 This CATEGO S narrow schiz- FA ophrenia with 95% confi- Cu discrepancy may be related to issues of sam- m pling, interview methodology, or actual dence intervals from eight 15 H centres in the WHO change over time and remains to be clarified Determinants of Outcome 0C) Study. (B) Incidence of 0 by future reports. CATEGO S, P, and 0 10i A major prevalence study of psychiatric broad schizophrenia with 0 morbidity carried out in the United Kingdom ._0a) 95% confidence limits from -0 between and found a eight centres in the WHO 5 April September 1993,13 determinants ofoutcome .5 prevalence rate of 0 4% for functional psy- study. Data from J7ablensky C- chosis among persons aged 16-64 living in pri- et. al.'0 vate households. This rate is even lower than 0 L that found in the national comorbidity survey 6oB but as 37% of those who screened positive for Cu B Cu co 5 psychosis refused a second diagnostic inter- 0 60_ view, the true prevalence may be higher.'4 At 0 4 0 present, it seems that the lifetime prevalence of 0 0 330 _ schizophrenia in the western world lies some- C- where between 0 4% and 1-4%, and may have C.) C 220 TI decreased over the past decade. T .5'a ,o- + i C "INCIDENCE" DATA v,\ Prevalence of schizophrenia can be influenced NX by factors such as change in treatment, change It 00A in mortality rate, and changes in the age and sex structure of the population, and therefore, examination of incidence rates may be more informative. Ideally, such studies should be based on community incidence samples but, as this is difficult to achieve, case registers and There is little variation between centres for hospital admission data are commonly used. narrowly defined schizophrenia with rates Eagles and Whalley'5 first reported a decline ranging only between 7 and 14/100 000, (fig in the diagnosis of schizophrenia among first 1A). Although the parsimonious conclusion admissions in Scotland between 1969 and would be that the rates for narrowly defined 1978. There have since been 14 papers exam- schizophrenia are the same, the confidence ining this issue in England,'6-'0 Scotland,"'3 intervals for these estimates were wide and Denmark,'425 New Zealand,'6 Canada,'7 there may not have been sufficient statistical Ireland,'8 the United States,'9 and the power to detect differences. Netherlands.30 Those based on national statis- The incidence rates for broadly defined tics have found a large (40%-50%) decline in schizophrenia do seem to vary between coun- first admission rates for schizophrenia during tries 16 to 42/100 000 per and 17 18 25 26 (range year), the 1970s and the 1980s. Findings http://jnnp.bmj.com/ the rates for centres in the developing world based on case register data have been less con- are about twice as high as those in the devel- sistent and indeed, two such studies, from oped world (fig 1B). Further studies of schizo- Camberwell"7 and Salford'8 in the United phrenia in the developing world are needed to Kingdom, actually found a slight increase in replicate and further investigate these interest- the incidence of schizophrenia during the ing findings, and the problem of same period. Others have reported a decrease in the developing world can no longer remain a in first admission rates for schizophrenia low priority for funding agencies and govern- among female patients only." 2830 on September 29, 2021 by guest. Protected copyright. ments. On the whole, however, the variation The major question is whether the decrease in incidence rates for schizophrenia world noted in first admission rates corresponds to wide is very small compared with illnesses an actual decrease in the incidence of the con- such as ischaemic heart disease or cancer, dition. Many factors influence this apparent which are known to have major environmental "administrative decline" in schizophrenia: (1) risk factors. The introduction of more restrictive diagnos- tic criteria for schizophrenia may cause a shift to diagnoses such as "borderline states"24 or Time trends affective psychosis.'930 (2) The move to com- PREVALENCE DATA munity care over the past two decades could Two major prevalence studies of psychiatric have affected hospital admission rates.'7 (3) illness have been carried out in the United Clinicians have become more reluctant to States, which indicate a decrease in prevalence make a diagnosis of schizophrenia on the first of schizophrenia over one decade. The hospital admission,'4 and this could lead to a Epidemiological Catchment Area (ECA) spurious fall in incidence rates over the last Study surveyed 17 803 persons between 1980 few years of the period under observation. The and 1984 and found a lifetime prevalence of policies of private health insurance companies schizophrenia of 1-4%." The National regarding schizophrenia may be partly respon- Comorbidity