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Schizophrenia Research 60 (2003) 239 ­ 258 www.elsevier.com/locate/schres

Review

Childhood developmental abnormalities in schizophrenia: evidence from high-risk studies

Laura T. Niemi*, Jaana M. Suvisaari, Annamari Tuulio-Henriksson, Jouko K. Lonnqvist ¨

Department of Mental Health and Alcohol Research, KTL, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland Received 14 September 2001; accepted 13 February 2002

Abstract According to cohort studies, individuals who develop schizophrenia in adulthood show developmental abnormalities in childhood. These include delays in attainment of speech and motor milestones, problems in social adjustment, and poorer academic and cognitive performance. Another method of investigating developmental abnormalities associated with schizophrenia is the high-risk (HR) method, which follows up longitudinally the development of children at high risk for schizophrenia. Most HR studies have investigated children who have a parent with schizophrenia. This review summarizes findings concerning childhood and adolescent development from 16 HR studies and compares them with findings from cohort, conscript, and family studies. We specifically addressed two questions: (1) Does the development of HR children differ from that of control children? (2) Which developmental factors, if any, predict the development of schizophrenia-spectrum disorders in adulthood? While the answer to the first question is affirmative, there may be other mechanisms involved in addition to having a parent with schizophrenia. Factors which appear to predict schizophrenia include problems in motor and neurological development, deficits in attention and verbal short-term memory, poor social competence, positive formal thought disorder-like symptoms, higher scores on psychosis-related scales in the MMPI, and severe instability of early rearing environment. D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Childhood developmental abnormalities; Schizophrenia; High-risk method

1. Introduction The hypothesis that schizophrenia is a neurodevelopmental disorder is supported by several lines of evidence (Weinberger, 1995). Abnormalities in brain development and maturation seem to begin prenatally,

Corresponding author. Tel.: +358-9-4744-8894; fax: +358-94744-8478. E-mail address: [email protected] (L.T. Niemi).

*

but may continue throughout childhood (Woods, 1998). Minor physical anomalies, manifesting as slight anatomical defects of the head, hair, eyes, mouth, hands, and feet, and thought to be caused by some injury during the first or second trimester of fetal life, are more common among patients with schizophrenia than in their unaffected siblings or the general population (Murphy and Owen, 1996; Ismail et al., 1998). Obstetric complications, particularly hypoxicischemia-related complications, increase the risk for

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later development of schizophrenia (Zornberg et al., 2000; Geddes and Lawrie, 1995). Neuropathological findings suggest abnormalities in brain development among patients with schizophrenia; absence of gliosis suggests, although does not prove, that they may be of fetal origin (Heckers, 1997; Dwork, 1997). Infections and malnutrition during pregnancy may also increase the risk for later developing schizophrenia (Susser et al., 1996; Mednick et al., 1988; Barr et al., 1990; Brown et al., 2000). If schizophrenia is a consequence of abnormal neurodevelopment, it seems reasonable to assume that abnormality in development would somehow manifest itself during childhood. Follow-back, cohort and conscript studies have demonstrated associations between adult-onset schizophrenia and delays or abnormalities in childhood or adolescent emotional, cognitive, motor and/or social development. These include delays in the attainment of early childhood motor milestones (Jones et al., 1994), problems in motor coordination (Crow et al., 1995; Rosso et al., 2000) as well as other problems in neuromotor development (Fish et al., 1992; Walker et al., 1999; Cannon et al., 1999; Rosso et al., 2000), worse performance in cognitive tests or lower IQ than among control children (Crow et al., 1995; David et al., 1997; Kremen et al., 1998; Davidson et al., 1999; Cannon et al., 2000), problems with speech (DeLisi et al., 1991; Jones et al., 1994; Bearden et al., 2000), and difficulties in social adjustment (Walker et al., 1993; Crow et al., 1995; Malmberg et al., 1998; Davidson et al., 1999; Bearden et al., 2000). However, two Finnish cohort studies found no difference in school marks in academic subjects between children who later developed schizophrenia and other cohort members (Isohanni et al., 1998; Cannon et al., 1999), the other even found that excellent school marks were more common among males who later developed schizophrenia than among males with no psychiatric disorders (Isohanni et al., 1999). There are certain weaknesses in these study designs. Deficient data, sampling problems, and the different practices of doctors when examining patients and recording findings, may have caused bias in follow-back studies. Although cohort and conscript studies are prospective and the data reliable, they can never provide very detailed information because thousands of individuals are typically assessed. As the

morbidity of schizophrenia in the general population is quite low, a study method has been developed to enrich the sample with individuals who later develop schizophrenia. This method is called the High-Risk (HR) method. High-Risk (HR) research refers to a method of studying the etiology of a disorder by investigating individuals who have an increased risk for developing it (Cornblatt and Obuchowski, 1997). The most important risk factors for schizophrenia are genetic: heritability estimates from the most recent twin studies are as high as 83% (Cannon et al., 1998; Cardno et al., 1999). Because conclusive evidence for any particular environmental factor being a risk factor for schizophrenia has been lacking, it has not been possible to identify children with an increased risk of developing schizophrenia because of an exposure to an environmental risk factor, and the only feasible method to identify such children has been to investigate those with a positive family history of the disorder. HR studies of schizophrenia have typically followed up the offspring of an affected parent(s), because the risk of developing schizophrenia among such individuals is approximately 10% increasing to almost 50% if both parents are affected, compared with 1% risk in the general population (Gottesmann, 1994). HR research for schizophrenia started in the 1920s with small studies of children of psychiatrically ill mothers. The New York Infant Study, begun in 1952, was the first to add longitudinal follow-up to the study design (Fish et al., 1992). HR studies of schizophrenia attempt to study genetic and environmental risk factors and their interaction in the etiology of schizophrenia, and to identify early indicators of emerging schizophrenia. To simplify, the approximate contribution of genetic risk can be studied by comparing HR offspring with control children, and the approximate contribution of environmental factors by comparing HR offspring who develop schizophrenia with those who remain unaffected. Indicators of emerging schizophrenia can be studied by repeated examinations through childhood and adolescence, and then in adulthood by comparing offspring who developed schizophrenia with those who did not. The HR method is better for studying such indicators, for example neuropsychological deficits, because the functioning of persons who already have schizophre-

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nia may simply reflect epiphenomena related to the disorder (Mednick and McNeil, 1968). The advantage of the HR method is that the information is prospectively collected and can be quite detailed. When adulthood psychiatric morbidity and its determinants among HR children are investigated, an ideal control group exists already: those HR children who remained unaffected. These benefits of HR research outweigh the disadvantages of the method, the most important of these being that HR children who develop schizophrenia represent a highly familial form of schizophrenia, and the findings may not be generalizable to less familial forms of the disorder. The aim of this review is to summarize the findings from HR studies concerning childhood development. We specifically wanted to address two questions: (1) Does the development of HR children differ from that of control children? (2) Which developmental factors, if any, predict the development of schizophrenia-spectrum disorders in adulthood?

