Schizophrenia which affects approximately 1 percent of the population, usually begins before age 25 and persists throughout life. The illness is a life long debilitating condition for about 40% of patients and is enormously costly in both social and economic terms. Despite the presence of delusions, hallucinations and cognitive impairment which characterize the illness, overall life expectancy is not altered (although there is a significantly increased risk-of suicide in the early years).

Schizophrenia is usually viewed as a functional psychosis, a label which implies that the symptoms arise from the disorderly activity of neurons without accompanying anatomical and pathological alterations of brain structure. This view is due to the failure of pathologists to find convincing pathological changes associated with the disease in the first seven decades of the century. Over the last ten years things have changed considerably. Recent CT and MRI scan, and also postmortem studies show that various brain areas of schizophrenic patients are altered.

HISTORY

The two key people in the history of Schizophrenia were Emil Kraepelin and Eugene Blealer. Kraepelin organized the seriously mentally ill patients by three diagnostic groups: dementia praecox, manic depressive psychosis, and paranoia. Kraeplin’s description of dementia praecox emphasize a chronic deteriorating course, in addition to including such clinical phenomena as hallucinations and delusions. Kraepelin reported that approximately 4% of his patients had complete recoveries and 13% had significant remissions. The term "manic depressive psychosis" identified patients who experienced episodes of illness separated by virtually complete remissions. Patients diagnosed as having paranoia had as their major symptom persistent persecutors delusions.

Blealer coined the term "Schizophrenia", which means split mindedness, in reference to the theoretical schism between thought, emotion, and behavior. Unfortunately, this term historically has caused confusion with split personality (also called multiple personality), a completely different disorder from schizophrenia. Blealer’s definition of schizophrenia differed from Kraeplin’s dementia praecox in-two major ways: first, Blealer did not feel that deterioration was a necessary symptom of the disorder; Second, Bleuler divided the symptoms into fundamental (primary) and accessory (secondary) symptoms. The most important fundamental syndrome was a thought disorder characterized by associational disturbances, particularly looseness. The other fundamental symptoms were affective disturbances, autism, and ambivalence. Accessory disorders included hallucinations and delusions. Both Kraepelin and Bleuler assumed that there was an underlying biological basis for this disorder.

Gabriel Langfeldt, unlike Blealer, derived his criteria from empirical experience, rather than a theoretical formulation. Langfeldt divided the disorder into true schizophrenia and schizophreniform psychosis. The diagnosis of true schizophrenia rests on the findings of depersonalization, autism, emotional blunting, insidious onset, and feelings of derealization and unreality, True schizophrenia is often referred to as nuclear schizophrenia, process schizophrenia, or non-remitting schizophrenia.

Kurt Schnider described a number of so-called first rank symptoms of schizophrenia that he considered in no way specific for the disease, but of great pragmatic value in making a diagnosis. These include the hearing of one’s thought spoken aloud, auditory hallucinations that comment on the patient’s behavior, somatic hallucinations, the experience of having one’s thoughts controlled, the spreading of one’s thoughts to others, and the experience of having one’s actions controlled or influenced from outside. Schizophrenia, Schnider pointed out, also can be diagnosed on the basis of second-rank symptoms, which include other forms of hallucination, perplexity, depressive and euphoric disorder of affect, and emotional blunting.

EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

The rates for the age group 15 years and over, range from .30 to 1.2 per 100. Pooled studies show an incidence of approximately 1 per 1000 population. Approximately 200,000 new cases are diagnosed each year in the United States, with approximately 2 million worldwide. In the United States, the life time prevalence is about 1%: that is, about 2 million Americans suffer from schizophrenia.

AGE, SEX, AND RACE

The peak age of onset for men is between age 15 and 25 and for women, between 25 and 35. There is no difference in the prevalence of schizophrenia between males and females, or between different races.

CULTURAL AND SOCIOECONOMIC CONSIDERATIONS

Schizophrenia has been described in all cultures and socioeconomic classes. In industrial nations there is a disproportionate number of schizophrenic patients in the lower socioeconomic classes. This has been explained by the "downward drift hypothesis," suggesting that the affected individuals either move into lower socioeconomic classes or fail to rise out of the lower socioeconomic classes because of the illness.

HEREDITY AND SUICIDE

The risk of becoming schizophrenic for an individual is increased if one member of the family already suffers from the disorder. Approximately 50% of patients with schizophrenia have attempted suicide and 20% succeeded during a 20-year follow up period.