Survey (NCS) interviewed 8098 sible for this effect.'9 (4) Changes in the age, people between 1990 and 1992 and found that sex, and ethnic structure of the population lifetime prevalence for the summary category over the period under study have not been 606 Schizophrenia J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from taken into account in most studies. The two MARITAL STATE areas of the United Kingdom which showed Schizophrenic patients have low rates of mar- an increased incidence of schizophrenia are riage and low fertility32-a challenge to geneti- both areas with a high proportion of immi- cists. Married patients have a better clinical grants.'7 18 Unfortunately, schizophrenia has and social outcome than single patients,1'0 such a low incidence that it may be impossible although marriage may, of course, reflect better to disentangle all these effects and reach any premorbid social adjustment and later age at firm conclusions regarding changes in inci- onset, which are both independent predictors dence in the developed world in recent of good outcome. However, the prevalence of decades.31 schizophrenia among separated or divorced people in the United States (2 9%) is similar to that among single people (2-1%), suggest- Characteristics of patients ing that marriage may confer an independent AGE AND SEX DISTRIBUTION protective effect.32 An interaction between Total lifetime risk for schizophrenia seems to marital state and gender was found in the one be equal in both sexes.1032 Schizophrenia can year follow up of the ECA study.44 Single occur at any age,3335 but onset is commonly in women were 14 times more likely to develop early adulthood-over 70% of incident cases schizophrenia than married women but single in the WHO 10 country study were between men were almost 50 times more likely to 15 and 35 years of age.'0 The mean age of develop schizophrenia than their married onset for male patients is three to four years counterparts. The role of marital state as a risk earlier than for female patients, irrespective of indicator or modifier for schizophrenia whether onset of schizophrenia is defined as deserves further study. the first sign of mental disorder, the first psy- chotic symptom, or the first hospital admis- ETHNICITY AND MIGRANT STATE sion.36-38 The peak age of onset for males is To date no single indigeneous ethnic group between 15 and 30 whereas females have a seems to have a significantly higher rate of slower and more even rate of onset with a peak schizophrenia than any other,10 although some between the ages of 20 and 35 and a second pockets of high prevalence may exist in iso- smaller peak after the age of 45, (fig 2). No lated areas like north Sweden.45 The west of satisfactory explanation yet exists for this sex Ireland46 47 and the Istrian peninsula in difference. A protective effect for female sex Croatia48 had previously been identified as hormones has been suggested,39 but has not high risk cultures but the higher rates origi- been proved empirically. The same pattern nally found among these peoples are now occurs across countries indicating that it is not thought to be due to methodological factors.49 an effect of cultural factors.10 Populations with increased prevalence, if care- fully identified, could be very useful for geneti- SOCIAL CLASS cists, but they seem to be local exceptions The long recognised association between rather than the general rule in the epidemiol- schizophrenia and low social class was con- ogy of schizophrenia.50 The ECA study found firmed by the ECA study, which showed that a higher prevalence for schizophrenia among http://jnnp.bmj.com/ schizophrenic patients in the United States black people than among white people in the were 10 times more likely to be in the lowest United States (2-1% v 1 -4%).32 However, when socioeconomic group than in the highest.35 controlled for age, gender, marital state, and Evidence from birth cohorts in Britain,40 41 and most importantly, socioeconomic group, the Finland42 show that this relation is not significant difference disappeared. Of course in a causal schizophrenic patients at birth have cross sectional study such as the ECA study, it is the same socioeconomic distribution as the not possible to state definitively that current general population. What is remarkable is the marital state and socioeconomic state com- on September 29, 2021 by guest. Protected copyright. steep decline in social state which accompa- pletely explain the association found between nies the illness and is evident even before the race and disorder, because schizophrenia can clinical onset.42 43 This decline is far greater lead to low social state and marital breakup. than that experienced by patients with severe affective disorder.4243 Schizophrenia in immigrants In 