2. General characteristics of the HR studies The articles reviewed here were identified by Medline searches using the key words ``schizophrenia'' and ``high-risk'' for papers published from January 1966 until February 2001, and from the bibliographies of the publications thus obtained. In addition, we searched Medline using the names of the principal investigators of each study. We only included studies in which the definition of high-risk status was based on genetic risk: having a biological relative with schizophrenia. However, we excluded adoption studies because adopted-away offspring of schizophrenic parents may not have been exposed to the same type of environmental factors as other HR children. Studies which included less than 20 schizophrenia HR offspring were excluded, with the exception of the first genuine HR study, the New York Infant Study. The following 16 HR studies are included in this review: the New York Infant Study, the High-Risk Studies of the National Collaborative Perinatal Project (NCPP), the Copenhagen High-Risk Study, the St. Louis Risk Research Project, the Minnesota HighRisk Study, the Israeli High-Risk Study, the Rochester Longitudinal Study, the New York High-Risk Study, the Stony Brook High-Risk Study, the University of

Rochester Child and Family Study, the Jerusalem Infant Development Study, the Swedish High-Risk Study, the Helsinki High-Risk Study, the Emory University Project, and the Edinburgh High-Risk Study. Table 1 summarizes their general characteristics. There may be small inaccuracies concerning sample sizes, birth years, and ages at follow-ups, because there was some variation in these between different publications from the same study. The reported sample size in the Minnesota HR Study includes only the first phase of the study conducted by Rolf during 1968­ 1969, because the sample size of the subsequent study by Marcus (conducted in 1972) was not available (Garmezy and Devine, 1984). The reported sample sizes in the New York HR Study and the Jerusalem Infant Development Study include siblings who were recruited into the studies later. The Rochester Longitudinal Study, the Jerusalem Infant Development Study and the Swedish HR Study began when the mothers were pregnant. Data collection in both NCPP HR studies also began when the mothers were pregnant, although the follow-ups as HR studies began only later. All the others began when the offspring were children or adolescents. The offspring have been followed-up until adulthood in the New York Infant Study, the Copenhagen HR Study, the Israeli HR Study, and the New York HR Study. The first reports from the ongoing follow-up of the Edinburgh HR Study have also been published (Johnstone et al., 2000). The New York Infant Study (Fish et al., 1992) was the first HR Study. It was initiated in 1952 to test the pandysmaturation hypothesis, which postulated that the inherited part in schizophrenia was a neurointegrative defect. Although the children underwent a comprehensive and systematic examination, the sample size was small, only 12 HR children and 12 controls (Fish, 1987). The Copenhagen HR Study (Parnas et al., 1999), the first statistically notable HR study, has a special focus on psychophysiological measurements and brain imaging, although it has also collected a wealth of obstetric and developmental data. Besides having one of the largest study samples, it also has the longest follow-up time. The National Collaborative Perinatal Project has collected information on pregnancy, delivery, and

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Table 1 General characteristics of the HR studies for schizophrenia Study The New York Infant Study (Fish, 1987) The Boston NCPP HR Study (Rieder et al., 1977) The Boston and Providence NCPP HR Study (Goldstein et al., 2000) The Copenhagen High-Risk Study (Mednick and Schulsinger, 1968) The Israeli HR Study (Marcus et al., 1987; Mirsky et al., 1995a) St. Louis Risk Research Project (Worland et al., 1984a) The Minnesota HR Study (Rolf, 1972; Garmezy and Devine, 1984) Beginning year 1952 Area New York, NY, USA 1959 Boston, MA, USA Boston, MA, USA; Providence, RI, USA Denmark Inclusion criteria Mother DSM-I sch Offspring's year of birth 1952 ­ 1953, 1959 ­ 1960 1959 ­ 1966 Sample size HR = 12, C = 12 HR = 93, C = a Follow-ups (age) 0, 9 ­ 10, 15 ­ 16, 18 ­ 19, 20 ­ 11, 27 ­ 34 years 0, 4, 8 months, 1, 4, 7 years 0, 4, 8 months, 1, 4, 7 years

1959

1959

Parent sch (criteria described in Rieder et al., 1975) Parent DSM-IV sch or aff

1959 ­ 1966

HRsch = 118, HRaff = 126, C = 165 HR = 207, C = 104

1962

Mother sch (project criteria, later DSM III) Parent sch (hospital records, later DSM-III-R) Parent DSM-II sch or aff

1942 ­ 1952

10 ­ 20, 15 ­ 25, 20 ­ 30, 28 ­ 38, 34 ­ 48 years 8 ­ 15, 14 ­ 21, 23 ­ 30, 31 ­ 40 years 7, 10, 13, 16, 19, 22, > 25 years 13 ­ 23 years

1964

Israel

1952 ­ 1959

HR = 50, C = 50

1966

St. Louis, MO, USA

1955 ­ 1961

1968

Minnesota, MN, USA

Mother DSM-II sch (case records, later project criteria described in Nuechterlein, 1984)

1952 ­ 1959

The Rochester Longitudinal Study (Sameroff et al., 1984, 1987) The New York High-Risk Study (Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling and Cornblatt, 1987, 1992; Erlenmeyer-Kimling et al., 1997, 2000) The Stony Brook High-Risk Project (Weintraub, 1987; Weintraub and Neale, 1984) The University of Rochester Child and Family Study (Wynne et al., 1987) The Jerusalem Infant Development Study (Marcus et al., 1981, 1993)

1970

Rochester, NY, USA

Mother DSM-II sch, de, or pd

1970 ­ 1973

A: 1971 B: 1977

NY, USA

A: Parent sch or aff (DSM II, later RDC) B: Parent RDC sch or aff

A: 1959 ­ 1965 B: 1965 ­ 1972

HRsch = 100, HRaff = 60, C = 130, Cphys = 78 HRsch = 28, Csch = 56, HRint = 26, Cint(HR) = 52, Int = 27, Cint = 54, Ext = 26, Cext = 52 HRsch = 29, HRde = 58, HRpd = 40, C = 57 A: HRsch = 84, HRaff = 67, C = 136 B: HRsch = 46, HRaff = 39, C = 65 HRsch = 80, HRmdd = 154, HRbp = 134, C = 176 HRsch = 20, HRaff = 38, HRop = 10, other = 77 HRsch = 29, other = 30, C = 27

0, 4 months, 1, 2.5, 4 years

six assessments, first 9 years, latest 30 years

1971

Stony Brook, NY, USA

Parent sch, bd, or mdd (DSM-II, later DSM III) Parent sch, aff, op, or other (DSM-II, later DSM III) Parent sch, pd, neu or affective disorder (DSM-II, later RDC)

1956 ­ 1964

7 ­ 15, 10 ­ 18, >18 years

1972

Rochester, NY, USA

1963 ­ 1972

4, 7, 10, 13 years

1973

Israel

1973 ­ 1977

0, 3, 14 days, 4, 8, 12 months, 7 ­ 14, 14 ­ 21 years

L.T. Niemi et al. / Schizophrenia Research 60 (2003) 239­258 Table 1 (continued ) Study The Swedish High Risk Study (McNeil and Kaij, 1987) Beginning Area year 1973 Southwest Sweden Inclusion criteria Mother RDC psychosis Offspring's year of birth 1973 ­ 1977 Sample size HRsch = 23, HRaff = 22, HRop = 8, HRschaff = 11, C = 103 HRsch = 204, C = 204 HRsch = 61, HRmdd = 33, C = 33 HRsch = 162, C = 36 Follow-ups (age)

