Schizophrenia
.... 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. 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. 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. 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. 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. 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. 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. 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. 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 durin...