1988, the psychiatric community was sur- prised by a report that the incidence of schizo- phrenia among the Afro-Caribbean population in Nottingham was more than 10 times higher Figure 2 Distribution of than in the general population.5' This finding age at first admission for 30- has been convincingly replicated in other cen- schizophrenia in males and --Female tres in the United Kingdom5>255 and in The females. Source: Htfner et al.38 Netherlands,56 although the incidence ratio is 20 -t= Male now to be rather lower when CO thought (3-5) the C denominator is adjusted for possible underre- U) a-41 porting in census data.5455 An increased inci- 10 i' / dence ratio for schizophrenia has also been found among African5455 and Asian54 immi- grants in the United Kingdom, indicating that 12-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 the effect is not confined to a single ethnic Age group (y) minority. Cannon, _Jones 607

The hospital admission rate for schizophre- der with intermediate outcome. Prognosis in J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from nia among migrants is higher in their host schizophrenia does not seem to worsen after country than in their country of origin,57-9 five years.507' which implicates factors occurring principally The effect of changes in diagnostic criteria after migration. The risk of schizophrenia is has been highlighted in a recent meta-analysis greater among second generation migrants of outcome studies over 100 years,70 which than first generation migrants,51-54 60 arguing found that prognosis for schizophrenia has against selective migration of preschizophrenic worsened over the past decade. The more persons. The fact that immigrants from poor restrictive definitions of schizophrenia post- countries tend to show higher rates of schizo- DSM-III, predict worse prognosis, partly as a phrenia than immigrants from affluent coun- "self fulfilling prophecy", as chronicity over six tries, implies that factors associated with months is already built into the definition of improved living conditions, industrialisation, the disorder.6 or urbanisation are involved. Obstetric com- plications and exposure to novel viruses during Predictors of course and outcome pregnancy have been proposed as biological Immutable factors-Patients from developing explanations,61 62 but empirical evidence is countries have a better outcome than patients lacking. One study has found an increased risk from developed countries,' 065 but it is not for schizophrenia among the siblings of United known which aspects of non-Western culture Kingdom born Afro-Caribbean schizophrenic are responsible for this effect. Possible social patients compared with the risk among sib- factors are lower levels of expressed emotion,72 lings of white patients,63 which could indicate stronger social support networks, or lack of a gene-environment interaction effect. stigma. Ethnicity may be related to outcome Despite these intriguing clues, the evidence but conclusions are preliminary.73 Other for a unique epidemic of schizophrenia among favourable prognostic factors are good pre- certain immigrant groups, although sugges- morbid social adjustment, female sex, being tive, is not conclusive. No studies have con- married, and later age at onset,'065 but these trolled adequately for possible confounders factors are unlikely to act independently.74 such as low socioeconomic class and marital Acute onset of illness and the experience of state, which may reduce the incidence ratio negative life events before illness are also even further. It is likely that ethnicity repre- related to better outcome.6575 sents a "proxy" variable for various social and Mutable factors-High levels of "expressed perhaps biological factors. Once these are con- emotion" among close relatives-namely, crit- trolled, there may be little or no residual effect icism, hostility and, overinvolvement76 77 -pre- of ethnicity itself but we would gain informa- dict early relapse. Substance misuse'078 also tion about other, perhaps preventable, risk fac- predicts poor prognosis. The important find- tors involved. The most parsiminious ing that delay in receiving treatment results in conclusion would be that schizophrenia in poorer outcome,79-8 might be due to bias, and immigrants is caused by the same factors that confounding with certain chemical character- cause schizophrenia in other groups but that istics resulting in delayed treatment, but it is these factors are more common, (and there- possible that a more biological process is fore more conspicious), after migration. The involved, with persistence of untreated posi- http://jnnp.bmj.com/ alternatives-that there are specific causes in tive symptoms altering the "hard wiring" in immigrants which do not occur in other popu- the brain. lations or that there is true interaction with ubiquitious factors causing schizophrenia in MORTALITY only some groups-both require further Standardised mortality ratios (SMRs) for research. schizophrenic patients are estimated to be two