243

0, 3 days, 3, 6 weeks, 3.5, 6 months, 1, 2, 6 years 15 years 0 ­ 5,1 ­ 6, 2 ­ 7 years, studied three times 1 year apart 16 ­ 25 years, follow-ups at 18-month intervals for 5 years

The Helsinki High Risk Study (Wrede et al., 1980) The Emory University Project (Goodman, 1987; Goodman and Emory, 1992) The Edinburgh High Risk Study (Hodges et al., 1999; Johnstone et al., 2000; Lawrie et al., 1999)

1974 1981

Helsinki, Finland Atlanta, GA, USA

Mother ICD-8 sch Mother DSM-III sch, mdd

1960 ­ 1964 1976 ­ 1981

1994

Scotland

two or more firstor second-degree relatives sch (DSM III-R)

1969 ­

aff = affective psychosis, C = control group, de = depression, ext = externalizer, HR = high-risk group, int = internalizer, mdd = major depressive disorder, neu = neuroses, op = other psychosis, other = other mental disorder, pd = personality disorder, phys = physical problem, sch = schizophrenia, schaff = schizoaffective. a Cohort study.

neonatal period, and assessed children's mental, motor, sensory, and physical development at several points during the first 7 years of life (Goldstein et al., 2000). The Boston NCPP HR Study initially consisted of offspring of parents with schizophrenia from the Boston NCPP sample (Rieder et al., 1977). The Boston and Providence NCPP HR Study extended the Boston NCPP HR Study sample to include offspring of parents with DSM-IV psychotic disorder from both sites, and is currently conducting a follow-up study on the sample (Goldstein et al., 2000). Both the New York and Israeli HR Studies have concentrated primarily on neuropsychological assessments, the main emphasis in the former being assessing attention dysfunction (Erlenmeyer-Kimling and Cornblatt, 1992), and in the latter attention deficit disorder-like neurointegrative deficits in HR offspring (Marcus et al., 1987). The third study with the primary focus on assessing attentional functioning was the Minnesota HR Study (Garmezy and Devine, 1984), which chose four high-risk groups: children having a mother with schizophrenia, children having a mother with psychopathology manifesting as internalizing symptoms, and children without genetic predisposition but considered vulnerable because of internalizing or externalizing behavior pathology (Rolf, 1972).

The Israeli HR Study also has studied the influence of the rearing environment: half of the index and controlchildren were raised on a kibbutz and the other half with their biological parents. The Stony Brook HR Project emphasised investigation of the family environment (Weintraub, 1987). The St. Louis Risk Research Project was more psychodynamically oriented than the other HR studies and also included offspring of parents with severe physical disorders (Worland et al., 1984a). The University of Rochester Child and Family Study concentrated on developmental relationships on parental and child's psychopathology and health, and on family system functioning (Wynne et al., 1987). The focus of the Swedish HR Study (McNeil et al., 1983) has been on intensive assessment of pre- and perinatal complications and early childhood development, which have also been the main interest in the Jerusalem Infant Development Study (Marcus et al., 1981). The Helsinki HR Study identified systematically all female patients born between 1916 and 1948 who had been treated because of schizophrenia in any of the mental hospitals of the city of Helsinki. Their offspring born in Helsinki between 1960 and 1964 formed the high-risk group (Wrede, 1984). Thus, the Helsinki HR Study, along with the NCPP HR studies,

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can be considered epidemiologically representative (Wrede, 1984; Goldstein et al., 2000). The Emory University Project assessed neuropsychiatric, social, and intellectual functioning of preschool-aged HR children (Goodman, 1987). The Edinburgh HR Study (Hodges et al., 1999) is the most recent HR study to begin, and uses a slightly different methodology from the others mentioned. The HR group, aged between 16 and 25 years at entry, has at least two first- or second-degree relatives suffering from schizophrenia. These individuals are followed up for 5 years, and are regularly monitored by neuropsychological assessment and magnetic resonance imaging (Hodges et al., 1999).

3. Neurological and motor development A large follow-up study on children with childhood-onset schizophrenia conducted in the 1940s observed deviations in neurologic maturation among them (Fish et al., 1992). This led Barbara Fish to propose that ``what was inherited in schizophrenia, at least in individuals with the earliest onset and most chronic course, was a neurointegrative defect'' (Fish et al., 1992). Specifically, she suggested that a neurointegrative disorder in infancy called pandysmaturation (PDM), consisting of concurrent transient retardation of motor and/or visual motor development, abnormal profile of function, and retarded skeletal growth, predicted later development of schizophrenia. She tested the hypothesis in the New York Infant Study (Fish et al., 1992), in which 7 out of 12 HR infants and 1 out of 12 controls were found to have had PDM. The seven HR subjects who received a diagnosis of schizophrenia or schizotypal or paranoid personality disorder in the adulthood follow-up had all had PDM in infancy. Several HR studies since then have investigated early childhood motor and neurological development. The Swedish HR Study found more neurological deviations among schizophrenia HR offspring than among controls already on the third to fourth day of life (Blennow and McNeil, 1991). The Rochester Longitudinal Study and Jerusalem Infant Development Study both included several assessment points during early childhood, particularly during the first year of life, and used the same instru-

ment, the Bayley Scales of Infant Development (Bayley, 1969; Sameroff et al., 1984; Marcus et al., 1981). Infants of mothers with schizophrenia obtained lower scores in the Bayley scales at the 4-month examination in both studies, but the difference diminished (Marcus et al., 1981) or disappeared completely (Sameroff et al., 1984) by the end of first year of life. Instead, the effect of social class on the Bayley Scores increased with age (Sameroff et al., 1984). The Emory University Project failed to find any relationship between mother's diagnosis and the presence of neurological signs in her offspring (Goodman, 1987). While these results would suggest that abnormalities in neuromotor development among offspring at high risk for schizophrenia diminish with age, this seems not to be the case. The Boston NCPP HR Study and Swedish HR Study, which investigated 6 ­7-yearold children, both found that schizophrenia HR offspring had more neuromotor deviations than control offspring (McNeil et al., 1993; Rieder and Nicholas, 1979). Problems in motor coordination were particularly common among schizophrenia HR offspring in the Boston NCPP Study (Rieder and Nicholas, 1979). Poor neurobehavioral functioning characterized schizophrenia HR children during school-age and adolescence in both the Israeli HR and Jerusalem Infant Development Studies (Marcus et al., 1985, 1987, 1993; Hans et al., 1999). Schizophrenia HR children had problems, e.g. in motor coordination, right ­ left orientation, and balance (Marcus et al., 1985). Based on a composite score, 48% of the schizophrenia HR children and 26% of the controls had poor neurobehavioral functioning in the Israeli HR Study, the respective figures in the Jerusalem Infant Development Study being 42% and 22% (Marcus et al., 1985, 1987, 1993; Hans et al., 1999). However, in the Jerusalem Infant Development Study, the higher rate of poor functioning among HR children was caused by male offspring, 73% of whom were poorly functioning compared with only 15% of the females (Hans et al., 1999). Another feature was that schizophrenia HR children had consistently poor functioning: 40% of the poor-functioning adolescents in the HR group had been poorly functioning already in the assessments conducted in infancy and school-age; none of the controls showed consistently poor functioning (Hans et al., 1999). All four HR offspring who received a schizophrenia-

