Although schizophrenia onset usually occurs in late adolescence or early adulthood, much research shows that its seeds are planted early in life and that the disorders eventual onset occurs at the end of a neurodevelopmental process leading to aberrant brain functioning. This, along with the fact that current therapies are far from fully effective, suggests that preventive treatments may be needed to achieve an ideal outcome for schizophrenia patients and those predisposed to the disorder. Among the many challenges to the prevention of schizophrenia is the problem of methodology. Prevention protocols have been implemented for other psychiatric disorders, but can these be applied to schizophrenia? Alternatively, do the unique features of this disorder require novel approaches?
Compared with many other targets of prevention programs, such as
drug abuse (1), depression (2,3), child abuse (4), aggression, conduct
disorder, and delinquency (58), schizophrenia has a low incidence
(about 1%). Any study designed to test a prevention strategy must
acknowledge this low incidence, as well as the predictability of
risk factors and the efficacy of interventions across different
subgroups. Without such attention, a prevention trial will likely
have minimal power to detect preventive impact. We will show how
3 epidemiologic terms indicating the predictability of a risk factor,
the frequency of that risk factor in the population, and the effectiveness
of a preventive intervention targeting that risk factor all work
together to determine the effect of an intervention strategy on
preventing a target outcome.
Understanding Risk and Protective Factors
Defining the Target Population
Modern prevention science is based on the concept of targeting or altering the known risk factors or enhancing the known protective factors that necessarily precede a disorders onset (9,10). A risk factor is an element that, when present, is associated with a higher probability of subsequent disorder than that experienced by the population without such a factor. A protective factor is one that lowers risk. For example, estrogen is believed to be a protective factor for schizophrenia, since female sex predicts a delayed onset and reduced prevalence of the disorder (11). By discovering gene variants that predispose to disorders, molecular genetic studies may lead to more precisely defined target populations. For example, the epsilon 4 variant of the apolipoprotein E gene has been shown to increase the risk for late-onset Alzheimers disease, the epsilon 2 variant protects against the disease, and other variants have no effect (12).
Although risk and protective factors must precede the outcome of interest, they may be either distant or proximal to onset. Genes and pregnancy and delivery complications are distal risk factors for schizophrenia (13), while drug use is a proximal risk factor for psychosis. Risk and protective factors can be further classified as modifiable or nonmodifiable. Carrying a susceptibility gene for schizophrenia is an example of a nonmodifiable risk factor (there is no gene therapy for schizophrenia). Pregnancy and delivery complications provide a good example of modifiable risk factors because these could be modified by good pre-, peri-, and postnatal care.
We can further classify risk and protective factors with regard to whether they impact individuals or groups. Risk factors occurring at the individual level, such as pregnancy and delivery complications, affect a single individual at a time, not an entire community. Other examples of individual risk factors include child abuse, head injury, and the neurotoxic effects of drug abuse. Risk factors that occur at the group level affect many individuals at once. For example, the school shooting in Columbine, Colorado, traumatized the entire school. Lack of resources in low-income areas leads to poor education, which can impact an entire school district.
Twin studies have provided a unique view of the nature of environmental risk factors for psychiatric disorders. The twin-study method allows researchers to estimate the relative importance of 3 main sets of risk factors on psychopathology: genes, shared environment, and unshared environment. Shared environment refers to any environmental feature shared by siblings. Examples include social class and the nature of discipline from parents. Unshared environment refers to any environmental feature that siblings do not share. Examples include head injuries and exposure to different peer groups. Twin studies suggest that most environmental risk factors for psychopathology are those not shared by siblings (14,15).
For any disease, understanding the parameters of the target population helps create a strategy for preventive intervention. We take as examples the prevention of 2 diseasespellagra and syphilisthat in the past were responsible for a large portion of mental disorders, including psychoses, worldwide. By understanding the effective prevention strategies for these known causes of mental disorders, we can compare alternative prevention strategies aimed at those processes where the etiology is not fully known. The first prevention strategy, illustrated by the prevention of pellagra-associated psychosis, involves the direct targeting of modifiable risk factors. In the southern US, pellagra was responsible for a large percentage of hospitalizations for mental disorders in the early part of the 20th century. After it was recognized that a dietary deficiency in riboflavin caused pellagra, direct targeting of this risk factor by dietary supplementation virtually eliminated this disease and its consequent psychosis in many parts of the world. This dietary strategy reaches a large segment of the population, and we can therefore refer to it as population-based.
Identifying risk factors can also lead to the development of interventions that target a specific group of individuals who share that risk factor. Untreated syphilis can lead to neurosyphilis with symptoms of grandiosity and psychotic behaviour, as well as dementia and depression. Although the disease has not been eliminated, antibiotic treatment has virtually eliminated the most serious mental conditions associated with its later stages. Two common targeted screening strategies involve screening couples before marriage and screening commercial sex workers. Appropriate treatment is then provided to those with positive serological tests. The geographic distribution of syphilis cases is also not random. Impoverished communities living with limited clinic access and in close proximity to trucking thoroughfares are at elevated risk for contracting the disease (16).
In these examples, prevention programs first screen target individuals based on a risk characteristic (for example, sex worker), but the intervention is directed at another factor that is known to be causal in the development of the disorder (syphilis infection). Another approach is to select a group based on a modifiable risk factor and then eliminate that risk factor. For example, improving the care of pregnant women with schizophrenia or pregnant women known to have partners with schizophrenia could reduce pregnancy and delivery complications and, consequently, the risk of schizophrenia in their children. As another example, some data suggest that the nature of family relationships may be a risk factor for symptoms of schizophrenia (for example, ). Thus, family interventions might reduce stressors that affect vulnerable family members. This could reduce the risk for schizophrenia among vulnerable adolescents.
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