to four times higher than the general popula- on September 29, 2021 by guest. Protected copyright. COURSE AND OUTCOME tion,82 and their life expectancy overall is 20% Outcome studies in schizophrenia are usually shorter than for the general population.8' The based on hospital treatment samples and may most common cause of death (in 10% of not be representative of the population of patients), is suicide-the risk of suicide is 20 schizophrenic patients64; indeed, the true nat- times higher than for the general population.828' ural course of schizophrenia is almost always Young men with a chronic illness are at partic- masked by treatment these days. The results of ular risk.84 More work needs to be carried out outcome studies are difficult to summarise to identify patients at risk of suicide, and to because the definitions of outcome and meth- determine the effect of secular trends such as ods of assessment used are so varied. deinstitutionalisation on suicide rates. Deaths However, all studies attest to the striking vari- from heart disease and from diseases of ability of course and outcome of schizophre- the respiratory and digestive system are also nia.64 At the extremes of outcome, 20% of increased among schizophrenic patients.828' patients seem to recover completely after one Certainly the lower socioeconomic status episode of psychosis,65-68 whereas 14%-19% of associated with schizophrenia carries with it patients develop a chronic unremitting psy- many risk factors for physical diseases, such as chosis and never fully recover.'0 65 69 In general, smoking and poor diet, all of which are pre- clinical outcome at five years seems to follow ventable. the rule of thirds: with about 35% of patients in the poor outcome category65 69; 36% in the Risk factors good outcome category,65707' and the remain- Until recently, research into the aetiology of 608 Schizophrenia

schizophrenia focused principally on family cordance) is substantially higher for MZ than J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from relationships and social stressors. A remark- DZ twins.94 Although the average probandwise able "paradigm shift" has taken place over the concordance in MZ twins is 46% (compared past decade; schizophrenia is now considered with 14% in DZ twins),95 the offspring of dis- to be a brain disease and emphasis is placed on cordant MZ twins have all been found to share biological determinants.89 The impetus for this the same risk of developing the disorder,96 rais- change came from neuroimaging and neu- ing the possibility that the unaffected MZ twin ropathological studies showing evidence of may represent an unexpressed genotype. brain abnormalities in schizophrenic Genetic factors are undoubtedly predominant patients.86 The timing of these pathological but there is evidence (discussed below) that changes is unclear but is likely to be a defect in non-genetic factors may be involved in the early brain development.86 Profound changes aetiology of schizophrenia. The average esti- have also occurred in hypotheses concerning mate of the proportion of liability attributable neurotransmitter abnormalities in schizophre- to non-genetic factors in schizophrenia is nia. The dopamine hypothesis has been exten- 0.18.94 sively revised and is no longer a considered a primary causative model-current research What is transmitted? focuses on the interaction between different The "schizophrenia spectrum" Certain psychi- neurotransmitter systems.87 atric illnesses and personality disorders, known as the schizophrenia spectrum, are GENETIC FACTORS thought to be genetically linked to schizophre- Family studies nia. The most important of these disorders is Schizophrenia runs in families. First degree schizotypal personality disorder, and the rela- relatives of schizophrenic patients have a mor- tive risk for schizotypal personality disorder in bid risk of developing schizophrenia which is the first degree relatives of schizophrenic 10 times higher than in the general popula- probands compared with controls is about tion.88 89 The excess risk of developing schizo- five.97 98 Parents of schizophrenic patients have a phrenia occurs principally among the children higher risk of schizotypal personality disorder and siblings of patients. Parents are at lower than siblings, suggesting that individuals who risk of developing schizophrenia, probably inherit this milder genetic vulnerability are because the low fertility associated with having responsible for the maintenance of schizophre- schizophrenia means that parents are, of nia in the