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spectrum diagnosis by adolescence had shown consistently poor neurobehavioral functioning (Hans et al., 1999). Also in the Israeli HR Study, eight of the nine individuals who later developed schizophreniaspectrum disorder had had poor neurobehavioral functioning (Marcus et al., 1987). The initial assessment of the New York HR Study found few differences between the schizophrenia HR and other groups in neuromotor functioning. Neuromotor deviance predicted affective flattening among the schizophrenia HR group in adolescence and identified 75% of those who developed schizophreniaspectrum psychoses in adulthood (Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling et al., 2000).

events, occupation of head of household, and disadvantaged minority status (Sameroff et al., 1993). The multiple risk score explained one-third to one-half of IQ variance at 4 and 13 years (Sameroff et al., 1993). The total number of risk factors was more important than any specific combination. The environmental risk score was found to be quite stable: the correlation between 4- and 13-year risk scores was 0.77, while the correlation between 4- and 13-year IQ scores was 0.72 (Sameroff et al., 1993). 4.2. Attention The New York HR Study (Erlenmeyer-Kimling and Cornblatt, 1992) assessed sustained attention, using tests of visual and auditory mode, distractibility, and short-term memory. The schizophrenia HR offspring scored poorest of all on each type of measure. Attentional dysfunction showed temporal stability and was correlated with behavioral adjustment among schizophrenia HR children, but not among affective disorder HR offspring or controls. The Attention Deviance Index (ADI), a composite score based on response indices from several instruments, also predicted adulthood social isolation score and adolescent anhedonia among schizophrenia HR offspring alone. The affective disorder HR offspring also showed mild attentional dysfunction in some measures, but in general they resembled more the controls than schizophrenia HR offspring. Childhood attentional deficit predicted 58% of the schizophrenia HR offspring who developed schizophrenia-related psychoses in adulthood (Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling and Cornblatt, 1992; Erlenmeyer-Kimling et al., 2000). The Minnesota HR Study found that a subgroup of schizophrenia HR offspring performed poorly on tasks that demanded sustained discrimination of signal and noise stimuli, consisting of different versions of the Continuous Performance Test (Nuechterlein, 1984). However, they did not differ from controls in other types of attentional measures (Driscoll, 1984). Also the Jerusalem Infant Development Study investigated attentional dysfunction, although it was not analysed separately but as a part of global neurobehavioral functioning (Hans et al., 1999). In the Israeli HR Study, poor attentional skills at the age of 11 predicted later development of schizophrenia (Mirsky et al., 1995a; Marcus et al., 1987) (Table 3).

4. Cognitive functioning 4.1. General intelligence Several HR studies (Rieder et al., 1977; Goldstein et al., 2000; Goodman, 1987; Mednick, 1968; Dworkin et al., 1993; Neale et al., 1984; Byrne et al., 1999), although not all (Sameroff et al., 1984, 1987; Worland et al., 1984b; Sohlberg and Yaniv, 1985; Klein and Salzman, 1984) found a lower IQ among schizophrenia HR children than among controls (Table 2). In some studies, the difference between HR and control children diminished with age (Goodman, 1987; Dworkin et al., 1993), while an opposite trend was found in the St. Louis Risk Research Project (Worland et al., 1982). Adulthood schizophrenia was not related to low IQ in the New York HR Study (Dworkin et al., 1993), but Edinburgh HR Study found a decline in IQ from the initial assessment among individuals who developed psychotic symptoms during the follow-up (Cosway et al., 2000). The Rochester Longitudinal Study (Sameroff et al., 1993) found in the early childhood assessments that low social status and severity of maternal illness were stronger predictors of low IQ than specific maternal diagnosis. Therefore, they created a multiple environmental risk score for the 13-year assessment by counting up the number of high-risk conditions present from 10 risk factors: mother's behavior, mother's developmental beliefs, mother's anxiety, mother's mental health, mother's educational attainment, family social support, family size, major stressful life

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Table 2 Findings of HR children in childhood and adolescence Age Neuromotor development (years) 0­2 Cognitive functioning Behavior and social adjustment . Absence of fear of strangers (SHR) (Naslund et al., 1984) ¨ . Low communicative competence (EUP) (Goodman, 1987) . Quiet (NYIS) (Fish, 1987) . Lower reactivity to the examiner (RLS) (Sameroff et al., 1984) Psychiatric symptoms

2­7

. Pandysmaturation (NYIS) . Low IQ (EUP) (Goodman, 1987) (Fish et al., 1992) . Different use of language . Passive (CHR, NYIS) (SHR) (Walker and Aylward, (Parnas et al., 1982; 1984) Fish, 1987) . Poorer psychomotor development during first year (RLS, JIDS) (Sameroff et al., 1984; Marcus et al., 1981), . Neuromotor deviations neonatally (SHR) (McNeil et al., 1993) . Low IQ (BNCPP, . Neurological deviation, BPNCPP) e.g. clumsiness, poor coordination, choreatic involuntary movements, poor balance, difficulty in crossing the body midline (SHR, BNCPP) (Rieder and Nicholas, 1979; McNeil et al., 1993)

. Expressed less affection, anxiety, and hostility (EUP) (Goodman, 1987) . More isolated and lonely (BNCPP, RLS) (Rieder and Nicholas, 1979; Sameroff et al., 1984) . Disturbed behavior (NYIS, EUP) (Fish, 1987; Goodman, 1987)

8 ­ 12

. Poor coordination, balance, and motor overflow (IHR) (Marcus et al., 1985) . Poor neurobehavioral functioning (JIDS) (Marcus et al., 1993; Hans et al., 1999) . Dyslexia, poor neurological maturation (NYIS) (Fish, 1987) . Poorer gross motor skills (NYHR) (Erlenmeyer-Kimling et al., 2000)

. Lower IQ (CHR, IHR, NYHR, SB) (Mednick and Schulsinger, 1968; Mednick et al., 1987; Sohlberg, 1985; Dworkin et al., 1993; Neale et al., 1984), . Attentional dysfunction (NYHR, SB, MHR) (Erlenmeyer-Kimling and Cornblatt, 1992; Erlenmeyer-Kimling et al., 2000; Weintraub, 1987; Garmezy and Devine, 1984), . Poor concentration (IHR) (Sohlberg, 1985; Lifshitz et al., 1985) . Some evidence of formal thought disorder (SB, NYHR) (Weintraub, 1987; Bolinskey et al., 2001) . Poorer memory (NYHR) (Erlenmeyer-Kimling et al., 2000)

.

. . .

. .

.

