Kraepelin translated Morel’s démence précoce into dementia precox, a term that emphasized the change in cognition (dementia) and early onset (precox) of the disorder. Patients with dementia precox were described as having a long-term deteriorating course and the clinical symptoms of hallucinations and delusions. Kraepelin distinguished these patients from those who underwent distinct episodes of illness alternating with periods of normal functioning, which he classified as having manic-depressive psychosis. Another condition, called paranoia, was characterized by persistent persecutory delusions. These patients lacked the deteriorating course of dementia precox and the intermittent symptoms of mani-cdepressive psychosis.

Bleuler coined the term schizophrenia, which replaced dementia precox in the literature. He chose the term to express the presence of schisms between thought, emotion, and behavior in patients with the disorder. Bleuler stressed that, unlike Kraepelin’s concept of dementia precox, schizophrenia need not have a deteriorating course. This term is often misconstrued, especially by lay people, to mean split personality. Split personality, called dissociative identity disorder in the text revision of the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), differs completely from schizophrenia (see Chapter 16).

Schizophrenia is equally prevalent in men and women. The two genders differ, however, in the onset and course of illness. Onset is earlier in men than in women. More than one half of all male schizophrenia patients but only one third of all female schizophrenia patients are first admitted to a psychiatric hospital before age 25 years. The peak ages of onset are 10 to 25 years for men and 25 to 35 years for women. Unlike men, women display a bimodal age distribution, with a second peak occurring in middle age. Approximately 3 to 10 percent of women with schizophrenia present with disease onset after age 40 years. About 90 percent of patients in treatment for schizophrenia are between 15 and 55 years old. Onset of schizophrenia before age 10 years or after age 60 years is extremely rare. Some studies have indicated that men are more likely to be impaired by negative symptoms (described in what follows) than are women and that women are more likely to have better social functioning than are men prior to disease onset. In general, the outcome for female schizophrenia patients is better than that for male schizophrenia patients. When onset occurs after age 45 years, the disorder is characterized as late-onset schizophrenia.

The use of psychopharmacologic drugs, open-door policies in hospitals, deinstitutionalization in state hospitals, emphasis on rehabilitation, and community-based care for patients have all led to an increase in the marriage and fertility rates among persons with schizophrenia. Because of these factors, the number of children born to parents with schizophrenia is continually increasing. The fertility rate for persons with schizophrenia is close to that for the general population. First-degree biological relatives of persons with schizophrenia have a ten-times-greater risk for developing the disease than the general population.

Persons with schizophrenia have a higher mortality rate from accidents and natural causes than the general population. Institution- or treatment-related variables do not explain the increased mortality rate, but the higher rate may be related to the fact that the diagnosis and treatment of medical and surgical conditions in schizophrenia patients can be clinical challenges. Several studies have shown that up to 80 percent of all schizophrenia patients have significant concurrent medical illnesses and that up to 50 percent of these conditions may be undiagnosed.

Persons who develop schizophrenia are more likely to have been born in the winter and early spring and less likely to have been born in late spring and summer. In the Northern Hemisphere, including the United States, persons with schizophrenia are more often born in the months from January to April. In the Southern Hemisphere, persons with schizophrenia are more often born in the months from July to September. Season-specific risk factors, such as a virus or a seasonal change in diet, may be operative. Another hypothesis is that persons with a genetic predisposition for schizophrenia have a decreased biological advantage to survive season-specific insults.

Studies have pointed to gestational and birth complications, exposure to influenza epidemics or maternal starvation during pregnancy, Rhesus factor incompatibility, and an excess of winter births in the etiology of schizophrenia. The nature of these factors suggests a neurodevelopmental pathological process in schizophrenia, but the exact pathophysiological mechanism associated with these risk factors is not known.

Evidence that prenatal malnutrition may play a role in schizophrenia was derived from the studies of the Dutch “Hunger Winter” of 1944 to 1945. Severe caloric restriction in the western Netherlands was associated with substantially decreased fertility, increased mortality, and diminished birthweight. Unlike most other famines, it was time limited, and the extent and timing of caloric restriction and psychiatric outcomes were well documented. Exposure to the peak of the famine during the periconceptional period was associated with a significant, twofold increased risk of schizophrenia. In a subsequent study, this cohort exposed to famine in early gestation also showed an increase in risk of schizoid personality disorders.

Epidemiological data show a high incidence of schizophrenia after prenatal exposure to influenza during several epidemics of the disease. Some studies show that the frequency of schizophrenia is increased following exposure to influenza—which occurs in the winter—during the second trimester of pregnancy. Other data supporting a viral hypothesis are an increased number of physical anomalies at birth, an increased rate of pregnancy and birth complications, seasonality of birth consistent with viral infection, geographical clusters of adult cases, and seasonality of hospitalizations.