population.89 Within the cluster of necessity, "selected for health", and have symptoms and signs which comprise the already survived much of the period of risk.90 diagnostic entity of schizotypal personality dis- However, "familiality" of an illness does not order aloofness, poor rapport, social dys- necessarily indicate a genetic effect and can function, odd speech patterns, and avoidant also be due to environmental factors. symptoms in particular predict genetic vul- Adoption studies and twin studies allow these nerability to schizophrenia.99 effects to be examined separately. Other disorders which form part of the schizophrenia spectrum are schizoaffective dis- Adoption studies order,'00 paranoid personality disorder,98 and Results from the influential Danish adoption schizoid personality disorder,91 97 although http://jnnp.bmj.com/ study91 show that the risk for schizophrenia there is some debate about the second.98 No among the biological first degree relatives of excess of anxiety disorder or alcoholism has the schizophrenic adoptees is almost eight been found in the relatives of schizophrenic times higher than the risk among biological patients compared with the relatives of con- relatives of control adoptees.92 Preliminary trols, indicating that the genetic transmission results from another large adoption study of schizophrenia and schizophrenia spectrum

being carried out in Finland concur with these disorders is relatively specific and does not on September 29, 2021 by guest. Protected copyright. findings.93 An increased risk of schizophrenia, include a generalised liability to all psychiatric in the absence of any contact with biological illness.9 97 10' The debate about whether affec- relatives, indicates that the familial aggre- tive disorders occur to excess in the relatives of gation of schizophrenia is due largely to schizophrenic patients has not yet been genetic factors and not to some other aspect of resolved,8810102 although relatives of schizo- the familial environment. Of course the phrenic patients seem to have an increased adopted-away child has still spent the prenatal predisposition to develop psychotic symptoms period with the biological mother and there- as part of an affective illness.'o' fore prenatal environmental risk factors cannot be ruled out. However, the risk of schizophrenia spectrum disorders, (see DEVELOPMENTAL ABNORMALITIES below), was also increased in the paternal half Evidence for developmental abnormalities in siblings of the schizophrenic adoptees, schizophrenia has come from two sources of who shared neither the prenatal nor familial prospective data: (a) high risk studies and (b) environment.9 general population birth cohorts. Twin studies High risk studies Twelve major twin studies of schizophrenia The high risk study design involves following have been carried out, all of which show that up offspring of schizophrenic mothers until the risk for schizophrenia in the co-twin of a they have passed through the period of risk for schizophrenic proband (the probandwise con- schizophrenia. Only the Copenhagen high risk Cannon, 3rones 609

study'03 has completed follow up of its * Motor development milestones, in particu- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from probands, but because probands were recruited lar walking, were delayed by an average of at age 15 there are no data on early develop- 1-2 months ment. The second generation ofhigh risk studies * More speech problems (odds ratio/OR 2-8) in schizophrenia, which were started during the * Lower educational test scores at ages 8, 1 1, middle and late 1970s, began their observations and 15 on high risk children from the time of birth. * Preference for solitary play at age 4 (OR The most influential of these studies are the 2-1) New York High Risk Project,'04 the Jerusalem * When the children were aged 4, health visi- Infant Development Study,'05 and the high risk tors rated the mother as having below aver- study of Barbara Fish.'06 As the subjects are age mothering skills and understanding of now still in their teens and 20s, full information her child (OR 5 8): a finding which may on outcome in the cohorts will not be available indicate deviance in the child, the mother, for another 10 years or so, but interesting data or both. on infant and early childhood development The National Child Development Survey, also among the high risk children have already been known as the British perinatal mortality published and show a high degree of consis- survey, comprises all those born in the week tency between studies. 