What makes children at high risk for schizophrenia?

Introduction

By the 1960s, it had been well established that schizophrenia often ran in families. The general population rate for the disorder is about 1 percent. In contrast, it has been estimated that children who have one biological parent with schizophrenia have a 10 to 15 percent chance of developing the disorder. When both biological parents are diagnosed with schizophrenia, the risk rate is thought to be around 40 percent. It is apparent, therefore, that offspring of schizophrenic parents are indeed at heightened risk for developing the disorder.

The term “high risk” has been applied to biological offspring of schizophrenic parents, because they are known to be at genetic risk for the disorder shown by their parents. Numerous researchers have studied high-risk children and adolescents to shed light on the origins of schizophrenia. Traditional studies focused on the high-risk children of schizophrenic parents, and the second generation of high-risk studies studied adolescents and young adults with a family history of schizophrenia and treated them in early intervention programs.

The importance of research on children at risk for schizophrenia stems from a need to understand the precursors of the illness. Over the years, researchers have studied schizophrenia from many different perspectives and with a variety of methods. Despite many decades of work, however, investigators have been unsuccessful in identifying the causes or developing a cure. Some progress has been made in clarifying the nature and course of schizophrenia, and there have been considerable advances in the pharmacological treatment of symptoms; however, the precursors and the origins remain a mystery.

Because the onset of schizophrenia usually occurs in late adolescence or early adulthood, patients typically do not come to the attention of investigators until they have been experiencing symptoms for some period of time. At that point, researchers have to rely on the patient and other informants for information about the nature of the individual’s adjustment before the onset of the illness. These retrospective accounts of the patient’s functioning are often sketchy and can be biased in various ways. Yet it is well accepted that progress toward the ultimate goal—the prevention of schizophrenia—will not be achieved until researchers are able to identify individuals who are vulnerable to the disorder.

In response to this concern, several investigators emphasized the importance of studying the development of individuals known to be at heightened statistical risk for schizophrenia. Specifically, it was proposed that repeated assessments should be conducted so that data on all aspects of the development of at-risk children would be available by the time they enter the adult risk period for schizophrenia. In this way, it might be possible to identify precursors of the illness in subjects who had not yet received any treatment for the disorder. Another major advantage of studying subjects before the provision of treatment is that it makes it possible to differentiate true precursors of the illness from the consequences or side effects of treatment for the illness.

Methodological Issues

One of the major challenges in conducting high-risk research is locating the sample. As previously stated, schizophrenia is a relatively rare disorder in that it occurs in about 1 percent of the general population. Moreover, because most schizophrenic patients experience an onset of illness in late adolescence or early adulthood, they are less likely to marry or have children. This is especially true of male schizophrenic patients. Consequently, the majority of the subjects of high-risk research are offspring of schizophrenic mothers. Further, of the schizophrenic women who do have children, a substantial portion do not keep their children but instead give them up for adoption. This further complicates the task of identifying samples of high-risk children. To be assured of identifying a sample of adequate size, researchers in this field establish formal arrangements with local treatment facilities to increase their chances of identifying all the high-risk children in their geographic area.

Another important issue confronted by high-risk researchers is the question of when the study should be initiated. Most investigators are interested in identifying the very earliest signs of vulnerability for schizophrenia. Therefore, it is desirable to initiate a high-risk study with infant subjects. In this way, investigators will be able to examine the entire premorbid life course of patients. If there are any markers of vulnerability apparent in infancy, they will be able to identify them. The investigator who initiates a study of infant subjects, however, must wait an extended period of time to gather any information about their adult psychiatric outcomes. To reduce the period between the initiation of the study and the entry of the subjects into the major risk period for schizophrenia, most investigators have initiated high-risk projects on subjects who are in middle or late childhood.

The problem of attrition (loss of subjects) is another aspect of concern to high-risk researchers. As mentioned, the long-term goal is to compare those high-risk children who succumb to schizophrenia to those who do not. Consequently, the most crucial information will be provided only when the researchers are knowledgeable about the adult psychiatric outcome of the subjects. Because a sample of one hundred high-risk children may eventually yield only ten to fifteen schizophrenic patients, it is of critical importance to investigators that they maintain contact with all subjects so that they can determine their adult psychiatric outcomes.