. Depressive (RLS) (Sameroff et al., 1984) . Hyperactive (BNCPP) (Rieder and Nicholas, 1979) . Immature (BNCPP) (Rieder and Nicholas, 1979) . Increased activity, impulsivity, distractibility, and emotional lability (BNCPP) (Rieder and Nicholas, 1979) . Higher in psychopathology Disturbing and aggressive (StL) (Worland et al., school behavior (CHR, SB) 1984a, 1979) (Mednick and Schulsinger, . More clinical involvement 1968; Weintraub and (e.g. need for residential Neale, 1984) treatment, special school Lower cognitive and social for emotional problems, competence in school (SB, IHR) externalizing and/or Problems in internalizing) (SB) interpersonal relations (Weintraub, 1987) Social isolation (IHS, . Tendency to anhedonia NYIS, EHR, MHR) or euphoria, depression, (Nagler and Glueck, 1985; and aggression (IHR) Garmezy and Devine, 1984; (Nagler and Fish, 1987; Glueck, 1985) Hodges et al., 1999; Johnstone et al., 2000) Low self-esteem (IHS) (Nagler and Glueck, 1985) Early offending behavior (EHR) (Hodges et al., 1999; Johnstone et al., 2000) Poor affective control (NYIS, IHS) (Fish, 1987; Nagler and Glueck, 1985)

L.T. Niemi et al. / Schizophrenia Research 60 (2003) 239­258 Table 2 (continued ) Age Neuromotor development (years) 13 ­ 19 . Poorer coordination and balance, lower perceptual-motor and visual motor functioning (IHR) (Sohlberg, 1985; Lifshitz et al., 1985; Marcus et al., 1985) . Poorer neurobehavioral functioning (JIDS) (Hans et al., 1999) Cognitive functioning . Low IQ (CHR, SB, EHR) (Mednick and Schulsinger, 1968; Neale et al., 1984; Weintraub, 1987; Byrne et al., 1999; Weintraub and Neale, 1984) . Greater decrease in IQ scores between 7 and 16 years of age (StL) (Worland et al., 1982) . Worse in arithmetic tests and spelling (IHR) (Sohlberg, 1985; Lifshitz et al., 1985; Ayalon and Merom, 1985) . Evidence of formal thought disorder (CHR, SB) (Weintraub, 1987) . Attentional dysfunction (NYHR, SB, IHR) (Erlenmeyer-Kimling and Cornblatt, 1992; Weintraub, 1987; Sohlberg, 1985; Lifshitz et al., 1985) . Poor executive functioning (EHR) (Byrne et al., 1999) . Deficient ability to ignore irrelevant input (SB) (Weintraub, 1987) . Problems in learning and memory (EHR) (Byrne et al., 1999) Behavior and social adjustment . Disturbed (aggressive or withdrawn) behavior (SB, CHR, IHR) (Mednick and Schulsinger, 1968; Weintraub and Neale, 1984; Nagler and Glueck, 1985; Marcus et al., 1987) . Poor peer relations (IHR) (Ayalon and Merom, 1985) . Problems in school adjustment (IHR, StL) (Ayalon and Merom, 1985; James and Worland, 1983) . Poor social competence (SB, NYHR) (Weintraub and Neale, 1984; Dworkin et al., 1993) Psychiatric symptoms

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. Greater affective flattening, reduced smiling (NYHR) (Dworkin et al., 1993) . More anxious (IHR) (Kugelmass et al., 1995) . More clinical involvement (e.g. need for residential treatment, special school for emotional problems, externalizing and/or internalizing) (SB) (Weintraub, 1987) . Poorly adjusted (CHR) (Mednick and Schulsinger, 1968)

BNCPP = Boston NCPP HR Study, BPNCPP = Boston and Providence NCPP Study, CHR = Copenhagen High Risk Study, EHR = Edinburgh High Risk Study, EUP = Emory University Project, IHR = Israel High Risk Study, JIDS = Jerusalem Infant Development Study, MHR = Minnesota HR Study, NYHR = New York High Risk Study, NYIS = New York Infant Study, RLS = Rochester Longitudinal Study, SB = Stony Brook High Risk Study, SHR = Swedish HR Study, StL = St. Louis Risk Research Project.

4.3. Other cognitive functions Several HR studies have investigated positive formal thought disorder-like symptoms. HR children in the Copenhagen HR Study tended to give more idiosyncratic and fragmented associations in the single-word association test (Mednick and Schulsinger, 1968). The children in the Stony Brook HR Study were found to have cognitive slippage--poor control of thoughts and verbal expression--at school-age and adolescence (Weintraub, 1987). The New York HR Study assessed the occurrence of thought disorder

among HR children retrospectively from videotaped interviews conducted at age 9, and found that positive thought disorder could be observed already at that age and was predictive of adulthood schizophrenia-spectrum disorders (Ott et al., 2001). Other abnormalities in cognitive functioning among HR children include poor concentration (Sohlberg, 1985; Lifshitz et al., 1985), decreased ability to ignore irrelevant input (Weintraub, 1987), poor performance on mathematics and spelling (Ayalon and Merom, 1985), poor executive function, poor mental coding/encoding and learning, and poor memory (Byrne et al., 1999).

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Verbal short-term memory deficit predicted 83% of the HR offspring who developed schizophreniarelated psychosis in the New York HR Study (Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling and Cornblatt, 1992; Erlenmeyer-Kimling et al., 2000).

5. Behavior and social adjustment 5.1. Social adjustment The Rochester Longitudinal Study (Sameroff et al., 1984) investigated social adjustment during the first 4 years, and found more abnormalities in social adjustment among offspring of mothers with depressive disorder than among schizophrenia HR offspring (Sameroff et al., 1984). Severity and chronicity of maternal illness and low social status were more powerful predictors of poor social adjustment than maternal diagnosis (Sameroff et al., 1984, 1987). Instead, several HR studies found more problems in social adjustment among school-aged (Nagler and Glueck, 1985; Hodges et al., 1999; Johnstone et al., 2000) and adolescent HR offspring (Nagler and Glueck, 1985; Marcus et al., 1987; Dworkin et al., 1993; Hodges et al., 1999; Johnstone et al., 2000; Ayalon and Merom, 1985; James and Worland, 1983; Rolf, 1972). The teachers (Olin et al., 1995; Weintraub and Neale, 1984; James and Worland, 1983) or peers (Ayalon and Merom, 1985) rated them as being more aggressive, disruptive or withdrawn, or having poorer concentration and less participation in class (Ayalon and Merom, 1985) and as being susceptible to future emotional or psychotic problems (Olin et al., 1995). They also had problems in peer relations as judged by both teachers (Ayalon and Merom, 1985; Rolf, 1972) and peers themselves (Weintraub and Neale, 1984; Ayalon and Merom, 1985; Garmezy and Devine, 1984; Rolf, 1972). As exception were the offspring of mothers with paranoid schizophrenia in the Helsinki HR Study, who were rated by teachers as having higher school motivation and better social adjustment than controls from the same class (Wrede, 1984). Impaired psychosocial function also predicted later development of schizophrenia or other Axis I disorders. In the Israeli HR Study, eight of the nine children who later received a schizophrenia-spectrum diagnosis had behaved undesirably (Marcus et al., 1987).