3-9 March 1958. Forty patients with schizo- The developmental abnormalities found in phrenia were identified from this cohort. An 25%-56% of high risk children during different investigation of childhood behavioural charac- stages of childhood can be summarised as fol- teristics found that at the age of 7 patients lows: were rated by their teachers as more socially * Neonatal period: hypoactivity; extreme varia- maladjusted than controls.41 Findings regard- tion in alertness; hypotonia; poor "cuddli- ing low IQ were similar to the 1946 cohort. ness" These developmental findings are presumed * Infancy: a delay in acquisition of develop- to show differences in the way the brain is mental milestones and a disordered pattern developing. Whether or not the developmental of acquisition of milestones-termed differences themselves modify risk, they have "pandysmaturation" by Fish'06 107 to be explained by any aetiological theory of * Early childhood: soft neurological signs, in schizophrenia, genetic or otherwise, and add a particular poor motor coordination longitudinal aspect to the phenotype. * Late childhood: deficits in information pro- cessing and deficits in attention. NON-GENETIC ENVIRONMENTAL RISK FACTORS The question which remains to be answered is Birth complications whether the children who have displayed these Case-control studies have found that schizo- neurodevelopmental abnormalities throughout phrenic patients as a group expernence more childhood will develop schizophrenia or a schiz- birth complications than controls,'09 but studies ophrenia spectrum disorder in adulthood. may have been subject to many types of bias Results from general population birth cohort including recall, selection, and publication studies (discussed below) and from a study bias."10 Three studies have used a cohort fol- based on examination of childhood "home low up design and have found modest http://jnnp.bmj.com/ movies" of schizophrenic patients'08 have repli- increases in relative risk (about 2) for schizo- cated some of these developmental findings. phrenia associated with certain birth complica- tions: chronic fetal hypoxia,"' low maternal weight,"'2 and rhesus incompatibility.'3 General population studies Population based cohort studies can overcome Place and time ofbirth

the problem of generalisability associated with There is a small increase in risk for schizophre- on September 29, 2021 by guest. Protected copyright. high risk studies. Unfortunately the information nia (OR 1.15), among people born in winter collected during childhood, although safe from or early spring.' '4 The reason for this season- selection and information bias, is often not of-birth effect is unknown, although it may be ideal. In the United Kingdom, two such studies due to infectious diseases."5 Being born in a have now reported findings concerning schizo- city seems to be associated with a slight phrenia.40 41 increase in risk for schizophrenia (OR 1 38), The National Survey of Health and after adjusting for socioeconomic factors,"6 Development, also referred to as the British although not all studies have found such an 1946 birth cohort, comprises a sample of 5362 effect.40 Urbanisation, like social class, is a people born in the week 3-9 March 1946, who proxy measure for many other risk-increasing have been regularly followed up over four agents which are likely to operate synergisti- decades. Jones and colleagues40 identified all cally. cases of schizophrenia (30 in total) from this cohort and using the detailed, unbiased assess- Prenatal risk factors ments made during childhood, investigated Ecological studies have shown a modest childhood developmental risk factors for adult increase in risk of schizophrenia (OR 2 0), schizophrenia in these patients using the associated with exposure to influenza in the remaining sample as a comparison group. second trimester of fetal life, particularly for Children who went on to develop schizophrenia the 1957 influenza epidemic."7-"9 Cohort fol- as adults could be distinguished from their low up studies have had low power to examine peers in the following ways: this association,'20 121 and the case remains 610 Schizophrenia

unproved. Nutritional deficiency during the Gene-environment interaction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from first trimester may also increase risk (OR Traditional aetiological models have consid- 2 0).122 123 One intriguing, although unrepli- ered vulnerability to schizophrenia as the sum cated, study from Finland found that the risk of the impact of genetic and environmental of schizophrenia was higher (OR 6 2) among risk factors-an additive model. But the con- offspring of women who lost their spouse dur- cept of gene-environment interaction that is, ing pregnancy than for those whose spouse genes controlling sensitivity to the disease- died during the child's first year, possibly indi- predisposing effects of the environment, can cating that severe maternal stress can affect no longer be neglected,128 with many examples fetal development.'24 being found in the fields of medicine'29 and psychiatry. 