ETIOLOGY

NEUROTRANSMITTERS

The dopamine hypothesis, the major neurotransmitter hypothesis for schizophrenia, states that there is a hyperactivity of dopaminergic systems in schizophrenia. The major support for this hypothesis is that all effective anti-psychotic drugs bind to dopamine receptors. The clinical potency of anti-psychotic drugs is closely correlated to their binding affinity to D2 receptors, the dopamine receptor subtype that does not stimulate adenylate cyclase. The observation that administration of amphetamine or levodopa exacerbates the symptoms of some, but not all schizophrenic patients, lends additional support to this hypothesis. However, there are three major problems with this hypothesis. First, dopamine antagonists are effective in treating all psychosis. Dopaminergic hyperactivity, therefore, is not uniquely associated with schizophrenia. Second, although anti-psychotic drugs reach the brain very quickly to block the dopamine receptors, the maximal clinical effects can take as long as 6 weeks to develop. Third, although some research has demonstrated supportive neurochemical evidence, the majority of studies have not found confirmatory data.

Of the five dopaminergic tracts in the CNS, the mesocortical and the mesolimbic tracts have received the most attention in schizophrenia. Both of these tracts have their cell bodies in the substantia nigra and the ventral tegmental area. It has been observed in animal studies that long term neuroleptic administration causes the firing rate of some neurons in these tracts to decrease. In addition neuroleptics that have few extrapyramidal side effects do not decease the firing rate in dopaminergic neurons of nigrostriatal tract.

Virtually every known neurotransmitter has been studied in schizophrenia. There is some evidence that norepinephrine activity is increased in schizophrenia. This idea is supported by postmortem findings, increased CSF MHPG in some schizophrenic patients, and the fact that amphetamine, which can produce a paranoid schizophrenic-like clinical picture, acts on both dopaminergic and noradrenergic neurons. Because of its function as an inhibitory transmitter, GABA may play a role in schizophrenia. Presumably , decreased GABA activity can result in hyperactivity of dopaminergic neurons. Some of neurochemical evidence supports this hypothesis, and it has been observed that a small number of patients with schizophrenia improve with benzodiazepine.

NEUROPATHOLOGY

There have been two types of neuropathological studies of schizophrenia-studies of neurotransmitters and neurodegeneration the neurotransmitter studies have measured neurotransmitter concentration and receptor properties in specific areas of brains postmortem. The neurodegenerative studies have looked for areas of cell loss or abnormal histology in brain tissue.

NEUROTRANSMITTER STUDIES

Many postmortem neurotransmitter studies have reported increased numbers of D2 receptors in the basal ganglia and the limbic system (particularly the amygdala, nucleus accumbens, and hippocampus).

NEURODEGENERATIVE STUDIES

1. BRAIN WEIGHT

The results produced by three recent studies seem to be reasonably consistent. Each found a significant decrease in brain weight in schizophrenic patients compared with controls after adjusting for such factors as height, weight, sex and year of birth. Brown (1986) reported an average reduction of some 100 g or 6%, Pakkenberg (1987) reported a loss of 109 g or 8% and Bruten (1990) in a large prospective study reported a 30 g. loss from each hemisphere (approximately 5% of formalin fixed brain weight)

2. BRAIN LENGTH AREAS AND VOLUME

To date only two postmortem studies have examined these parameters. Bruton (1990) found significant (4%) reduction in brain length in both male and female schizophrenics. A separate analysis showed that both left and right hemispheres were equally reduced in length. Pakkenberg addressed the problem of brain volume. She found significant reduction in volume of the cerebral hemispheres (loss of 12%) and central prey matter (loss of 6%). No loss in the white matter volume was found. No separate analysis of sex or laterality was made. A recent MRI study has also reported significant reduction in coronal brain area.

3. VENTRICULAR SYSTEM

Several early pneumo-encephalogram studies of the ventricular system in schizophrenia have shown evidence of ventricular dilation. However, the ethical problems of such a difficult procedure tempted few to replicate these findings and their significance were gradually forgotten. The advent of computer tomography (a safer scanning procedure) revitalized clinical interest in the problem and to date over 100 CT or MRI studies have been carried out and the majority reported varying degrees of ventricular enlargement in schizophrenic patients. Postmortem studies have also shown ventricular enlargement.

BRAIN AREAS AFFECTED

A planimetric study of the archival material from the Voget collection revealed considerable reduction in the volume of temporal lobe structures (hippocampal formation, amygdala, parahippocampal gyrus) and a moderate reduction of the inner pallidal segment (-20%) in schizophrenic subjects. The outer pallidal segment, caudate, putamen and nucleus accumbens did not show significant volume differences.

THERAPY

Anti-psychotics (also called neuroleptics or major tranquilizers) are the major drugs used for treatment of schizophrenia. These include the phenothiazines, butyrophenones, thioxanthenes, dibenzoxazepine, and oxoindoles. Although much less effective than antipsychotics, electroconvulsive treatment (ECT) may be indicated for catatonic patients or patients who for some reason cannot take neuroleptics

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