Schizophrenia

Risk Factors of Psychosis: Identifying Vulnerable Populations Premorbidly


By Su-chin Serene Olin and Sarnoff A. Mednick
Schizophrenia Bulletin, Vol. 22, No. 2, 1996
National Institute of Mental Health

Abstract

This article reviews premorbid indicators of psychosis that may be relevant to primary intervention. These risk markers are divided into two categories: (1) precursors related to early etiological factors (family psychiatric history, perinatal and obstetric complications, neurobehavior deficits, early parental separation, institutionalization, and poor family function) and (2) precursors signaling latent mental illness (personality measurements indicating proneness to psychosis, and teacher ratings indicating emotional lability, social anxiety, social withdrawal, passivity, poor peer relations, and disruptive and aggressive behavior). Because teacher ratings have been shown to be powerful predictors of adult mental breakdown, part of this article focuses on a specific study that assesses such ratings as predictors of psychosis in a high-risk population. Risk indicators may also provide clues about protective factors relevant for primary prevention.

Schizophrenia Bulletin, 22(2): 223-240, 1996.


Among the many studies investigating premorbid indicators of schizophrenia are some well-known high-risk (HR) longitudinal projects (e.g., Chapman and Chapman 1987; Erlenmeyer-Kimling and Cornblatt 1987; Fish 1987; Goldstein 1987; Marcus et al. 1987; Mednick et al. 1987, Tienari et al. 1987). The HR method was developed to study etiology and -- more relevant to the purpose of this issue -- to identify premorbid characteristics that could be used to target individuals for primary prevention. The powerful effects of hospitalization, potent drug treatments, and life conditions engendered by schizophrenia likely are responsible for the differences found between schizophrenia patients and controls, limiting the usefulness of etiological hypotheses based on research with individuals already diagnosed with the disorder. The HR approach was developed to avoid these difficulties.

Many of the HR studies define risk status genetically, selecting offspring of parents, especially mothers, who have schizophrenia. There are several advantages to using such HR populations. First, a higher yield of psychopathology has been noted among children of mothers with schizophrenia than among children in the general population: the population risk for schizophrenia is 1 percent, but the risk for children whose mothers have chronic schizophrenia is 16 percent -- and even higher if the father also has schizophrenia or is in the schizophrenia spectrum (Kallmann 1938; Parnas et al. 1993). Further, when HR subjects are first assessed, their biological and behavioral reactions are not heavily colored by the consequences of their illness. And because no one -- including experimenters, relatives, teachers, friends, and the subjects themselves -- knows which HR subjects will develop schizophrenia, the premorbid data are not biased. Another advantage is the fact that life event information is relatively current rather than retrospective and that new data can be systematically and uniformly obtained. In addition, ideal controls for those who develop schizophrenia may be found among the HR children who do not. Finally, the HR design encourages the examination of gene-environment interactions. If studies include children who have both parents in the spectrum, those with one parent in the spectrum, and those at low risk, interaction of genetic predisposition with environmental stressors can be studied. In general, genetic risk studies have found that environmental stresses associated with schizophrenia in subjects genetically predisposed to develop the disorder are not associated with schizophrenia in those not at genetic risk.

Most of the HR longitudinal studies were begun in the 1960s and 1970s and were heterogeneous with respect to the initial ages (infancy through young adulthood) of the cohorts followed. At this writing, only a few of the HR studies have followed their subjects to the point where diagnostic outcomes have been obtained. While a variety of interesting variables have been found to distinguish HR children from controls (see Asarnow 1988 for review), not all HR children eventually break down. The primary challenge to researchers is distinguishing the HR children who will develop schizophrenia from those who will not. The aim of this article is to identify characteristics that could be used in primary prevention. The focus, therefore, is on premorbid traits characteristic of HR subjects who have passed through most of the risk period for schizophrenia. Such indicators provide tools for identifying the HR individuals most likely to break down. These indicators in turn have important implications for delaying or reducing later psychosis. To this end, relevant findings from longitudinal studies that have presented diagnostic outcomes will be examined. Recent findings from the Copenhagen 1962 HR for Schizophrenia Project will be emphasized in particular. The only HR study to follow subjects almost past the age of risk (mean-42 years) and to determine lifetime diagnostic outcomes, the Copenhagen 1962 HR Project has the largest number of schizophrenia cases and spectrum disorders to date (see table 1). Findings from follow-back studies are also presented where relevant.

