Schizophrenia is sometimes considered the most devastating of the mental illnesses because its onset is early in a patient’s life, and its symptoms can be destructive to the patient and to the patient’s family and friends. Although schizophrenia is usually discussed as if it were a single disease, this diagnostic category can include a variety of disorders that present with somewhat similar behavioral symptoms. Schizophrenia probably comprises a group of disorders with heterogeneous causes and definitely includes patients whose clinical presentations, treatment responses , and courses of illness were varied.

HISTORY: Emil Kraepelin, a noted German psychiatrist, observed that among hospitalized psychotic patients there were two types of clinical course. The first seemed to be characterized by exacerbation’s and remissions in mood and cognitive functioning which he called "manic depression", and a second type characterized by a chronic psychotic course with its onset in youth and deteriorating social functioning which he called "dementia praecox." In 1911 Eugene Bleuler, a Swiss psychiatrist, coined the term "schizophrenia" for dementia praecox ,as a way of describing the disease as a splitting of psychological functioning.

EPIDEMIOLOGY: The prevalence of schizophrenia in the general population is about 1% for lifetime risk, about an 0.5 in 1000 incidence of recorded or treated cases per year in the United States. The schizophrenic syndrome has a similar world-wide incidence, the only cultural differences being that the prognosis for recovery seems better in rural environments than in urban settings. The prevalence rate is eight times higher in the lower than in the higher socioeconomic classes. Since the parents of schizophrenics have a social class distribution similar to that of the general population, lower position of the patients appears to be as a result of the illness rather than as a cause.

Since the highest incidence of schizophrenia is in young people, whose illnesses often become chronic, the number of cases is constantly increasing. Seventy percent of schizophrenics become ill between 15 and 35 years, and the illness affects males more than females. Peak onset in males lies between 15 and 24 years and in females between 25 and 35 years. There are slight ethnic differences with a high incidence in the Scandinavian countries and in non-whites. The chronicity of the illness presents an enormous cost. A recent study notes that although schizophrenia affects only one twelfth as many persons as myocardial infarction, the cost is six times as great.

CLINICAL FEATURES: The two most common affective presentations of schizophrenia are reduced emotional responsiveness or even anhedonia and overly active and inappropriate emotions. Feeling tones include blunted affect and ambivalence, anxiety, terror, perplexity, or exaltation.

Hallucinations may occur in any of the five sensory modalities. Auditory hallucinations are the most common and the patient may complain of hearing one or more voices which may be threatening, obscene, accusatory, or insulting. Illusions may also occur which may be difficult to distinguish from hallucinations.

Schizophrenics also display non-perceptual disorders of thought and include disorders of content, form, and process. Delusions are the most obvious examples of a disorder of content and may be quite varied. The patient may also lack a clear sense of where his/her own body, mind, and influence end and where those of other animate or inanimate objects begin. Disorders of form include looseness of associations, incoherence, tangentiality, and mutism; and are often observed in the speech, writings, and drawings of the patient. Disorders of process include flight of ideas, thought blocking, impaired attention, poverty of thought and content of speech, and circumstantiality. Patients with schizophrenia may be quite agitated and have little impulse control when acutely ill. They may have decreased social sensitivity and impulsive behaviors may be highly destructive, including suicide (50% of patients attempt suicide and 10% succeed) and homicide which may be in response to hallucinations commanding the patient to act.

Schizophrenics are usually oriented to person, time, and place, memory is usually intact, and classically they have little insight into their illnesses. These patients usually manifest only subtle neurological findings including agraphesthesia, dysdiadochokinesia, deficits in skilled motor activities, reduction of the nystagmus response, and deficits in smooth pursuit eye movements.

COURSE: The course of schizophrenia often begins with prodromal symptoms (social withdrawal, peculiar behavior, lack of personal hygiene, flat affect, odd beliefs, superstitions, unusual perceptions, lack of initiative, interest, or energy). The onset of more pronounced symptoms may be acute (days) or gradual (months). The onset is usually in adolescence, and there may be an identifiable precipitating traumatic event. The prodromal symptoms may be present for a year before a diagnosis is made. The decline in psychosocial functioning is accompanied by the tendency for the patient to become downwardly mobile in social class.

The classical course of schizophrenia is one of exacerbation’s and relative remissions with failure to return to baseline functioning after each relapse. Sometimes a clinically observable post-psychotic depression follows an acute episode, and a vulnerability to stress is often lifelong. Deterioration progresses for an average of five years, at which point most patients reach a plateau. Positive symptoms tend to become less severe with time, but the socially debilitating negative symptoms may increase. The patient’s life is characterized by aimlessness, inactivity, frequent hospitalizations, and, in urban settings, hopelessness and poverty.