The question of how to select an appropriate comparison group is salient to high-risk researchers. One of the ultimate goals is to identify specific signs of vulnerability to schizophrenia. An important question is whether the signs identified by researchers are simply manifestations of vulnerability to any adult psychiatric disorder or signs of specific vulnerability to schizophrenia. To address this question, it is necessary to include groups of children whose parents have psychiatric disorders other than schizophrenia.

Early Studies

Conducting longitudinal studies of these high-risk children is an efficient way of studying individuals who are most likely to develop schizophrenia. The first large-scale prospective longitudinal study of high-risk children was initiated in Denmark in the mid-1960s by Sarnoff Mednick and Fini Schulsinger. They followed a group of one hundred children who had at least one schizophrenic parent and two hundred comparison children whose parents had no psychiatric disorder. Since the Danish study was initiated, a number of other research groups have started similar high-risk research programs.

A second longitudinal study of particular note is the New York High-Risk Project, led by L. Erlenmeyer-Kimling. Erlenmeyer-Kimling and her associates followed two independent series of three groups of children: children with at least one schizophrenic parent, children with one or two parents with major affective disorder (typically depression), and children whose parents were not diagnosed with or described having a mental illness. One notable feature of the New York High-Risk Project is that the investigators included an at-risk comparison group, consisting of offspring of other psychiatrically disturbed individuals. Comparisons between high-risk offspring (children with at least one schizophrenic parent) and offspring of mood-disordered parents is especially useful in identifying behavioral precursors that are specifically associated with the later development of schizophrenia rather than an adult psychiatric outcome in general.

Research Findings

The results from studies of high-risk children suggest that the predisposition for schizophrenia may be detectable at an early age. Reports on the developmental characteristics of high-risk children have revealed some important differences between children of schizophrenic parents and children whose parents have no mental illness. The differences that have been found tend to fall into three general areas: motor functions, cognitive functions, and social adjustment. When compared with children of parents without reported or diagnosed mental illness, high-risk subjects have been found to show a variety of impairments in motor development and motor abilities. Infant offspring of schizophrenic parents tend to show delays in the development of motor skills, such as crawling and walking. Similarly, studies of high-risk subjects in their middle childhood and early adolescent years reveal deficits in fine and gross motor skills and coordination. It is important to emphasize, however, that these deficiencies are not of such a severe magnitude that the child would be viewed as clinically impaired in motor skills. However, the deficiencies are apparent when high-risk children, as a group, are compared with children of parents without mental illness.

Numerous studies have found that children at high risk for schizophrenia also show impairments in cognitive functions. Although their scores on standardized tests of intelligence are within the normal range, they tend to be slightly below those of children of parents who are not high-risk. With regard to specific abilities, investigators have found that high-risk children show deficiencies in their capacity to maintain and focus attention. These deficiencies are apparent as early as the preschool years and involve the processing of both auditory and visual information. Recall that the New York High-Risk Project included a comparison group of offspring of individuals with affective illnesses such as depression. The results of the project, which started in 1971 and has now followed the offspring from childhood to mid-adulthood, indicated that attention deviance, impairments in gross motor skills, and memory deficits were relatively unique to risk for schizophrenia. That is, these deficits were more prevalent in high-risk children (offspring of schizophrenic parents) than among offspring of affectively ill parents. Erlenmeyer-Kimling and associates have noted that among all the neurobehavioral predictors of later development of schizophrenia, attention deviance appears to be the most specifically related to genetic risk for schizophrenia. In the New York High-Risk Project, the offspring of schizophrenic parents showed more attention deviance than either the offspring of affectively ill parents or the offspring of parents who were not considered high-risk. Because attention deficits have been found so consistently in high-risk children, some researchers in the field have suggested that these deficits may be a key marker of risk for schizophrenia.