130 Heavy cannabis intake Both psychosocial and biological environ- Heavy cannabis consumption at the age of 18 mental factors may interact with genetic vul- was associated with an increased risk, adjusted nerability to increase the risk for for confounders, of later psychosis (OR 2 3) in schizophrenia. Initial results from the Finnish a large cohort of military conscripts in adoption study of schizophrenia show a Sweden.125 A dose-response relation was con- greater risk of psychosis among the biological vincing but the direction of causality remains offspring of schizophrenic mothers who were in question. placed in poorly functioning adoptive homes than among those in well functioning adoptive Cerebral ventricular enlargement homes.93 High risk children who were reared Small case-control studies have been the in a kibbutz had increased rates of schizophre- mainstay of neuroimaging research in schizo- nia in adulthood compared with those who phrenia and findings are remarkably contra- were reared in family homes, whereas control dictory. 126 It is likely that the previously (low risk) children reared in a kibbutz had no mentioned problems of bias, confounding, increased risk of psychopathology.'3' A series and inadequate power are at least partly of analyses from the Copenhagen high risk responsible. The most consistent finding is study has shown that birth complications may that schizophrenic patients have larger lateral interact with genetic factors to increase the cerebral ventricles than controls. The level of risk of schizophrenia.92 132133 risk associated with ventricular enlargement, In other words, the pathogenic effects of adjusted for intracranial volume, age, sex, eth- birth complications, an adverse adoptive nicity, and social class, is about 2-0, although home, or some aspect of life in a kibbutz seem the whole notion of categorical definitions of to increase risk of schizophrenia only in chil- pathology in terms of enlargement or shrink- dren who already have some degree of genetic age has been challenged.'27 vulnerability. Although the evidence is prelim- inary, it indicates that the environment should RISK FACTORS AS CLUES TO AETIOLOGY no longer be considered a "nuisance variable" Examination of the effect sizes of various risk by psychiatric geneticists. Common environ- factors can give clues to causation. The table mental factors may work in combination with shows that only genetic risk factors come any- rare high risk genotypes to maintain schizo- where near the effect size expected for a strong phrenia in the population. http://jnnp.bmj.com/ causal agent in schizophrenia. However, the existence of so many environmental risk factors NEW STRATEGIES IN MOLECULAR GENETICS with small effect sizes cannot be ignored. These The search for the "psychosis gene"'134 has met may be proxy measures for an as yet unrecog- with substantial difficulties, including lack of a nised major environmental causal agent, or may valid phenotype; the possibility of genetic het- act additively with each other or with chance erogeneity; the possibility of environmental

events. They could also indicate the existence effects acting alone or in combination with on September 29, 2021 by guest. Protected copyright. of gene-environment interactions. genetic factors; and lack of knowledge about the exact mode of transmission.94 Traditional linkage techniques are only able to exclude the existence of single major genes. As the genetic Best estimate sizes ofvarious genetic and environmental risk factorsfor schizophrenia aetiology of schizophrenia is likely to be com- (expressed as odds ratios or relative risks) plex, involving genes of small effect, new tech- Best estimate of niques, and strategies are necessary.9094 134 Category of nrsk factor Specific risk factors effect size Genetic* MZ twin of schizophrenic patients 46 Linkage studies Child of two parents with schizophrenia 40 for of DZ twin of schizophrenic patient 14 Linkage strategies detecting genes small Child of one schizophrenic patient 10 effect include non-parametric techniques, Sibling of schizophrenic patient 10 such as Parent of schizophrenic patient 5 affected sib pair and affected relative Developmentalt Delayed milestones 3 pair approaches, which make no assumptions Speech problems 3 about mode of transmission. A recent Cerebral ventricular enlargement 2 varia- Postnatal Immigrant/ethnic minority status 5 tion on the sib pair design is the quantitative environmentt Chronic cannabis consumption 2 trait locus which involves Solitariness as child 2 approach measuring Prenatal and perinatal Birth complications 2 liability to schizophrenia as a continuous vari- environmentt Severe undemutrition (1st trimester) 2 able in 136 The Maternal influenza (2nd trimester) 2 siblings.135 application of the Born in city 1-4 techniques of behavioural genetics to the study Born in winter/early spring 1.1 of schizophrenia is likely to prove a fruitful *Relative risks; todds ratios area for the future.'35 Cannon,3'ones 611