PROGNOSIS: Schizophrenia does not always run a debilitating course. A variety of factors are associated with good and poor prognoses. Factors associated with a positive prognosis include a late onset, the presence of obvious precipitating factors, an acute onset, a good pre-morbid history, and familial support. The range of recovery rates in the literature is 10-60%, and a reasonable estimate is that 20-30% are able to lead somewhat normal lives. Approximately 20-30% of patients continue to experience moderate symptoms while 40-60% of patients remain significantly impaired for their entire lives.

DIAGNOSTIC TYPES: There are classically five types of schizophrenia: disorganized, catatonic, paranoid, undifferentiated, and residual. Paranoid type is characterized by a preoccupation with one or more systematized delusions or with frequent auditory hallucinations related to single theme. Catatonic type is characterized by a psychomotor disturbance which may involve stupor, negativism, rigidity, excitement, or posturing. The disorganized type is characterized by incoherence, looseness of associations, inappropriate affect, or disorganized behavior. The undifferentiated category is reserved for those who do not fit neatly into one of the other categories, while those who lack psychotic symptoms but who still manifest a disturbance are classified as residual type. Recently, it has been reported that patients with chronic schizophrenia can be segregated into three syndromes which are partially confluent with the classical divisions described above. These include the psychomotor poverty syndrome (poverty of speech, flatness of affect, decreased spontaneous movement); disorganization syndrome (disorders of form of thought, inappropriate affect); and reality distortion syndrome (delusions and hallucinations).

ETIOLOGY: The cause of schizophrenia is, at present, unknown. The disease is, most likely, a heterogeneous disorder and the etiological factors discussed below are not mutually exclusive. The present model of the cause of schizophrenia is a stress-diathesis model whereby an individual with a specific biological predisposition (diathesis) will develop the disease if acted upon by a stress which itself could be biological (e.g., infection) or psychological.

NEUROPATHOLOGICAL STUDIES: Many studies of gross brain structure in schizophrenics have been undertaken in order to provide some clue as to the underlying cause of the disease. Recent studies have found significant decreases in brain weight (up to 8%) in schizophrenic patients when compared with controls. Furthermore, significant reductions in brain length (up to 7 mm.) were found, as well as reductions in the volume of the cerebral hemispheres, cerebral cortex, and central gray matter. Also, CT studies of the brains of schizophrenic brains have shown enlargement of the lateral and third ventricles in 10-50% of patients and cortical atrophy in 10-35% of patients. MRI studies have recently demonstrated significant reductions in the amount of temporal lobe gray matter in schizophrenics, particularly at the level of the parahippocampal gyrus, amygdala and anterior hippocampus. This reduction in volume was due to a decrease in the number of neurons which was not accompanied by gliosis, the usual glial cell reaction to neuronal damage. Reduction of cerebral blood flow in frontal lobes using xenon inhalation and PET scanning has been described inconsistently.

Neuropathological studies indicate that the brains of schizophrenics suffer from a developmental abnormality and not a neurodegenerative or destructive lesion which preferentially, but not exclusively, affects the medial temporal lobe. Medial temporal lobe structures are believed to have a crucial role in the integration and processing of the input from the association cortex and are thought to be central in the integration of affect and intellect. Dysfunction in this system could result in the clinical symptoms that form the core of the schizophrenia syndrome. The cause of the anomaly is probably genetic and affects brain development in the third trimester. The asymmetrical pattern of development of the human brain (the left hemisphere develops one to two weeks later than the right hemisphere) explains why such a defect affecting both hemispheres simultaneously will disproportionately affect the left (dominant) hemisphere.

GENETICS: Investigations into the population genetics of schizophrenia have produced data consistent with a genetic basis for schizophrenia. These studies have shown that 10--15% of the offspring of a schizophrenic parent are at risk for the disease. Furthermore, the coincidence of schizophrenia in monozygotic twins is roughly 60%. Additional evidence for a genetic factor comes from studies that demonstrate that the chances of a child of schizophrenic parents of developing the disease are identical, whether the child is raised by the natural parents or by adoptive, non-schizophrenic parents.