Table 1. Overview and diagnostic outcomes of the longitudinal high-risk studies included in this review
Study Age at start Risk marker Control group(s) Age at last followup Diagnostic (spectrum) outcome at last followup in risk group
New York Infant Study (Fish 1987; Fish et al. 1992) Birth Biological offspring of mothers with schizophrenia (n=10) Biological offspring of lower socioeconomic status mothers (n=12) 27-34 yrs 1 schizophrenia
6 schizotypal or paranoid personality disorder
NIMH Israeli Kibbutz-City Study (Marcus et al. 1987) 8.1-14.8 yrs Biological offspring of parent with schizophrenia (n=100) Biological offspring of psychiatrically normal parents (n=100) 21-28 yrs 5 schizophrenia
1 probable schizophrenia
3 schizoid personality disorder
New York High-Risk Project (Erlenmeyer- Kimling et al. 1995) 7-12 yrs; 9.5 yrs average Biological offspring of one or both parents with schizophrenia (n=63) Biological offspring of parents with major affective or schizoaffective disorder and of psychiatrically normal parents (n=143) 31.1 yrs average 6 schizophrenia
6 schizoaffective (mainly schizophrenia) disorders
3 unspecified functional psychosis
10 schizotypal and paranoid personality disorder
Copenhagen High-Risk Project (Mednick et al. 1987; Parnas et al. 1993) 9-20 yrs; 15.1 yrs average Biological offspring of mothers with severe schizophrenia (n=207) Matched control offspring of parents and grandparents with no history of psychiatric hospitalization (n=104) 42 yrs average 33 schizophrenia
10 schizophrenia- associated psychosis
46 schizotypal and paranoid personality disorder
Obstetric Copenhagen High-Risk Project (Mednick et al. 1971) 11-13 yrs Biological offspring of parent(s) with schizophrenia (n=72) Matched control offspring of parents with psychiatric disorders1 and of psychiatrically normal parents (n=193) 32-34 yrs 16 schizophrenia
11 schizophrenia- spectrum disorder
Finnish Adoptive Family Study (Tienari et al. 1987, 1994) 7-57 yrs Adopted away offspring of biological mothers with schizophrenia and spectrum mothers (n=155) Matched adopted away offspring of biological parents with no record of psychosis (n=186) Assessed in 5/92; no age range reported 9 schizophrenia
4 spectrum psychosis
55 "soft spectrum" nonpsychotic personality disorder
UCLA High-Risk Project (Goldstein 1987) 14-19 yrs Behaviorally disturbed adolescents from families with negative parental attributes (outpatient clinic population) (n=31) Behaviorally disturbed adolescents from families characterized by benign parental attributes (n=20) 29-34 yrs 12 spectrum outcome
Wisconsin Psychosis- Proneness Project (Chapman and Chapman 1987; Chapman et al. 1994) College students Subjects scoring at least 2 SDs above mean on the Perceptual Aberration/ Magical Ideation, Physical Anhedonia, or Impulsive Nonconformity scales (n=355) Subjects scoring less than 0.5 SD above mean on any scale (n=153) 10 yrs later, about 30 yrs 5 schizophrenia
8 psychosis
Note. -- SD = standard deviation; Perceptual Aberration Scale (Chapman et al. 1978); Magical Ideation Scale (Eckblad and Chapman 1983); Physical Anhedonia Scale (Chapman et al. 1976); Impulsive Nonconformity Scale (Chapman et al. 1984).
1
Between 1972 and 1993, some psychiatric parents received diagnoses in spectrum disorders. Their classification is currently being reconsidered.

Premorbid characteristics can be divided into two categories: (1) early childhood precursors related to possible etiological factors, including family psychiatric history, perinatal and obstetric complications, neurointegrative deficits, early parental separation, institutionalization, and family functioning; and (2) later precursors of mental illness revealed by (a) teacher ratings (emotional lability, social anxiety, social withdrawal, poor peer relations, and disruptive and aggressive behaviors) and by (b) paper-and-pencil measures of personality variables indicating proneness to psychosis. Because teacher ratings may prove useful in anticipating and preventing mental health problems, a significant part of this article focuses on their accuracy, as determined by other studies, in predicting mental illness. Finally, implications of these findings for primary prevention will be discussed.

I. Early Precursors of Etiological Interest

Family Psychiatric History. To date, the HR studies that have collected data on diagnostic outcome found higher rates of psychiatric disorder, including schizophrenia-spectrum disorders, in children of parents with schizophrenia (Fish et al. 1992; Erlenmeyer-Kimling et al. 1993; Marcus et al. 1993; Parnas et al. 1993). In the Copenhagen 1962 HR Project, 12 percent of subjects whose mothers, but not fathers, had schizophrenia developed the disorder (based on the lifetime DSM-III-R [American Psychiatric Association 1987] diagnoses determined when the subjects averaged 42 years of age). (See table 2.) Of those who had both mother and father in the schizophrenia spectrum, 25 percent developed schizophrenia. If offspring diagnostic outcomes in addition to schizophrenia are included (i.e., schizotypal personality disorder [SPD] and atypical psychosis [broad spectrum]), 30 percent of those whose mothers had schizophrenia, but whose fathers did not, had a broad-spectrum diagnosis.1 This broad spectrum outcome rate increases to 55 percent in those with two parents with schizophrenia (Parnas et al. 1993).


1Schizoid personality disorder is not included in the schizophrenia spectrum here, although some have placed it in the spectrum. Studies have indicated that schizoid personality disorder may not be genetically related to schizophrenia (e.g., Kety 1988). In the Copenhagen 1962 HR Project, all but one case of schizoid personality disorder were comorbid with SPD. Since SPD did not aggregate as an independent category among these offspring, perhaps it does not belong to the schizophrenia spectrum. Introversion and affective nonresponsiveness without cognitive and behavioral peculiarities do not appear to be related to schizophrenia.

Table 2. Copenhagen 1962 High-Risk Project: Hierarchical frequencies of lifetime DSM-III-R diagnoses in high-risk (HR) and low-risk (LR) subjects
DSM-III-R diagnosis HR (n=207) LR (n=104)
Axis I functional psychosis
    Schizophrenia 31 2
    Schizoaffective disorder 1 0
    Schizophreniform psychosis 1 0
    Atypical psychosis 7 1
        Total 40 3
Cluster A personality disorders
    Schizotypal personality 36 5
    Paranoid personality 5 0
    Schizoid personality 1 0
        Total 42 5
Other Axis I and II disorders
    Major depression 9 8
    Organic brain syndrome 5 5
    Substance abuse 12 5
    Other Axis I disorder 6 7
    Other Axis II disorder 10 8
        Total 42 33
Note. -- DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (American Psychiatric Association 1987).