When compared with children of parents without psychiatric disorders, offspring of schizophrenic parents tend to manifest a higher rate of behavioral problems. These include a higher rate of aggressive behaviors, as well as an increased frequency of social withdrawal. In general, children of schizophrenic parents are perceived as less socially competent than comparison children. It is important to take into consideration, however, that children of parents with other psychiatric disorders are also found to show problems with social adjustment. Consequently, it is unlikely that behavioral adjustment problems are uniquely characteristic of risk for schizophrenia.

Research Applications

The goal of high-risk research is to identify factors that can successfully predict those who are most likely to develop subsequent cases of schizophrenia or schizophrenia-related disorders. Only a subgroup—in fact, a minority—of high-risk children will eventually manifest schizophrenia. The most significant question, therefore, is not what differentiates high-risk children from a comparison group, but rather what differentiates high-risk children who develop schizophrenia from high-risk children who do not. Even those individuals who are predicted to be at heightened risk who do not eventually develop schizophrenia are interesting and potentially informative. The high-risk offspring who do not develop schizophrenia can inform investigators about resiliency factors that are likely to be important. Only a few high-risk research projects have followed their subjects all the way into adulthood. Only limited data are thus available regarding the childhood characteristics that predict adult psychiatric outcome. The findings from these studies confirm the predictions made by the researchers. Specifically, the high-risk children who eventually develop schizophrenia show more evidence of motor abnormalities, memory deficits, and attention dysfunction in childhood than those who do not.

The findings of neurobehavioral abnormalities in preschizophrenic individuals during childhood are consistent with the etiologic hypotheses held by most researchers in the field. Specifically, such abnormalities would be expected in a disorder that is presumed to be attributable to a central nervous system impairment that is, at least in part, genetically determined. These findings are consistent with the hypothesis that an early brain insult may manifest itself in neurobehavioral abnormalities early on but can remain latent (unexpressed) as clinical symptoms for many years.

Limitations

Like all approaches to research, the high-risk method has some limitations. One limitation concerns whether the findings from these studies can be generalized to a wider population. Although it is true that schizophrenia tends to run in families, it is also true that the majority of schizophrenic patients do not have a schizophrenic parent; children of schizophrenic parents may represent a unique subgroup of schizophrenic patients. The fact that they have a parent with the illness may mean that they have a higher genetic loading for the disorder than do schizophrenic patients whose parents have no mental illness. Moreover, there are undoubtedly some environmental stresses associated with being reared by a schizophrenic parent. In sum, high-risk children who become schizophrenic patients may differ from other schizophrenic patients both in terms of genetic factors and in terms of environment. Some other problems with the method mentioned above include subject attrition and the extensive waiting period required before adult psychiatric outcome is determined.

Some investigators have attempted to address the issue of identifying markers of vulnerability with alternative methodologies. For example, one group has used childhood home movies of adult-onset schizophrenic patients as a database for identifying infant and early childhood precursors. Up to this point, the findings from these studies are consistent with those from high-risk research. Others have studied siblings of schizophrenic individuals who are within the period of greatest risk for the development of the disorder (ages eighteen through thirty). Biological siblings of individuals with schizophrenia are at heightened risk for the development of schizophrenia, typically approximately ten to fourteen times greater than the general population.

Implications of Genetic High-Risk Studies

Based on the research findings, there is good reason to believe that individuals who develop schizophrenia in adulthood manifested signs of vulnerability long before the onset of the disorder, perhaps as early as infancy. These findings have some important implications. First, they provide some clues to etiology; they suggest that the neuropathological process underlying schizophrenia is one that begins long before the onset of the clinical symptoms that define the illness. Therefore, the search for the biological bases of this illness must encompass the entire premorbid life course. Second, the findings suggest that it may be possible to identify individuals who are at risk for schizophrenia so that preventive interventions can be provided.

Early Intervention and Preventive Medication

Findings based on the first generation of high-risk studies provide the framework for establishing the validity of prodromal clinical indicators and for understanding the nature of the premorbid as well as the earliest prodromal (prepsychotic) phases of schizophrenia.

