Schizophrenia is a serious mental illness that causes major psychosocial impairment and disability for many of those affected. Recent advances in epidemiology and the neurosciences are prompting considerations of schizophrenia from a preventive perspective. Elucidation of risk factors and risk markers is crucial for targeting future preventive efforts. This article provides an overview of some of the risk factors and risk markers that have been identified as potentially important in the context of schizophrenia.
While risk factors are those antecedents that are thought to have a causal role in the development of the disorder, risk markers are biological or neuropsychological traits that indicate a genetic tendency toward developing the illness. Thus, a risk marker can be thought of as a form of risk factor that is not causal. Synonymous or closely related terms include elementary phenotype, endophenotype, intermediate phenotype, risk indicator, risk marker, trait marker, vulnerability indicator, and vulnerability marker.[29-33] Such markers are characteristics seen in an individual with the disorder, in those at high risk for the disorder, and in some unaffected relatives, and they may offer clues to biological mechanisms associated with disease susceptibility. Some of these traits may be more closely related to the genotype than are the clinical manifestations of the disorder. As such, markers or endophenotypes represent an intermediate expression between causative mechanisms, such as genes, and overt symptoms, because symptoms of schizophrenia may be remote from the effects of the genotype itself. An endophenotype is associated with the illness in the population, is heritable, is state-independent (ie, a trait marker), cosegregates with illness within affected families, and is found in nonaffected family members at higher rates than in the general population.
Potential risk markers include a variety of neurocognitive deficits, including impairments in attention and memory domains[37-39]; several electrophysiologic findings, such as impairments in prepulse inhibition[29,40-43]; and smooth pursuit eye-tracking abnormalities.[32,44-47] The high prevalence of one of the best-replicated endophenotypes, eye-tracking dysfunction (reduced gain during smooth pursuit and increased saccade frequency), in patients and their relatives suggests that this deficit may be a genetically transmitted trait marker. The antisaccade task, in which patients are instructed to move their eyes in the direction opposite of a visual target, also has been studied[48,49] as a risk marker. Research has demonstrated that antisaccade deficits are more common in those with schizotypal personality disorder and in first-degree relatives of patients with schizophrenia than in controls.
Olfactory identification deficits, that is, subtle impairments in the ability to identify various odors, have been receiving increased research attention as a marker of schizophrenia. These impairments have been documented in both medicated and neuroleptic-naive individuals with schizophrenia. Such deficits are presumably related to dysfunction in central olfactory brain regions, and smell identification may be a measure of the functional integrity of the limbic system and orbitofrontal cortex. Structural abnormalities of the olfactory system (such as low olfactory bulb volume), which also may be present in first-degree family members, may serve as endophenotypic markers of genetic vulnerability.
Features of schizotypy may be risk markers for schizophrenia, and some studies show that schizotypy scores discriminate between relatives of patients with schizophrenia and normal comparison controls without affected relatives. With further research, specific structural brain abnormalities[57,58] and neurochemical markers[59,60] also may be shown to be risk markers for schizophrenia. Some risk markers, such as dermatoglyphic (fingerprint) abnormalities and minor physical anomalies (subtle structural abnormalities found primarily in the craniofacial region and hands), may reflect abnormalities during fetal development. Dermatoglyphic findings[61-64] and minor physical anomalies[65-68] may be genetically determined or related to environmental insults during the early stages of central nervous system development. Such indicators are of interest to researchers because they may represent persistent markers of fetal development during early pregnancy, a time of major brain development.
Some of the risk markers discussed here may be nonspecific. To achieve acceptable predictive power in estimating an individual's future risk, a range of risk factors and risk markers may need to be assessed. Currently, none of the measures of elevated risk has predictive performance satisfactory enough to enable widespread clinical use. However, as measures are refined, it may become possible to develop tools to identify high-risk individuals who could then be included in indicated preventive intervention strategies.
A risk factor is a measurable characteristic that precedes an outcome and is significantly associated with that outcome. Causal risk factors are of particular importance in understanding the cause and pathophysiologic characteristics of schizophrenia. Nonetheless, noncausal risk markers, or traits that are not recognized symptoms of the disease but reflect an underlying genetic tendency toward it, may be helpful in efforts to identify asymptomatic individuals at particularly elevated risk, especially in the context of genetic risk (ie, family history of schizophrenia). Studying various risk factors and risk markers may eventually lead to better elucidation of multivariate risk profiles by enabling us to develop risk scores based on multiple risk factors and risk markers. Some of the many future research questions include (1) Which risk factors are responsible for the greatest population attributable risks? (2) How do risk factors, both genetic and environmental in nature, interact to elevate risk? (3) In what ways are the various risk markers correlated with one another, or to what extent are they nonoverlapping? and (4) What combination of risk factors and risk markers is most useful for risk stratification? These and other questions involving risk factors and risk markers will be addressed as the field moves closer to a prevention perspective for schizophrenia and for other serious mental illnesses.