The New York HR Project has also demonstrated how having a parent with schizophrenia affects outcomes. Schizophrenia and unspecified functional psychotic outcomes are directly associated with having a parent with schizophrenia, but not with having an affective parent or a psychiatrically normal parent. The rates of all schizophrenia-related psychosis, however, did not differ between the children of parents with schizophrenia or affective disorder; the children of affective parents had a higher rate of schizoaffective (mainly schizophrenia) disorder than the children of parents with schizophrenia. Furthermore, schizoaffective (mainly schizophrenia) disorder occurred at comparable rates in children with schizophrenia and those that were normal. Thus, while narrowly defined schizophrenia aggregates in relatives of individuals with schizophrenia, psychotic affective disorders may not share a familial lability with schizophrenia (Erlenmeyer-Kimling et al. 1995).

Although the above findings indicate the importance of genetics, they do not rule out environmental factors. In a longitudinal study on children of disturbed parents who were followed from birth to 5 years, mothers with schizophrenia were found to provide a poorer environment characterized by less play stimulation, fewer learning experiences, and less emotional and verbal involvement than depressed and well mothers (Goodman 1987). As discussed later, such poor environments might contribute to adult psychosis.

Several adoption studies have nevertheless demonstrated the importance of genetic factors independent of the environment. Several studies have found a greater prevalence of schizophrenia among adoptees (or foster children) of biological parents with schizophrenia than among adopted children of control parents (Heston 1966; Rosenthal et al. 1971; Tienari et al. 1987, 1994). Studies have also found a higher incidence of schizophrenia in the biological relatives of adoptees with schizophrenia than among control adoptees (Kety et al. 1975; Kety and Ingraham 1992).

Obstetric Complications. In the Copenhagen 1962 HR Project, Mednick et al. (1987) found that HR subjects who later developed schizophrenia experienced significantly more (and more severe) perinatal complications than those who did not. Using the subsample of these HR subjects who underwent computed tomography scans in 1980, Cannon et al. (1989) found that delivery complications associated with periventricular damage increased the risk for schizophrenia in subjects who were genetically vulnerable. This finding indicates that whatever the nature of the genetic predisposition, it was already expressed at the time of delivery so that it could interact with delivery complications. Genetic predisposition might consist, at least in part, of a disturbance of fetal neural and perhaps vascular development that makes the fetal brain more vulnerable to the stress of delivery.

In a recent study using the Danish perinatal cohort of 9,125 children, Barr et al. (submitted for publication b) also found that the interaction of delivery complications and family history predicts schizophrenia in offspring. Delivery complications alone were not associated with later schizophrenia. The evidence that prenatal and obstetric complications are risk factors has been consistently reported, particularly in studies employing perinatal medical records rather than recollection (McNeil 1991; Murray et al. 1992; Barr et al., submitted for publication b). Adults with schizophrenia have more frequent and more severe obstetric complications than controls.

This line of research led to a series of studies to test the hypothesis that influenza during gestation could increase the risk for adult schizophrenia (Mednick et al. 1988, 1994; Barr et al. 1990; Mednick 1994). The finding that maternal influenza during the second trimester of gestation does appear to increase risk for schizophrenia in offspring has been independently replicated in several countries (Adams et al. 1993; McGrath et al. 1994; Kunugi et al. 1995). Recent findings indicate that maternal influenza may have this effect by producing deficits in habituation and visual attention processes that interfere with later cognitive development (Mednick 1994).

Neurological Abnormalities. Many HR studies have described neurointegrative deficits in children at risk for schizophrenia (see Fish et al. 1992 for review). Very few data are available, however, on the stability of neurobehavioral deficits over time, particularly on their power as predictors of actual breakdown. In the New York Infant Study, Fish (1987) found that neurointegrative deficits, termed "pandysmaturation" (PDM), involving motor or visual-motor skills during infancy were related to severity of psychopathology at age 10. Of the 12 HR children who demonstrated PDM in infancy, 7 later developed spectrum disorders (1 schizophrenia, 5 schizotypal, 1 paranoid personality disorder). These deficits were associated with low birth weight but not with obstetric complications. (Note that the number of cases was very small.) Fish et al. (1992) suggested that low birth weight may reflect earlier onset of neurointegrative deficits in utero and that obstetric complications produce deficits only in genetically vulnerable individuals.

In the National Institute of Mental Health (NIMH) Israeli Kibbutz-City Study (Marcus et al. 1987), "attention deficit disorder-like" neurobehavioral deficits assessed at a mean age of 11.4 years were associated with later spectrum disorders. Of the 24 HR children with neurobehavior deficits, 5 developed schizophrenia, while none of the 26 HR children without neurobehavioral deficits did. Of the 9 individuals who later suffered schizophrenia-spectrum disorders, exhibited poor neurobehavioral signs (hyperkinesis, poor concentration, motor dyscoordination, perceptual signs, and poor verbal abilities) in childhood. The one exception had a nonpsychotic diagnosis of schizoid personality disorder combined with an affective diagnosis.

More recent analyses with adult outcome measures in the New York HR Project have suggested that attentional dysfunction measured in childhood by the Continuous Performance Test (Rosvold et al. 1956), the Attention Span Task (Erlenmeyer-Kimling et al. 1983), and the Digit Span Subtest (Wechsler 1949) may be associated with later nonparanoid psychosis (Erlenmeyer-Kimling et al. 1993). In addition, attentional deficits were detected several years before social dysfunction (insensitivity and indifference to others, social isolation) emerged in a group of HR children, suggesting that attentional dysfunction not only may be a marker of schizophrenic lability but also has an active role in the schizophrenic process (Comblatt et al. 1992). Perhaps social deficits result from cognitive dysfunction and the reaction of others.