Viral theories stem from the fact that several specific such theories have the power to explain the particular localization of pathology necessary to account for a range of manifestations in schizophrenia without overt febrile encephalitis.

Substance abuse is common in schizophrenia. The lifetime prevalence of any drug abuse (other than tobacco) is often much greater than 50 percent. For all drugs of abuse (other than tobacco), abuse is associated with poorer function. In one
population-based study, the lifetime prevalence of alcohol within schizophrenia was 40 percent. Alcohol abuse increases risk of hospitalization and, in some patients, may increase psychotic symptoms. People with schizophrenia have an increased prevalence of abuse of common street drugs. There has been particular interest in the association between cannabis and schizophrenia. Those reporting high levels of cannabis use (more than 50 occasions) were at sixfold-increased risk of schizophrenia compared to nonusers. The use of amphetamines, cocaine, and similar drugs should raise particular concern because of their marked ability to increase psychotic symptoms.

The prevalence of schizophrenia has been correlated with local population density in cities with populations of more than 1 million people. The correlation is weaker in cities of 100,000 to 500,000 people and is absent in cities with fewer than 10,000 people. The effect of population density is consistent with the observation that the incidence of schizophrenia in children of either one or two parents with schizophrenia is twice as high in cities as in rural communities. These observations suggest that social stressors in urban settings may affect the development of schizophrenia in persons at risk.

There is a genetic contribution to some, perhaps all, forms of schizophrenia, and a high proportion of the variance in liability to schizophrenia is due to additive genetic effects. For example, schizophrenia and schizophrenia-related disorders (e.g., schizotypal, schizoid, and paranoid personality disorders) occur at an increased rate among the biological relatives of patients with schizophrenia. The likelihood of a person’s having schizophrenia is correlated with the closeness of the relationship to an affected relative (e.g., first-degree or second-degree relative). In the case of monozygotic twins, who have identical genetic endowment, there is an approximately 50 percent concordance rate for schizophrenia. This rate is four to five times the concordance rate in dizygotic twins or the rate of occurrence found in other first-degree relatives (i.e., siblings, parents, or offspring). The role of genetic factors is further reflected in the drop-off in the occurrence of schizophrenia among second- and third-degree relatives, in whom one would hypothesize a decreased genetic loading. The finding of a higher rate of schizophrenia among the biological relatives of an adopted-away person who develops schizophrenia, as compared to the adoptive, nonbiological relatives who rear the patient, provides further support to the genetic contribution in the etiology of schizophrenia. Nevertheless, the monozygotic twin data clearly demonstrate the fact that individuals who are genetically vulnerable to schizophrenia do not inevitably develop schizophrenia; other factors (e.g., environment) must be involved in determining a schizophrenia outcome. If a vulnerability-liability model of schizophrenia is correct in its postulation of an environmental influence, then other biological or psychosocial environment factors may prevent or cause schizophrenia in the genetically vulnerable individual.

There is robust data indicating that the age of the father has a direct correlation with the development of schizophrenia. In studies of schizophrenic patients with no history of illness in either the maternal or paternal line, it was found that those born from fathers older the age of 60 years were vulnerable to developing the disorder. Presumably spermatogenesis in older men is subject to greater epigenetic damage than that in younger men.

The modes of genetic transmission in schizophrenia are unknown, but several genes appear to make a contribution to schizophrenia vulnerability. Linkage and association genetic studies have provided strong evidence for nine linkage sites: 1q, 5q, 6p, 6q, 8p, 10p, 13q, 15q, and 22q. Further analyses of these chromosomal sites have led to the identification of specific candidate genes, and the best current candidates are
α7 nicotinic receptor, DISC 1, GRM 3, COMT, NRG 1, RGS 4, and G72. Recently, mutations of the genes dystrobrevin (DTNBP1) and neureglin 1 have been found to be associated with negative features of schizophrenia.

In the 19th century, neuropathologists failed to find a neuropathological basis for schizophrenia, and thus they classified schizophrenia as a functional disorder. By the end of the 20th century, however, researchers had made significant strides in revealing a potential neuropathological basis for schizophrenia, primarily in the limbic system and the basal ganglia, including neuropathological or neurochemical abnormalities in the cerebral cortex, the thalamus, and the brainstem. The loss of brain volume widely reported in schizophrenic brains appears to result from reduced density of the axons, dendrites, and synapses that mediate associative functions of the brain. Synaptic density is highest at age 1 year, then is pared down to adult values in early adolescence. One theory, based in part on the observation that patients often develop schizophrenic symptoms during adolescence, holds that schizophrenia results from excessive pruning of synapses during this phase of development.