After a false positive report of linkage on studies of risk factors and developmental J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.604 on 1 June 1996. Downloaded from chromosome 5,137 current interest centres on abnormalities in those with known genetic vul- chromosome 22138 and particularly on chro- nerability for schizophrenia-for example, sib- mosome 6.139 A large study of 265 Irish multi- lings; the use of new molecular genetic plex families has found evidence for linkage on strategies-including behavioural genetics- chromosome 6p24-22 using a model assuming and the study of gene-environment interac- a broad phenotype and genetic heterogene- tions. If current progress in epidemiological ity.'39 This locus is thought to confer suscepti- and genetic research in schizophrenia contin- bility to schizophrenia in 1 5%-30% of ues, it is likely that the aetiology of this com- families studied. plex disorder will at least begin to be unravelled before the "decade of the brain" is Association studies over. Allellic association studies, which compare the MC is supported by a Wellcome Trust Research Training frequency of marker alleles in a sample of Fellowship in clinical epidemiology. patients compared with ethnically matched controls, are another method useful for exam- ining genes of small effect."37 An association 1 Cooper JE, Kendell RE, Gurland BJ, et al. Psychiatric between HLA A9 and schizophrenia has been diagnosis in New York and London. Oxford: Oxford University Press, 1972. found, but this effect is weak (OR 1 6), and its 2 American Psychiatric Association. Diagnostic and statistical significance is uncertain.90 Another promising manual. 3rd ed. Washington DC: APA, 1980. 3 American Psychiatric Association. Diagnostic and statistical area for the future is the use of newly devel- manual. 3rd ed, revised. Washington DC: APA, 1987. oped DNA polymorphisms to examine candi- 4 American Psychiatric Association. Diagnostic and statistical manual. 4th ed. Washington DC: APA, 1994. date genes (genes coding for proteins which 5 World Health Organisation. TheICD-10 classification of are likely a priori to be involved in the patho- mental and behavioural disorders: diagnostic criteria for research. Geneva, Switzerland: WHO, 1994. genesis of schizophrenia)-for example, genes 6 Andreasen N. Changing concepts of schizophrenia and involved in neurodevelopment. 140 This the ahistorical fallacy. Am Jf Psychiatry 1994;151: 1405-7. approach offers the possibility of elucidating 7 Plum F. Prospects for research on schizophrenia. 3. the cause of schizophrenia at a cellular level, Neuropsychology. Neuropathological findings. Neuro- sciences ResearchProgram Bulletin 1972;10:384-8. bridging the gap between epidemiology and 8 Lewis G, Pelosi A. The case-control study in psychiatry. the basic sciences. Brj Psychiatry 1990;157: 197-207. 9 WingJK, Cooper JE, Sartorius N. The measurement and classification of psychiatric symptoms. Cambridge: Cambridge University Press. 1974. 10 Jablensky A, Sartorius N, Emberg G, et al. Schizophrenia: Conclusion manifestations, incidence and course in different cul- Schizophrenia occurs in all countries and in all tures. A World Health Organisation ten country study. races. On the whole, there is little variation Psychol Med 1992; monograph supplement 20. in 11 Keith SJ, Regier DA, Rae DS. Schizophrenic disorders. incidence or prevalence between countries, In: Robins LN, Regier DA, eds. 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The prevalence of psychiatric morbidity. OPCS survey of psychiatric morbidity in among patients. However, on the positive side, Great Britain. BrJ Psychiatry 1996;168:1-3. the clinical outcome is not as hopeless as previ- 15 Eagles JM, Whalley U. Decline in the diagnosis of schizo- phrenia among first admissions to the Scottish mental ously thought-almost 20% of patients make a hospitals from 1969-78. Br J Psychiatry 1985;146: full recovery after the first episode of psychosis 151-4. and there is suggestive, although not conclu- 16 Der G, Gupta S, Murray RM. Is schizophrenia disappear- ing? Lancet 1990;335:513-6. on September 29, 2021 by guest. Protected copyright. sive, evidence for a decrease in incidence in 17 Castle D, Wessley S, Der G, Murray RM. The incidence of the developing operationally-defined schizophrenia in Camberwell world. 1965-84. BrJPsychiatry 1991;159:790-4. The aggregation of schizophrenia in fami- 18 Bamrah JS, Freeman HL, Goldberg DP. 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