Using the newer Copenhagen 1972 HR Project, Lafosse (1994) examined 265 children, some of whose parents (mother or both mother and father) had schizophrenia. Data collected when these children were age 12 included a neurological examination, part of which was the Stott Motor Test (Stott 1966). In 1992, when the psychiatric status of these individuals (then 35 years old) was ascertained, 16 were found to have developed schizophrenia. At 12 years old, the 16 HR individuals diagnosed with schizophrenia in 1992 had evidenced significantly greater deficits in motor coordination than 16 HR individuals diagnosed with affective disorders and 40 with normal outcomes. In an earlier review of HR studies, Mednick and Silverton (1988) noted that poor motor coordination is probably the most consistently reported risk indicator distinguishing HR from low-risk children. Taken together, these findings suggest that assessing difficulties with motor coordination may be an important aid in early identification.

Neurointegrative deficits have also been reported in follow-back studies. Walker and Lewine (1990), examining home movies of schizophrenia patients and their siblings filmed during the first 5 years of the patients' lives, were able to identify the children that developed schizophrenia. These children were found to be less responsive and to have poorer eye contact, less positive affect, and poorer fine and gross motor coordination. Several studies examining childhood records of schizophrenia patients and controls have also noted developmental retardation and neurological disorders among the children who developed the disorder (O'Neal and Robins 1958; Ricks and Nameche 1966; Watt 1972).

Early Separation and Institutionalization. Psychodynamic theorists have long maintained that early disruption of the caregiver-child bond can lead to mental disturbance. Psychotic disorders are presumed to be associated with the earliest disruption of bonding (Fromm-Reichman 1959; Mahler et al. 1975; Robbins 1992). Using data from the Danish perinatal cohort of 9,125 children, Barr et al. (submitted for publication a) found that elevated levels of separation during the first year of life were associated with increased risk for schizophrenia only if there was a family history of schizophrenia. The researchers speculated that early separation led to attachment difficulties for these HR children. It is interesting to note that for children without a family history of psychiatric disorder, very early separation was associated with increased risk of psychiatric hospitalization for nonpsychotic disorders. The assumption in this line of research is that early separation leads to later deviance. The likelihood that children who suffer early separation may subsequently have many other family traumas cannot be ruled out. If we wish to ascribe the later adult deviance to very early separation, later family traumas must be controlled.

Based on the Copenhagen 1962 HR sample, Walker et al. (1981) found that maternal and paternal separation during the first 10 years of life did not predict future schizophrenia for children placed in foster care or in the care of relatives. On the contrary, when separation did not result in institutionalization, the absence of a mother with schizophrenia was associated with decreased schizophrenic symptomatology in males. Maternal absence associated with institutional rearing, however, significantly predicted future schizophrenia in males but not in females. These results have been replicated using the lifetime diagnoses reported in the most recent diagnostic followup (Gutkind and Mednick, in preparation).

These findings imply that poor family environment associated with a disturbed parent is a risk factor, particularly for boys. In addition, they indicate that future psychosis may be avoided if the genetically vulnerable child experiences a positive foster placement.

Family Functioning. The above finding that separation from a disturbed parent may have beneficial effects is supported by the Finnish Adoptive Family Study. Tienari et al. (1994) found that the children who had mothers with schizophrenia but who had a positive adoptive experience were protected from later schizophrenia, while the genetically vulnerable individuals who experienced a disturbed adoptive family tended to develop the disorder. This finding suggests that a positive rearing experience can protect at-risk individuals against future psychosis.

The NIMH Israeli Kibbutz-City Study also found an association between poor parenting and later psychopathology. Marcus et al. (1987) found that inconsistent parenting, overinvolvement, and hostility toward the child predicted schizophrenia-spectrum outcomes. In the Copenhagen 1962 HR Project, mothers with schizophrenia varied in the ability to provide for their children. HR children whose mothers were socially unstable and promiscuous were at greater risk for later schizophrenia (Talovic 1984). Future schizophrenia patients also reported less satisfactory relationships with their parents than individuals with schizotypal and normal outcomes did (Burman et al. 1987).

The University of California, Los Angeles (UCLA) Family Project, which did not use parent psychiatric status as a risk factor, followed the families of disturbed adolescents identified in an outpatient clinic (Goldstein 1987). The aim of the study was to identify parental attributes that may be precursors of schizophrenia, specifically communication deviance (CD) and affective style (AS). CD refers to a parent's inability to establish and maintain a shared focus with the teenager. AS, which is a construct orthogonal to CD, refers to parental affective attitudes that are negative, critical, intrusive, and guilt inducing. Among the adolescents Goldstein studied, those who later developed schizophrenia-spectrum disorder were characterized by a combination of high CD and negative AS in family functioning. In contrast, those with good outcomes had low CD and positive AS parents, indicating that healthy parental attributes may be a protective factor.

Other studies support the UCLA Family Project findings. In Norway, Rund (1986, 1994) found that CD, expressed hostility, and overinvolvement characterized families in which offspring developed schizophrenia. Additionally, negative AS characterized by high expressed emotion in the family has been widely reported to predict relapse in individuals who are already diagnosed with schizophrenia (Bebbington and Kuipers 1994).