Since the late l990s, several clinicians and investigators in North America, Europe, and Australia have begun to identify and treat adolescents and young adults at clinical risk for schizophrenia or in the prodromal phase of the disorder. In nearly all these programs, targeted at-risk individuals are treated preemptively with low doses of atypical antipsychotic medications such as risperidone (Risperdal) and olanzapine (Zyprexa). The goal of this treatment is to prevent the onset of the illness, or at least to halt the progression to illness. However, because no one is certain how many individuals in the clinically at-risk group would actually develop schizophrenia if left untreated, early intervention in schizophrenia is an ethically complex issue that has met with some controversy.

Patrick McGorry and Alison Yung, leaders of the Australian research group, one of the first to initiate an early intervention program, have been outspoken proponents of the preventive medication strategy. They argue that the premorbid phase and the prodromal phase are windows of opportunity for intervention. Indeed, some research suggests that the longer the duration of untreated psychosis, the poorer the disease outcome. However, the prodromal phase—the period directly preceding the onset of psychosis—can be determined only retrospectively. Development of schizophrenia is neither inevitable or predetermined for any of the at-risk individuals enrolled in these early intervention programs. Therefore, there will be individuals in the treatment group who would have never developed the illness; these are known as false positives.

Defining At-Risk Clinical Status

To minimize the number of false positives, careful screening and identification of the at-risk population is critical. McGorry, Yung, and associates consider individuals meeting any of their definitions of at-risk mental state as being at ultra-high risk. They define at-risk mental status as attenuated (subsyndromal) psychotic symptoms; transient psychotic symptoms that resolve within one week; or genetic risk for schizophrenia that was accompanied by marked decline in functioning over a six-month period. Other clinical research teams, such as the one led by Barbara Cornblatt and Todd Lencz, have adopted additional criteria for defining at-risk mental status. The expanded criteria include subsyndromal negative symptoms of schizophrenia such as social withdrawal, depressed mood, reduced motivation, sleep disturbance, and anxiety. The advantage of this approach is that it enables earlier identification of clinical high-risk individuals and therefore possible earlier enrollment in the preventive treatment program. The researchers note that many, but not all, of the at-risk individuals may later show attenuated psychotic symptoms. Regardless of their definition of at-risk mental status, there is consensus among the early intervention researchers that individuals who enroll in these programs must be either symptomatic or subjectively distressed, be seeking treatment, and equally important, must give their informed consent.

Treatment Issues

Early intervention programs have been criticized because although the predictive accuracy of presumed prodromal signs and symptoms has not been established, many research clinicians are treating at-risk individuals with antipsychotic medications. Although the newer antipsychotic medications have lower risks of extrapyramidal symptoms and tardive dyskinesia, they are nonetheless associated with significant weight gain, sexual side effects, and long-term medical complications such as diabetes and cardiovascular problems. Others point out that the effects of long-term treatment with atypical antipsychotic medications on the developing adolescent brain are unknown. One distinctive aspect of Cornblatt and Lencz’s early intervention program in New York is that the first line of treatment offers alternatives to antipsychotic medications. According to preliminary reports, treatment with antidepressants, antianxiety medications, and mood stabilizers has been equally effective as antipsychotics in terms of improving the functioning of the clinically at-risk participants.

Preliminary Outcomes

The interim findings of early intervention studies have become available. Overall, the studies are consistent in terms of the percentage of at-risk individuals who had developed a psychotic disorder within approximately two years. The results of a multisite longitudinal study of at-risk individuals in North America revealed that 35 percent of the group developed psychosis. McGorry’s group reported that 40 percent of their at-risk participants developed psychosis. Genetic risk with functional decline was a strong predictor of later psychotic outcome. The possibility that the percentage of at-risk individuals who developed schizophrenia or another psychotic disorder over that time period might have been considerably higher had they not been enrolled in an early intervention program cannot be ruled out.

Clearly, there are potential advantages and disadvantages associated with this second generation of high-risk research. The advances in high-risk research indicate that there are several methods for viewing the developmental course of schizophrenia. These methods include not only prospectively following genetically high-risk individuals through the age of risk, but also following clinically high-risk individuals and intervening preemptively, while collecting information regarding their neurocognitive, social, psychophysiological, and clinical functioning.

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