It is evident that in seeking to understand the genetics of schizophrenia a single gene will not prove to be the ultimate cause. Instead, it is more likely that a defect in the control of neurodevelopment will be found whose end result is a set of structural changes which predispose to later schizophrenia. The complexity of brain development might permit a variety of genetically determined events so as to produce a similar morphological and clinical phenotype; environmental interference with the same developmental processes may mimic the pathological and psychological picture. Schizophrenia is probably etiologically heterogeneous and the disease may occur only when an individual inherits several contributory genes or when an individual with one or more abnormal genotypes also suffers fetal insult.

DOPAMINE HYPOTHESIS: The dopamine hypothesis states, in it’s simplest terms, that there is a hyperactivity of dopaminergic systems in schizophrenia. This theory developed out of the discovery that virtually all effective anti-psychotic drugs are dopamine receptor antagonists. Specifically, the clinical potency of anti-psychotic drugs is closely correlated with their binding affinity to the D2 class of dopamine receptors, the dopamine receptor subclass that does not stimulate adenylate cyclase. The observation that the administration of two dopaminergic agonists; amphetamine and L-dopa, exacerbates the symptoms of many schizophrenic patients, lends additional support to the hypothesis.

A significant role for dopamine in the pathophysiology of schizophrenia is consistent with recent reports that have measured plasma concentrations of the major dopamine metabolite, homovanillic acid (HVA). Some of these studies report a positive correlation between high pre-treatment concentrations of HVA and two factors; severity of psychotic symptoms and treatment response to anti-psychotic drugs. Studies of plasma HVA have also reported that, after a transient increase in plasma HVA concentrations, there is a steady decline in HVA concentration, which is correlated with symptom improvement in some patients.

There are two major problems with the dopamine hypothesis. First, dopamine antagonists are effective treatment in virtually all psychotic and agitated patients, regardless of the diagnosis. Response to dopaminergic antagonists, therefore, is not uniquely associated with schizophrenia. Second, some electrophysiological data suggest that dopaminergic neurons may increase their firing rate in response to chronic exposure to anti-psychotic drugs. These data imply that the initial abnormality in schizophrenia may involve a hypo-dopaminergic state. The precise role of dopamine in the pathophysiology of schizophrenia remains unclear.

Of the dopaminergic tracts in the CNS, the mesocortical and the mesolimbic tracts have received the most attention in schizophrenia research. Both of these tracts have their cell bodies in the substantia nigra and the ventral segmental area. One objection to focusing on these tracts, is that the D2 receptors are much less common than D1 receptors on the target neurons of these tracts. For this reason, some investigators have focused on the neostriatal tract and on the basal ganglia in general because this is the brain area richest in D2 receptors.

A recent advance in this area has been the cloning and sequencing of two forms of the human D2 receptor, a short (415 residues) and a long (444 residues) form. The long form is thought to be the predominant one in most brain regions. The receptor is related to the beta-adrenergic receptor and has seven putative transmembrane domains and a large third cytoplasmic loop, which may be involved in the regulation of interactions between the receptor and G -proteins. Most recently, dopamine receptors that are neither D1 nor D2 have been identified and their role in the physiology of schizophrenia is currently under investigation.

OTHER NEUROTRANSM1TTER SYSTEMS: 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 the finding of norepinephrine metabolites in the CSF, and the finding that amphetamine, which can produce a paranoid schizophrenia-like illness, acts on both dopaminergic and noradrenergic neurons. Because of its function as an inhibitory neurotransmitter, GABA may play a role Presumably, a GABA deficiency could in hyperactivity of dopaminergic neurons. Some neurochemical evidence supports this hypothesis, and a small number of patients with schizophrenia improve with benzodiazepine treatment. Currently, the receptors mediating the anti-psychotic activity of the new drug clozapine are under investigation as are the action of the sigma receptor antagonists.

TREATMENT: The major treatment for schizophrenia is the use of neuroleptic drugs including phenothiazines, butyrophenones, thioxanthrenes, dibenzoxazepine, and oxoindoles. The goal of treatment is to decrease as many of the symptoms as possible. As long as hallucinations, delusions, and disorganized thinking persist, the accepted practice is to increase the dosage of the medication until reaching a maximum decrease in symptoms. The most frequent limiting factor is the appearance of extrapyramidal side effects, the most common of which are dystonia, restlessness, and Parkinsonism. These occur most commonly in the first two to four months of drug use. Tarditive dyskinesia, a syndrome of choreoathetotic movements of the mouth, lips, tongue, extremities, or trunk, is associated with the use of neuroleptics for six months or more.

Although much less effective than anti-psychotics, psychotherapy, insulin coma therapy, electroshock therapy, and prefrontal lobotomy have all been used as treatment options for those patients who cannot be controlled by medication.

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