II. Late Precursors Which Signal Future Psychosis

Behavioral Precursors. Social dysfunction and behavioral deviance reported by teachers are reliable predictors of later schizophrenia. Followup and follow-back studies have quite consistently reported behavioral deviance evident from childhood or adolescence. Followup studies of schizophrenia patients who were referred to child guidance clinics reveal that they were mostly shy and withdrawn, had poor peer relationships, and tended to do poorly in school (Offord and Cross 1969). They also demonstrated antisocial behavior, mainly within the family, and tended to have family histories of mental illness. Follow-back studies of schizophrenia patients' school records also revealed shy and passive behavior in childhood and adolescence (Offord and Cross 1969; Watt 1972). Most schizophrenia patients, however, are not distinguishable from their peers in childhood. Deviant behaviors tend to become more prominent in adolescence, a time of life that may present more socially challenging situations. Sex differences in social adjustment have also been noted (Watt and Lubensky 1976; John et al. 1982; Kohlberg et al. 1984), with males showing more antisocial behaviors and females showing more passivity and withdrawal.

In the NIMH Israeli Kibbutz-City Study, several types of premorbid behavior were represented among the nine children who developed spectrum disorders. These behaviors ranged from extreme shyness and social withdrawal to aggressive and antisocial behavior, as well as combinations of both (Hans et al. 1992). In addition, social withdrawal was found to be associated with motor signs in the HR group (not just in the nine schizophrenia-spectrum outcomes).

Copenhagen HR Study assessing the predictive value of teacher-rated behaviors. A recent study using the Copenhagen 1962 HR Project assessed the predictive validity of school teachers' behavior ratings when subjects were 15 years old (Olin et al. 1995). At that time, a 29-item true-false questionnaire was distributed to the teacher who best knew each subject. The teachers had at least 3 years of contact with the subjects. The questionnaires, completed in 1962, were examined to determine how the teachers had described the individuals identified in 1989 to be schizotypal or to have schizophrenia.

A likelihood ratio approach following Schum and Pfeiffer (1977) was taken to identify school behaviors that distinguished the schizophrenia group from other diagnostic groups. Three types of discrimination within the HR group (with mothers having schizophrenia) were attempted: (1) schizophrenia subjects versus subjects with no mental illness (NMI), (2) schizophrenia subjects versus those with other nonpsychotic conditions in most cases requiring hospitalization, and (3) schizophrenia subjects versus those diagnosed as being schizotypal or having paranoid personality disorders. Based on reported differences between male and female preschizophrenic behavior (e.g., Watt 1972, 1978; Watt and Lubensky 1976; Schwartzman et al. 1985), school behavior was analyzed separately by gender. Behaviors that distinguished subjects who developed schizophrenia from those with other outcomes are presented in table 3. The sensitivity and specificity of these behaviors are presented, as well as their positive predictive power (i.e., the probability of having adult schizophrenia given the presence of the deviant behavior) and negative predictive power (i.e., the probability of not having a schizophrenia outcome given the absence of the deviant behavior). As can be seen, taken individually these behaviors are fairly sensitive and specific in predicting future schizophrenia and have moderately high positive and negative predictive powers.

Table 3. Teacher-rated behaviors that distinguished individuals diagnosed with schizophrenia from those with other outcomes
Characteristics Sensitivity1 Specificity2 Positive predictive
power
3
Negative predictive
power
4
Schizophrenia vs. no mental illness
Females
Teacher predicts future emotional or psychotic problems 0.30 0.97 0.75 0.82
Nervous 0.46 0.82 0.45 0.82
Males
Disciplinary problem 0.39 0.96 0.88 0.71
Teacher predicts future emotional or psychotic problems 0.43 0.88 0.67 0.73
Repeated a grade 0.29 0.96 0.80 0.73
Disturbs class with inappropriate behavior 0.50 0.82 0.64 0.72
Emotional reaction persists; high-strung 0.40 0.85 0.60 0.72
Lonely and rejected by peers 0.44 0.82 0.58 0.71
Treated by psychologist for problem 0.36 0.86 0.57 0.73
Easily excited or irritated 0.41 0.82 0.58 0.69
Schizophrenia vs. schizotypal or paranoid personality disorders
Females
Normal emotional reaction (is not overly sensitive or insensitive) 0.73 0.55 0.62 0.67
Not uneasy about criticism 0.67 0.60 0.67 0.60
Males
Disciplinary problem 0.39 0.96 1.00 0.70
Disturbs class with inappropriate behavior 0.50 0.89 0.75 0.72
Lonely and rejected by peers 0.44 0.88 0.70 0.70
Less nervous 0.56 0.68 0.53 0.71
Schizophrenia vs. nonpsychotic disorders
Females
Lonely and rejected by peers 0.36 0.93 1.00 0.67
Nervous 0.46 0.85 0.71 0.65
Uneasy about criticism 0.33 0.91 0.80 0.56
Rarely takes part in spontaneous activity 0.50 0.75 0.63 0.64
Teacher predicts future psychotic or emotional problems 0.30 0.90 0.75 0.56
Average intelligence 0.86 0.36 0.57 1.00
Passivity 0.27 0.92 0.75 0.58
Males
Lonely and rejected by peers 0.44 0.89 0.78 0.64
Repeated a grade 0.29 0.93 0.80 0.57
Passivity 0.25 0.94 0.80 0.59
Teacher predicts future psychotic or emotional problems 0.43 0.82 0.67 0.62
Emotional reaction persists; high-strung 0.40 0.82 0.67 0.61
1Sensitivity = p (true/schizophrenia) i.e., probability of a true response given a diagnosis of schizophrenia.
2
Specificity = p (false/other outcome) = 1 -p (true/other outcome) i.e., probability of a false response given an outcome other than schizophrenia.
3
Positive predictive power = probability of having adult schizophrenia given the presence of a deviant characteristic.
4
Negative predictive power = probability of not having a schizophrenia diagnosis given the absence of a deviant characteristic.

