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Schizophrenia is a disease of the brain that manifests with multiple signs and symptoms involving thought, perception, emotion, movement, and behavior. Schizophrenia affects less than 1 percent of the world's population (approximately 0.85 percent). The number of affected persons markedly increases if schizophrenia spectrum disorders are included in prevalence estimates. The concept of schizophrenia spectrum disorders is derived from observations of

Detailed knowledge of the cause or causes of schizophrenia is lacking. Genetic factors are important in some (perhaps all) cases, but it is not yet clear which genes are deviant, how they contribute to pathophysiology, or whether the same or different genes are involved in all cases that have a genetic etiology. Other early influences, variously marked by gestational and birth complications and winter birth excess, must be involved in the causal pathways for schizophrenia, but the pathophysiological mechanisms underlying the involvement of those factors are not yet known. Various versions of viral and immune theories of causation are plausible, but no virus or immune mechanism has yet been established as an etiological factor in schizophrenia, scizophrenia, scitzophrenia

Schizophrenia syndrome probably represents more than one etiological and disease process, and a developmental abnormality may increase the risk for subsequent disease pathogeneity. However, although there are sporadic reports of gliosis in schizophrenic brains that may indicate the presence of a disease process and

Increasing information on the neurobiology of brain development has led to considerable new knowledge of the mechanisms of pathogenic influences. It is now clear that subtle deviations in brain development could create 

Principal hypotheses regarding causation include the altered expression of genes, neuroimmunovirology factors, and AIDS


Schizophrenia and schizophrenialike manifestations occur at an increased rate among the biological relatives of patients with schizophrenia. The increased rate is most evident in the case of monozygotic twins, who have an identical genetic endowment and a concordance rate for


The past 20 years have seen a gradual evolution from the concept of schizophrenia as a disorder involving discrete areas of the brain to a disorder of brain neural circuits. A major stimulus for the change in perspective was the development of neuroanatomical theories based on knowledge of dopamine pathways in the brain and of brain-behavior relations (Figure 14.1-1) (Figure Not Available) . Delineation of the mesolimbic and mesocortical dopaminergic pathways in the brain led to hypotheses postulating the involvement of the limbic system, the

Dopamine and schizophrenia

The dopamine hypothesis of schizophrenia arose from two sets of observations of drug action relating to the dopaminergic system. Drugs that increase activity disturbances in schizophrenia is suggested by the capacity of dopamine-stimulating drugs to worsen schizophrenic symptoms or to induce psychosis. In

The most decisive clinical testing of the dopamine hypothesis has been at the level of observed drug action and symptom manipulation. Studies aimed at measuring abnormal concentrations of dopamine or its metabolites in blood, urine, and


International Classification of Diseases and Related Health Problems (ICD) has been achieved with publication of the fourth edition of DSM (DSM-IV) and the 10th revision of ICD (ICD-10).


Extensive data on the long-term course of schizophrenia have been accrued following the introduction of antipsychotic drug treatment to supplement observations on the natural course of the disease made prior to the availability of effective therapy. Despite evidence to the contrary, there has been a long-standing tendency to presume the inevitability of a deteriorating course, with the outcome being exceptionally poor in most cases. In their pioneering descriptions,

The course of the illness of schizophrenia can be divided into three general epochs. The first epoch is onset. Onset is insidious in about half of patients, with the earliest signs of involvement occurring many years before the more blatant manifestations of psychosis appear. In other cases onset is relatively sudden or acute, with the onset of psychotic symptoms marking a sharp deviation in development. The insidious onset of schizophrenia tends to be characterized by increasing emotional withdrawal, diminishing social engagement and social drive, and idiosyncratic responses to

Recent studies have shown that the underlying deterioration associated with schizophrenia occurs principally during the first and second epochs of illness rather than over the remaining course. However, complications caused by the illness lead to ever-increasing impediments to normal existence, so that secondary effects may be progressive even though the primary pathology has reached a


The antipsychotic drugs used to treat schizophrenia have a wide variety of mechanisms of action, but all share the capacity to occupy postsynaptic dopamine receptors in the brain. The clinical effect of those compounds is to diminish symptom expression and reduce relapse rates. They are particularly effective with the psychotic aspects of the illness and are also effective in treating psychosis associated with illnesses other than schizophrenia. Pharmacologically,

Clozapine, referred to as an atypical antipsychotic because of its unique mechanism of action, was shown during the 1970s to have a differential effect in patients resistant to the therapeutic effects of standard antipsychotic drugs. However, there is an approximately 1 to 2 percent risk of agranulocytosis associated with the use of clozapine. The potentially lethal cessation in the production of white blood cell elements was associated with a series of deaths in Finland during the mid-1970s and led to the decreased use of clozapine in Europe and failure to market the drug in the United States. Interest in clozapine in the United States was rekindled by the results of a recent large-scale multicenter study that yielded convincing evidence of clozapine's effectiveness in ameliorating psychotic symptoms in approximately one third of schizophrenic patients who had previously been nonresponsive to antipsychotics. Consistent with the worldwide experience in the 1980s, the study also showed that clozapine could be used with relative safety within the context of careful monitoring for agranulocytosis. The development of clozapine represents the first incremental gain in the effectiveness of the pharmacological agents used to treat schizophrenia since the 

ECT was frequently used in the treatment of patients with schizophrenia prior to the 1952 introduction of antipsychotic drugs. ECT is particularly effective in the treatment of catatonic stupor and excitement, but generally produces results similar to those obtained with antipsychotics, namely, a reduction in psychosis rather than a reversal of long-term functional impairments. Although ECT is now safe and painless, its use is restricted, in part by litigation and societal attitudes but also because any therapeutic advantage gained in an initial series of treatments is not easily maintained. Also, there is no indication that ECT is effective in