In the Copenhagen HR Study, within the HR group, males who later developed schizophrenia had more often disrupted class with inappropriate behavior, were emotionally highly strung, lonely, and judged by their teachers as susceptible to future emotional or psychotic problems (Olin et al., 1995). Females who later developed schizophrenia were more nervous and judged by their teachers as susceptible to future emotional or psychotic problems (Olin et al., 1995). The HR adolescents who later developed schizophrenia also experienced more interpersonal difficulties and showed disruptive behavior (Parnas et al., 1982). In the New York HR Study, childhood behavioral problems were associated with clinical outcome in adult subjects without substance abuse (Amminger et al., 1999). Among these subjects, those with adult schizophrenia-spectrum psychoses had had significantly more behavioral problems as children, while there were no such between group differences among those with substance abuse (Amminger et al., 1999). Childhood behavioral problems were also associated with higher frequency of comorbidity of Axis I disorders in adulthood (Amminger et al., 2000). 5.2. Mother­ infant interaction The Rochester Longitudinal Study found that when the children were 4 months of age, both depressed mothers and those with schizophrenia were less spontaneous and less in proximity to their children than controls, but the effect of maternal diagnosis had disappeared by the 12-month assessment. However, the severity and chronicity of maternal illness were associated with problems in mother ­ infant interaction at both the assessments (Sameroff et al., 1984). In the Emory University Project, mothers with schizophrenia showed less affectional involvement and responsiveness to their children than control mothers, and this also significantly affected the child's IQ (Goodman and Brumley, 1990). The child-rearing environment of mothers with schizophrenia was significantly poorer, while mother's education or severity of illness had no effect (Goodman and Brumley, 1990). The mother ­ infant interaction was evaluated regularly during the first 2 years of the Swedish HR Study (Persson-Blennow et al., 1988). Interaction was consistently more negative among schizophrenia HR group than among

L.T. Niemi et al. / Schizophrenia Research 60 (2003) 239­258 Table 3 Factors predicting schizophrenia among HR offspring Study The New York Infant Study (Fish, 1987) The Copenhagen High-Risk Study (Mednick and Schulsinger, 1968) Sample size HR = 12, C = 12 HR = 207, C = 104 Findings . Pandysmaturation (Fish et al., 1992)

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Israeli HR Study (Marcus et al., 1987; Mirsky et al., 1995a) The New York High Risk Study (Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling and Cornblatt, 1987, 1992; Erlenmeyer-Kimling et al., 1997, 2000)

HR = 50, C = 50

A: HRsch = 84, HRaff = 67, C = 136 B: HRsch = 46, HRaff = 39, C = 65

The Jerusalem Infant Development Study (Hans et al., 1999)

HR = 29, C = 27

. Institutional care (Walker et al., 1981; Cannon et al., 1990) . Severe instability of early rearing environment (Walker et al., 1981; Cannon et al., 1990) . Passivity in infancy (rated by parents) (Parnas et al., 1982) . Inappropriate behavior (Mednick and Schulsinger, 1968; Olin et al., 1995; Parnas et al., 1982) . Emotionally highly-strung (Mednick and Schulsinger, 1968; Olin et al., 1995; Parnas et al., 1982) . Lonely, susceptible (by teachers) to future emotional or psychotic symptoms (Olin et al., 1995) . Poor affective control (Mednick and Schulsinger, 1968; Olin et al., 1995; Parnas et al., 1982) . Higher scores on the frequency and psychoticism scales of the MMPI (Parnas et al., 1999) . Poor neurobehavioral functioning (Marcus et al., 1987) . Undesirable behavior (Marcus et al., 1987) . Higher anxiety ratings (Kugelmass et al., 1995) . Deficits in verbal short-term memory (Erlenmeyer-Kimling et al., 2000) . Attentional deficit (Erlenmeyer-Kimling et al., 2000) . Deficit in gross motor skills (Erlenmeyer-Kimling et al., 2000) . Behavioral problems (Amminger et al., 1999) . Positive formal thought disorder (NYHR) (Ott et al., 2001) . High scores on Schizophrenia Proneness Scale (MMPI-derived) (NYHR) (Bolinskey et al., 2001) . Poor neurobehavioral functioning (Hans et al., 1999)

controls (Naslund et al., 1985; McNeil et al., 1985; ¨ Persson-Blennow et al., 1986), and anxious attachment at age 1 was more common among schizophrenia HR children (Naslund et al., 1984). Compared with con¨ trols, schizophrenia HR offspring also more often showed a total absence of fear of strangers during the first year of life (Naslund et al., 1984). Mental disturb¨ ance at 6 years, measured by Children's Global Assessment Score, was related in the HR group to maternal psychotic episodes during the offspring's early childhood (6 months to 2 years) (McNeil and Kaij, 1987). None of the studies which assessed mother ­ infant interaction has completed an adulthood follow-up.

6. Psychiatric symptoms At the outset of the Copenhagen HR Study (Mednick and Schulsinger, 1968), children who were

already mentally ill in the initial assessment were excluded. However, the psychiatric interview rated 24% of the HR children as poorly or relatively poorly adjusted, as opposed to only 1% of the low-risk children (Mednick and Schulsinger, 1968). Also several other HR studies found more non-specific psychopathology among HR offspring at their initial assessment (Worland et al., 1984a; Weintraub, 1987; Kugelmass et al., 1995), and higher anxiety ratings at age 16 were predictive of future development of schizophrenia in the Israeli HR Study (Kugelmass et al., 1995). Both Copenhagen and New York HR studies used MMPI. In the Copenhagen HR Study, schizophrenia HR children who later developed schizophrenia scored higher than those who remained unaffected on the frequency and psychoticism scales of the MMPI (Parnas et al., 1999). The New York HR Study developed a new scale, Schizophrenia Proneness

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Scale, from the MMPI-answers of the HR offspring and found it an effective predictor of schizophreniaspectrum disorders (Bolinskey et al., 2001).

7. Other findings 7.1. Stability of rearing environment The Copenhagen HR Study collected data on institutional child care and parental absence during the first 10 years of life (Mednick and Schulsinger, 1968). Initially, it was observed that the absence of parents during childhood increased the risk of later developing schizophrenia. However, this association was found to be mediated by the type of care provided to children of absent parents (Walker et al., 1981). While institutional care was strongly associated with later development of schizophrenia, especially among HR males, the absence of an affected mother seemed to be beneficial for offspring who had been placed with relatives or unaffected foster parents. Father's absence was related only to antisocial traits among HR males (Walker et al., 1981). Severe instability of early rearing environment was particularly found to increase the risk of later developing of schizophrenia with predominantly positive symptoms (Cannon et al., 1990). The same study (Schiffman et al., 2002) used a psychosocial interview at the beginning of the study to assess the relationships of the children with their parents. They found that the HR children had worse relationships with their mothers and a trend towards having worse relationship with their fathers than control children. Poor relationship with both parents was associated with later development of schizophrenia among the HR-offspring (Schiffman et al., 2002). 7.2. Structural brain abnormalities The Edinburgh HR Study (Lawrie et al., 1999) is the first to include brain imaging as part of their longitudinal follow-up. In the initial magnetic resonance imaging assessment, HR adolescents were compared with matched controls and patients having their first episode of schizophrenia. The general pattern was that the findings of high-risk individuals were midway between those of controls and those of first episode

patients. Significant difference emerged in the volume of the left amygdala ­ hippocampal complex, which was significantly smaller in the first episode patients than in the other two groups, and significantly smaller among HR individuals than among controls. HR individuals also had significantly smaller thalamus than the control group. Within the high-risk group, individuals with at least one affected first-degree relative had smaller regional brain volumes and greater ventricular volumes than individuals with only second-degree relatives with schizophrenia, suggesting that structural brain abnormalities are largely genetically mediated (Lawrie et al., 1999). In the Copenhagen HR Study, HR and control offspring underwent a computed tomographic scan of the brain in the adulthood. As in the Edinburgh HR Study, cortical and ventricular cerebrospinal fluid­ brain ratios increased linearly with increasing genetic risk (Cannon et al., 1993). Genetic risk interacted with birth complications in predicting enlargement of the ventricular system (Cannon et al., 1993). In comparing HR individuals with schizophrenia, schizotypal personality disorders and unaffected HR individuals, equal degree of sulcal enlargement was found among both HR individuals with schizophrenia and schizotypal personality disorder, while ventricular enlargement was evident only among HR individuals who developed schizophrenia (Cannon et al., 1994). Future follow-ups of the Edinburgh HR Study will show whether these findings will be replicated. 7.3. Physical anhedonia The New York HR Study investigated physical anhedonia among HR children, as measured with the Physical Anhedonia Scale (PAS) (Freedman et al., 1998). PAS scores were directly related to lack of empathy in adulthood and to suspicious solitude. Male schizophrenia HR children had higher PAS scores than their female counterparts, and high scores were associated with poor social outcome in adulthood (Freedman et al., 1998).