Schizophrenia versus NMI. 2 Very few items in the school report distinguished the girls who were later diagnosed with schizophrenia from NMI females; however, the teachers did predict future psychotic problems for the adolescents later diagnosed with schizophrenia. For males, teacher ratings were among the best predictors of future psychotic problems. Compared to those who had normal outcomes, the adolescent males later diagnosed with schizophrenia were more likely to pose discipline problems, to disturb the class, to be emotionally reactive and easily excited, and to have been treated by a school psychologist. In addition, they were also more likely to be lonely and rejected by their peers.


2Although not reported in the Olin et al. (1995) study, HR subjects were also compared to the low risk (ERA NMI (i.e., those whose parents and grandparents had no psychiatric hospitalization record). The results of this comparison are highly similar to those obtained by comparing the HR-NMI and schizophrenia subjects. The same behaviors distinguished the males with schizophrenia from the LR-NMI males. Females with schizophrenia were found to be more distinguishable from the LR-NMI females than from the HR-NMI females. In addition to being judged more likely to develop future psychotic problems and to being more nervous, female schizophrenia subjects were also more likely to be rejected by peers, more high-strung, less likely to react to praise, more shy, more excitable, less spontaneous, and more passive than the LR-NMI females.


Schizophrenia versus SPD. Adolescent girls with SPD did not differ markedly from those with schizophrenia outcomes. The future SPD females, however, were more uneasy regarding criticism either more or less sensitive than the females later diagnosed with schizophrenia. Antisocial, aggressive, disturbing behavior in school distinguished the male schizophrenia subjects from the SPD males, who were more often seen as being nervous than the former.

Schizophrenia versus other nonpsychotic disorders. The female schizophrenia subjects were most different from the women with nonpsychotic psychiatric outcomes. In school, they were more frequently judged to be abnormally lonely, rejected, nervous, passive, and uneasy about criticism. In addition, the teachers judged (correctly) that they were prone to psychotic or emotional problems. The likely reason they were better distinguished from the other nonpsychotic females than from NMI or SPD subjects is that many of the other nonpsychotic females were diagnosed as depressed. The teachers also tended to predict psychotic outcomes for the males who would later be diagnosed with schizophrenia and not to make such predictions for the males with nonpsychotic psychiatric outcomes. The male schizophrenia subjects were more likely to repeat a grade in school and were judged to be lonely, rejected, and high-strung.

Diagnostic efficacy of the school report. A standard receiver operating characteristic (ROC) analysis (Swets and Pickett 1982; Hsiao et al. 1989; Mossman and Somoza 1989) was used to evaluate the school report's efficacy in differentiating HR children who later developed schizophrenia from those with more benign outcomes. Individual bits of predictive information (i.e., specific school behaviors) from the school report were combined to provide aggregate indices for discriminating the schizophrenia group from the other three. This technique is especially useful in an intervention context since it provides an objective basis for identifying levels of true positives (i.e., those correctly identified as future schizophrenia sufferers) given levels of false positives (i.e., those wrongly predicted to develop schizophrenia).

Our results indicate that specific school behaviors taken as an aggregate have greater predictive power than individual school behaviors. Overall, males who developed schizophrenia were particularly distinguished from males who later had NMI and from those later diagnosed with SPD. By contrast, females later diagnosed with schizophrenia were more distinct from females who later had other nonpsychotic disorders (than from those who had no adult mental illness). In general, the discrimination between future schizophrenia subjects and the NMI or SPD subjects was more powerful for males than for females, which is consistent with their more easily observed antisocial behavior and the numerous reports of poorer premorbid social competence (e.g., Klorman et al. 1977; Kokes et al. 1977; Ziegler et al. 1977; Goldstein 1988).

To illustrate how the ROC technique could be useful for intervention purposes, an ROC curve for the schizophrenia versus NMI male comparison is displayed in figure 1. The ROC curve for the females is also presented to illustrate the better discrimination for males than for females. The ROC curve represents all true positives and false positives that can be obtained by selecting different thresholds based on the school report. The true positive rate is equivalent to the sensitivity of the school report (sensitivity of the school report is the probability that the school report will identify individuals who later are found to have schizophrenia). The false positive rate corresponds to one minus the specificity of the school report (specificity of the school report is the probability that the school report will correctly identify individuals as not having schizophrenia that were given a non-schizophrenia outcome). One strategy for selecting a threshold is to decide on the desired tolerance for false positives or misses. Fixing a miss probability is equivalent to setting a desired hit rate because they must total 1.0. Specifying a smaller false positive rate results in a smaller hit rate (lower left comer of the ROC curve). Likewise, the false positive rate is necessarily higher with an increased hit rate (upper right corner of the ROC curve). Deciding on a threshold depends of course on the effectiveness and cost of the intervention program, the cost incurred by an individual who experiences an unneeded intervention, and the cost to potential psychotics who do not undergo treatment intervention.

For example, if, based on cost-benefit analyses of an intervention program, we decide to tolerate a false positive rate below 0.2 for the males, then we can directly read from figure 1 the rate of true positives we will attain, namely 0.6. That is, predictions based on school records of which individuals in this HR sample will eventually have a schizophrenia or an NMI outcome will target 60 percent of those who eventually are diagnosed with schizophrenia and 20 percent of those who turn out to have NMI.

