Schizophrenia is one of our most important public health problems. It is a common, tragic, and devastating mental illness that typically strikes young people just when they are maturing into adulthood. Once it strikes, morbidity is high (60 percent of patients are receiving disability benefits within the first year after onset), (1) as is mortality (the suicide rate is 10 percent). (2) Despite the fact that people with schizophrenia are all around us (the lifetime prevalence is 1 percent worldwide), (2) this illness is often misunderstood, and people with schizophrenia are stigmatized by both the medical profession and the public.
Our understanding of the causation of schizophrenia has increased in the past several decades. Schizophrenia is a disease of the brain that is expressed clinically as a disease of the mind. Both its symptoms and signs and its associated cognitive abnormalities are too diverse to permit its localization in a single region of the brain. The working hypothesis shared by most investigators is that schizophrenia is a disease of neural connectivity caused by multiple factors that affect brain development. (3,4,5)
Our current model of the causation of schizophrenia is very similar to that used to understand cancer. That is, schizophrenia probably occurs as a consequence of multiple "hits," which include some combination of inherited genetic factors and external, nongenetic factors that affect the regulation and expression of genes governing brain function or that injure the brain directly. Some people may have a genetic predisposition that requires a convergence of additional factors to produce the expression of the disorder. This convergence results in abnormalities in brain development and maturation, a process that is ongoing during the first two decades of life. (6) The abnormalities are typically not focal but, rather, involve distributed neural circuits and neurotransmitter systems. When the connectivity and communication within neural circuitry are disrupted, patients have a variety of symptoms and impairments in cognition. Behind this diversity, however, is a final common pathway that defines the illness. For schizophrenia, it is misregulation of information processing in the brain. Ongoing etiologic studies must focus on finding the origins of abnormalities that lie beneath the clinical surface.
The symptoms and signs of schizophrenia are very diverse, and they encompass the entire range of human mental activity. They include abnormalities in perception (hallucinations), inferential thinking (delusions), language (disorganized speech), social and motor behavior (disorganized behavior and abnormal or stereotyped movements), and initiation of goal-directed activity (avolition), as well as impoverishment of speech and mental creativity (alogia), blunting of emotional expression (flattened affect), and loss of the ability to experience pleasure (anhedonia). These symptoms and signs occur in patterns that may not overlap; one patient may have hallucinations and affective flattening, whereas another has disorganized speech and avolition. The diversity and nonoverlapping pattern of symptoms and signs suggest a more basic and unifying problem: abnormalities in neural circuits and fundamental cognitive mechanisms. (7,8)
Patients with schizophrenia also have impairment in many different cognitive systems, such as memory, attention, and executive function. This is often referred to as a generalized deficit, and its existence provides additional support for the likelihood that the disorder is the result of a basic process such as a general impairment in the coordination of information processing. (7,8) Unlike other mental illnesses that are also characterized by deficits in multiple cognitive systems (e.g., Alzheimer's disease), however, schizophrenia does not usually involve deterioration or progress to dementia. Instead, the degree of impairment is relatively stable after an initial fulminant course, which may last for several years. After that point, cognitive function may even improve. (9)
Schizophrenia also differs from the classic dementias in that there are no visible neuropathological markers such as plaques, tangles, or Lewy bodies. The gliosis that is a marker of neuronal death in neurodegenerative diseases is not present in schizophrenia. This suggests that the etiology and pathophysiology of schizophrenia must be related to maturational or developmental brain processes such as formation of neurites, synaptogenesis, neuronal pruning, or apoptosis. (1,4,5,10) This defines the period for the changes that result in schizophrenia as sometime between the beginning of neuron formation and migration (around the second trimester) and young adult life. Although this is a long period, it focuses our thinking about pathophysiology and etiology by suggesting the importance of examining the molecular processes that regulate and shape brain development and the external factors that may influence those processes.
The most typical age for the onset of schizophrenia is during the late teens and early 20s, a time when brain maturation is reaching completion (6); this suggests that the pathogenesis of the disease must involve a neurodevelopmental process related to the final stages of "brain sculpturing," such as pruning or activity-dependent changes (psychological experiences that affect brain plasticity). (4)
As discussed by Mortensen et al. in this issue of the Journal, (11) schizophrenia runs in families, and twin and adoption studies indicate that such familial aggregation is largely accounted for by genetic factors. However, the same studies also indicate that familial genetic transmission can account for only a portion of the cases of schizophrenia; for example, the concordance rate in monozygotic twins is approximately 40 percent, suggesting that nongenetic factors must also have a role. Genetically, schizophrenia resembles other complex illnesses, such as diabetes mellitus, in that it is nonmendelian, probably polygenic, and probably multifactorial. Recent linkage, association, and candidate-gene studies suggest multiple susceptibility loci, including some on chromosomes 6, 8, and 22. (12)
Not only are multiple genes probably involved, but the nongenetic factors are likely to be multiple as well, as demonstrated by the study by Mortensen et al. (11) They found that both a family history of schizophrenia and nongenetic factors, such as birth during the winter and birth in an urban area, increased the relative risk of schizophrenia. These findings highlight the probability that the clinical manifestations of schizophrenia result from an unfortunate convergence of interacting causal factors. Their results suggest that infections during pregnancy or childhood and other factors related to urban birth may play a part in causing schizophrenia. Other possible nongenetic factors contributing to increased risk include the effects of poor nutrition on fetal and childhood brain development, exposure to toxins that damage neurons or affect neurotransmitter systems (e.g., alcohol, amphetamines, and retinoids), and exposure to radiation that might induce mutations. (12)
Since schizophrenia persists as an illness despite the fact that the majority of its victims do not marry or procreate, and since it appears to have the same lifetime prevalence throughout the world, it seems likely that multiple different, nonspecific, nongenetic factors that affect neurodevelopment are implicated. Such nongenetic factors could come into play at any time during brain development and may primarily affect the regulation of the expression of the many genes that influence brain development and function.
The causation of schizophrenia is clearly a complicated matter. As our understanding of it progresses, however, our hope for improving the lives of patients with the disease increases. If we are able to identify the critical periods in brain development during which causative factors work their mischief, and if we can delineate the molecular and cellular processes that impair brain development and neural connectivity, then we can begin to identify preventive techniques that could be implemented before injury occurs. We can also potentially improve the treatment of schizophrenia, which currently focuses on reversing abnormal neural communication by blocking dopamine or serotonin receptors. Although newer treatments such as the recently developed atypical neuroleptic drugs have already substantially improved the outcome of schizophrenia, they remain blunt instruments that have relatively generalized effects on neurotransmitter systems. As we identify more precisely the cascade of events leading to schizophrenia -- neurodevelopmental abnormalities that lead to neural misconnections that lead, in turn, to impaired cognitive processing -- we will also identify better and more specific targets for future treatment.