8. Discussion This review set out to answer two questions: does the development of children at high risk for schizo-

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phrenia differ from that of control children? and if it does, which developmental factors predict the later development of schizophrenia? The answer to the first question is affirmative. Children at high risk for schizophrenia have more developmental problems than controls. They have abnormalities in neurological and motor development from infancy on, which continue through school-age and adolescence. Many, but not all HR studies have found lower IQ, attentional deficits and poorer school and social adjustment among schizophrenia HR children than controls. These findings, however, are not specific to schizophrenia; offspring at high risk for other disorders also tend to show similar developmental problems, although usually milder than those experienced by schizophrenia HR children. The Rochester HR Study found that during early childhood, severity and chronicity of maternal illness were stronger predictors of childhood developmental problems than specific maternal diagnosis, and an even stronger predictor was social status. A recent study investigating childhood neuromotor functioning and behavior problems found that maltreatment was often a stronger predictor of poor functioning among children than parental schizophrenia (Bergman et al., 1997). Part of these developmental problems may thus have been caused by living in a nonoptimal family environment, rather than by having a high risk for developing schizophrenia. Our second question was which developmental factors predict later development of schizophrenia. Only a few high-risk studies have conducted adulthood follow-ups. The Copenhagen HR Study found that institutionalization (Walker et al., 1981) and severe instability of the early rearing environment (Parnas et al., 1985) predicted later development of schizophrenia. Poor relationship with both parents also predicted later development of schizophrenia (Schiffman et al., 2002). The Israeli HR Study found that Axis I disorders were more prevalent among the kibbutzreared HR offspring than those reared by their own parents, or control offspring (Mirsky et al., 1995b). Although these findings concerning rearing environment have received little attention lately, they complement results from the Finnish adoptive family study suggesting that an unstable or otherwise nonoptimal rearing environment interacts with genetic risk in elevating the risk of schizophrenia (Wahlberg et al.,

1997). Thus, it is possible that supportive measures for the family, particularly during early childhood, may help prevent schizophrenia among HR children. Most HR studies that have addressed this issue have found that schizophrenia HR children have more problems in neurological and motor development than controls from infancy on (Rund and Borg, 1999; McNeil et al., 1993; Hans et al., 1999; Fish, 1984; Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling et al., 2000). In the New York Infant and the New York HR Studies, neurological dysfunction in infancy or childhood was associated with later development of schizophrenia-spectrum disorders (Fish, 1984; Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling et al., 2000). There seems to be a continuity between childhood developmental problems in neuromotor functioning and neurological signs in adult patients with schizophrenia. A recent review concluded that the prevalence of most neurological signs is higher among patients with schizophrenia than controls, and particularly impaired motor coordination seems to be specific to schizophrenia (Boks et al., 2000). Interestingly, motor uncoordination was the most common finding differentiating HR children from controls in many HR studies, too. However, a recent cohort study found that deviance in motor coordination in childhood predicted both adult schizophrenia and being an unaffected sibling of a patient with schizophrenia (Rosso et al., 2000). This could suggest that deviance in motor coordination may be associated with the genetic risk for developing schizophrenia but is not necessary an indicator for developing it. The familial association could be explained by other factors, too. In a recent study, maltreatment but not parental psychopathology was found to affect on children's neuromotor functioning (Bergman et al., 1997). The same study observed that maltreatment of children was quite common in families with a schizophrenic parent (Bergman et al., 1997). Thus, it is possible that some of the observed differences in neuromotor development between schizophrenia HR and control children are related to other family characteristics than having a parent with schizophrenia. The most consistently found neurocognitive deficit among schizophrenia HR children was attentional deficit (Sohlberg, 1985; Lifshitz et al., 1985; Erlenmeyer-Kimling and Cornblatt, 1992; Weintraub, 1987; Garmezy and Devine, 1984). Childhood atten-

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tional deficit also predicted 58% of the schizophrenia HR subjects in the New York HR Study who developed schizophrenia-spectrum psychoses in adulthood (Erlenmeyer-Kimling, 2000; Erlenmeyer-Kimling and Cornblatt, 1992; Erlenmeyer-Kimling et al., 2000). Bleuler (1950) already regarded attentional deficit as one of the fundamental symptoms of schizophrenia. Family studies have since found that attentional deficits are evident in both patients with schizophrenia and their unaffected first-degree relatives, although they are less severe among relatives (Michie et al., 2000). The deficit in patients is independent of clinical state, suggesting that the impairment is traitrather than state-dependent (Michie et al., 2000). Deficit in sustained attention is regarded as one of the most promising phenotypic indicators of vulnerability to schizophrenia for genetic studies (Michie et al., 2000). It is also one of the key features of ``schizotaxia'', a term introduced by Meehl (1989) to describe the premorbid neurological substrate of schizophrenia which precedes but does not necessarily proceed to schizophrenia (Tsuang et al., 2000). The Edinburgh HR Study found that the left amygdala ­ hippocampal complex was significantly smaller among HR adolescents than among controls. However, McGorry and Velakoulis found among individuals with ultra high-risk (UHR) for developing psychosis that those UHR-individuals who did not develop psychosis within 12 months had smaller hippocampal volume compared to controls, while larger left hippocampal volume was associated with a higher risk of psychosis within that time (Velakoulis et al., 2000). Future MRI-follow-ups of the Edinburgh Study will show which of their initial findings are predictive of future development of schizophrenia. Both the New York and the Copenhagen HR Study found that schizophrenia HR children who later developed schizophrenia scored higher on psychosisrelated MMPI-scales (Parnas et al., 1999; Bolinskey et al., 2001). This finding complements the recent observation from a cohort study that childhood possible or definite psychotic symptoms predict the development of schizophreniform disorder in adulthood (Poulton et al., 2000). Children with psychotic-like symptoms in clinical settings should perhaps be followed up through childhood and adolescence even after their presenting problems have resolved, particularly if they have a family history of schizophrenia.