Summary of school report findings. The findings described above have several implications. First, note that the substantive findings reported here that differentiate schizophrenia subjects from NMIs are quite similar to other findings (e.g., Offord and Cross 1969; Watt 1972, 1978; Watt and Lubensky 1976; Watt et al. 1982). These other studies, using child guidance or school records of individuals with schizophrenia and of controls, have also reported the gender differences noted here. Such similarities suggest that our findings are generalizable to an unselected population. Second, the accuracy of the teachers' predictions of future psychosis suggests that such ratings may be useful in other settings to help identify children who may be vulnerable to psychosis when they grow up. The fact that HR subjects who had other outcomes were used for comparison indicates that these behaviors may have some diagnostic specificity for schizophrenia. Third, the findings also add to a growing body of literature supporting the hypothesis that schizophrenia does not appear suddenly in early adulthood. The findings of this study indicate that the people who will be diagnosed with schizophrenia are already evidencing deviant behaviors before early adulthood. We have also shown in other analyses using this same population that the type of premorbid deviance is highly consonant with the schizophrenia symptomatology later evidenced: among individuals who develop schizophrenia, those who are disruptive and aggressive in school later develop predominantly positive symptoms, while those who are passive and withdrawn in school develop predominantly negative symptoms (Cannon et al. 1990).

Copenhagen HR study examining behaviors that predict schizophrenia-spectrum disorders. A second study using the same Copenhagen 1962 HR Study (Tyrka et al. 1995) illustrates a method of discrimination, called taxametry, developed by Golden and Meehl (Meehl 1973; Golden and Meehl 1979; Golden 1982). In this study, a few measures of behavior obtained when the subjects were 15 years old were combined to determine how well the measures differentiate subjects with a future schizophrenia-spectrum diagnosis. The selection of the predictive measures was guided by our conception (in agreement with Meehl [1962, 1989, 1990]) that the basic genetic condition of the schizophrenia-spectrum group of diagnoses is best approximated by the characteristics of the SPD diagnosis. Schizophrenia is a complication of this genetic condition and is brought on by unkind environments such as perinatal birth complications (i.e., the diathesis-stress model).

The premorbid data examined were selected from the same school report we have just discussed, a psychiatric interview (conducted by Professor Fini Schulsinger), and a word association test, all of which were administered in 1962 when the average age of subjects was 15. The six indicators of schizotypy and the items representing them are presented in table 4. Subjects who tend to have positive scores on most indicators are defined as taxon members; those who tend to have negative scores on most indicators, nontaxon members. As a whole, these indicators were fairly sensitive in predicting schizotypy taxon membership in 67 percent (of 33) and 73 percent (of 48) of individuals who developed schizophrenia and spectrum disorders, respectively. In addition, a significantly greater proportion of taxon members (40%) had spectrum outcomes compared to nontaxon (the complement) members (16%), suggesting that taxon classification is not simply sensitive to all mental illness, but is modestly specific to spectrum disorders.

Table 4. Composition of the six indicators of schizotypy
Indicator and source Item
Social withdrawal
Psychiatric interview No friends during childhood
No friends during and after adolescence
Has never been a member of any club
Avoids active, social contact with peers
Teacher's report Rejected by peers
Appears content with isolation
Social anxiety
Psychiatric interview Tense during interview
Finds it extremely difficult to make friends
Uncomfortable in the presence of strangers
Teacher's report Anxious and restrained with peers
Anxious and restrained with the teacher
Appears to be a nervous individual
Passivity
Teacher's report Waits passively for instructions
Rarely takes part in spontaneous activities
Behavior is marked by passivity
Flat affect
Psychiatric interview Affect flat or inappropriate during interview
Facial expression flat or inappropriate
Schizoid
Teacher's report Seldom laughs or smiles; serious expression
Doesn't react when praised or encouraged
Peculiarity
Psychiatric interview Queer, peculiar, eccentric, distrustful, or superstitious
Poor prognosis
Psychiatric interview Prognosis bad or dubious
Teacher's report Likely to develop psychiatric or emotional problems

Personality variables. In the 1970s, Chapman and colleagues developed a longitudinal research strategy for identifying psychosis-prone individuals by their traits using paper-and-pencil self-report questionnaires and an interview of psychotic-like experiences (Chapman and Chapman 1987). This method, which may overcome the limited generalizability of findings to which the genetic risk method is prone, offers the opportunity to select a wider variety of psychosis-prone individuals. At a recent 10 year followup interview of more than 500 college students, 14 reported a DSM-III-R psychosis: 5 schizophrenia, 3 psychosis not otherwise specified, 1 delusional disorder, 3 bipolar psychosis, and 2 major depression and psychosis (Chapman et al. 1994). The Perceptual Aberration (Chapman et al. 1978) and Magical Ideation (Eckblad and Chapman 1983) scales were found to be good indicators of proneness to psychosis. Compared to low scorers, higher scorers on these scales tended to have more psychotic-like experiences or schizotypal symptoms. A substantial number of these high scorers reported having psychotic relatives. Of these psychosis-prone subjects, 40 to 45 percent would not have been so identified on the basis of having psychotic relatives, suggesting that these indicators are more powerful predictors than family psychiatric history alone. In particular, college students who scored high on both the Social Anhedonia (Eckblad et al. 1982) and Magical Ideation scales had a higher rate of clinical psychosis than low scorers. In contrast, those who scored high on the Physical Anhedonia (Chapman et al. 1976) and Impulsive Nonconformity (Chapman et al. 1984) scales were not at greater risk for clinical psychosis. Although the Perceptual Aberration and Magical Ideation scales predicted psychosis in general, they did not successfully predict schizophrenia in particular.

Summary of Behavior Precursors and Personality Traits. Individual behaviors and personality variables that have been observed to characterize children and adolescents who later develop schizophrenia or spectrum disorders include emotional lability, social anxiety, withdrawal, passivity, flat affect, and peculiarity. Sex differences in school behaviors have also been noted, with preschizophrenia males exhibiting more antisocial behaviors than preschizophrenia females. Young adult personality traits that distinguish those who later become clinically psychotic include perceptual aberrations, magical ideation, and social anhedonia.

Conclusion

As can be seen, several premorbid characteristics have been identified to be risk markers for future psychosis. These premorbid characteristics fall into two categories: (1) Precursors related to early etiological factors, including a family history of schizophrenia, delivery complications, maternal exposure to influenza (particularly during the second trimester), neurobehavior deficits, early (first year of life) parental separation, institutional rearing, and distressed family functioning; and (2) social and behavioral precursors of mental illness identified by teachers and clinicians and personality variables revealed by interviews and questionnaires. Teachers more frequently judged both males and females later diagnosed with schizophrenia to be emotionally labile and more susceptible to future emotional or psychological breakdown. They also more frequently rated males as disruptive, disciplinary problems, anxious, lonely and rejected by peers, and more likely to have repeated a grade, while, in contrast, they rated females as nervous and withdrawn. Individuals later diagnosed in the schizophrenia spectrum were judged by teachers and the interviewing psychiatrist to be socially withdrawn, socially anxious, passive, flat in affect, and peculiar and to have a poor prognosis. These preschizophrenia characteristics have also been described in other genetic and nongenetic risk populations (Offord and Cross 1969; Watt 1972, 1978; Watt and Lubensky 1976; Watt et al. 1982; Janes et al. 1983; Kohlberg et al. 1984; Schwartzman et al. 1985). In young adults not found to be at genetic risk for schizophrenia, personality variables related to perceptual aberration, magical ideation, and social anhedonia predicted future psychosis but not schizophrenia in particular.

In general, the above findings underscore the importance of the interaction between genetic vulnerability, environmental attributes, and individual traits. Aside from very early parental separation, institutionalization, and neurobehavior deficits, these premorbid characteristics have also been identified as risk factors in individuals not at genetic risk (e.g., individuals selected on the basis of disturbed traits), suggesting that such characteristics could be used in identifying at-risk individuals in the general population. Identifying risk factors in turn indicates protective factors relevant for primary prevention. For example, as maternal mental illness is a risk indicator, maternal mental health is a protective factor. Women diagnosed with schizophrenia and other psychiatric disorders have been reported to suffer from more stress during pregnancy and to engage in risk-increasing behaviors such as using medication and alcohol, smoking and seeking prenatal care late in pregnancy (Ragin et al. 1975; Wrede et al. 1984; Goodman 1987; McNeil and Kaij 1987; Sameroff et al. 1987). Such behaviors are likely associated with perinatal and obstetric complications that could increase the risk of future psychosis in genetically vulnerable individuals. These findings indicate the importance of providing better prenatal care for mentally ill women. Genetic and nongenetic risk studies also indicate the importance of environmental factors. Psychosocial interventions for mentally ill women and for families in distress could protect against future psychosis. Mentally and emotionally healthy parents, or at least those with adequate psychosocial support, are more likely to provide stable home environments and the emotional support essential for healthy child development.

The identification of premorbid behaviors that distinguish individuals later diagnosed with schizophrenia adds to the growing literature supporting the hypothesis that schizophrenia is a developmental disorder. Teachers, in particular, can be especially helpful in identifying adolescents at risk for future psychosis. Given that the average adolescent spends a substantial amount of time in school, teachers are in a unique position to assess how adolescents cope with the social and cognitive demands of school and to compare their adjustment with that of peers. The consistent picture of preschizophrenic behaviors provided by followup and follow-back studies using teacher ratings points to the predictive utility of teachers' perceptions in primary intervention.

Taken together, a variety of risk indicators could be combined to provide a multiple risk index. Early etiological factors by themselves may be difficult to assess in settings involving behaviorally deviant children or adolescents, but they can be readily obtained through interviews with family members. As Rutter (1979) pointed out, the greater the number of risk factors, the heavier the load on the developmental system. These early etiological precursors are likely to increase the predictive power of more current information. Ideally, a risk index that includes early developmental history and current behavior deviance could be created for each individual to target individuals for early intervention programs.

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Acknowledgment

This research was supported by the National Institute of Mental Health grant MH-46014 and the National Institute of Mental Health Research Scientist Award MH-00619 to Dr. Mednick.

The Authors

Su-chin Serene Olin, M.A., is Senior Research Assistant, Department of Psychology, University of Southern California, Center for Longitudinal Research, Social Science Research Institute, Allan Hancock Foundation, Los Angeles, CA.

Sarnoff A. Mednick, Ph.D., Dr. Med., is Professor of Psychology, Social Science Research Institute, University of Southern California, Los Angeles, CA, and is on the Board of Directors, Institute for Preventive Medicine, Copenhagen, Denmark.


This article, originally from the Schizophrenia Bulletin, is in the public domain and may be reproduced or copied without requesting the author's permission.

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