Cohort and conscript studies have rather consistently found that low IQ increases the risk of developing schizophrenia. Findings from HR studies are more diverse. Some studies have failed to find any difference in overall IQ between HR subjects and controls (Mednick and Schulsinger, 1968; Sameroff et al., 1984, 1987, 1993; Worland et al., 1984a; Klein and Salzman, 1984; Sohlberg, 1985; Lifshitz et al., 1985), while others have shown lower IQ among schizophrenia HR offspring (Rieder et al., 1977; Goldstein et al., 2000; Goodman, 1987; Neale et al., 1984; Byrne et al., 1999). However, adulthood schizophrenia was not related to IQ in the New York HR Study (Dworkin et al., 1993). The Edinburgh HR Study found a decline in IQ from the initial assessment among individuals who developed psychotic symptoms during the follow-up (Cosway et al., 2000). The relationship between childhood IQ and later development of schizophrenia has not been assessed in the other HR studies. The Philadelphia NCPP cohort study found that subjects who later developed schizophrenia and their siblings both performed worse than controls in verbal and nonverbal cognitive tests at 4 and 7 years (Cannon et al., 2000), suggesting that low IQ may be associated with the genetic risk of developing schizophrenia but is not necessarily a risk factor for it. Low IQ could also reflect other risk factors that are more prevalent in these families, as suggested by the Rochester Longitudinal Study (Sameroff et al., 1998). However, a recent family study found that schizophrenic patients had significantly lower premorbid IQ than their relatives and controls (Gilvarry et al., 2000). One reason for these disparate findings could be the different ages at assessment. It is also possible that low IQ is associated with an environmental risk factor for schizophrenia but is not a risk factor itself. The 1966 North Finland birth cohort found that severe perinatal brain damage is associated with increased risk for developing schizophrenia (Jones et al., 1998). However, the overall evidence from cohort studies for low IQ being a risk factor for schizophrenia is strong, while the evidence against it from high-risk studies is rather weak. Some HR studies and many cohort studies too have found that poor social competence predicted later development of schizophrenia (Mirsky et al., 1995b;

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Olin et al., 1995; David et al., 1997; Bearden et al., 2000; Davidson et al., 1999; Jones et al., 1994). Disruptive school behavior predicted later development of schizophrenia in the Copenhagen and Israeli HR studies (Mirsky et al., 1995b; Olin et al., 1995). It is not clear whether problems in social adjustment are risk factors for schizophrenia or merely early manifestations of emerging schizophrenia (Ellison et al., 1998). However, poor social and school adjustment seem to be among the most commonly found development abnormalities in pre-schizophrenic individuals. Although HR offspring who develop schizophrenia are not representative of all persons with schizophrenia because only a minority of the latter have an affected parent(s), findings from cohort studies support the validity of these cognitive and behavioral markers as vulnerability indicators of schizophrenia. Their sensitivity and specificity on the population level are unacceptably low, but they might be useful in identifying the most vulnerable high-risk children for preventive programs. A limitation worth considering is whether the HR samples these studies have identified are representative of all parents with schizophrenia and their offspring. Several HR studies emphasised, when selecting their samples, the severity and chronicity of the disorder among parents. This may have amplified the morbid risk of schizophrenia observed among offspring in these studies, because severity of illness of the proband may correlate with the risk of schizophrenia among relatives, increase the instability of the rearing environment, and also cause pronounced assortative mating (Parnas et al., 1993). On the other hand, some studies did not allow the offspring to have any major psychiatric problems in the initial assessment, whereas other HR studies have found that many HR offspring already show psychiatric problems in childhood. The New York HR Study selected only intact families, and the sample may thus include parents with less severe and more atypical forms of the disorder. Overall, findings from high-risk studies support the neurodevelopmental theory of schizophrenia: children with genetic risk of schizophrenia have more developmental problems than control children, and many of these are predictive of future schizophrenia. However, none of the developmental precursors identified are specific for schizophrenia, and none provides a nec-

essary and sufficient relationship with it (Jones and Tarrant, 1999). Most individuals who have problems in childhood development, even within the high-risk group, do not develop schizophrenia. Conversely, even if the average performance on most measures is poorer among schizophrenia high-risk subjects, the performance of individual high-risk subjects is usually within the normal range. The concept of schizophrenia as a neurodevelopmental disorder may carry with it an unwarranted determinism, which may lead to therapeutic nihilism (Lieberman, 1999). There are several facts about developmental psychopathology worth remembering here. Firstly, genetic influences are probabilistic, not deterministic (Rutter and Sroufe, 2000). Secondly, for many developmental outcomes, it is the quantity rather than quality of risk factors that is most predictive (Sameroff, 2000). Thirdly, positive experiences in adolescence and adulthood can have a crucial influence in protecting from some adulthood psychiatric disorders, provided that they bring about a substantial change in life opportunities or in selfconcept (Rutter and Sroufe, 2000). Whether they can also have an impact on the diminishing risk for developing schizophrenia is unknown. Fourthly, a child's development includes factors that protect from developmental problems, and these are usually simply the positive pole of the risk factors (Sameroff, 2000). It is not yet known whether there are factors that protect high-risk individuals from developing schizophrenia, although findings from the Finnish Adoptive Study suggest that low communication deviance in the childhood rearing environment could be one such factor (Wahlberg et al., 1997). With the exception of the Edinburgh HR Study, all the other high-risk studies reviewed in this article were started 30­ 40 years ago. The result of this is that many studies used methods that are outdated and sometimes focused on less relevant subjects in their assessments. Yet another problem is that only approximately 10% of HR children develop schizophrenia, making the predictions concerning vulnerability indicators unprecise. Therefore, the threshold for starting a new high-risk study using similar kind of design as those started in the 1960s and 1970s would be high for any researcher. Besides the case-selection method used in the Edinburgh HR Study, other case selection methods have been suggested. Yung et al. have developed criteria which can identify individuals at

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high risk of onset of psychosis within a brief followup time. These are: attenuated psychotic symptoms occurring several times per week, this change in mental state having been present at least 1 week OR transient psychotic symptoms having resolved spontaneously within 1 week OR family history of a firstdegree relative with any psychotic disorder or schizotypal personality disorder in the individual and any change in mental state or functioning which results in a loss of 30 points or more on the Global Assessment of Functioning scale for at least 1 month (Yung et al., 1998). The transition rate to psychosis during 6 months was 40% among individuals selected using these criteria. However, while these criteria are suitable for the investigation of factors immediately preceding the onset of psychosis which promote or prevent the development of psychosis, they are not helpful in the investigation of childhood developmental factors associated with schizophrenia. Another method is the longitudinal assessment of individuals at considerably high risk for schizophrenia and other psychotic disorders because of a genetic abnormality, such as chromosome 22q11 deletion (Murphy and Owen, 2001) or t(1:11)(q43, q21) translocation (Clair et al., 1990), or because of an extreme exposure to environmental risk factors possibly associated with schizophrenia, such as very preterm birth, prenatal viral infection or childhood central nervous system infection. The fourth possibility is to use liability indicators detected by HR studies, such as attentional deficits or MMPI-derived scales, or to use other scales developed to identify psychosis-prone individuals (Chapman and Chapman, 1987). However, it may be difficult to find a sufficient number of such individuals and findings from these special groups may not be generalizable to other patients with schizophrenia. Only a few HR studies have conducted adulthood follow-ups which are necessary to reveal which of the developmental abnormalities predict future development of schizophrenia and related disorders and could, therefore, function as vulnerability indicators. Those that have, the high-risk studies from Copenhagen, New York and Israel, have provided invaluable information for research on the etiology of schizophrenia. Hopefully, this database will be enlarged in the future by follow-ups from the other older HR studies, as well as the more recent ones.

Acknowledgements This study was supported by grant from the Theodore and Vada Stanley Foundation. Dr. Niemi was supported by grants from the Finnish Foundation for Psychiatric Research, and from Finnish Psychiatric Association. The authors would like to thank Jari Haukka, Ph.D. for his contribution in the manuscript preparation.

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